Indoline derivative and application thereof

Abstract

The invention discloses an indoline derivative and application thereof. According to the invention, the regulation effect of the derivative on the chemotaxis and secretion functions of ILC3 is evaluated; it is found that the derivative has a promoting effect on chemotaxis of ILC3 to an inflammatory site and up-regulation of IL-22 expression, has very remarkable effects on mouse ulcerative colitis (UC) induced by DSS, mouse Crohn disease (CD) induced by TNBS, acute lung injury induced by lipopolysaccharide (LPS), mouse psoriasis induced by imiquimod and other diseases in vivo, and is superior to existing clinical treatment drugs. Good development and application prospects are realized.

Description

TECHNICAL FIELD

[0001] The present application relates to an indoline derivative and its use; in particular, it relates to a class of indoline derivatives and their use in the preparation of drugs for regulating the chemotaxis of type III innate lymphocytes (ILC3) to inflammatory sites and the expression of IL-22. BACKGROUND

[0002] Non-controllable inflammatory diseases related to epithelial barrier defects are a class of complex diseases caused by epithelial damage and local immune imbalance, including digestive system diseases (Crohn's disease, ulcerative colitis, necrotizing enterocolitis, colorectal cancer, gastritis, etc.); immune system diseases (graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, etc.); endocrine system diseases (type I diabetes, type II diabetes, diabetic foot ulcer, non-alcoholic steatohepatitis, etc.); skin diseases (skin repair after burns, skin wound repair, herpes, etc.); respiratory system diseases (chronic obstructive pulmonary disease, acute lung injury, bronchial asthma, etc.). The common feature of these diseases is that the epithelial barrier function is impaired, the local tissue is continuously inflamed, and then the tissue is damaged, pathological remodeling and dysfunction. Current treatment methods mainly rely on glucocorticoids, immunosuppressants or biological agents, which can alleviate inflammation to some extent, but the efficacy is limited and long-term use is often accompanied by problems such as infection, drug resistance and systemic toxicity. Therefore, it is of great clinical value to develop new treatment strategies that can repair the epithelial barrier and regulate local immune responses. SUMMARY

[0003] The purpose of the present application is to provide an indoline derivative that can promote the chemotaxis of ILC3 to inflammatory sites and up-regulate the expression of IL-22, and has a significant improvement effect on DSS-induced mouse ulcerative colitis (UC), TNBS-induced mouse Crohn's disease (CD), lipopolysaccharide (LPS)-induced mouse acute lung injury and imiquimod-induced mouse psoriasis in vivo by evaluating the regulatory effect of the compound on ILC3 chemotaxis and IL-22 expression.

[0004] Another purpose of the present application is to provide the use of the indoline derivative.

[0005] Technical solution: The indoline derivative or its pharmaceutically acceptable salt according to the present application, the chemical structural formula of the indoline derivative is shown as formula (I): In the formula, R1 is selected from H or halogen; R2 is selected from H, halogen or -COOR6; R3 is selected from -NR7R8, -NHCOR9 or -COOR 10 or -CONHR 11 ; R4 is selected from H, halogen or -OR 12; R5is selected from H, C1-C6alkyl or -(CH2)nNR 13 R 14 ; R6is selected from C1-C6alkyl; R7and R8are independently selected from H or C1-C6alkyl; R9is selected from C1-C6alkyl, -(CH2)nNR 15 R 16 , -(CH2)nR 17 or -NR 18 R 19 ; R 10 is selected from H or -(CH2)nNR 20 R 21 ; R 11 is selected from H, C1-C6alkyl or -(CH2)nNR 22 R 23 ; R 12 is selected from H or C1-C6alkyl; R 13 and R 14 are independently selected from C1-C6alkyl or form, together with the attached N, a 5-7 membered nitrogen containing heterocyclic ring, preferably said nitrogen containing heterocyclic ring is substituted with one or more C1-C6alkyl; R 15 and R 16 are independently selected from C1-C6alkyl, or R 15 and R 16 form, together with the attached N, a 5-7 membered nitrogen containing heterocyclic ring, preferably said nitrogen containing heterocyclic ring is substituted with one or more C1-C6alkyl; R 17 is selected from NH2substituted phenyl ring or 5-7 membered cycloalkyl; R 18 and R 19 are independently selected from C1-C6alkyl; R 20 and R 21 are independently selected from C1-C6alkyl, or R 20 and R 21 form, together with the attached N, a 5-7 membered nitrogen containing heterocyclic ring, preferably said nitrogen containing heterocyclic ring is substituted with one or more C1-C6alkyl; R 22 and R 23 are H or C1-C6alkyl, or R 22 and R 23 form, together with the attached N, a 5-7 membered nitrogen containing heterocyclic ring, preferably said nitrogen containing heterocyclic ring is substituted with one or more C1-C6alkyl; R 24 and R 25 are independently selected from C1-C6alkyl, or R 24 and R 25The nitrogen-containing heterocycle connected to the N forms a 5-7 member nitrogen-containing heterocycle, optionally substituted by one or more C1-C6 alkyl groups; In each substituent, n is independently selected from 1, 2, 3, or 4.

[0006] Furthermore, R1 is selected from H or a halogen; R2 is selected from H or a halogen; R3 is selected from -NHCOR9; R4 is selected from H or a halogen; R5 is selected from H or a C1-C6 alkyl group; R9 is selected from -(CH2)nNR. 15 R 16 ; R 15 and R 16 Independently selected from C1-C6 alkyl or R 15 and R 16 The nitrogen-containing heterocycle connected to it forms a 5-7 membered nitrogen-containing heterocycle, wherein the nitrogen-containing heterocycle is substituted by one or more C1-C6 alkyl groups; n is selected from 1, 2, 3 or 4.

[0007] Furthermore, R 15 and R 16 It is independently selected from methyl or ethyl.

[0008] Furthermore, R 15 and R 16 It forms a tetrahydropyrrole ring, morpholine ring, piperazine ring, piperidine ring, or N-methylpiperidine ring with the attached N.

[0009] Furthermore, R1 is selected from H or halogen; R2 is selected from H or halogen; R3 is selected from -COOR. 10 R4 is selected from H or halogens; R5 is selected from H or C1-C6 alkyl groups; R 10 Selected from H or -(CH2)nNR 20 R 21 ; R 20 and R 21 Independently selected from C1-C6 alkyl or R 20 and R 21 The nitrogen-containing heterocycle connected to it forms a 5-7 membered nitrogen-containing heterocycle, wherein the nitrogen-containing heterocycle is substituted by one or more C1-C6 alkyl groups; n is selected from 1, 2, 3 or 4.

[0010] Furthermore, R 20 and R 21 It is independently selected from methyl or ethyl.

[0011] Furthermore, R 20 and R 21 It forms a tetrahydropyrrole ring, morpholine ring, piperazine ring, piperidine ring, or N-methylpiperazine ring with the attached N.

[0012] Further, R3 is selected from the following groups: .

[0013] Further, R1 is selected from H, R2 is selected from H, R4 is selected from H, and R5 is selected from H or CH3.

[0014] Further, the indoline derivative or the pharmaceutically acceptable salt thereof is selected from the following compounds: .

[0015] Further, the structure of the indoline derivative is selected from one of the following compounds: .

[0016] Further, the present application provides a pharmaceutical composition comprising the indoline derivative or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0017] Further, the present application provides the use of the indoline derivative or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a modulator of ILC3 cell chemotaxis.

[0018] Further, the present application also provides the use of the indoline derivative or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a drug for modulating IL-22 expression.

[0019] Further, the present application also provides the use of the indoline derivative or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a drug for preventing / treating a disease.

[0020] Further, the disease is a disease caused by insufficient IL-22 expression.

[0021] Further, the disease is selected from one of the following: a digestive system disease (Crohn's disease, ulcerative colitis, necrotizing enterocolitis, colorectal cancer, gastritis, etc.); an immune system disease (graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, etc.); an endocrine system disease (type I diabetes, type II diabetes, diabetic foot ulcer, non-alcoholic steatohepatitis, etc.); a skin disease (skin repair after burns, skin wound repair, herpes, psoriasis, etc.); a respiratory system disease (chronic obstructive pulmonary disease, acute lung injury, bronchial asthma, etc.).

[0022] Further, the disease is selected from one of the following: ulcerative colitis, Crohn's disease, acute lung injury, and psoriasis.

[0023] Further, the disease is selected from ulcerative colitis or Crohn's disease.

[0024] In the present application, IL-22 is a cytokine with a molecular weight of about 15-20 kDa, which belongs to the IL-10 family and plays a unique role in maintaining epithelial barrier function and responding to tissue damage. Unlike most classic immune factors, IL-22 does not directly act on immune cells, but mainly targets non-hematopoietic epithelial cells. By binding to its receptor complex IL-22R1 and IL-10R2, IL-22 can activate key signaling pathways such as JAK1 / TYK2-STAT3, induce the expression of antibacterial peptides and mucin proteins, promote epithelial proliferation and tight junction protein stability, and thus effectively enhance epithelial barrier function. Among them, IL-22 exhibits a high degree of "tissue-specific" protective effect under different disease backgrounds, and its biological effects have been confirmed to be closely related to many types of diseases, including digestive system diseases, immune system diseases, endocrine system diseases, skin diseases, respiratory system diseases, etc. For example, in ulcerative colitis (UC), IL-22 significantly enhances the expression of tight junction proteins such as ZO-1 and Occludin, promotes intestinal epithelial cell regeneration and differentiation, repairs damaged barriers and reduces intestinal flora translocation, thereby maintaining intestinal homeostasis; in acute lung injury, IL-22 can promote alveolar epithelial cell repair and limit the spread of inflammatory factors to the alveolar cavity, thereby effectively reducing lung tissue damage in acute inflammation; in psoriasis, IL-22 drives the proliferation of keratinocytes and the secretion of antibacterial peptides to a certain extent, thereby rebuilding the skin barrier function and resisting pathogen invasion; in the diabetic foot ulcer model, IL-22 binds to the IL-22R receptor to activate the STAT3 signaling pathway, induce re-epithelialization and tissue remodeling, and up-regulate the levels of antibacterial peptides Defb1 and S100a9, thereby promoting wound healing and reducing the risk of infection. As can be seen, IL-22 is an important cytokine with a wide range of protective effects across different organs and tissues.

[0025] Based on the central role of IL-22 in epithelial barrier protection, upregulation of IL-22 levels has become a potential therapeutic strategy. Among the various sources of IL-22, type 3 innate lymphoid cells (ILC3) are considered the most important and the most rapid secretors. ILC3 is widely distributed in barrier tissues such as intestinal mucosa, lung, skin and respiratory mucosa, and its characteristic transcription factor is RORγt. Under the driving of inflammation-related factors (such as IL-23 and IL-1β) or microbial signals, ILC3 can rapidly secrete a large amount of IL-22 without antigen presentation, and directly participate in tissue defense and repair; compared with adaptive immune cells, the response of ILC3 is more rapid, especially in the early stage of disease, which can play a role in barrier protection. Therefore, the number and functional status of ILC3 have a decisive significance in the occurrence and remission of non-controllable inflammatory diseases related to epithelial barrier defects, such as autoimmune diseases, chronic refractory wounds on the body surface, metabolic diseases and respiratory diseases. At present, the known ways to regulate IL-22 focus on improving the directional migration of ILC3 in inflammatory tissues to improve the aggregation degree of ILC3 at the lesion site. In intestinal inflammation, CCL25-CCR9 signal drives ILC3 to conduct "intestinal homing" along the villi, enhances its recruitment at the mucosal barrier and secretion of IL-22; retinoic acid upregulates the protein expression of CCR9 and α4β7 in ILC3 by activating RARα, induces its migration to the intestine, thereby promoting tissue remodeling and repair process, and maintaining tissue homeostasis. In respiratory tract infection, the microbial metabolites mediated by the intestinal-lung axis can promote the recruitment of ILC3 in the lung, thereby improving epithelial repair after lung injury. Therefore, by developing the chemotaxis of ILC3 to the inflammatory site and upregulating the level of IL-22, it is expected to provide a new direction for the treatment of non-controllable inflammatory diseases related to epithelial barrier defects.

[0026] In the present invention, "C1-C6" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched-chain saturated hydrocarbon groups, the hydrocarbon groups having the number of carbon atoms indicated; such as "C1-6 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, etc.; "nitrogen-containing heterocyclyl" refers to a cyclic group containing at least one nitrogen atom; the nitrogen-containing heterocyclyl contains 5 to 7 ring members; typical heterocyclyl groups include but are not limited to tetrahydropyrrole, morpholine, piperazine, piperidine, hydrogenated pyrimidine, 1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, tetrahydrofuran, tetrahydropyran, pyridone, etc.; optionally, the nitrogen-containing heterocyclyl is also substituted by one or more C1-6 alkyl or halogen; "halogen" refers to a fluorine, chlorine, bromine or iodine group.

[0027] Beneficial effects: Compared with the prior art, the indoline derivative disclosed by the application has the following remarkable advantages: the indoline derivative disclosed by the application can effectively regulate the chemotaxis of ILC3 cells to an inflammation site, increase the expression of IL-22, and has a very remarkable effect on treating diseases such as colitis, acute lung injury and psoriasis, is superior to existing clinical treatment drugs, and has a very good development and application prospect. DETAILED DESCRIPTION

[0028] In order to more clearly illustrate the technical solutions of the present application, the technical solutions of the present application are further described in detail below.

[0029] Example 1 Synthesis of compound 1: Compounds I-1 and I-2 were purchased from a certain biopharmaceutical technology company in Shanghai; I-1 (100 mg, 0.74 mmol) and I-2 (358 mg, 1.11 mmol) were dissolved in acetonitrile (8 mL), and then potassium hydroxide (83 mg, 1.48 mmol) was added, and the temperature was raised to 35 ℃, and the reaction was carried out for 1.5 h; after the reaction was completed, the reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate (10 mL), transferred to a separatory funnel, extracted with water (30 mL), and then washed with saturated sodium chloride solution; the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude product I-3 (70 mg, yield: 49 %), which was directly used in the next step without purification.

[0030] Compound I-3 (70 mg, 0.36 mmol) and I-4 (54 mg, 0.36 mmol) were dissolved in methanol (5 mL), and then sodium carbonate (77 mg, 0.72 mmol) was added, and the reaction was carried out at room temperature for 5 h under nitrogen protection; after the reaction was completed, the filtrate was filtered, the filter cake was washed with methanol and water, and the crude product was dried and oven-dried; column chromatography purification (DCM: MeOH = 100:1-10:1) obtained purple solid 1 (23 mg, yield: 35 %). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.14 (s, 1H), 10.93 (s,1H), 8.76 (dd, J = 7.9, 1.2 Hz, 1H), 7.73 (dd, J= 8.4, 5.6 Hz, 1H), 7.30 – 7.21(m, 2H), 7.02 (td, J = 7.6, 1.1 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 6.84-6.80 (m,1H) ppm; 13 C NMR (126 MHz, DMSO- d 6 ) δ 187.29, 171.26, 169.26, 141.64, 138.97,130.12, 127.62, 127.52, 125.43, 121.85, 121.73, 116.46, 110.16, 107.84,101.18, 100.96. ESI-MS (m / z) 281.07 [M+H] + .

[0031] Example 2 Synthesis of compound 2: Dissolve I-5 (100 mg, 0.74 mmol) and I-2 (358 mg, 1.11 mmol) in acetonitrile (8 mL), then add potassium hydroxide (83 mg, 1.48 mmol), and warm to 35 ℃, react for 1.5 h. After monitoring the reaction completion by LC-MS, concentrate the reaction solution under reduced pressure, dissolve in ethyl acetate (10 mL), transfer to a separatory funnel, add water (30 mL) to extract and wash, then wash with saturated sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain crude I-6 (69 mg, yield: 49 %), which is directly used in the next step without purification.

[0032] Dissolve compound I-6 (69 mg, 0.36 mmol) and I-4 (54 mg, 0.36 mmol) in methanol (5 mL), then add sodium carbonate (77 mg, 0.72 mmol), and react at room temperature for 5 h under nitrogen protection. After monitoring the reaction completion by LC-MS, filter, wash the filter cake with methanol and water, and dry in an oven to obtain a crude product, which is purified by column chromatography (DCM: MeOH = 10:1) to obtain purple solid 2 (70 mg, yield: 70 %). 1 H NMR (500 MHz, DMSO- d 6 ) δ10.98 (s, 1H), 8.74 (d, J = 7.8 Hz,1H), 7.49-7.43 (m, 3H), 7.25 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.7 Hz, 1H), 6.90(d, J = 7.8 Hz, 1H) ppm; 13 C NMR (126 MHz, DMSO- d 6 ) δ 188.53, 171.32, 158.77,156.88, 149.61, 141.61, 139.18, 129.99, 125.17, 121.90, 121.77, 115.38,110.65, 110.46, 110.13, 107.70. ESI-MS (m / z) 281.07 [M+H] + .

[0033] Example 3 Synthesis of compound 3: Dissolve I-7 (100 mg, 0.57 mmol) and I-2 (358 mg, 0.85 mmol) in acetonitrile (8 mL), then add potassium hydroxide (64 mg, 1.14 mmol), and warm to 35 ℃ for 1.5 h. After the reaction is completed, monitor by LC-MS, concentrate the reaction solution under reduced pressure, dissolve in ethyl acetate (10 mL), transfer to a separatory funnel, add water (30 mL) to extract and wash, then dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain crude I-8 (44 mg, yield: 33%), which is directly used in the next step without purification.

[0034] Dissolve compound I-9 (44 mg, 0.19 mmol) and I-4 (31 mg, 0.21 mmol) in methanol (4 mL), then add sodium carbonate (40 mg, 0.38 mmol), and react at room temperature for 5 h under nitrogen protection; after the reaction is completed, monitor by LC-MS, filter, wash the filter cake with methanol and water, and dry to obtain a crude product, which is purified by column chromatography (DCM: MeOH = 200:1- 50:1) to obtain purple solid 3 (51 mg, yield: 85 %). 1H NMR (500 MHz, DMSO- d 6 ) δ 11.13 (s, 1H), 8.77 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 8.11 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H),7.28 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 3.85(s, 3H) ppm; 13 C NMR (126 MHz, DMSO- d 6 ) δ 188.21, 171.14, 165.98, 155.77, 141.97,138.54, 137.99, 130.51, 125.96, 125.58, 122.70, 121.90, 121.75, 119.59,114.02, 110.23, 109.07, 52.55 ppm. ESI-MS (m / z) 321.08 [M+H] + .

[0035] Example 4 Synthesis of compound 4: Compound II-1 (100 mg, 0.44 mmol) and II-2 (77.4 mg, 0.44 mmol) were dissolved in methanol (10 mL), then sodium carbonate (93.7 mg, 0.88 mmol) was added, and the reaction was carried out at room temperature for 5 h under nitrogen protection; after the reaction was completed, water (30 mL) was added to quench the reaction, and a solid was precipitated; the solid was filtered, the filter cake was washed with methanol and water, and dried to obtain a crude product, which was purified by column chromatography (ethyl acetate: petroleum ether = 50:1-5:1) to obtain purple solid 4 (142.1 mg, yield: 94%). 1 HNMR (500 MHz, DMSO- d 6 ) δ11.10 (s, 1H), 11.00 (s, 1H), 8.97 - 8.83 (m, 1H), 7.65 (t, J = 6.9 Hz, 1H), 7.58 (q, J = 6.5 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.04 (q, J = 6.4 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H) ppm. 13 C NMR (101 MHz, DMSO- d 6 ) δ 189.37, 170.99, 153.02, 140.25, 139.75, 137.85, 131.57, 127.11, 125.03, 123.97, 122.17, 119.45, 114.13, 113.39, 111.77, 105.40 ppm. ESI-MS (m / z) 340.99 [M+H] + 。 Example 5

[0036] Synthesis of compound 5: Compound II-3 (150 mg, 0.78 mmol) and II-2 (137 mg, 0.78 mmol) were dissolved in methanol (15 mL), then sodium carbonate (165 mg, 1.56 mmol) was added, and the reaction was carried out at room temperature for 5 h under nitrogen protection. After the reaction was completed by LC-MS monitoring, the filter cake was washed with methanol and water, and dried to obtain a crude product. Purification by column chromatography (DCM: MeOH = 100:1-10:1) gave compound II-4 (220 mg, yield: 97%).

[0037] Compound II-4 (50 mg, 0.16 mmol) was dissolved in ethanol (4 mL), and 4 drops of concentrated sulfuric acid were added dropwise. The temperature was raised to 70 °C, and the reaction was carried out overnight. After the reaction was completed by LC-MS monitoring, water (10 mL) was added to quench the reaction, and a large amount of solid was precipitated. The filter cake was dried to obtain a crude product, which was purified by column chromatography (DCM: MeOH = 200:1-50:1) to give purple solid 5 (21 mg, yield: 38%). 1 HNMR (500 MHz, DMSO- d6 ) δ 11.26 (s, 1H), 11.10 (s, 1H), 9.45 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.1 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 4.33 (q, J = 7.1 Hz,2H), 1.35 (t, J = 7.0 Hz, 3H) ppm. 13 C NMR (126 MHz, DMSO- d 6 ) δ 189.21, 171.66,166.43, 153.01, 144.95, 139.71, 137.76, 131.14, 126.28, 125.08, 123.40,122.16, 121.91, 119.53, 114.08, 109.82, 105.52, 60.83, 14.82 ppm. HR-MS(ESI): 333.0876 [M-H] - . Example 6

[0038] Synthesis of compound 6: Compound II-4 (80 mg, 0.26 mmol), PyBOP (135.3 mg, 0.26 mmol) and DIPEA (33.6 mg, 0.26 mmol) were dissolved in DMF (2 mL), stirred for 30 min, then compound II-5 (41.7 mg, 0.32 mmol) was added, and reacted at room temperature for 5 h; after monitoring the reaction completion by LC-MS, water (10 mL) was added to quench, and a large amount of solid was precipitated, which was filtered and dried to obtain a crude product, which was purified by column chromatography (DCM: MeOH = 100:1-15:1) to obtain purple solid 6 (53.6 mg, yield: 50 %). 1 H NMR (400 MHz, DMSO- d6 ) δ 11.08 (s, 2H), 8.84 (d, J = 1.8 Hz, 1H), 7.66 (d, J =7.6 Hz, 1H), 7.62 – 7.55 (m, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 8.0,1.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 3.52 (t, J = 6.3Hz, 6H), 3.17 (s, 1H), 2.45 (dd, J = 12.8, 6.7 Hz, 6H) ppm. 13 C NMR (126 MHz, DMSO- d 6 ) δ 189.27, 171.46, 169.83, 153.04, 142.29, 139.44, 137.77, 129.07,124.98, 124.22, 122.02, 121.59, 119.49, 114.06, 109.71, 106.13, 60.29, 58.52,53.43, 46.03 ppm. ESI-MS (m / z) 419.16 [M+H] + . Example 7

[0039] Synthesis of compound 7: Compound II-4 (50 mg, 0.16 mmol), PyBOP (84.8 mg, 0.16 mmol) and DIPEA (42.6 mg, 0.33 mmol) were dissolved in DMF (3 mL), stirred for 30 min, then compound II-6 (23.1 mg, 0.2 mmol) was added, and the reaction was allowed to proceed at room temperature for 4 h; after the reaction was completed as monitored by LC-MS, water (10 mL) was added to quench the reaction, and a large amount of solid precipitated, which was filtered and dried to obtain a crude product, which was purified by column chromatography (DCM:MeOH = 100:1-50:1) to obtain a purple solid, which was dissolved in ethyl acetate (2 mL) and methanol (1 mL), EA-HCl (4 mL) was added, and the mixture was stirred at room temperature for 2 h, and a solid precipitated, which was filtered, and the filter cake was washed with ethyl acetate to obtain a purple solid 7 (52.4 mg, yield: 80%). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.26 (s, 1H),11.09 (s, 1H), 9.43 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H),7.58 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.99(d, J = 8.2 Hz, 1H), 4.38 (t, J = 5.9 Hz, 2H), 2.81 (t, J = 5.9 Hz, 2H), 2.59 (t, J =6.1 Hz, 4H), 1.70 (d, J = 3.8 Hz, 4H) ppm. 13 C NMR (126 MHz, DMSO- d 6 ) δ189.13, 171.65, 166.36, 152.98, 145.01, 139.68, 137.72, 131.15, 126.34, 124.98, 123.26, 122.14, 121.93, 119.51, 114.08, 109.83, 105.48, 64.12, 54.59, 54.51, 23.72 ppm. ESI-MS (m / z) 404.15 [M+H] + . Example 8

[0040] Synthesis of compound 8: Compound II-4 (100 mg, 0.33 mmol) and compound II-7 (51.7 mg, 0.4 mmol) were dissolved in DMF (4 mL), then EDCI (62.7 mg, 0.33 mmol) and HOBT (44.2 mg, 0.33 mmol) were added, and the reaction was carried out at room temperature for 5 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and a large amount of solid was precipitated. The solid was filtered and dried to obtain a crude product. Purification by column chromatography (DCM: MeOH = 300:1-80:1) gave purple solid 8 (17.8 mg, yield: 13%). 1 H NMR (500MHz, DMSO- d 6 ) δ 11.29 (s, 1H), 11.12 (s, 1H), 9.45 (s, 1H), 7.89 (dd, J = 8.2,1.7 Hz, 1H), 7.66 (d, J = 6.9 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 7.9Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 4.41 (t, J = 5.8 Hz,2H), 2.78 (s, 2H), 2.60 (s, 4H), 1.55 (p, J = 5.6 Hz, 4H), 1.26 – 1.18 (m, 2H)ppm. 13C NMR (126 MHz, DMSO- d 6 ) δ 189.16, 171.64, 166.34, 153.00, 145.02, 139.69,137.74, 131.17, 126.34, 124.94, 123.26, 122.16, 121.93, 119.52, 114.10,109.84, 105.49, 62.55, 57.34, 54.67, 25.95, 24.22 ppm. ESI-MS (m / z) 418.17 [M+H] + . Example 9

[0041] Synthesis of compound 9: Compound II-4 (80 mg, 0.27 mmol) and compound II-8 (24.1 mg, 0.27 mmol) were dissolved in DMF (3 mL), then EDCI (63.3 mg, 0.33 mmol) and catalytic amount of DMAP were added, and the reaction was carried out at room temperature for 3 h. After the reaction was completed by LC-MS monitoring, water (10 mL) was added to quench, extracted with EA (30 mL x 3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was rotary evaporated. Purification by column chromatography (DCM: MeOH = 300: 1-20: 1) gave purple solid 9 (80.2 mg, yield: 58 %). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.30 (s, 1H), 11.11 (s, 1H), 9.45(s, 1H), 7.93 (dd, J = 8.2, 1.8 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.62 – 7.56(m, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.05 (t, J = 7.3 Hz, 1H), 7.01 (d, J = 8.1 Hz,1H), 4.47 (t, J = 5.5 Hz, 2H), 2.98 (s, 2H), 2.50 (s, 6H) ppm. 13C NMR (126 MHz, DMSO- d 6 ) δ 189.21, 171.63, 166.22, 153.01, 145.13, 139.73, 137.79, 131.32,126.39, 125.02, 122.97, 122.17, 121.94, 119.50, 114.11, 109.84, 105.44,57.09, 45.99, 44.95 ppm. ESI-MS (m / z) 378.14 [M+H] + . Example 10

[0042] Synthesis of compound 10: Compound II-3 (100 mg, 0.52 mmol) and II-9 (0.16 mL, 0.91 mmol) were dissolved in anhydrous DMF (3 mL), then a few grains of DMAP and pyridine (0.07 mL, 0.85 mmol) were added, and the reaction was carried out at room temperature for 5 h under nitrogen protection. After the reaction was completed by LC-MS monitoring, a 0.1 N HC1 (10 mL) solution was added, and a large amount of solid was precipitated, which was filtered and dried to obtain yellow solid II-10 (180 mg, yield: 97 %), which was directly used in the next step without purification.

[0043] Compound II-10 (80 mg, 0.22 mmol) and II-11 (15 mg, 0.34 mmol) were dissolved in acetonitrile (5 mL), then pyridine (0.03 mL, 0.03 mmol) was added, and the reaction was carried out at room temperature for 2.5 h under nitrogen protection; after the reaction was completed by LC-MS monitoring, the reaction solution was concentrated to obtain crude product II-12 (48 mg, yield: 92 %), which was directly used in the next step without purification.

[0044] Compound II-12 (48 mg, 0.22 mmol) and II-2 (40 mg, 0.22 mmol) were dissolved in methanol (5 mL), then sodium carbonate (48 mg, 0.45 mmol) was added, and the reaction was carried out at room temperature for 5 h under nitrogen protection. After the reaction was completed by LC-MS monitoring, filtration, the filter cake was washed with methanol and water, and dried to obtain a crude product, which was purified by column chromatography (DCM: MeOH = 100:1-10:1) to obtain purple solid 10 (60 mg, yield: 81 %). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.10 (s, 1H), 11.07(s, 1H), 9.25 (s, 1H), 8.27 (t, J = 5.6 Hz, 1H), 7.70 (dd, J = 15.3, 7.8 Hz, 2H),7.59 (t, J = 7.4 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.92(d, J = 8.2 Hz, 1H), 3.29 (d, J = 6.2 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H) ppm. 13 C NMR(126 MHz, DMSO- d 6 ) δ 189.00, 171.66, 167.00, 153.00, 143.25, 139.29, 137.69,129.04, 128.59, 124.94, 124.87, 122.02, 121.67, 119.52, 114.03, 109.19,106.29, 34.56, 15.41. HR-MS (ESI): 332.1030 [M-H] - . Example 11

[0045] Synthesis of compound 11: Compound II-13 (100 mg, 0.52 mmol) and II-2 (91 mg, 0.52 mmol) were dissolved in methanol (10 mL), then sodium carbonate (110 mg, 1.04 mmol) was added, and the reaction was carried out at room temperature for 5 h under nitrogen protection. After the reaction was completed by LC-MS monitoring, the filter cake was washed with methanol and water, and dried to obtain a crude product, which was purified by column chromatography (DCM: MeOH = 100:1-20:1) to obtain purple solid II-14 (122 mg, yield: 76%).

[0046] Compound II-14 (156 mg, 0.51 mmol) was dissolved in methanol (50 mL), then Pd / C (16 mg, 0.1 eq) was added, hydrogen was introduced, and the reaction was carried out at room temperature for 6 h; after the reaction was completed by LC-MS monitoring, the filter cake was filtered through diatomite, and the filtrate was concentrated to obtain purple solid II-15 (140 mg, yield: 99%).

[0047] Compound II-15 (175 mg, 0.63 mmol) was dissolved in 10% dilute acetic acid (10 mL), potassium cyanate (512 mg, 6.3 mmol) was dissolved in warm water (5 mL), the two solutions were mixed evenly, and the reaction was carried out at 90°C overnight; after the reaction was completed by LC-MS monitoring, it was extracted with EA (30 mL x 3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain a crude product. Purification by column chromatography (DCM: MeOH = 200:1-30:1) to obtain purple solid 11 (30 mg, yield: 15%). 1 H NMR (500 MHz, DMSO- d 6 ) δ 10.99 (s, 1H), 10.70 (s, 1H), 8.59 (s, 1H), 8.42(s, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.60 – 7.55 (m, 2H), 7.42 (d, J = 7.9 Hz, 1H),7.02 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.72 (s, 2H) ppm. 13 C NMR (101MHz, DMSO-d 6 ) δ 187.99, 170.37, 155.68, 151.91, 137.64, 136.51, 135.11, 133.88,123.66, 120.89, 120.59, 119.67, 118.43, 115.30, 112.85, 108.63, 106.57 ppm.ESI-MS (m / z) 321.09 [M+H] + . Example 12

[0048] Synthesis of compound 12: Compound II-15 (150 mg, 0.54 mmol) was dissolved in DCM (10 mL), DIPEA (462.7 mg, 3.58 mmol) was added, compound II-17 (385 mg, 3.58 mmol) was added under ice-bath, and the reaction was carried out at 40 °C overnight under nitrogen protection. After the reaction was completed by LC-MS monitoring, the solvent was evaporated to obtain a crude product, which was dissolved in DCM (30 mL), washed with saturated sodium carbonate solution (20 mL x 2), and then washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to obtain a crude product. Purification by column chromatography (PE: EA = 20: 1- pure EA) yielded purple solid 12 (49 mg, yield: 26 %). 1 H NMR (500MHz, DMSO- d 6 ) δ 11.00 (s, 1H), 10.75 (s, 1H), 8.78 (s, 1H), 8.23 (s, 1H), 7.64(d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.25 (d, J =10.5 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 2.94 (s, 6H)ppm. 13 C NMR (101 MHz, DMSO- d 6 )δ 187.83, 170.50, 155.80, 151.88, 137.53, 136.47, 135.88, 133.72, 123.65, 123.00, 120.57, 118.78, 118.45, 112.84, 108.27, 106.65, 35.62 ppm. ESI-MS (m / z) 349.13 [M+H] + . Example 13

[0049] Synthesis of compound 13: Compound II-15 (200 mg, 0.72 mmol), compound II-18 (204.3 mg, 1.08 mmol), EDCI (138.1 mg, 0.72 mmol) and HOBT (97.3 mg, 0.72 mmol) were dissolved in DMF (4 mL), then added, and reacted at room temperature for 5 h. After LC-MS monitoring showed that the reaction was completed, water (10 mL) was added to quench, and a large amount of solid was precipitated. After filtration and drying, the crude product was obtained, and column chromatography purification (DCM: MeOH = 200:1-20:1) gave a purple solid. The purple solid was dissolved in ethyl acetate (2 mL) and methanol (1 mL), EA-HCl (4 mL) was added, and stirred at room temperature for 2 h. A solid was precipitated, filtered, and the filter cake was washed with ethyl acetate to obtain purple solid 13 (134.4 mg, yield: 54 %). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 10.90 (s, 1H), 10.51 (s, 1H), 9.04 (d, J = 13.1 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.61 –7.50 (m, 2H), 7.43 (d, J = 8.1 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.89 (d, J = 8.4Hz, 1H), 3.93 (t, J = 5.9 Hz, 2H), 2.68 – 2.59 (m, 3H), 1.24 (s, 1H) ppm. ESI-MS (m / z) 349.13 [M+H]+ . Example 14

[0050] Synthesis of compound 14: Compound II-15 (50 mg, 0.18 mmol) and II-19 (21 mg, 0.20 mmol) were dissolved in DMF (2 mL), then EDCI (35 mg, 0.18 mmol) and HOBT (24 mg, 0.18 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by LC-MS, water (10 mL) was added to quench the reaction, and a large amount of solid precipitated. The solid was filtered and dried to obtain the crude product, which was purified by column chromatography (DCM: MeOH = 100:1-20:1) to obtain purple solid 14 (40 mg, yield: 61 %). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.01 (s, 1H), 10.79 (s, 1H), 9.58 (s, 1H), 8.89 (d, J = 2.1 Hz, 1H),7.65 (d, J = 7.6 Hz, 1H), 7.61 – 7.54 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 3.08 (s, 2H), 2.32 (s, 6H) ppm. 13 C NMR(126 MHz, DMSO- d 6 ) δ 189.00, 171.52, 168.59, 152.97, 138.94, 137.66, 137.60,132.94, 124.79, 122.33, 121.93, 121.81, 119.54, 118.08, 113.95, 109.64,107.23, 63.60, 45.85(2C) ppm. HR-MS (ESI): 363.1429 [M+H] + . Example 15

[0051] Synthesis of compound 15: Compound II-15 (100 mg, 0.36 mmol) and II-20 (57.7 mg, 0.44 mmol) were dissolved in DMF (3 mL), then EDCI (69.1 mg, 0.36 mmol) and HOBT (48.6 mg, 0.36 mmol) were added, and the reaction was carried out at room temperature for 6 h. After the reaction was completed by LC-MS monitoring, water (10 mL) was added to quench it, and a large amount of solid was precipitated. The solid was filtered and dried to obtain a crude product. Purification by column chromatography (DCM: MeOH = 100:1-20:1) gave purple solid 15 (101.1 mg, yield: 72 %). 1 H NMR (400MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 10.95 (s, 1H), 10.81 (s, 1H), 9.11 (d, J = 2.1 Hz,1H), 7.66 (d, J = 7.6 Hz, 1H), 7.62 – 7.56 (m, 1H), 7.53 (dd, J = 8.4, 2.1 Hz,1H), 7.43 (d, J = 8.1 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H),4.13 (s, 2H), 3.24 (q, J = 7.3 Hz, 4H), 1.27 (t, J = 7.3 Hz, 6H) ppm. 13 C NMR (101MHz, DMSO- d 6 ) δ 188.01, 170.37, 151.91, 138.04, 137.01, 136.61, 131.24, 123.75,120.99, 120.79, 120.67, 118.41, 116.56, 112.94, 108.83, 105.84, 47.86, 44.69,8.44 ppm. ESI-MS (m / z) 391.17 [M+H] + . Example 16

[0052] Synthesis of compound 16: Compound II-15 (70 mg, 0.25 mmol) and II-21 (36 mg, 0.28 mmol) were dissolved in DMF (3 mL), then EDCI (48 mg, 0.25 mmol) and HOBT (32 mg, 0.25 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by LC-MS, water (10 mL) was added to quench the reaction, and a large amount of solid precipitated. The solid was filtered and dried to obtain the crude product, which was purified by column chromatography (DCM:MeOH = 150:1-30:1) to obtain purple solid 16 (38 mg, yield: 39%). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.03 (s, 1H), 10.84 (s, 1H), 9.86 (s, 1H), 8.94 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.63 – 7.53 (m, 2H), 7.42 (d, J = 8.1 Hz, 1H), 7.03 (t, J = 7.4 Hz,1H), 6.85 (d, J = 8.4 Hz, 1H), 3.51 (s, 2H), 2.82 (d, J = 6.4 Hz, 4H), 1.90 –1.74 (m, 4H) ppm. 13 C NMR (126 MHz, DMSO- d 6 ) δ 189.05, 171.50, 152.98, 138.99,137.74, 137.64, 132.79, 124.81, 122.24, 121.96, 121.83, 119.51, 118.03,113.98, 109.71, 107.14, 58.93, 54.34(2C), 31.42, 23.77(2C) ppm. HR-MS (ESI):389.1593 [M+H] + . Example 17

[0053] Synthesis of compound 17: Compound II-15 (100 mg, 0.36 mmol) and II-22 (63 mg, 0.40 mmol) were dissolved in DMF (4 mL), then EDCI (69 mg, 0.36 mmol) and HOBT (49 mg, 0.36 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by LC-MS, water (15 mL) was added to quench the reaction, and a large amount of solid precipitated. The solid was filtered and dried to obtain the crude product, which was purified by column chromatography (DCM:MeOH = 100:1-10:1) to obtain purple solid 17 (119 mg, yield: 56%). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.02 (s, 1H), 10.86 – 10.79 (m, 1H), 9.65 (s, 1H), 8.91 (d, J = 2.1Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.61 – 7.52 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H),7.03 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 3.03 (s, 2H), 2.64 (s, 8H),2.34 (s, 3H) ppm. 13 C NMR (126 MHz, DMSO- d 6 ) δ 189.02, 171.51, 168.10, 152.98,138.97, 137.72, 137.62, 132.87, 124.80, 122.36, 121.93, 121.82, 119.54,118.08, 113.96, 109.67, 107.20, 61.68, 55.36, 54.54, 52.22, 49.06, 46.10 ppm.HR-MS (ESI): 418.1854 [M+H] + . Example 18

[0054] Synthesis of compound 18: Compound II-15 (50 mg, 0.18 mmol) and II-23 (28 mg, 0.20 mmol) were dissolved in DMF (2 mL), then EDCI (35 mg, 0.18 mmol) and HOBT (24 mg, 0.18 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by LC-MS, water (10 mL) was added to quench the reaction, and a large amount of solid precipitated. The solid was filtered and dried to obtain a crude product, which was purified by column chromatography (DCM: MeOH = 200:1-50:1) to obtain purple solid 18 (47 mg, yield: 54%). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.01 (s, 1H), 10.80 (s, 1H), 9.65 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H),7.66 (d, J = 7.5 Hz, 1H), 7.60 – 7.53 (m, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 3.66 (t, J = 4.6 Hz, 4H), 3.14 (s, 2H),2.55 (t, J = 4.6 Hz, 4H) ppm. 13 C NMR (126 MHz, DMSO- d 6 ) δ 189.00, 171.53, 168.10,152.96, 138.96, 137.71, 137.61, 132.87, 124.82, 122.48, 121.92, 121.83,119.54, 118.21, 113.94, 109.65, 107.19, 66.66(2C), 62.41, 53.70(2C) ppm. HR-MS (ESI): 405.1546 [M+H] + 。 Example 19

[0055] Synthesis of compound 19: Compound II-15 (50 mg, 0.18 mmol) and II-24 (50 mg, 0.20 mmol) were dissolved in DMF (2 mL), then EDCI (35 mg, 0.18 mmol) and HOBT (24 mg, 0.18 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by LC-MS, water (10 mL) was added to quench the reaction, and a large amount of solid precipitated, which was filtered and dried to obtain a crude product. Purification by column chromatography (DCM:MeOH = 100:1-20:1) gave a purple solid, which was dissolved in ethyl acetate (2 mL), EA-HCl (2 mL) was added, and stirring was performed at room temperature for 2 h. A solid precipitated, which was filtered and washed with ethyl acetate, and dried to obtain a purple solid 19 (31 mg, yield: 38%). 11 H NMR (500 MHz, DMSO- d 6 ) δ 11.01 (s, 1H), 10.81 (d, J = 5.8 Hz, 1H), 10.21(dd, J = 19.1, 8.3 Hz, 1H), 8.93 (t, J = 2.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H),7.61 – 7.54 (m, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 7.9 Hz, 1H), 7.37-7.30 (m, 2H), 7.07 – 6.99 (m, 1H), 6.83 (d, J = 8.4 Hz, 1H), 3.70 (d, J = 6.8 Hz,2H) ppm. 13 C NMR (126 MHz, DMSO- d 6 ) δ 189.00, 171.49, 168.79, 152.97, 138.93,137.61, 137.55, 133.53, 130.89(4C), 124.76, 123.53, 121.93, 121.80, 119.54,117.67, 113.96, 109.68, 107.27, 42.90 ppm. HR-MS (ESI): 411.1438 [M+H]+ . Example 20

[0056] Synthesis of compound 20: Compound II-13 (500 mg, 2.6 mmol) was dissolved in methanol (100 mL), then Pd / C (50 mg, 0.1 eq) was added, hydrogen was input, and reaction was carried out at room temperature for 12 h. After LC-MS monitoring reaction was completed, filtration was carried out through diatomite, and the filtrate was concentrated to obtain brown solid II-25 (417 mg, yield: 99 %). Without purification, it was directly used in the next step.

[0057] Compound II-25 (200 mg, 1.3 mmol) and compound II-26 (204.3 mg, 2.0 mmol) were dissolved in DMF (5 mL), then PyBOP (676.5 mg, 1.3 mmol) and DIPEA (336 mg, 2.6 mmol) were added, and reaction was carried out at room temperature for 6 h. After LC-MS monitoring reaction was completed, water (30 mL) was added for quenching, extraction was carried out with EA (30 mL x 3), saturated sodium chloride solution was used for washing (30 mL), anhydrous sodium sulfate was used for drying, filtration was carried out under suction, and the filtrate was rotary dried to obtain a crude product. Purification was carried out through column chromatography (DCM:MeOH = 200:1-30:1) to obtain orange red solid II-27 (305.2 mg, yield: 95 %).

[0058] Compound II-27 (300 mg, 1.22 mmol) and II-2 (213.7 mg, 1.22 mmol) were dissolved in methanol (10 mL), then sodium carbonate (258.7 mg, 2.44 mmol) was added, reaction was carried out at room temperature for 5 h under nitrogen protection. After LC-MS monitoring reaction was completed, water (30 mL) was added for quenching reaction, a large amount of solid was precipitated, filtration was carried out, the filter cake was washed with methanol and water, and oven drying was carried out to obtain a crude product. Purification was carried out through column chromatography (DCM:MeOH = 100:1-20:1) to obtain purple solid 20 (277.6 mg, yield: 63 %). 1 HNMR (400 MHz, DMSO- d 6 ) δ 11.02 (s, 1H), 10.83 (s, 1H), 9.84 (s, 1H), 8.89 (d, J =2.3 Hz, 1H), 7.65 (d, J= 7.5 Hz, 1H), 7.62 – 7.54 (m, 2H), 7.41 (d, J = 8.0 Hz,1H), 7.03 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 3.04 (q, J = 7.3 Hz, 6H),2.19 (d, J = 6.9 Hz, 2H), 2.09 (hept, J = 6.5 Hz, 1H) ppm. 13 C NMR (101 MHz, DMSO- d 6 ) δ 187.93, 170.43, 169.65, 151.90, 137.78, 136.52, 136.29, 132.61, 123.70,120.96, 120.80, 120.69, 118.44, 116.73, 112.88, 108.53, 106.26, 44.84, 25.09,21.76 ppm. ESI-MS (m / z) 362.15 [M+H] + 。 Example 21

[0059] Synthesis of compound 21: Compound II-25 (100 mg, 0.62 mmol) and compound II-28 (119.2 mg, 0.93 mmol) were dissolved in DMF (5 mL), then EDCI (118.9 mg, 0.62 mmol) and HOBT (83.8 mg, 0.62 mmol) were added, and the reaction was carried out at room temperature for 6 h. After the reaction was completed, water (30 mL) was added to quench, extracted with EA (30 mL x 3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain a crude product. Purification by column chromatography (DCM: MeOH = 200:1-60:1) gave compound II-29 (158.3 mg, yield: 94 %) as an orange-red solid.

[0060] Compound II-29 (100 mg, 0.37 mmol) and II-2 (64.8 mg, 0.37 mmol) were dissolved in methanol (10 mL), then sodium carbonate (78.5 mg, 0.74 mmol) was added, and the reaction was carried out at room temperature for 5 h under nitrogen protection. After the reaction was completed by LC-MS monitoring, water (30 mL) was added to quench the reaction, and a large amount of solid was precipitated. The solid was filtered, the filter cake was washed with methanol and water, and dried to obtain a crude product. Purification by column chromatography (DCM: MeOH = 300:1-50:1) gave purple solid 21 (55.6 mg, yield: 40%). 1 HNMR (400 MHz, DMSO- d 6 ) δ 11.02 (s, 1H), 10.83 (s, 1H), 9.84 (s, 1H), 8.89 (d, J =2.3 Hz, 1H), 7.65 (d, J = 7.1 Hz, 1H), 7.63 – 7.54 (m, 2H), 7.42 (d, J = 8.1 Hz,1H), 7.03 (t, J = 7.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 2.31 (d, J = 6.4 Hz, 2H),2.28 – 2.21 (m, 1H), 1.76 (dq, J = 11.4, 6.1 Hz, 2H), 1.66 – 1.58 (m, 2H), 1.55– 1.48 (m, 2H), 1.35 (s, 2H) ppm. 13 C NMR (101 MHz, DMSO- d 6 ) δ 189.00, 171.50,170.95, 152.98, 138.85, 137.59, 137.32, 133.76, 124.76, 121.96, 121.87,121.77, 119.52, 117.72, 113.96, 109.60, 107.35, 45.81, 37.27, 32.40, 25.01ppm. ESI-MS (m / z) 388.16 [M+H] + 。 Example 22

[0061] Synthesis of compound 22: Compound II-15 (116 mg, 0.42 mmol) and II-30 (118 mg, 1.01 mmol) were dissolved in DCM:THF = 2:1 (8 mL:4 mL), then EDCI (80 mg, 0.42 mmol) and HOBT (57 mg, 0.42 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated to give a crude product, which was purified by column chromatography (DCM:MeOH = 100:1-10:1) to give purple solid 22 (95 mg, yield: 68%). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.04 (s, 1H), 10.84 (s, 1H), 10.13 (s, 1H), 8.92 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.58 (td, J = 6.0, 2.9 Hz, 2H), 7.42 (d, J = 8.1 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 2.70 (t, J = 7.2 Hz, 2H), 2.55 (s, 6H), 1.24 (d, J = 8.2 Hz, 2H) ppm. 13 C NMR (126 MHz, DMSO- d 6 ) δ 189.00, 171.49, 169.42, 152.97, 138.90, 137.60, 137.45, 133.53, 124.76, 121.91, 121.83, 121.79, 119.52, 117.61, 113.96, 109.67, 107.28, 54.86, 45.86, 45.84, 44.49 ppm. HR-MS (ESI): 377.1633 [M+H] + . Example 23

[0062] Synthesis of compound 23: Compound II-25 (100 mg, 0.62 mmol) and compound II-31 (87.1 mg, 0.75 mmol) were dissolved in DMF (5 mL), then EDCI (118.9 mg, 0.62 mmol) and HOBT (83.8 mg, 0.62 mmol) were added, and the mixture was stirred at room temperature for 6 h. After the reaction was completed as monitored by LC-MS, water (30 mL) was added to quench the reaction, and the mixture was extracted with EA (30 mL x 3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Purification by column chromatography (DCM:MeOH = 300:1-75:1) gave compound II-32 (128.5 mg, yield: 80%) as an orange-red solid.

[0063] Compound II-32 (100 mg, 0.39 mmol) and II-2 (68.3 mg, 0.39 mmol) were dissolved in methanol (10 mL), then sodium carbonate (82.7 mg, 0.78 mmol) was added, and the mixture was stirred at room temperature for 4 h under nitrogen protection. After the reaction was completed as monitored by LC-MS, water (30 mL) was added to quench the reaction, and a large amount of solid was precipitated, which was filtered, washed with methanol and water, and dried to give a crude product. Purification by column chromatography (DCM:MeOH = 200:1-20:1) gave compound 23 (85.1 mg, yield: 58%) as a purple solid. 1 HNMR (400 MHz, DMSO- d 6 ) δ 11.02 (s, 1H), 10.79 (s, 1H), 9.84 (s, 1H), 8.88 (d, J =2.1 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.63 – 7.54 (m, 2H), 7.42 (d, J = 8.0 Hz,1H), 7.02 (t, J = 7.3 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 2.34 – 2.26 (m, 2H),1.63 – 1.46 (m, 3H), 0.91 (d, J= 6.4 Hz, 6H) ppm. 13 C NMR (101 MHz, DMSO- d 6 ) δ 187.93, 170.43, 151.90, 137.79, 136.52, 136.20, 132.71, 123.68, 120.81, 120.69, 118.44, 116.56, 112.88, 108.52, 106.25, 33.69, 26.73, 21.74 ppm. ESI-MS (m / z) 376.16 [M+H] + . Example 24

[0064] Synthesis of compound 24: Compound II-33 (50 mg, 0.30 mmol) and II-2 (53 mg, 0.30 mmol) were dissolved in methanol (5 mL), then sodium carbonate (64 mg, 0.61 mmol) was added, and the reaction was carried out at room temperature for 5 h under nitrogen protection. After the reaction was completed by LC-MS monitoring, the filter cake was washed with methanol and water, and dried to obtain a crude product, which was purified by column chromatography (DCM: MeOH = 150:1-30:1) to obtain purple solid 24 (55 mg, yield: 65%). 1 H NMR (500 MHz, DMSO- d 6 ) δ 10.97 (s, 1H), 8.80(dd, J = 8.7, 5.9 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.41(d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 6.84 (td, J = 9.3, 2.6 Hz, 1H), 6.71(dd, J = 9.1, 2.6 Hz, 1H) ppm. 13 C NMR (126 MHz, DMSO- d 6 ) δ188.56, 171.28, 152.54, 137.98, 137.96, 137.11, 126.33, 126.26, 124.34, 121.27, 119.01, 113.46, 107.63, 107.45, 97.68, 97.47 ppm. ESI-MS (m / z): 101.07 [M+H] + . Example 25

[0065] Synthesis of compound 25: Compound II-34 (50 mg, 0.28 mmol) and II-2 (50 mg, 0.28 mmol) were dissolved in methanol (5 mL), then sodium carbonate (60 mg, 0.56 mmol) was added, and the reaction was carried out at room temperature for 5 h under nitrogen protection. After the reaction was completed by LC-MS monitoring, the filter cake was washed with methanol and water, and dried to obtain a crude product, which was purified by column chromatography (DCM: MeOH = 200:1-40:1) to obtain purple solid 25 (61 mg, yield: 75%). 1 H NMR (500 MHz, DMSO- d 6 ) δ 10.80 (s, 1H), 8.74 (dd, J = 8.9, 4.0 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 6.60 (dd, J = 8.7, 2.6 Hz, 1H), 6.46 (d, J = 2.5 Hz, 1H), 3.80 (s, 3H) ppm. 13 C NMR (126 MHz, DMSO- d 6) δ 188.69, 172.12, 161.43, 152.83, 143.61, 137.16, 136.75, 126.87, 124.56, 121.21, 119.60, 115.12, 113.75, 107.98, 107.23, 96.61, 55.83 ppm. ESI-MS (m / z): 293.09 [M+H] + . Example 26

[0066] Synthesis of compound 26: Compound III-1 (50 mg, 0.19 mmol) and III-2 (53 mg, 0.23 mmol) were dissolved in anhydrous DMF (3 mL), then sodium hydride (14 mg, 0.57 mmol) was added, and the reaction was stirred at room temperature for 1.5 h. After the reaction was monitored to completion by LC-MS, water (10 mL) was added to quench the reaction, and a solid precipitated, which was filtered and dried to give a crude product. Purification by column chromatography (DCM: MeOH = 200:1-50:1) gave purple solid 26 (36 mg, yield: 56%). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.08 (s, 1H), 8.80 (dd, J = 7.8, 1.2 Hz, 1H), 7.65 (d, J = 6.8 Hz, 1H), 7.59-7.56 (m, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.32 (td, J = 7.7, 1.3 Hz, 1H), 7.13 – 6.99 (m, 3H), 3.90 (t, 2H), 2.53 (t, J = 6.5 Hz, 2H), 2.20 (s, 6H) ppm. 13 C NMR (126 MHz, DMSO- d 6 ) δ188.50, 168.98, 152.45, 141.19, 138.58, 137.14, 129.12, 124.48, 124.39, 121.64, 121.35, 120.70, 119.02, 113.46, 108.57, 105.44, 56.15, 45.27(2C), 37.32 ppm. HR-MS (ESI): 334.1568 [M+H] + . Example 27

[0067] Synthesis of compound 27: Compound III-1 (100 mg, 0.38 mmol) and III-3 (78 mg, 0.46 mmol) were dissolved in anhydrous DMF (5 mL), then sodium hydride (27 mg, 1.14 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was monitored to be completed by LC-MS, water (10 mL) was added to quench the reaction, and a solid was precipitated. The solid was filtered and dried to give a crude product. The crude product was purified by column chromatography (DCM: MeOH = 150:1-40:1) to give purple solid 27 (51 mg, yield: 37%). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.09 (s, 1H), 8.81 (dd, J = 7.8, 1.2 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.58 (td, J = 7.7, 7.2, 1.3 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.32 (td, J = 7.7, 1.3 Hz, 1H), 7.14 –7.06 (m, 2H), 7.02 (t, J = 7.4 Hz, 1H), 3.93 (t, J = 6.7 Hz, 2H), 2.70 (t, J = 6.8 Hz, 2H), 2.52 (s, 4H), 1.67-1.64 (m, 4H) ppm. 13 C NMR (126 MHz, DMSO- d 6 )δ 188.52, 168.94, 152.45, 141.19, 138.61, 137.16, 129.14, 124.50, 124.40, 121.67, 121.37, 120.72, 119.03, 113.47, 108.58, 105.44, 53.65(2C), 52.79, 38.50, 23.14(2C) ppm. HR-MS (ESI): 360.1730 [M+H] + . Example 28

[0068] Synthesis of compound 28: Compound II-13 (200 mg, 1.04 mmol) was dissolved in dry DMF (4 mL), sodium hydride (25 mg, 1.04 mmol) was added under ice-bath, stirred for 5 min, then potassium iodide (442 mg, 1.56 mmol) was added, and the reaction was allowed to warm to room temperature overnight. After the reaction was monitored to be completed by LC-MS, saturated aqueous ammonium chloride solution (10 mL) was added to quench, extracted with ethyl acetate twice, washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude III-4 (135 mg, yield: 63 %), which was used in the next step without purification.

[0069] Compound III-4 (135 mg, 0.66 mmol) and II-2 (115 mg, 0.66 mmol) were dissolved in methanol (10 mL), sodium carbonate (139 mg, 1.13 mmol) was added, and the reaction was allowed to proceed at room temperature for 5 h under nitrogen protection. After the reaction was monitored to be completed by LC-MS, it was filtered, the filter cake was washed with methanol and water, and the filter cake was dried to give the crude III-5 (200 mg, yield: 95 %), which was used in the next step without purification.

[0070] Compound III-5 (325 mg, 1.01 mmol) was dissolved in methanol (50 mL), Pd / C (33 mg, 0.1 eq) was added, hydrogen was introduced, and the reaction was allowed to proceed at room temperature for 6 h. After the reaction was monitored to be completed by LC-MS, it was filtered through diatomite, and the filtrate was concentrated under reduced pressure to give purple solid III-6 (205 mg, yield: 70 %), which was used in the next step without purification.

[0071] Compound III-6 (100 mg, 0.34 mmol) and II-30 (44 mg, 0.38 mmol) were dissolved in DCM:THF = 2:1 (8 mL:4 mL), then EDCI (65 mg, 0.34 mmol) and HOBT (46 mg, 0.34 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (DCM:MeOH = 100:1-10:1) to give purple solid 28 (30 mg, yield: 23%). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.07 (s, 1H), 10.26 (s, 1H), 8.98 (s, 1H), 7.66 (t, J = 6.7 Hz, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.11 - 6.96 (m, 2H), 3.25 (s, 3H), 2.85 (d, J = 7.3 Hz, 2H), 2.72 (s, 6H), 2.66 (d, J = 17.8 Hz, 2H) ppm. 13 C NMR (126 MHz, DMSO- d 6 ) δ 168.29, 139.16, 137.71, 124.83, 121.93, 121.41, 121.08, 119.52,117.47, 108.54, 106.15, 53.57, 43.15(2C), 31.60, 26.36 ppm. HR-MS (ESI): 391.1745 [M+H] + . Example 29

[0072] Synthesis of compound 29: Compound II-3 (300 mg, 1.57 mmol) was dissolved in anhydrous DMF (10 mL), sodium hydride (151.2 mg, 6.3 mmol) was added under ice-bath, stirred for 5 min, then methyl iodide (894.2 mg, 6.3 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed by LC-MS monitoring, saturated aqueous ammonium chloride solution (30 mL) was added to quench, extracted with ethyl acetate three times (30 mL x 3), then washed with saturated sodium chloride solution (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was slurried with dichloromethane: n-hexane = 1:5 to give compound III-7 (221.2 mg, yield 64.3 %).

[0073] Compound III-7 (100 mg, 0.46 mmol) was dissolved in methanol: water = 2:1 (14 mL: 7 mL), then potassium carbonate (829.3 mg, 6 mmol) was added, and the reaction was allowed to proceed overnight at 85 °C. After the reaction was completed by LC-MS monitoring, water (30 mL) was added to quench; 2 N dilute hydrochloric acid was used to adjust pH = 3, extracted with ethyl acetate three times (30 mL x 3), then washed with saturated sodium chloride solution (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. Purification by column chromatography (DCM:MeOH = 100:1-20:1) gave orange solid III-8 (90 mg, 96 %).

[0074] Compound III-8 (122 mg, 0.6 mmol) and compound II-2 (105.1 mg, 0.6 mmol) were dissolved in methanol (15 mL), then sodium carbonate (127.2 mg, 1.2 mmol) was added, and the reaction was allowed to proceed at room temperature for 5 h under nitrogen protection. After the reaction was completed by LC-MS monitoring, the filtrate was washed with methanol and water, and the filter cake was dried to give a crude product, which was purified by column chromatography (DCM:MeOH = 100:1-10:1) to give purple solid 29 (43.9 mg, yield 23 %). 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.68 (s,1H), 11.13 (s, 1H), 9.45 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.71 – 7.55 (m,2H), 7.43 (d, J= 7.6 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H),3.31 (s, 3H) ppm. ESI-MS (m / z): 321.08 [M+H] + .

[0075] Example 30 Synthesis of compound 6 hydrochloride: Compound 6 (200 mg, 0.48 mmol) was dissolved in ethyl acetate (5 mL), EA-HCl (3 mL) was added, solid precipitated, suction filtered, the filter cake was washed with ethyl acetate to give purple solid 6-HCl (203 mg, yield: 94 %). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.18 (s, 1H), 11.10 (s, 1H), 8.91 (s, 1H), 7.66 (d, J = 7.5Hz, 1H), 7.63 – 7.56 (m, 1H), 7.46 – 7.37 (m, 2H), 7.04 (t, J = 7.4 Hz, 1H),6.99 (d, J = 8.0 Hz, 1H), 5.38 (s, 1H), 4.26 (s, 2H), 3.79 (t, J = 5.3 Hz, 2H),3.54 (s, 4H), 3.26 – 3.08 (m, 4H) ppm. ESI-MS (m / z): 419.17 [M+H] + . Example 31

[0076] Synthesis of compound 15 hydrochloride: Compound 15 (200 mg, 0.52 mmol) was dissolved in ethyl acetate (5 mL), EA-HCl (2 mL) was added, solid precipitated, suction filtered, the filter cake was washed with ethyl acetate to give purple solid 15-HCl (211 mg, yield: 95 %). 1 H NMR (400 MHz, DMSO- d 6) δ 11.06 (s, 1H), 10.95 (s, 1H), 10.85 (s, 1H), 9.12 (d, J =2.3 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.59 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.53(dd, J = 8.4, 2.1 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.07 – 7.01 (m, 1H), 6.90(d, J = 8.4 Hz, 1H), 4.16 (d, J = 4.8 Hz, 2H), 3.26 (dt, J = 7.5, 4.3 Hz, 4H), 1.27(t, J = 7.3 Hz, 6H) ppm. ESI-MS (m / z): 391.17 [M+H] + .

[0077] Example 32 Study on the effect of compounds on promoting ILC3 chemotaxis Experimental methods: 1) Colon tissue separation and pretreatment Pathogen-free mice were euthanized by cervical dislocation and immersed in 75% alcohol for 10 minutes. The small intestine, starting from the stomach end and extending to the cecum, was cut with scissors, and the free tissue outside the mouse intestine was separated with forceps. Subsequently, the small intestinal tissue was placed in pre-cooled PBS at 4 ℃ to remove the mesentery, adipose tissue, and Peyer's lymph nodes of the small intestine. The intestinal tissue was cut along the long axis of the intestine and washed twice in pre-cooled PBS to remove feces and mucus. 2) Isolation of single cells The colon was cut into pieces of about 2 cm with scissors, transferred into 50 mL sterile EP tubes, 10 mL of wash solution 1 (PBS containing 1 mM DTT) was added to each tube, and the tubes were shaken vigorously at 220 rpm and 37 °C for 10 min. The centrifuge tubes were removed and shaken manually for 2 min, then the intestinal tissue was transferred into 15 mL centrifuge tubes containing 10 mL PBS and shaken manually for another 2 min. The PBS-washed intestinal tissue was removed with forceps and transferred into 50 mL centrifuge tubes containing 10 mL of wash solution 2 (PBS containing 30 mM EDTA), shaken vigorously at 220 rpm and 37 °C for 10 min. The tubes were removed and placed in a six-well plate containing digestion solution (5 mL of 1640 complete medium containing 150 pg / mL DNase I and 200 U / mL collagenase VIII for one large intestine), and the tissue was cut into pieces of about 0.5 cm and incubated at 37 °C in a CO2 incubator with 5% CO2 concentration for 90 min. The digestion solution was collected, filtered through a 70 pm cell strainer into a 50 mL sterile EP tube, centrifuged at 4 °C and 400 g for 10 min, and the cell pellets were resuspended and combined. Each sample was centrifuged at 800 g for 10 min using 4 mL of 40% Percoll and 2.5 mL of 80% Percoll working solution, and the middle layer cells were collected and washed once with PBS, then resuspended in RPMI 1640 medium containing 20% FBS; 3) Flow sorting ILC3 ILC3 were purified and sorted by BD FACS ARIA II, serial mouse antibodies as follows CD3e, CD5, CD19, CD11b, CD11c, NK1.1, KLRG1; CD90.2, CD45; for detecting the expression of cytokines, the obtained intestinal mucosa lamina propria lymphocytes were stimulated and incubated with freshly prepared cell stimulation culture solution at 37℃, 5% CO2 incubator for 4h, then the cells were collected for staining; antibodies and flow cytometry FACS used the following antibodies and corresponding dilutions: when staining, the single cell suspension was incubated with Fc blocking agent for 10 minutes, flow detection surface antibodies CD45, CD3e, CD127, CD11b, CD11c, Ly6G and Ly6C were added, and incubated at 4℃ in the dark for 30 min; 1 mL PBS was added, mixed and washed once, centrifuged at 500 g for 5 min, and the supernatant was discarded; 1 mL of fixation / breaking membrane working solution was added, the cells were vortexed, and incubated at room temperature in the dark for 30 min; centrifuged at 700 g for 5 min, and 1 mL of fixation / breaking membrane buffer was added for washing once; RORyt antibody and IL-22 antibody were added and mixed, and incubated at room temperature in the dark for 30 min; PBS was added, mixed and washed, and centrifuged at 700 g for 5 min. The supernatant was discarded, the cells were resuspended with 300 μL PBS, and then detected on the machine, and analyzed by FlowJo software; 4) In vitro chemotaxis assay For mouse chemotaxis assay, Transwell chamber (Corning, Cat#3415, MA, USA) was used to measure the migration ability of ILC3 cells in 24-well plate; ILC3 were purified and sorted by BD FACS ARIA II, with a density of 1×10 6Cells were co-incubated with each compound for 48 h, then centrifuged into the top chamber of a transwell plate, and the bottom chamber was loaded with 600 μL of medium and 1 μg / mL of rmMadcam-1; the cells were incubated at 37 °C for 2 h, and the number of cells in the lower layer was accurately counted using a cell counter; then the cells in the lower chamber were collected, 1 mL of Trizol reagent was added for grinding, and a tissue homogenate was prepared; then, the homogenate was transferred to an RNase-free 1.5 mL EP tube, lysed on ice for 10 min; 200 μL of chloroform was added, shaken vigorously, and placed on ice for 3-5 min, then centrifuged at 12000 rpm, 4 °C for 15 min. The supernatant was carefully pipetted into a new RNase-free 1.5 mL EP tube, an equal volume of pre-cooled isopropanol was added, and the mixture was placed in an ice bath for 30 min, then centrifuged at 12000 rpm, 4 °C for 10 min, and the supernatant was discarded; the precipitate was washed with 75% ethanol-DEPC solution, and then dried on a flat paper, thus obtaining total RNA. Then, 10 μL of DEPC-treated water was added for dissolution; 1 μL of the total RNA solution was diluted 100-fold, and the OD values at 260 nm and 280 nm were measured using a full-wavelength enzyme marker; when the ratio of OD260 / OD280 was between 1.8 and 2.0, cDNA synthesis and qPCR amplification were performed using a reverse transcription kit; the threshold cycle (Ct) values of each group were recorded, and the 2 -ΔΔCt method was used for calculation and analysis (the expression of the control gene Gapdh was set to 1 to correct the expression of the target gene); Experimental results: as shown in Table 1, compared with the untreated group, compounds 1-29 at a concentration of 10 μM could promote the chemotaxis of ILC3 and up-regulate the expression of Il22 mRNA, and compounds 4, 6, 12, 13, 14, 15, 21, 22 and 29 had particularly significant effects; all-trans retinoic acid (ATRA) was used as a positive control based on the literature report that ATRA could significantly up-regulate the expression of ILC3 surface chemotactic factors and integrins and promote their migration, thereby verifying the reliability of the experimental system and providing a reference for the effects of the compounds.

[0078] Table 1. Effects of compounds 2-31 on the chemotaxis and mRNA expression of ILC3 Il22 δ ILC3 cell number a ]] <![CDATA[ Il22 mRNA expression b ]]> δ + + δ +++ +++ 1 ++ ++ 2 +++ +++ 3 ++ + 4 ++++ ++++ 5 ++ ++ 6 ++++ ++++ 7 ++ ++ 8 ++ ++ 9 ++ ++ 10 + + 11 + + 12 ++++ ++++ 13 +++ ++++ 14 ++++ ++++ 15 ++++ ++++ 16 ++ +++ 17 ++ ++ 18 +++ +++ 19 + + 20 ++ ++ 21 ++++ ++++ 22 ++++ ++++ 23 ++ ++ 24 + + 25 ++ ++ 26 ++ ++ 27 ++ ++ 28 ++ ++ 29 ++++ ++++ a. Note: <20,000 chemotactic cells are indicated by +, 20,000<chemotactic cells<30,000 are indicated by ++, 30,000<chemotactic cells<35,000 are indicated by +++, and 35,000<chemotactic cells<40,000 are indicated by +++++. ATRA represents all-trans retinoic acid; ​B. Remarks: 1.0 < Il22 mRNA expression < 1.4 is denoted as +, 1.4 < Il22 mRNA expression < 2.0 is denoted as ++, 2.0 < Il22 mRNA < 3.0 expression is denoted as ++++, and Il22 mRNA > 3.0 is denoted as +++++. rmIL-23 represents recombinant mouse IL-23 protein.

[0079] Example 33 Effect on dextran sulfate sodium (DSS)-induced colitis in mice Experimental method: 1). Establishment of mouse UC model Female C57BL / 6 mice, weighing 20 ± 2 g, 6 - 8 weeks old, were allowed to freely drink 2.5% DSS solution for 7 days, and then switched to distilled water for 3 days to establish an acute UC model in mice; the day when the modeling started was recorded as d1, and the body weight of the mice at this time was recorded as the initial body weight. 2). Pharmacodynamic evaluation of anti-mouse UC To investigate the anti-UC effect of indoline derivatives, the mice were randomly divided into the following groups: normal group, DSS group, compound 6, 14, 15 (1 mg / kg) groups, and positive drug 5-ASA (200 mg / kg) group; 5-ASA, as a classic clinical anti-inflammatory drug, has been widely used in the treatment of UC, so it was selected as the positive control to verify the reliability of the experimental system and compare the efficacy of the compounds; on the day of modeling, compound 6, 14, 15, and 5-ASA (0.1 mL / 10 g) were administered by gavage; during the experiment, the body weight, diarrhea index, and fecal occult blood of each group of mice were observed and recorded daily according to the scoring rules in Table 1, and the disease activity index (DAI) score was calculated, DAI score = (body weight score + diarrhea score + fecal occult blood score) / 3; after the experiment, the colon tissue was taken 1 cm away from the anus, the colon length was measured with a ruler and photographed; the levels of inflammatory factors in the colon tissue were detected by qPCR.

[0080] Experimental results: 1). Effect on the disease activity index (DAI) score of colitis mice After successful establishment of the DSS-induced colitis model in mice, in addition to weight loss, the feces became soft, the water content increased, and fecal occult blood or even bloody stools occurred; as shown in Table 2, compared with the Normal group, the DAI score of the DSS group mice increased significantly, and the activity frequency decreased, and they often curled up in the corner of the cage; compared with the DSS group mice, compound 6, 14, 15 (1 mg / kg) and 5-ASA (200 mg / kg) could significantly improve DSS-induced colonic inflammation in mice, the DAI score decreased significantly, and the hair of the mice was shiny, and the overall condition was good, and the effects of compounds 6, 14, and 15 were significantly better than the positive drug 5-ASA.

[0081] Table 2. Effects on DAI scores of colitis mice Note: Compared with Normal group, ##P<0.01; Compared with DSS group, *P<0.05, **P<0.01. 2), Effects on colon length of colitis mice The colon of colitis mice was significantly shortened, so the disease severity of colitis mice could be evaluated by colon length. As shown in Table 3, compared with Normal group, the colon length of DSS group mice was significantly shortened, and the appearance could be seen that the internal feces was not shaped and the color was darker; Compound 6, 14, 15 (1 mg / kg) and 5-ASA (200 mg / kg) could inhibit the shortening of colon of mice, and the effects of Compound 6, 14, 15 were significantly better than that of 5-ASA.

[0082] Table 3. Effects on colon length of colitis mice Note: Compared with Normal group, ##P<0.01; Compared with DSS group, **P<0.01. 3), Effects on expression of inflammatory factors of colitis mice Because DSS induced the destruction of intestinal epithelial barrier, the external pathogens and harmful bacteria were more likely to enter the intestinal cavity and invade the lamina propria, triggering immune overactivation to cause inflammatory response, and in this process, inflammatory factors such as TNF-α, IL-1β and IL-6 were released; therefore, the mRNA expression of pro-inflammatory factors in colon tissues of mice in each group was detected; the results were shown in Table 4. Compared with Normal group, the mRNA expression of TNF-α, IL-1β and IL-6 in colon tissues of DSS mice was significantly up-regulated, and Compound 6, 14, 15 (1 mg / kg) and 5-ASA (200 mg / kg) could down-regulate the level; among them, the effects of Compound 6, 14, 15 were significantly better than that of 5-ASA. δ 、 Il1 and Il6

[0083] Table 4. Effects on mRNA expression of inflammatory factors of colitis mice Note: Compared with Normal group ## P <0.01; Compared with DSS group P <0.05, ** P <0.01. 4), Effects on mRNA expression of TFF3 in colon tissues of colitis mice Il22 The mRNA expression of TFF3 in colon tissues of colitis mice was significantly up-regulated, and Compound 6, 14, 15 (1 mg / kg) and 5-ASA (200 mg / kg) could down-regulate the level; among them, the effects of Compound 6, 14, 15 were significantly better than that of 5-ASA.​ As shown in Table 5, in the colon tissues of DSS-induced colitis mice Il22 mRNA expression decreased significantly, suggesting that the mucosal protection function was impaired; after treatment with compounds 6, 14, 15 (1 mg / kg), the colon tissues Il22 mRNA expression was significantly up-regulated, suggesting that it may restore the colon mucosal barrier function by up-regulating IL-22 levels, thereby improving mouse UC; among them, the effects of compounds 6, 14 and 15 were significantly better than 5-ASA.

[0084] Table 5. Effects on mRNA expression in colon tissues of colitis mice Il22 mRNA expression Note: Compared with the Normal group ## P <0.01; compared with the DSS group P <0.01.

[0085] Example 34 Effects on DSS-induced colitis in mice Experimental method: 1) Establishment of mouse colitis model Male BALB / c mice, weighing 20 ± 2 g, 6-8 weeks old, were raised in a SPF barrier environment for one week. The night before the formal experiment, the mice were fasted and the distilled water was replaced with 5% glucose solution for free drinking to supplement energy and avoid massive death after modeling. On the experimental day, the mice were anesthetized with isoflurane, the hair around the anus was moistened with normal saline, and 2.5% TNBS modeling solution was slowly injected into the anus 2-3 cm through a 12-gauge enema needle. The enema needle was carefully pulled out to avoid leakage. After the TNBS modeling solution was injected, the mouse tail was lifted to keep it upright for about 3 min to ensure that the modeling solution and colon tissue were in close contact, thereby improving the success rate of modeling. 2) Evaluation of anti-colitis efficacy in mice To investigate the anti-colitis effect of indoline derivatives, mice were randomly divided into the following groups: normal group, TNBS group, compound 6, 7, 14, 15 (1 mg / kg) and positive control 5-ASA (200 mg / kg) group; 5-ASA is a classic clinical anti-inflammatory drug, widely used in UC and experimental enteritis model, 5-ASA is selected as a positive control to verify the reliability of the experimental model and compare the efficacy of the compounds; after modeling, the mice were normally fed and watered, and 4-6 h later, compound 6, 7, 14, 15 and 5-ASA (0.1 mL / 10 g) were administered by gavage for 7 consecutive days; During the experiment, the mice were weighed daily, and the mice were observed for death and diarrhea and blood in stool; After the experiment, the mice were anesthetized with isoflurane and sacrificed by cervical dislocation, the colon tissue of the mice was isolated, the length was measured and the photo was taken. According to the colon congestion, intestinal wall thickening, ulceration and ulceration number and range, the macroscopic score of TNBS-induced colitis mice was evaluated (macroscopic score), the score range was 0~10; Then the colon tissue was fixed in 4% formaldehyde solution for HE staining, the remaining part was carefully wrapped with tin paper and placed in-80 ℃ refrigerator for standby, and the level of inflammatory factors in colon tissue was detected by qPCR method; Experimental results: 1) Effect on colon length of colitis mice The colon is significantly shortened under the condition of colitis, so the severity of colitis mice can be evaluated by colon length; As shown in Table 11, compared with the Normal group, the colon length of the TNBS group mice was significantly shortened, and the appearance could be seen that the internal feces was not shaped and the color was darker; After gavage administration of 6, 7, 14, 15 (1 mg / kg) and 5-ASA (200 mg / kg), the colon shortening of mice was inhibited; Among them, the effects of compounds 6, 14 and 15 were obviously better than that of 5-ASA.

[0086] Table 11. Effect on colon length of colitis mice Note: compared with the Normal group ## P <0.01; compared with the TNBS group P <0.05, P <0.01. 2) Effect on colon macroscopic score of colitis mice Compared with the Normal group, the TNBS-induced mouse colon showed significant intestinal wall thickening, hyperemia and edema, and multiple ulceration and other typical inflammatory features, and the macroscopic score was significantly increased. After continuous administration of 6, 7, 14, 15 and 5-ASA, the thickening and hyperemia of the intestinal wall of the mouse colon were reduced, the ulceration was reduced, and the overall macroscopic injury score was significantly lower than that of the TNBS group, indicating that compounds 6, 7, 14 and 15 have a protective effect on TNBS-induced colon mucosa damage. Among them, the effects of compounds 6, 14 and 15 are obviously better than that of 5-ASA.

[0087] Table 12. Effect on the macroscopic score of the colon of colitis mice Note: Compared with the Normal group ## P <0.01; compared with the TNBS group P <0.05, P <0.01. 3) Effect on the expression of inflammatory factors in the colon of colitis mice TNBS induces intestinal epithelial barrier damage, making it easier for external pathogens and harmful bacteria to enter the intestinal lumen and invade the lamina propria, triggering immune overactivation and leading to inflammatory reactions. In this process, inflammatory factors such as TNF-a, IL-1b and IL-6 are released. The mRNA expression of pro-inflammatory factors in the colon tissues of mice in each group was detected. As shown in Table 6, compared with the Normal group, the mRNA expression of TNF-a, IL-1b and IL-6 in the colon tissues of TNBS mice was significantly up-regulated, while the mRNA expression of TNF-a, IL-1b and IL-6 was down-regulated after gavage with compounds 6, 7, 14, 15 and 5-ASA, and the effects of compounds 6, 14 and 15 were obviously better than that of 5-ASA. δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ 、 Il1 and Il6

[0088] Table 13. Effect on the mRNA expression of inflammatory factors in the colon of colitis mice Note: Compared with the Normal group ## P <0.01; compared with the TNBS group P <0.05, P <0.01. 4) Effect on the IL-22 level in the colon tissues of colitis mice In the colon tissues of TNBS-induced colitis mice, the mRNA expression of IL-22 was significantly decreased, indicating that the mucosal barrier function was impaired. After treatment with compounds 6, 7, 14, 15 and 5-ASA, the colon tissues Il22 Il22 ​​The mRNA expression was significantly upregulated, confirming that it exerts its anti-colitis effect by upregulating IL-22 levels and enhancing colonic mucosal repair function; among them, compounds 6, 7, 14, and 15 were significantly more effective than 5-ASA.

[0089] Table 14. Effects of colonic inflammation on mice Il22 Effect of mRNA expression Note: Compared with the Normal group ## P <0.01; compared with the TNBS group** P <0.01.

[0090] Example 35 Effects of sodium dextran sulfate (DSS) on colitis induced in mice Experimental methods: 1) Establishment of an acute lung injury model in mice Male C57BL / 6 mice, weighing 20 ± 2 g and aged 6-8 weeks, were housed in an SPF-grade barrier environment for one week. The mice were fasted the night before the experiment, and their double-distilled water was replaced with 5% glucose solution for free drinking to supplement their energy and prevent mass mortality after modeling. On the day of the experiment, LPS (10 mg / kg) was administered intraperitoneally to induce acute lung injury. After the injection, the mice were returned to normal housing conditions, and lung tissue and related samples were collected at predetermined time points for subsequent analysis. 2) Evaluation of efficacy against acute lung injury in mice To investigate the anti-acute lung injury effect of indoline derivatives, mice were randomly divided into the following groups: normal group, LPS group, compound 6, 7, 14 (1 mg / kg), and positive control dexamethasone (Dex, 5 mg / kg). Dex, as a classic glucocorticoid anti-inflammatory drug, has been widely used in acute inflammation and lung injury models. Dex was selected as a positive control to verify the reliability of the experimental system and compare the anti-inflammatory effects of the compounds. Compound 6, 7, 14, and Dex (0.1 mL / 10 g) were administered by gavage for 5 consecutive days before modeling. On day 6, LPS (10 mg / kg) was administered by intraperitoneal injection to induce acute lung injury. After injection, the mice were returned to normal feeding conditions, and bronchoalveolar lavage fluid was collected 12 h later, and MPO activity was detected using a kit. Experimental results: 1) Effect on MPO activity in bronchoalveolar lavage fluid The results are shown in Table 6. The MPO activity in the bronchoalveolar lavage fluid of mice in the LPS group was significantly increased, indicating a significant increase in neutrophil activation and inflammation levels. Compared with the LPS group, the MPO activity in the bronchoalveolar lavage fluid of the groups treated with compounds 6, 7, 14 and Dex was significantly decreased, supporting their protective effect in acute injury. Among them, compounds 6, 7 and 14 were significantly more effective than Dex.

[0091] Table 6. Effects on MPO activity in bronchoalveolar lavage fluid of mice with acute lung injury Note: Compared with the Normal group ## P <0.01; compared with the LPS group* P <0.05,** P <0.01 2) In lung tissue Il6 Effect of mRNA expression In mice with LPS-induced acute lung injury, lung tissue Il6 The mRNA level decreased significantly, indicating impaired alveolar barrier function; the results are shown in Table 7. After treatment with indoline derivatives 6, 7, 14 and Dex, Il6 The significantly increased mRNA expression suggests that it may exert a protective effect against acute lung injury by upregulating IL-22 levels and improving the integrity of the alveolar epithelial barrier; among them, compounds 6, 7, and 14 were significantly more effective than Dex.

[0092] Table 7. Effects of acute lung injury on lung tissue in mice Il6 Effect of mRNA expression Note: Compared with the Normal group ## P <0.01; compared with the LPS group* P <0.05,** P <0.01.

[0093] Example 36 Effects of sodium dextran sulfate (DSS) on colitis induced in mice Experimental methods: 1) Preparation of indoline derivative ointment Preparation of blank ointment: (1) Preparation of oil phase: Weigh out white petrolatum, light liquid paraffin, glyceryl monostearate, ethylparaben and cetyl alcohol, heat to 65 ℃, stir to dissolve, slowly add to the dissolved raw material, continue to stir and mix evenly, and set aside; (2) Preparation of water phase: weigh purified water and Tween 80, heat to 70°C, stir to dissolve and prepare for use; (3) Emulsification: slowly add water phase to oil phase, keep at 65°C, homogenize, continue stirring for 30 min; (3) Cooling, stop heating, continue stirring, gradually reduce to room temperature and cool into paste, fill.

[0094] (4) Preparation of 0.1% indoline derivative ointment and 1% dexamethasone ointment: weigh 0.05 g of indoline derivative and benzovindole respectively into a small amount of propylene glycol, and place in the above condensed blank ointment base, finally add water to 10 g, and grind with a mortar to obtain 0.1% indoline derivative and benzovindole ointment; 2) Establishment of mouse psoriasis model Male BALB / c mice, weighing 20 ± 2 g, 6-8 weeks old, were raised in a SPF barrier environment for one week; On the experimental day, the hair on the back of the mice was shaved in a 2x3 cm area, the skin surface was disinfected with 75% ethanol, and then 62.5 mg of 5% imiquimod ointment was applied topically at regular intervals every day for 6 consecutive days to induce psoriasis-like dermatitis model, and the control group was applied with the same amount of blank cream base; 3) Evaluation of anti-mouse psoriasis efficacy To investigate the anti-acute lung injury effect of indoline derivatives, the mice were randomly divided into the following groups: normal group, IMQ group, compound 14 (0.1%) and positive control Benvitimod (0.1%) group. Benvitimod, as a drug approved for clinical treatment of psoriasis, can significantly alleviate inflammatory response, and is selected as a positive control to verify the reliability of the model and compare the effect of the compound; except for the normal group, the rest of the groups were applied with 62.5 mg of 5% IMQ cream after shaving the back (2x3 cm area), then applied with 14 and Benvitimod (0.1%) ointment, for 6 consecutive days, and the normal group was applied with the same amount of blank ointment; the degree of erythema, scales, and skin thickening were recorded and scored daily. All mice were sacrificed on the 7th day, and the back skin lesion tissues were taken, and the expression of inflammatory factor Il6 and epithelial barrier protection factor Il22 mRNA was detected by qPCR method; Experimental results: 1) Effect on psoriasis lesions in mice Continuous external use of IMQ can cause typical psoriasis-like skin damage, including skin thickening, erythema, scale accumulation, and inflammatory infiltration; the use of Benvitimod ointment as a positive control is based on its exact clinical anti-psoriasis effect; compared with the IMQ group, the skin of mice in the compound 14 and Benvitimod (0.1%) treatment groups improved significantly, with reduced erythema and scales.

[0095] Table 8. Effects of IMQ on skin lesions in psoriatic mice Note: Compared with the Normal group ## P <0.01; compared with the IMQ group* P <0.05,** P <0.01. 2) Effects on the skin of psoriatic mice Il6 Effect of mRNA expression Compared with the Normal group, IMQ mice had higher concentrations of certain substances in their skin tissue. Il6 mRNA expression was significantly upregulated, while compound 14 and Benvitimod (0.1%) ointment downregulated its level after topical administration; among them, compound 14 was significantly more effective than Benvitimod.

[0096] Table 9. Effects of IMQ-induced psoriasis on mouse skin tissue Il6 Effect of mRNA expression Note: Compared with the Normal group ## P <0.01; compared with the IMQ group* P <0.05,** P <0.01. 3) Effects on the skin of psoriatic mice Il22 Effect of mRNA expression In IMQ-induced psoriatic mouse skin tissue Il22 The mRNA expression was significantly decreased, indicating impaired skin and mucous membrane protective function; after treatment with compound 14 and Benvitimod (0.1%) ointment, the skin tissue... Il22 The mRNA expression was significantly upregulated, suggesting that it may improve psoriasis in mice by restoring the skin and mucous membrane barrier function by upregulating IL-22 levels; among them, compound 14 was significantly more effective than Benvitimod.

[0097] Table 10. Effects of IMQ on skin lesions in psoriatic mice Note: Compared with the Normal group ## P <0.01; compared with the IMQ group* P <0.05,** P <0.01.

Claims

1. An indoline derivative or a pharmaceutically acceptable salt thereof, characterized in that, The chemical structural formula of the indoline derivative is shown in formula (I): In the formula, R1 is selected from H or halogen; R2 is selected from H, halogen or -COOR6; R3 is selected from -NR7R8, -NHCOR9 or -COOR 10 or -CONHR 11 R4 is selected from H, halogens, or -OR. 12 R5 is selected from H, C1-C6 alkyl groups, or -(CH2)nNR. 13 R 14 R6 is selected from C1-C6 alkyl; R7 and R8 are independently selected from H or C1-C6 alkyl; R9 is selected from C1-C6 alkyl, -(CH2)nNR 15 R 16 - (CH2)nR 17 or -NR 18 R 19 ;R 10 Selected from H or -(CH2)nNR 20 R 21 ;R 11 Selected from H, C1-C6 alkyl groups or -(CH2)nNR 22 R 23 ;R 12 Selected from H or C1-C6 alkyl; R 13 and R 14 Independently selected from C1-C6 alkyl groups or forming a 5-7 membered nitrogen-containing heterocycle with the attached N; R 15 and R 16 Independently selected from C1-C6 alkyl or R 15 and R 16 It forms a 5-7 member nitrogen-containing heterocycle with the attached N; R 17 Selected from NH2-substituted benzene rings or 5-7 membered cycloalkyl groups; R 18 and R 19 Independently selected from C1-C6 alkyl groups; R 20 and R 21 Independently selected from C1-C6 alkyl or R 20 and R 21 It forms a 5-7 member nitrogen-containing heterocycle with the attached N; R 22 and R 23 Selected from H or C1-C6 alkyl or R 22 and R 23 It forms a 5-7 member nitrogen-containing heterocycle with the attached N; R 24 and R 25 Independently selected as C1-C6 alkyl or R 24 and R 25 It forms a 5-7 member nitrogen-containing heterocycle with the attached N; Among them, R 13 and R 14 R 15 and R 16 R 20 and R 21 R 22 and R 23 R 24 and R 25 The nitrogen-containing heterocycles in the mixture are all replaced by one or more C1-C6 alkyl groups; The number n in each substituent is independently selected from 1, 2, 3, or 4.

2. The indoline derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R1 is selected from H or a halogen; R2 is selected from H or a halogen; R3 is selected from -NHCOR9; R4 is selected from H or a halogen; R5 is selected from H or a C1-C6 alkyl group; R9 is selected from -(CH2)nNR. 15 R 16 ;R 15 and R 16 Independently selected from C1-C6 alkyl or R 15 and R 16 The nitrogen-containing heterocycle connected to the N forms a 5-7 membered nitrogen-containing heterocycle, wherein the nitrogen-containing heterocycle is substituted by one or more C1-C6 alkyl groups; Where n is selected from 1, 2, 3 or 4.

3. The indoline derivative or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that, The R 15 and R 16 Independently selected from methyl or ethyl or R 15 and R 16 It forms a tetrahydropyrrole ring, morpholine ring, piperazine ring, piperidine ring, or N-methylpiperazine ring with the attached N.

4. The indoline derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R1 is selected from H or halogen; R2 is selected from H or halogen; R3 is selected from -COOR. 10 R4 is selected from H or halogens; R5 is selected from H or C1-C6 alkyl groups; R 10 Selected from H or -(CH2)nNR 20 R 21 ;R 20 and R 21 Independently selected from C1-C6 alkyl or R 20 and R 21 The nitrogen-containing heterocycle connected to the N forms a 5-7 membered nitrogen-containing heterocycle, wherein the nitrogen-containing heterocycle is substituted by one or more C1-C6 alkyl groups; Where n is selected from 1, 2, 3 or 4.

5. The indoline derivative or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that, The R 20 and R 21 Independently selected from methyl or ethyl or R 20 and R 21 It forms a tetrahydropyrrole ring, morpholine ring, piperazine ring, piperidine ring, or N-methylpiperazine ring with the attached N.

6. The indoline derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R1 is H, R2 is H, R4 is H, and R5 is H or CH3; R3 is selected from the following groups: 。 7. The indoline derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The indoline derivatives or pharmaceutically acceptable salts thereof are selected from the following compounds: 。 8. A pharmaceutical composition comprising an indoline derivative as described in any one of claims 1-7 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

9. Use of the indoline derivatives of claims 1-7 or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 8, in the preparation of ILC3 cell chemotactic regulators or in the preparation of medicaments regulating IL-22 expression.

10. Use of the indoline derivatives of claims 1-7 or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 8, in the preparation of a medicament for the prevention / treatment of diseases caused by insufficient IL-22 expression.

11. The disease as described in claim 10, characterized in that, The disease mentioned is one of the following: digestive system disease, immune system disease, endocrine system disease, skin disease, or respiratory system disease; The digestive system diseases mentioned include Crohn's disease, ulcerative colitis, necrotizing enterocolitis, colorectal cancer, and gastritis; Immune system diseases include graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus; Endocrine disorders include type 1 diabetes, type 2 diabetes, diabetic foot ulcers, and non-alcoholic steatohepatitis. Skin diseases include post-burn skin repair, skin trauma repair, herpes, and psoriasis; Respiratory diseases include chronic obstructive pulmonary disease, acute lung injury, and bronchial asthma.

12. The disease as described in claim 11, wherein the disease is selected from ulcerative colitis, Crohn's disease, acute lung injury, and psoriasis.

13. The disease as described in claim 11, wherein the disease is selected from ulcerative colitis or Crohn's disease.

Images