Benzo-7-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivatives and preparation methods and uses thereof

Abstract

The benzo-7-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivative of the present invention has a structure as shown in the following formula (I): wherein R is selected from -H, -F, -CH 3 , ‑CF 3 ,‑OCH 3 , one of the Ph groups. The present invention also provides a method for preparing a benzo seven-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivative. The present invention also provides the use of a benzo seven-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivative as a RIPK1 inhibitor. The present invention also provides the use of a class of benzo seven-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivatives in the preparation of drugs for treating multiple sclerosis. The benzo seven-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivatives of the present invention can inhibit the activity of RIPK1, reduce inflammatory damage, and can be used as drugs for treating multiple sclerosis.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a benzo seven-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivative, a preparation method and use thereof. Background Art

[0002] Multiple sclerosis (MS) is a degenerative disease of the central nervous system (CNS) that causes focal inflammatory demyelination in the white matter of the brain and spinal cord, resulting in motor and cognitive impairment.

[0003] MS is prone to occur in young and middle-aged people, with an average age of onset of 30 years old. It has the characteristics of high relapse rate and high disability rate. It is the main cause of neurological dysfunction and loss of labor force in young and middle-aged people. At present, there are about 2.8 million people suffering from the disease worldwide, and about 40,000 people in my country suffer from the disease. The incidence trend is increasing year by year, and the age of onset tends to be younger. MS was included in the "China's First List of Rare Diseases" in 2018. At present, the golden treatment method for MS recommended at home and abroad is disease-modifying treatment (DMT). Only 10% of patients receive DMT treatment clinically, and 90% of patients are still in a state of no drug available due to various reasons such as side effects and relapses caused by intermittent medication. Therefore, a new treatment method and strategy is urgently needed.

[0004] Receptor interacting protein 1 (RIP1) kinase is a serine / threonine protein kinase, abbreviated as RIPK1, which is involved in apoptosis and non-apoptotic cell death: necroptosis. RIPK1 kinase activity was originally thought to induce inflammation by controlling a highly inflammatory form of cell death called programmed necrosis, but later studies have shown that activated RIPK1 can also directly regulate the production of inflammatory cytokines and certain forms of apoptosis. In addition, in addition to acting downstream of TNF receptor 1 (TNFR1), RIPK1 has also been shown to be a key driver of inflammation downstream of various other pathways (FasL, TRAIL, TLR3 and TLR4). Studies have found that activation of RIPK1 kinase is present in pathological samples of neurodegenerative diseases such as MS and ALS. Inhibiting the activity of RIPK1 kinase can reduce necroptosis caused by TNF and other factors, thereby exerting an anti-inflammatory effect. Therefore, the development of RIPK1 small molecule inhibitors may have broad therapeutic potential for neurodegenerative diseases such as multiple sclerosis.

[0005] At present, there are many RIPK1 inhibitors under development in the world. Among them, DNL747, a RIPK1 inhibitor jointly developed by Sanofi and Denali Therapeutics, is a small molecule inhibitor that can penetrate the blood-brain barrier (brain penetration) and is used to treat neurological diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). It is currently in Phase II clinical research. For another example, the application number is 202180029050.0, and the name of the invention is ECLITASERTIB for the treatment of conditions involving systemic excessive inflammatory response. The proposed RIPK1 inhibitor regimen includes administering to subjects in need a RIPK1 inhibitor comprising (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine-3-yl)-4H-1,2,4-triazole-3-carboxamide and / or its pharmaceutically acceptable salts, tautomers, stereoisomers or stereoisomer mixtures. Summary of the invention

[0006] In view of the broad therapeutic potential of RIPK1 small molecule inhibitors, the present invention provides a class of benzo seven-membered nitrogen-oxyheterocyclic indole-2-carboxamide derivatives that are different from existing RIPK1 inhibitors, and a preparation method and use thereof.

[0007] In order to achieve the above object, the present invention provides the following technical solutions:

[0008] The benzo seven-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivative of the present invention is specifically: N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazin-3-yl)-7-phenyl-1H-indole-2-carboxamide derivative, and its structure is shown in the following formula (I):

[0009]

[0010] Wherein, R is selected from one of -H, -F, -CH3, -CF3, -OCH3, -Ph groups.

[0011] Preferably, the -F group comprises:

[0012] Single substituent: one of 2-F, 3-F, 4-F;

[0013] The -CH3 group includes:

[0014] Single substituent: one of 2-CH3, 3-CH3, 4-CH3;

[0015] or a disubstituted group: 2-CH3, 3-CH3; 2-CH3, 4-CH3; 2-CH3, 5-CH3; 2-CH3, 6-CH3; 3-CH3, 4-CH3 or any combination thereof;

[0016] The -OCH3 group includes: one of 2-OCH3, 3-OCH3, and 4-OCH3;

[0017] The -Ph group includes one of 2-Ph, 3-Ph and 4-Ph.

[0018] Further preferably, the N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazin-3-yl)-7-phenyl-1H-indole-2-carboxamide derivative of the present invention is selected from:

[0019] Compound 1: (S)-7-(4-fluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, structural formula:

[0020]

[0021] Or compound 2: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-7-phenyl-1H-indole-2-carboxamide, the structural formula is:

[0022]

[0023] or compound 3: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(p-tolyl)-1H-indole-2-carboxamide;

[0024]

[0025] Or compound 4: (S)-7-(2-fluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0026]

[0027] Or compound 5: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-7-(m-tolyl)-1H-indole-2-carboxamide, the structural formula is:

[0028]

[0029] Or compound six: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide, with the structural formula;

[0030]

[0031] Or compound seven: (S)-7-(2-methoxyphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0032]

[0033] Or compound eight: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-7-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide, the structural formula is:

[0034]

[0035] Or compound nine: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-7-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide, the structural formula is:

[0036]

[0037] Or compound ten: (S)-7-(4-methoxyphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0038]

[0039] Or compound 11: (S)-7-(3-methoxyphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0040]

[0041] Or compound twelve: (S)-7-(3-fluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0042]

[0043] Or compound 13: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-7-(o-tolyl)-1H-indole-2-carboxamide, the structural formula is:

[0044]

[0045] Or compound fourteen: (S)-7-([1,1'-biphenyl]-4-yl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0046]

[0047] Or compound 15: (S)-7-([1,1'-biphenyl]-2-yl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0048]

[0049] Or compound 16: (S)-7-([1,1'-biphenyl]-3-yl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0050]

[0051] Or compound seventeen: (S)-7-(2,3-dimethylphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0052]

[0053] Or compound 18: (S)-7-(2,6-dimethylphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0054]

[0055] Or compound 19: (S)-7-(2,4-dimethylphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0056]

[0057] Or compound 20: (S)-7-(2,5-dimethylphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0058]

[0059] Or compound 21: (S)-7-(3,4-dimethylphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0060]

[0061] Or compound 22: (S)-7-(2,3-difluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0062]

[0063] Or compound 23: (S)-7-(2,4-difluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0064]

[0065] Or compound twenty-four: (S)-7-(2,5-difluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0066]

[0067] Or compound 25: (S)-7-(2,6-difluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0068]

[0069] Or compound 26: (S)-7-(3,4-difluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is:

[0070]

[0071] One of the above compounds.

[0072] The N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazin-3-yl)-7-phenyl-1H-indole-2-carboxamide derivative is prepared by the following reaction:

[0073]

[0074] The specific steps are as follows:

[0075] Step S1: In an organic solvent, the compound of formula (III) is used as a raw material to undergo a Suzuki coupling reaction with substituted phenylboronic acid, Pd(Ph3)4 and Cs2CO3 to obtain a compound of formula (IV):

[0076] Step S2: hydrolyzing the compound of formula (IV) with sodium hydroxide in a mixed solvent of water and ethanol to obtain a compound of formula (V);

[0077] Step S3: In an organic solvent, the compound of formula (V) undergoes a condensation reaction with the compound of formula (II), HATU and DIPEA to obtain a compound of formula (VI).

[0078] In step (1), the organic solvent is selected from DMF or dioxane, H2O; preferably, the organic solvent is dioxane, H2O, and the volume ratio of dioxane:H2O is 4:1;

[0079] In step (1), the reaction temperature is 25°C-100°C; preferably, the reaction temperature is 100°C.

[0080] In step (1), the reaction time is 1 h-5 h; preferably, the reaction time is 3 h.

[0081] In step (1), the amount of the compound of formula (II) and Pd(PPh3)4 ranges from 1:0.05 to 0.2; the preferred amount is 1:0.1.

[0082] In step (1), the amount of the compound of formula (II) and Cs2CO3 ranges from 1:1.0 to 2.5; preferably, the amount is 1:2.0.

[0083] In step (2), the organic solvent is selected from MeOH or EtOH, H2O; preferably, the organic solvent is selected from EtOH, H2O, and the volume ratio of EtOH:H2O is 1:1.

[0084] In step (2), the reaction temperature is 0°C-100°C; the preferred reaction temperature is 95°C.

[0085] In step (2), the reaction time is 1-5 h; preferably, the reaction time is 2 h.

[0086] In step (3), the organic solvent is selected from DMF and DMSO; the preferred organic solvent is DMF.

[0087] In step (3), the reaction temperature is 0°C-60°C; the preferred reaction temperature is 25°C.

[0088] In step (3), the reaction time is 1 h-5 h; the preferred reaction time is 3 h.

[0089] In step (3), the ratio of the compound of formula (VII) to the substance of formula (II) is in the range of 1:1.0 to 1.5; preferably, the ratio is 1:1.0.

[0090] In step (3), the amount of the compound of formula (IV) to HATU ranges from 1:1.0 to 1.5; the preferred amount is 1:1.0.

[0091] In step (3), the amount of the compound of formula (IV) and DIPEA ranges from 1:1.0 to 3.0; the preferred amount is 1:2.5.

[0092] The present invention also provides a class of benzo seven-membered nitrogen-oxyheterocyclic indole-2-carboxamide derivatives for use as RIPK1 inhibitors.

[0093] The present invention also provides a class of benzo seven-membered nitrogen oxygen heterocyclic indole-2-carboxamide derivatives for use in preparing drugs for treating multiple sclerosis.

[0094] Beneficial effects: The benzo seven-membered nitrogen-oxyheterocyclic indole-2-carboxamide derivative of the present invention can inhibit the activity of RIPK1, reduce inflammatory damage, and can be used as a drug for treating multiple sclerosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Figure 1 This is a diagram showing the effect of Example 1 on the expression of the inflammatory cytokine IL-6. DETAILED DESCRIPTION

[0096] The present invention is further described in detail with reference to the following specific examples. The process, conditions, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art and are not particularly limited by the present invention.

[0097] The raw materials used in the following examples are all commercially available analytically pure chemicals.

[0098] The present invention is further illustrated with reference to the figures and examples, but is not intended to limit the present invention in any way.

[0099] Example 1: Preparation of (S)-7-(4-fluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, i.e., Compound 1;

[0100] First, prepare ethyl 7-(4-fluorophenyl)-1H-indole-2-carboxylate (hereinafter referred to as 1a):

[0101] 2 (100 mg, 0.37 mmol), 4-fluorophenylboronic acid (62.4 mg, 0.45 mmol), Cs2CO3 (242.0 mg, 0.74 mmol), Pd(PPh3)4 (43.8 mg, 0.038 mmol) were added to a three-necked flask, 4 mL of dioxane:H2O (4:1) was added under nitrogen protection, and the mixture was heated to 100°C for 3 h. The reaction mixture was cooled to room temperature, 15 mL of water was added, and ethyl acetate (3×20 ml) was added for extraction. The organic phases were combined and washed with saturated brine (3×20 ml), the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to provide a crude product. Purification by silica gel chromatography (petroleum ether / ethyl acetate=10:1) gave 1a as a white solid 122 mg (71%).

[0102] Next, 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid (hereinafter referred to as 1b) was prepared:

[0103] 1a (314 mg, 1.08 mmol) was dissolved in 5 ml of EtOH:H2O (1:1) solution, and NaOH (10.8 mg, 2.69 mmol) was added under magnetic stirring, and the reaction mixture was stirred at 95°C for 2 hours. The reaction mixture was cooled to room temperature, 15 mL of 5% hydrochloric acid was added, and then ethyl acetate (3×20 ml) was added for extraction, the organic phases were combined and washed with saturated brine (3×20 ml), the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to provide 274 mg of a crude product, which was directly used in the next step.

[0104] Preparation of (S)-7-(4-fluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide (hereinafter referred to as 1c):

[0105] 1b (274 g, 1.08 mmol) and (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (224 mg, 1.08 mmol) were dissolved in 5 mL of DMF, and DIPEA (139.1 mg, 2.69 mmol) and HATU (410 mg, 1.08 mmol) were added under magnetic stirring, and the reaction mixture was stirred at room temperature for 3 hours. 10 mL of water was added, and then ethyl acetate (3×20 ml) was added for extraction, and the organic phases were combined and washed with saturated brine (3×20 ml), and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to provide a crude product. Purification by silica gel chromatography (petroleum ether / ethyl acetate=12:1) gave 1c as a white solid 324 mg (70%).

[0106] 1b (274 g, 1.08 mmol) and (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (224 mg, 1.08 mmol) were dissolved in 5 mL of DMF, and DIPEA (139.1 mg, 2.69 mmol) and HATU (410 mg, 1.08 mmol) were added under magnetic stirring, and the reaction mixture was stirred at room temperature for 3 hours. 10 mL of water was added, and then ethyl acetate (3×20 ml) was added for extraction, the organic phases were combined, and washed with saturated brine (3×20 ml), the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to provide a crude product. Purification by silica gel chromatography (petroleum ether / ethyl acetate=12:1) gave 1c as a white solid 324 mg (70%). The molecular formula of 1c is:

[0107]

[0108] 1 H NMR (400MHz, CDCl3) δ9.13 (s, 1H), 8.01 (d, J = 8.0Hz, 1H), 7.66-7.64 (m, 1H), 7.39-7.36 ( m,2H),7.34-7.07(m,9H),5.20-5.13(m,1H),4.73-4.69(m,1H),4.41(t,J=12.0Hz,1H).

[0109] Example 2, preparation of the compound 2. The preparation method of the compound 2 is basically the same as that of Example 1, except that 7-phenyl-1H-indole-2-carboxylic acid (100 mg, 0.42 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound 2, 125 mg (72%) of white solid. 1 HNMR (400MHz, CDCl3) δ9.11 (s, 1H), 7.67 (d, J = 8.0Hz, 1H), 7.62-7.56 (m, 2H), 7.54-7.46 (m, 2H), 7.44-7. 24(m,8H),7.09-7.07(m,1H),5.12-4.99(m,1H),4.85-4.72(m,1H),4.28(t,J=10.0Hz,1H),3.46(s,3H).

[0110] Example 3, the preparation method of compound three is basically the same as that of Example 1, except that 7-(p-tolyl)-1H-indole-2-carboxylic acid (100 mg, 0.40 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound three, 121 mg (70%) of white solid. 1 H NMR (400MHz, CDCl3) δ9.12 (s, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.47-7.42 (m, 3H), 7.33-7.18 (m, 8H), 7.08 (d ,J=4.0Hz,1H),5.09-5.02(m,1H),4.80-4.75(m,1H),4.29(t,J=12.0Hz,1H),3.45(s,3H),2.42(s,3H).

[0111] Example 4, the preparation method of the compound four is basically the same as that of Example 1, except that 7-(2-fluorophenyl)-1H-indole-2-carboxylic acid (100 mg, 0.39 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound four, a white solid 113 mg (67%). δ 9.25 (s, 1H), 7.73-7.62 (m, 2H), 7.43-7.30 (m, 2H), 7.29-7.20 (m, 6H), 7.18-7.07 (m, 3H), 5.11-4.98 (m, 1H), 4.76-4.65 (m, 1H), 4.28 (t, J = 10.0 Hz, 1H), 3.39 (s, 3H).

[0112] Example 5, the preparation method of compound five is basically the same as that of Example 1, except that 7-(m-tolyl)-1H-indole-2-carboxylic acid (100 mg, 0.40 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound five, 118 mg (68%) of white solid. 1 H NMR(400MHz, CDCl3)δ9.09(s,1H),7.81(d,J=8.0Hz,1H),7.62(d,J=8.0Hz,1H),7.36-7.28(m,1H),7.28-7.12(m,9 H),7.08(d,J=1.9Hz,1H),5.16-5.09(m,1H),4.73-4.69(m,1H),4.36(t,J=12.0Hz,1H),3.43(s,3H),2.39(s,3H).

[0113] Example 6, the preparation method of compound six is ​​basically the same as that of Example 1, except that 7-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic acid (100 mg, 0.33 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound six, a white solid 102 mg (65%). 1 HNMR(400MHz, CDCl3)δ9.16-9.05(m,1H),7.81-7.54(m,3H),7.52-7.29(m,3H),7.22-7 .00(m,7H),5.02-4.90(m,1H),4.73-4.60(m,1H),4.34-4.17(m,1H),3.44-3.43(m,3H).

[0114] Example 7, the preparation method of compound VII is basically the same as that of Example 1, except that 7-(2-methoxyphenyl)-1H-indole-2-carboxylic acid (100 mg, 0.37 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound VII, a white solid 93 mg (56%). 1 HNMR(400MHz, CDCl3)δ9.20(s,1H),7.66(d,J=8.0Hz,1H),7.49(d,J=8.0Hz,1H),7.37-7.33(m,2H),7.28-7.15(m,6H),7.09 (d,J=4.0Hz,1H),7.05-6.94(m,2H),5.07-5.01(m,1H),4.74-4.70(m,1H),4.25(t,J=10.0Hz,1H),3.68(s,3H),3.38(s,3H).

[0115] Example 8, the preparation method of compound VIII is basically the same as that of Example 1, except that 7-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic acid (100 mg, 0.33 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound VIII, a white solid 99 mg (63%).

[0116] 1 H NMR (400MHz, CDCl3) δ9.15 (s, 1H), 7.98 (d, J = 8.0Hz, 1H), 7.68-7.64 (m, 3H), 7.49 (d, J = 8.0Hz, 2H), 7.26-7. 19(m,6H),7.08(d,J=1.7Hz,1H),5.14-5.07(m,1H),4.68-4.63(m,1H),4.38(t,J=10.0Hz,1H),3.44(s,3H).

[0117] Example 9, the preparation method of compound nine is basically the same as that of Example 1, except that 7-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxylic acid (100 mg, 0.33 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound nine, a white solid 86 mg (55%).

[0118] 1 H NMR (400MHz, CDCl3) δ9.02 (s, 1H), 7.96 (d, J = 8.0Hz, 1H), 7.72-7.60 (m, 3H), 7.57-7.48 (m, 2H), 7.28-7.21 (m, 4H), 7.20-7.17(m,2H),7.09(d,J=1.8Hz,1H),5.18-5.11(m,1H),4.71-4.66(m,1H),4.39(t,J=12.0Hz,1H),3.43(s,3H)

[0119] Example 10, the preparation method of compound ten is basically the same as that of Example 1, except that 7-(4-methoxyphenyl)-1H-indole-2-carboxylic acid (100 mg, 0.37 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound ten, a white solid 106 mg (64%).

[0120] 1H NMR(400MHz, CDCl3)δ9.25(s,1H),7.71(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),7.46(d,J=4.0Hz,2H),7.32-7.19(m,6H),7 .11(s,1H),7.01(d,J=4.0Hz,2H),5.17-5.07(m,1H),4.77-4.73(m,1H),4.34(t,J=10.0Hz,1H),3.87(s,3H),3.44(s,3H).

[0121] Example 11. The preparation method of compound 11 is basically the same as that of Example 1, except that 7-(3-methoxyphenyl)-1H-indole-2-carboxylic acid (100 mg, 0.37 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound 11, a white solid 103 mg (62%). 1 HNMR(400MHz, CDCl3)δ9.28(s,1H),7.81(d,J=4.0Hz,1H),7.66(d,J=8.0Hz,1H),7.42-7.33(m,1H),7.31-7.18(m,7H),7.15-7.11(m ,1H),7.10-7.05(m,2H),6.98-6.90(m,1H),5.20-5.10(m,1H),4.78-4.71(m,1H),4.37(t,J=12.0Hz,1H),3.84(s,3H),3.44(s,3H).

[0122] Example 12, the preparation method of compound twelve is basically the same as that of Example 1, except that 7-(3-fluorophenyl)-1H-indole-2-carboxylic acid (100 mg, 0.48 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound twelve, 111 mg (66%) of white solid. 1 HNMR (400MHz, CDCl3) δ9.16 (s, 1H), 8.07 (d, J = 4.0Hz, 1H), 7.69-7.58 (m, 1H), 7.37-7.29 (m, 1H) ,7.25-6.97(m,9H),5.20-5.07(m,1H),4.73-4.61(m,1H),4.40(t,J=10.0Hz,1H),3.43(s,3H).

[0123] Example 13, the preparation method of compound thirteen is basically the same as that of Example 1, except that 7-(o-tolyl)-1H-indole-2-carboxylic acid (100 mg, 0.40 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound thirteen, a white solid 119 mg (70%). 1 HNMR (400MHz, CDCl3) δ8.95 (s, 1H), 7.69 (d, J = 8.0Hz, 1H), 7.36-7.20 (m, 10H), 7.19-7.09 (m, 2H), 5.08-4.96 (m, 1H), 4.79-4.74 (m, 1H), 4.27 (t, J = 10.0Hz, 1H), 3.46 (s, 3H), 2.09 (s, 3H).

[0124] Example 14. The preparation method of compound fourteen is basically the same as that of Example 1, except that 7-([1,1'-biphenyl]-4-yl)-1H-indole-2-carboxylic acid (100 mg, 0.32 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound fourteen, a white solid 104 mg (67%).

[0125] 1 H NMR (400MHz, CDCl3) δ9.46 (s, 1H), 8.10 (d, J = 8.0Hz, 1H), 7.71-7.69 (m, 5H), 7.58-7.49 (m, 4H), 7.46-7. 39(m,1H),7.35-7.10(m,7H),5.26-5.16(m,1H),4.76-4.68(m,1H),4.42(t,J=12.0Hz,1H),3.39(s,3H).

[0126] Example 15. The preparation method of compound 15 is basically the same as that of Example 1, except that 7-([1,1'-biphenyl]-2-yl)-1H-indole-2-carboxylic acid (100 mg, 0.32 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound 15 as a white solid, 109 mg (70%).

[0127] 1H NMR (400MHz, CDCl3) δ8.87 (s, 1H), 7.60-7.53 (m, 1H), 7.51-7.35 (m, 4H), 7.29 (d, J = 4.0Hz, 1H), 7.25-7.18 (m, 4H), 7.14- 7.01 (m, 7H), 6.94 (d, J = 4.0Hz, 1H), 5.02-4.95 (m, 1H), 4.73 (dd, J = 10.0, 6.0Hz, 1H), 4.23 (t, J = 10.0Hz, 1H), 3.43 (s, 3H).

[0128] Example 16. The preparation method of compound 16 is basically the same as that of Example 1, except that 7-([1,1'-biphenyl]-3-yl)-1H-indole-2-carboxylic acid (100 mg, 0.32 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound 16 as a white solid, 107 mg (69%).

[0129] 1 H NMR(400MHz, CDCl3)δ9.29(s,1H),7.82-7.81(m,1H),7.76-7.65(m,5H),7.62-7.47(m,4H),7.45-7.36(m,2H),7.32 -7.26(m,5H),7.17(d,J=4.0Hz,1H),5.19-5.12(m,1H),4.81(dd,J=1.0,8.5Hz,1H),4.42-4.37(m,1H),3.51(s,3H).

[0130] Example 17, the preparation method of compound 17 is basically the same as that of Example 1, except that 7-(2,3-dimethylphenyl)-1H-indole-2-carboxylic acid (100 mg, 0.32 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound 17, a white solid 114 mg (69%). 1 H NMR (400MHz, CDCl3) δ9.22-8.88(m,1H),7.68(d,J=8.0Hz,1H),7.61-7.46(m,1H),7.33-7.05(m,10H),5.12-4. 94(m,1H),4.75(dd,J=16.0,8.0Hz,1H),4.35-4.25(m,1H),3.49-3.44(m,3H),2.34(s,3H),2.02-1.89(m,3H).

[0131] Example 18, the preparation method of compound 18 is basically the same as that of Example 1, except that 7-(2,6-dimethylphenyl)-1H-indole-2-carboxylic acid (100 mg, 0.32 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound 18, 66 mg (40%) of white solid. 1 HNMR(600MHz, CDCl3)δ9.45(s,1H),7.55(d,J=6.0Hz,1H),7.29(d,J=6.0Hz,1H),7.25-7.14(m,3H),7.14-7.06(m,2H),7.02-6.94(m, 3H),6.87-6.83(m,2H),4.79-4.75(m,1H),4.60(dd,J=9.8,7.6Hz,1H),4.11(t,J=12.0Hz,1H),3.38(s,3H),1.70(s,3H),1.55(s,3H).

[0132] Example 19, the preparation method of compound 19 is basically the same as that of Example 1, except that 7-(2,4-dimethylphenyl)-1H-indole-2-carboxylic acid (100 mg, 0.32 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound 19, a white solid 109 mg (66%). 1 H NMR (400MHz, CDCl3) δ9.05 (s, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.54-7.45 (m, 1H), 7.29-6.99 (m, 10H), 5.0 7-4.95(m,1H),4.72(d,J=1.8Hz,1H),4.24(t,J=12.0Hz,1H),3.39(s,3H),2.34(s,3H),2.02(s,3H).

[0133] Example 20, the preparation method of compound 20 is basically the same as that of Example 1, except that 7-(2,5-dimethylphenyl)-1H-indole-2-carboxylic acid (100 mg, 0.32 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound 20, a white solid 99 mg (60%). 1HNMR(600MHz, CDCl3)δ8.80-8.62(m,1H),7.58(d,J=12.0Hz,1H),7.33-7.21(m,1H),7.21-7.09(m,6H),7.08-6 .98(m,4H),4.97-4.93(m,1H),4.74-4.65(m,1H),4.19(t,J=9.0Hz,1H),3.37(s,3H),2.26(s,3H),1.98(s,3H).

[0134] Example 21. The preparation method of compound twenty-one is basically the same as that of Example 1, except that 7-(3,4-dimethylphenyl)-1H-indole-2-carboxylic acid (100 mg, 0.32 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound twenty-one, a white solid 97 mg (59%). 1 H NMR (400MHz, CDCl3) δ9.18 (s, 1H), 7.82 (d, J = 8.0Hz, 1H), 7.61 (d, J = 8.0Hz, 1H), 7.27-7.14 (m, 9H), 7.09 (d, J = 1.9 Hz,1H),5.15-5.18(m,1H),4.70(dd,J=10.0,6.0Hz,1H),4.35(t,J=10.0Hz,1H),3.41(s,3H),2.29-2.28(m,6H).

[0135] Example 22, the preparation method of compound 22 is basically the same as that of Example 1, except that 7-(2,3-difluorophenyl)-1H-indole-2-carboxylic acid (100 mg, 0.37 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound 22, 111 mg (68%) of white solid. 1 H NMR (400MHz, CDCl3) δ9.28(s,1H),7.76(d,J=8.0Hz,1H),7.68(d,J=8.0Hz,1H),7.28-7.13(m,7H ),7.09-7.06(m,5H),5.08-5.02(m,1H),4.74-4.63(m,1H),4.31(t,J=10.0Hz,1H),3.42(s,3H).

[0136] Example 23, the preparation method of compound 23 is basically the same as that of Example 1, except that 2,6-dimethoxybenzoic acid (100 mg, 0.37 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound 23, a white solid 106 mg (65%).1 H NMR (600MHz, CDCl3) δ8.88 (s, 1H), 7.63 (d, J = 6.0Hz, 1H), 7.38-7.31 (m, 1H), 7.21-7.13 (m, 7H), 7.00 ( s,1H),6.94-6.85(m,2H),4.99-4.94(m,1H),4.73-4.67(m,1H),4.21(t,J=12.0Hz,1H),3.38(s,3H).

[0137] Example 24. The preparation method of compound twenty-four is basically the same as that of Example 1, except that 7-(2,5-difluorophenyl)-1H-indole-2-carboxylic acid (100 mg, 0.37 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound twenty-four, a light yellow solid 99 mg (61%).

[0138] 1 H NMR(400MHz, CDCl3)δ9.22(s,1H),7.71-7.65(m,2H),7.28-7.17(m,6H),7.13-7.00(m,4 H), 5.10-4.99 (m, 1H), 4.71 (dd, J = 9.7, 7.6Hz, 1H), 4.30 (t, J = 10.0Hz, 1H), 3.42 (s, 3H).

[0139] Example 25. The preparation method of compound 25 is basically the same as that of Example 1, except that 2,7-(2,6-difluorophenyl)-1H-indole-2-carboxylic acid (100 mg, 0.37 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound 25, 49 mg (30%) of yellow solid. 1 H NMR(600MHz, CDCl3)δ8.95(s,1H),7.64-7.53(m,1H),7.50(d,J=6.0Hz,1H),7.34(d,J=12.0Hz,1H),7.22-7.14(m,5H) ,6.95-6.92(m,2H),5.06(d,J=5.3Hz,1H),4.70(t,J=8.6Hz,1H),4.27(dd,J=14.3,6.4Hz,1H),3.42(d,J=6.3Hz,3H).

[0140] Example 26. The preparation method of compound 26 is basically the same as that of Example 1, except that 7-(3,4-difluorophenyl)-1H-indole-2-carboxylic acid (100 mg, 0.37 mmol) is used instead of 7-(4-fluorophenyl)-1H-indole-2-carboxylic acid to obtain compound 26 as a yellow solid, 106 mg (65%). 1 H NMR(400MHz, CDCl3)δ9.06(s,1H),8.24(d,J=4.0Hz,1H),7.64(d,J=8.0Hz,1H),7.34-7.28(m,3H),7.27-7.22(m,1H), 7.21-7.10(m,4H),7.09-7.01(m,2H),5.23-5.17(m,1H),4.68(dd,J=9.7,7.8Hz,1H),4.53-4.39(m,1H),3.48(s,3H).

[0141] The above is the preparation method of the compound involved in the present invention. The following will verify whether each compound is effective through the programmed cell necrosis RIPK1 inhibition experiment. The specific process is as shown in Example 27:

[0142] Embodiment 27

[0143] 1. Reagents

[0144] Dulbecco's modified Eagle's medium (DMEM), fetal bovine serum (FBS), penicillin-streptomycin liquid (100), phosphate buffered saline (PBS). Recombinant mouse / human TNF-α was purchased from Novoprotein (Shanghai, China). Z-VAD-fmk (T6013) was purchased from Targetmol (Targetmol, USA). Smac mimetic (HY-15989) was purchased from MedChemExpress (Monmouth Junction, NJ, USA).

[0145] 2. Cell Culture

[0146] HT-29 (NCI-DTP Cat# HT-29) and U937 cells were cultured in DMEM containing 10% FBS (v / v) RPM I-1640, 1% L-glutamine and 100 U / mL penicillin / streptomycin (v / v). U937 (ProcellC L-0239) was provided by Procell Life Science & Technology. Cells were grown at 37°C in a humidified atmosphere of 5% CO2 and were obtained from exponentially growing cultures in all experiments.

[0147] 3. Necrosis Induction and Cell Viability Assay

[0148] Cells were pretreated with z-VAD-fmk (30 μM) and Smac mimetics (15 nM) or cyclohexamide (350 μM) for 30 minutes, followed by TNF-α (20 ng / mL) for 12 or 16 hours (TSZ) to induce necrosis. TNF-α (20 ng / mL) and cyclohexamide (2 mM) were used to induce apoptosis for 24 hours. The compounds were incubated with cells exposed to one of the above combinations at the specified concentrations for 16 hours or 24 hours. The cells were then tested using the CellTiter-Glo Luminescent Cell Viability Assay Kit, and cell viability was calculated by detecting the chemiluminescence value, thereby obtaining the biological activity of the compound in inhibiting programmed cell necrosis.

[0149] Measured 10nM <EC 50 <10μM, as shown in the table below, 10nM <EC 50 <100nM(+++), 100nM <EC 50 <1μM(++), 1μM <EC 50 <10μM(+).

[0150] Table 1. Data on the inhibitory activity of compounds on RIPK1

[0151] serial number <![CDATA[EC 50 ]]> Example 1 ++ Example 2 +++ Example 3 + Example 4 +++ Example 5 ++ Example 6 ++ Example 7 ++ Example 8 + Example 9 + Example 10 + Embodiment 11 ++ Example 12 +++ Embodiment 13 +++ Embodiment 14 ++ Embodiment 15 ND Example 16 ND Embodiment 17 ++ Embodiment 18 + Embodiment 19 + Embodiment 20 + Embodiment 21 + Embodiment 22 ++ Embodiment 23 ++ Embodiment 24 +++ Embodiment 25 + Embodiment 26 ++

[0152] Results and evaluation: As can be seen from Table 1, the N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazin-3-yl)-7-phenyl-1H-indole-2-carboxamide derivatives prepared by the present invention exhibited high inhibitory activity against RIPK1. Among them, the inhibitory activity EC of Example 2 50 The value is less than 100nM.

[0153] Example 28: Experiment on inflammatory cytokine IL-6 induced by TNFα.

[0154] To measure TNF-α-induced IL-6 levels in serum, mice were sacrificed 2 h after TNF-α injection, and serum was collected for analysis of IL-6 using a mouse IL-6 ELISA kit (MultiSciences, Lianke). Figure 1 As shown, compared with the non-treatment group, the treatment group of Example 1 significantly reduced the level of IL-6 (P<0.01).

[0155] In summary, the present invention provides a class of N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazin-3-yl)-7-phenyl-1H-indole-2-carboxamide derivatives with good activity and novel structure as RIPK1 small molecule inhibitors, which can reduce TNF-α-induced necroptosis, thereby exerting an anti-inflammatory effect, and can be used to prepare drugs for treating inflammation-related diseases such as multiple sclerosis.

[0156] What is disclosed above is only a preferred embodiment of the present invention, which certainly cannot be used to limit the scope of rights of the present invention. A person skilled in the art can understand that all or part of the processes of the above embodiments and equivalent changes made according to the claims of the present invention still fall within the scope of the invention.

Claims

1. A benzo seven-membered nitrogen-oxygen heterocyclic indole-2-carboxamide derivative is specifically: N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazin-3-yl)-7-phenyl-1H-indole-2-carboxamide derivative, whose structure is shown in the following formula (I): in, R is selected from one of -H, -F, -CH3, -CF3, -OCH3, -Ph groups, and R is a monosubstituent or a disubstituent.

2. The benzo-7-membered nitrogen-oxyheterocyclic indole-2-carboxamide derivative according to claim 1, characterized in that: The -F group is selected from: Single substituent: one of 2-F, 3-F, 4-F; The -CH3 group is selected from: Single substituent: one of 2-CH3, 3-CH3, 4-CH3; or a disubstituted group: 2-CH3, 3-CH3; 2-CH3, 4-CH3; 2-CH3, 5-CH3; 2-CH3, 6-CH3; 3-CH3, 4-CH3 or any combination thereof; The -OCH3 group is selected from: 2-OCH3, 3-OCH3, 4-OCH3; The -Ph group is selected from: 2-Ph, 3-Ph, 4-Ph.

3. The benzo-7-membered nitrogen-oxyheterocyclic indole-2-carboxamide derivative according to claim 1, characterized in that: Selected from: Compound 1: (S)-7-(4-fluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, structural formula: Or compound 2: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-7-phenyl-1H-indole-2-carboxamide, the structural formula is: or compound 3: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(p-tolyl)-1H-indole-2-carboxamide; Or compound 4: (S)-7-(2-fluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 5: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-7-(m-tolyl)-1H-indole-2-carboxamide, the structural formula is: Or compound six: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-7-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide, with the structural formula; Or compound seven: (S)-7-(2-methoxyphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound eight: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-7-(4-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide, the structural formula is: Or compound nine: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-7-(3-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide, the structural formula is: Or compound ten: (S)-7-(4-methoxyphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 11: (S)-7-(3-methoxyphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound twelve: (S)-7-(3-fluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 13: (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-7-(o-tolyl)-1H-indole-2-carboxamide, the structural formula is: Or compound fourteen: (S)-7-([1,1'-biphenyl]-4-yl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 15: (S)-7-([1,1'-biphenyl]-2-yl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 16: (S)-7-([1,1'-biphenyl]-3-yl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound seventeen: (S)-7-(2,3-dimethylphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 18: (S)-7-(2,6-dimethylphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 19: (S)-7-(2,4-dimethylphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 20: (S)-7-(2,5-dimethylphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 21: (S)-7-(3,4-dimethylphenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 22: (S)-7-(2,3-difluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 23: (S)-7-(2,4-difluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound twenty-four: (S)-7-(2,5-difluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 25: (S)-7-(2,6-difluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: Or compound 26: (S)-7-(3,4-difluorophenyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-indole-2-carboxamide, the structural formula is: One of the above compounds.

4. The method for preparing the benzo-7-membered nitrogen-oxyheterocyclic indole-2-carboxamide derivative according to claim 1, characterized in that: The following steps are involved: Step S1: In an organic solvent, the compound of formula (III) is used as a raw material to undergo a Suzuki coupling reaction with substituted phenylboronic acid, Pd(Ph3)4 and Cs2CO3 to obtain a compound of formula (IV): Step S2: hydrolyzing the compound of formula (IV) with sodium hydroxide in a mixed solvent of water and ethanol to obtain a compound of formula (V); Step S3: In an organic solvent, the compound of formula (V) undergoes a condensation reaction with the compound of formula (II), HATU and DIPEA to obtain a compound of formula (VI); The reactions carried out by formula (III), formula (IV), formula (V) and formula (VI) are:

5. Use of the benzo seven-membered nitrogen-oxyheterocyclic indole-2-carboxamide derivative according to any one of claims 1 to 3 in the preparation of RIPK1 inhibitor drugs.

6. Use of the benzo seven-membered nitrogen-oxyheterocyclic indole-2-carboxamide derivative according to claim 5 in the preparation of RIPK1 inhibitor drugs, wherein the prepared RIPK1 inhibitor drugs are used to treat multiple sclerosis.

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