Non-classical ferroptosis inhibitor as well as preparation method and application thereof

Abstract

The invention provides a non-classical ferroptosis inhibitor as well as a preparation method and application thereof, and belongs to the technical field of chemical synthesis medicines. The invention synthesizes a compound with a good inhibition effect on ferroptosis, the compound can be used for preparing a ferroptosis inhibitor, and the structure of the compound is shown as a formula I in the specification. The compound can be used for preparing medicines for preventing and / or treating ferroptosis-related neurodegenerative diseases, tissue ischemia-reperfusion injury, cerebral apoplexy, cardiovascular diseases, renal failure, inflammation, cardiotoxicity, acute organ injury, chronic atrophic gastritis or diabetic complications and other diseases, and has a wide market prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis drugs, and in particular relates to a non-classical ferroptosis inhibitor and a preparation method and use thereof. Background Art

[0002] Cell death is an irreversible phenomenon in the life process. Through in-depth research on cell death, Dixon et al. discovered a new type of cell death in 2012 and named it "Ferroptosis". This new type of cell death is iron-dependent and is usually accompanied by the accumulation of intracellular iron and lipid peroxides. Ferroptosis is significantly different from apoptosis, necrosis and autophagy in terms of cell morphology and function. Morphologically, the morphological characteristics of ferroptosis are reduced mitochondrial volume, reduced mitochondrial membrane density, reduced or disappeared mitochondrial cristae, and rupture of the mitochondrial outer membrane.

[0003] In recent years, a series of studies have found that ferroptosis plays an important role in the occurrence and development of many diseases, and has become a research hotspot for the treatment and improvement of prognosis of related diseases such as neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular, renal failure, acute kidney injury, doxorubicin (DOX)-induced cardiotoxicity, acetaminophen-induced acute liver injury, and chronic atrophic gastritis. Therefore, the development of new ferroptosis inhibitors is a potential method for the treatment of these diseases.

[0004] At present, most of the small molecule inhibitors of ferroptosis are antioxidants or iron chelators. They include Ferrostatin-1 (Fer-1 for short), Liproxstatin-1, Zileuton, CPO, DFO, Deferasirox and Deferiprone. The redox balance in the body's internal environment is essential to health. Breaking the redox balance by non-selectively reducing the oxidation state may lead to diseases such as cancer and aging. In addition, iron is an essential trace element in organisms and the active center of many biological enzymes. The use of iron chelators will inevitably lead to anemia and many metabolic diseases as side effects. Therefore, it is of great significance to develop ferroptosis inhibitors that are neither antioxidants nor iron chelators. Summary of the invention

[0005] In order to solve the problems existing in the prior art, the object of the present invention is to provide a non-classical ferroptosis inhibitor and a preparation method and use thereof.

[0006] The present invention provides a compound represented by formula I, or a salt thereof, or a stereoisomer thereof:

[0007]

[0008] wherein ring A is a 3- to 8-membered heteroaromatic ring;

[0009] R1 is LXB1;

[0010] L is selected from none, C 1～6 Alkylene;

[0011] X is selected from none, O;

[0012] B1 is selected from the following groups which are unsubstituted or substituted by one or more B': phenyl, C 1～6 Alkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkyl, 3- to 8-membered heteroaryl;

[0013] B' is independently selected from halogen, SO2B4, nitro, C 1～6 Alkyl, C 1～6 Alkoxy, halogen substituted C 1～6 Alkyl, halogen substituted C 1～6 Alkoxy, NB2B3, phenyl which is unsubstituted or substituted by one or more B", 3-8-membered heterocycloalkyl which is unsubstituted or substituted by one or more B", 3-8-membered heteroaryl which is unsubstituted or substituted by one or more B";

[0014] B4 is selected from C 1～3 alkyl;

[0015] B2 and B3 are each independently selected from C 1～6 Alkyl; or B2 and B3 are connected to form a spiro ring;

[0016] B" are each independently selected from halogen, C 1～6 alkyl.

[0017] Further, the ring A is a 5- to 6-membered heteroaromatic ring;

[0018] R1 is LXB1;

[0019] L is selected from none, C 1～3 Alkylene;

[0020] X is selected from none, O;

[0021] B1 is selected from the following groups which are unsubstituted or substituted by one or more B': phenyl, C 1～4 Alkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heteroaryl;

[0022] B' is independently selected from halogen, SO2B4, nitro, C 1～4 Alkyl, C 1～3 Alkoxy, halogen substituted C 1～3 Alkyl, halogen substituted C 1～3Alkoxy, NB2B3, phenyl which is unsubstituted or substituted by one or more B", 5-6-membered heterocycloalkyl which is unsubstituted or substituted by one or more B", 5-6-membered heteroaryl which is unsubstituted or substituted by one or more B";

[0023] B2 and B3 are each independently selected from C 1～3 Alkyl; or B2 and B3 are connected to form a spiro ring;

[0024] B" are each independently selected from halogen, C 1～3 alkyl.

[0025] Furthermore, the compound is represented by formula II:

[0026]

[0027] wherein D is selected from N and CR1, E is selected from N and CR1, and one of D and E is N;

[0028] R1 is LXB1;

[0029] L is selected from none, C 1～3 Alkylene;

[0030] X is selected from none, O;

[0031] B1 is selected from the following groups which are unsubstituted or substituted by one or more B': phenyl, C 1～4 Alkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heteroaryl;

[0032] B' is independently selected from halogen, SO2B4, nitro, C 1～4 Alkyl, C 1～3 Alkoxy, halogen substituted C 1～3 Alkyl, halogen substituted C 1～3 Alkoxy, NB2B3, phenyl which is unsubstituted or substituted by one or more B", 5-6-membered heterocycloalkyl which is unsubstituted or substituted by one or more B", 5-6-membered heteroaryl which is unsubstituted or substituted by one or more B";

[0033] B2 and B3 are each independently selected from C 1～3 Alkyl; or B2 and B3 are connected to form a spiro ring;

[0034] B" are each independently selected from halogen, C 1～3 alkyl.

[0035] Furthermore, the compound is represented by Formula III or Formula IV:

[0036]

[0037]

[0038] Among them, R1 is LXB1;

[0039] L is selected from none, C 1～3 Alkylene;

[0040] X is selected from none, O;

[0041] B1 is selected from the following groups which are unsubstituted or substituted by one or more B': phenyl, C 1～4 Alkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heteroaryl;

[0042] B' is independently selected from halogen, SO2B4, nitro, C 1～4 Alkyl, C 1～3 Alkoxy, halogen substituted C 1～3 Alkyl, halogen substituted C 1～3 Alkoxy, NB2B3, phenyl which is unsubstituted or substituted by one or more B", 5-6-membered heterocycloalkyl which is unsubstituted or substituted by one or more B", 5-6-membered heteroaryl which is unsubstituted or substituted by one or more B";

[0043] B4 is selected from C 1～3 alkyl;

[0044] B2 and B3 are each independently selected from C 1～3 or B2 and B3 are connected to form a spiro ring, which is unsubstituted or substituted by one or more B5 B5 are each independently selected from C 1～3 Alkyl, halogen; B" are each independently selected from halogen, C 1～3 alkyl;

[0045] The heteroatom in the heterocycloalkyl group is one or more than two of O, N, and S, and the heteroatom in the heteroaryl group is one or more than two of O, N, and S.

[0046] Furthermore, the compound is one of the following compounds:

[0047]

[0048]

[0049] The present invention also provides a method for preparing the above compound, or a salt thereof, or a stereoisomer thereof, the method comprising the following steps:

[0050]

[0051] Phenazine-1-carboxylic acid reacts with compound A to obtain intermediate a; intermediate a undergoes condensation reaction to obtain;

[0052] Alternatively, the method comprises the following steps:

[0053]

[0054] Phenazine-1-carboxylic acid reacts with compound B to obtain intermediate b; intermediate b undergoes condensation reaction to obtain; or, phenazine-1-carboxylic acid reacts with compound B to obtain intermediate c; intermediate c undergoes condensation reaction to obtain;

[0055] wherein R1 is as described above.

[0056] Furthermore, the method comprises the following steps: the phenazine-1-carboxylic acid and compound A are reacted under the action of a condensing agent and a catalyst; the molar ratio of the phenazine-1-carboxylic acid, compound A, condensing agent and catalyst is 1:0.5-1.5:1-1.5:2-4; the solvent of the reaction is an organic solvent; the reaction temperature is 10-40°C and the reaction time is 6-10 hours;

[0057] The condensation reaction of the intermediate a comprises the following steps: a condensation reaction is carried out under the action of a halogenating agent and a base; the molar ratio of the intermediate a, the brominating agent and the base is 1:1-1.5:1-1.5; the solvent of the reaction is an organic solvent; the temperature of the reaction is 10-40°C and the time is 2-6 hours;

[0058] Alternatively, the condensation reaction of the intermediate a comprises the following steps: the solvent for the reaction of the intermediate a is an organic solvent; the reaction temperature is 110 to 130° C., and the reaction time is 10 to 14 hours;

[0059] Alternatively, the method comprises the following steps:

[0060] The phenazine-1-carboxylic acid and compound B react under the action of a condensing agent and a catalyst; the molar ratio of the phenazine-1-carboxylic acid, compound B, condensing agent and catalyst is 1:0.5-1.5:0.5-1.5:2-4; the solvent of the reaction is an organic solvent; the reaction temperature is 10-40°C and the reaction time is 6-10 hours;

[0061] The condensation reaction of the intermediates b and c comprises the following steps: a condensation reaction is carried out under the action of a halogenating agent and a catalyst; the molar ratio of the halogenating agent and the catalyst is 0.05-0.15:2-4; the reaction temperature is 10-40°C and the reaction time is 10-14 hours.

[0062] Furthermore, the condensing agent is O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate; the catalyst is N,N-diisopropylethylamine; the molar ratio of phenazine-1-carboxylic acid, compound A, condensing agent and catalyst is 1:1:1.1-1.2:3; the solvent of the reaction is N,N-dimethylformamide and dichloromethane; the reaction temperature is 15-35°C and the reaction time is 8 hours;

[0063] The condensation reaction of the intermediate a comprises the following steps: the halogenating agent is N-bromosuccinimide; the base is 1,8-diazabicyclo(5,4,0)-7-undecene; the molar ratio of the intermediate a, the brominating agent and the base is 1:1.1:1.1; the solvent of the reaction is ethyl acetate; the reaction temperature is 15-35°C and the reaction time is 4 hours;

[0064] Alternatively, the condensation reaction of the intermediate a comprises the following steps: the solvent for the reaction of the intermediate a is 1,4-dioxane; the reaction temperature is 120° C. and the reaction time is 12 hours;

[0065] Alternatively, the method comprises the following steps:

[0066] The condensing agent for the reaction of phenazine-1-carboxylic acid and compound B is O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid; the catalyst is N,N-diisopropylethylamine; the molar ratio of phenazine-1-carboxylic acid, compound B, condensing agent and catalyst is 1:1:1:3; the solvent for the reaction is acetonitrile; the reaction temperature is 15-35°C and the reaction time is 8 hours;

[0067] The condensation reaction of the intermediates b and c comprises the following steps: the halogenating agent is p-toluenesulfonyl chloride; the catalyst is N,N-diisopropylethylamine; the molar ratio of the halogenating agent to the catalyst is 0.1:3; the reaction temperature is 15-35°C and the reaction time is 12 hours.

[0068] The present invention also provides a pharmaceutical composition, which is a preparation prepared by using the above compound, or its salt, or its stereoisomer as an active ingredient and adding auxiliary agents commonly used in pharmacy.

[0069] The present invention also provides the use of the above compound, or a salt thereof, or a stereoisomer thereof, and the above pharmaceutical composition in the preparation of a ferroptosis inhibitor.

[0070] Furthermore, the ferroptosis inhibitor is a targeted drug for inhibiting cell ferroptosis.

[0071] Furthermore, the ferroptosis inhibitor is a drug for preventing and / or treating neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular disease, renal failure, inflammation, cardiotoxicity, acute organ damage, chronic atrophic gastritis or diabetic complications; preferably, the acute organ damage is acute liver damage.

[0072] Furthermore, the neurodegenerative diseases include Alzheimer's disease and Parkinson's disease; and the stroke includes infarction.

[0073] Furthermore, the preparation is an oral preparation or an intravenous injection preparation.

[0074] Definitions of terms used in the present invention: Unless otherwise specified, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms that are not specifically defined in the present invention, the meanings that can be given to them by those skilled in the art should be given according to the disclosure and context. Among them:

[0075] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0076] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. 1～6 Alkyl refers to straight or branched chain alkyl groups containing 1, 2, 3, 4, 5 or 6 carbon atoms, and so on.

[0077] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. The alkyl group may be straight or branched, and the alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl).

[0078] "Alkoxy" represents an alkyl group as described above with a specific number of carbon atoms attached through an oxygen bridge, unless otherwise specified. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy.

[0079] "Heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic group containing one to multiple heteroatoms. The heteroatoms referred to herein include, but are not limited to, oxygen, sulfur, and nitrogen. For example, furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.

[0080] The "5-6 membered heteroaryl group" refers to a heteroaryl group having 5 or 6 ring atoms.

[0081] "Halogen-substituted C 1～6 "Alkyl" refers to C 1～6A group in which one or more hydrogen atoms in an alkyl group are replaced by halogen atoms. For example, trifluoromethyl.

[0082] "Spirocyclic" refers to a polycyclic structure consisting of two or more ring structures linked together by the same atom.

[0083] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0084] The experimental results show that the compound prepared by the present invention has a good inhibitory effect on Ferroptosis, and the inhibition of Ferroptosis is not through the reduction mechanism and the chelation mechanism, and can be used to prepare non-chelated, non-reduced non-classical ferroptosis inhibitors. Therefore, the compound of the present invention can be used to prepare drugs for the prevention and / or treatment of diseases such as neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular, renal failure, inflammation, cardiotoxicity, acute organ damage, chronic atrophic gastritis or diabetic complications associated with ferroptosis, and has broad market prospects. The experimental results also further verify that the compound of the present invention can be used to treat chronic atrophic gastritis and can alleviate acute liver damage induced by acetaminophen.

[0085] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0086] The above contents of the present invention are further described in detail below through specific implementation methods in the form of examples. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0087] Figure 1 The chelating (A) and reducing (B) test results of compounds 31 and 48 of the present invention are shown.

[0088] Figure 2 Compound 31 of the present invention alleviates acute liver injury induced by acetaminophen: (A) The ferroptosis inhibitory activity of compound 31 and Fer-1 in the ferroptosis model induced by Erastin (10 μM) in LX-2 cells; (B) Hematoxylin and eosin (H&E) staining results of mouse liver tissue; (C) Analysis of mouse serum aspartate aminotransferase (ALT) and alanine aminotransferase (AST); (D) Analysis of mouse liver malondialdehyde (MDA) level.

[0089] Figure 3 The ferroptosis inhibitory activity of compound 31 and Fer-1 in the erastin (10 μM)-induced ferroptosis model in ES2 cells.

[0090] Figure 4 Compound 48 of the present invention alleviates chronic atrophic gastritis: (A) HE staining of gastric body; (B) Representative SPEM immunofluorescence staining. Blue, DAPI; Green, GSII; Red, GIF. GIF+GSII+ cells at the base of gastric mucosa represent SPEM cells. (C) Pathological scores of gastric body inflammation, atrophy, and mucous hyperplasia in each group of mice based on HE staining. (D) Immunofluorescence quantification of the number of GSII+ cells, GIF+ cells, and SPEM cells (GSII+GIF+) in each gland in the gastric body of each group of mice. DETAILED DESCRIPTION

[0091] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0092] The "normal temperature" or "room temperature" referred to in the present invention is 25±10°C.

[0093] Example 1. Synthesis of Compound 1

[0094] The synthetic route of compound 1 is as follows:

[0095]

[0096] Phenazine-1-carboxylic acid (1 g, 3.96 mmol, 1.00 eq), 2-methylpropionamidine (384.17 mg, 3.96 mmol, 1.00 eq), O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU) (2 g, 3.96 mmol, 1.20 eq) were dissolved in N, N-dimethylformamide (20 mL), and N, N-diisopropylethylamine (DIEA) (2.37 ml, 11.88 mmol, 3.00 eq) was added. The mixture was stirred at room temperature for 8 hours until a large amount of yellow solid was gradually precipitated. The mixture was filtered, washed with water, and vacuum dried to obtain intermediate a as a yellow solid (1134.28 mg, 3.45 mmol, 87%).

[0097] Intermediate a (1134.28 mg, 1.42 mmol, 1.00 eq) was dissolved in ethyl acetate, and N-bromosuccinimide (NBS) (759.45 mg, 1.56 mmol, 1.10 eq) and 1,8-diazabicyclo (5,4,0)-7-undecene (DBU) (637.49 mL, 1.56 mmol, 1.10 eq) were added, and the mixture was reacted at room temperature for four hours. After the reaction was completed by TLC monitoring, the solvent was removed under reduced pressure, and the target product compound 1 (986.23 mg, 1.27 mmol, 88%) was obtained by column chromatography.

[0098] Compound 1 1H NMR and HRMS data are as follows:

[0099] 1 H NMR (400MHz, CDCl3) δ8.71 (dd, J=7.0, 1.2Hz, 1H), 8.51 (dd, J=8.7, 1.3Hz, 1H), 8.38 (m, 1H), 8.28 (m, 3H), 7.99 (dd, J = 8.7, 7.1Hz, 1H), 7.92 (m, 2H), 7.56 (dd, J = 6.5, 3.7Hz, 3H).

[0100] HRMS m / z(ESI) Calculated value: C 20 H 12 N4O[M+H] + 325.1084; Actual value: 325.1083; HPLC purity = 98.9%.

[0101] Example 2, Synthesis of Compound 2

[0102]

[0103] The compound 2 was prepared by a similar synthesis method as in Example 1 with a yield of 74%.

[0104] Compound 2 1 H NMR and HRMS data are as follows:

[0105] 1 H NMR (400MHz, CDCl3) δ8.94 (dd, J=7.1, 1.2Hz, 1H), 8.37 (dd, J=8.7, 1.3Hz, 1H), 8. 22(dd,J=5.9,4.2Hz,1H),8.16(dd,J=5.8,4.1Hz,1H),7.87(m,3H),2.69(s,3H).

[0106] HRMS m / z(ESI) Calculated value: C 15 H 10 N4O[M+H] + 263.0927; Actual value: 263.0925; HPLC purity = 98.1%.

[0107] Example 3, Synthesis of Compound 3

[0108]

[0109] The compound 3 was prepared by a similar synthesis method as in Example 1 with a yield of 80%.

[0110] Compound 3 1H NMR and HRMS data are as follows:

[0111] 1 H NMR(400MHz, CDCl3) δ9.05(d,J=7.1Hz,1H),8.50(d,J=8.6Hz,1H),8.31(d,J=8.4Hz,2H), 7.99 (ddd, J=20.7, 11.1, 4.6Hz, 3H), 3.47 (dt, J=13.6, 6.8Hz, 1H), 1.40 (d, J=6.9Hz, 6H).

[0112] HRMS m / z(ESI) Calculated value: C 17 H 13 N4O[M+H] + 291.1240; Actual value: 291.1241; HPLC purity = 98.3%.

[0113] Example 4. Synthesis of Compound 4

[0114]

[0115] Compound 4 was prepared by a similar synthesis method as in Example 1 with a yield of 84%.

[0116] Compound 4 1 H NMR and HRMS data are as follows:

[0117] 1 H NMR (400MHz, CDCl3) δ9.04 (dd, J=7.2, 1.4Hz, 1H), 8.49 (m, 1H), 8.28 (m, 2H), 7.97 (ddd d,J=9.9,8.6,7.0,2.3Hz,3H),3.02(td,J=7.8,4.6Hz,1H),1.31(m,2H),1.11(m,2H).

[0118] HRMS m / z(ESI) Calculated value: C 17 H 12 N4O[M+H] + 289.1084; Actual value: 289.1082; HPLC purity = 98.0%.

[0119] Example 5. Synthesis of Compound 5

[0120]

[0121] Compound 5 was prepared by a similar synthesis method as in Example 1 with a yield of 88%.

[0122] Compound 51 H NMR and HRMS data are as follows:

[0123] 1 H NMR (400MHz, CDCl3) δ9.10 (dd, J=7.2, 1.3Hz, 1H), 8.49 (dd, J=8.7, 1.3Hz, 1H), 8.32 (m, 2H), 7.99 (m, 3H), 1.55 (s, 9H).

[0124] HRMS m / z(ESI) Calculated value: C 18 H 16 N4O[M+H] + 305.1397; Actual value: 305.1396; HPLC purity = 98.5%.

[0125] Example 6. Synthesis of Compound 6

[0126]

[0127] Compound 6 was prepared by a similar synthesis method as in Example 1 with a yield of 82%.

[0128] Compound 6 1 H NMR and HRMS data are as follows:

[0129] 1 H NMR (400MHz, CDCl3) δ8.71 (dd, J=7.1, 1.3Hz, 1H), 8.43 (dd, J=8.7, 1.3Hz, 1H), 8.31 (m, 1H), 8.1 8(m,1H),8.06(d,J=3.1Hz,1H),7.91(dd,J=8.7,7.1Hz,1H),7.83(m,2H),7.57(d,J=3.1Hz,1H).

[0130] HRMS m / z(ESI) Calculated value: C 17 H9N5OS[M+H] + 332.0601; Actual value: 332.0601; HPLC purity = 98.5%.

[0131] Example 7. Synthesis of Compound 7

[0132]

[0133] Compound 7 was prepared by a similar synthesis method as in Example 1 with a yield of 74%.

[0134] Compound 7 1 H NMR and HRMS data are as follows:

[0135] 1 H NMR (400MHz, CDCl3) δ8.94 (d, J = 7.1Hz, 1H), 8.63 (d, J = 8.4Hz, 1H), 8.51 (s, 1H), 8.40 (d, J = 8.4Hz, 1H), 8.20 (d, J = 8.4Hz, 1H), 7.89 (m, 4H), 6.50 (s, 1H).

[0136] HRMS m / z(ESI) Calculated value: C 17 H 10 N6O[M+H] + 315.0989; Actual value: 315.0988; HPLC purity = 98.6%.

[0137] Example 8. Synthesis of Compound 8

[0138]

[0139] Compound 8 was prepared by a similar synthesis method as in Example 1 with a yield of 85%.

[0140] Compound 8 1 H NMR and HRMS data are as follows:

[0141] 1 H NMR (400MHz, CDCl3) δ8.89(d,J=4.2Hz,1H),8.81(dd,J=7.0,1.2Hz,1H),8.52(dd,J=8.7,1.2Hz,1H),8.41(m,1H),8.3 3(d,J=7.8Hz,1H),8.28(dt,J=6.6,3.3Hz,1H),8.00(dd,J=8.7,7.1Hz,1H),7.92(m,3H),7.49(dd,J=7.1,5.2Hz,1H).

[0142] HRMS m / z(ESI) Calculated value: C 19 H 11 N5O[M+H] + 326.1036; Actual value: 326.1033; HPLC purity = 99.3%.

[0143] Example 9, Synthesis of Compound 9

[0144]

[0145] Compound 9 was prepared by a similar synthesis method as in Example 1 with a yield of 82%.

[0146] Compound 9 1 H NMR and HRMS data are as follows:

[0147] 1 H NMR (400MHz, CDCl3) δ9.52(s,1H),8.81(d,J=3.7Hz,1H),8.73(d,J=6.7Hz,1H),8.54(t,J=7.6Hz,2H),8.38(dd,J= 6.7,3.4Hz,1H),8.29(dd,J=6.6,3.4Hz,1H),8.01(m,1H),7.93(dd,J=6.8,3.3Hz,2H),7.51(dd,J=7.7,4.9Hz,1H).

[0148] HRMS m / z(ESI) Calculated value: C 19 H 11 N5O[M+H] + 326.1036; Actual value: 326.1037; HPLC purity = 98.6%.

[0149] Example 10. Synthesis of Compound 10

[0150]

[0151] Using a synthetic method similar to that of Example 1, compound 10 was prepared with a yield of 82%.

[0152] Compound 10 1 H NMR and HRMS data are as follows:

[0153] 1 H NMR (400MHz, CDCl3) δ8.86(d,J=5.9Hz,2H),8.72(dd,J=7.0,1.2Hz,1H),8.54(dd,J=8.7,1.2Hz,1H),8. 37(m,1H),8.30(m,1H),8.15(d,J=6.0Hz,2H),8.01(dd,J=8.7,7.1Hz,1H),7.93(dq,J=6.5,3.1Hz,2H).

[0154] HRMS m / z(ESI) Calculated value: C 19 H 11 N5O[M+H] + 326.1036; Actual value: 326.1032; HPLC purity = 98.1%.

[0155] Example 11. Synthesis of Compound 11

[0156]

[0157] Compound 11 was prepared by a synthetic method similar to that of Example 1 with a yield of 82%.

[0158] Compound 11 1 H NMR and HRMS data are as follows:

[0159] 1 H NMR (400MHz, DMSO) δ8.52(ddd,J=10.0,7.9,1.2Hz,2H),8.40(m,1H),8.35(m,1H),8.09(m,3H),7.58(d,J=3.9Hz,1H),7.27(d,J=4.0Hz,1H).

[0160] HRMS m / z(ESI) Calculated value: C 18 H9BrN4OS[M+H] + 408.9753; Actual value: 408.9754; HPLC purity = 96.2%.

[0161] Example 12. Synthesis of Compound 12

[0162]

[0163] Compound 12 was prepared by a similar synthesis method as in Example 1 with a yield of 74%.

[0164] Compound 12 1 H NMR and HRMS data are as follows:

[0165] 1 H NMR (400MHz, DMSO) δ8.70 (dd, J=6.9, 1.3Hz, 1H), 8.60 (dd, J=8.6, 1.2Hz, 1H), 8.34 (m, 2H), 8. 18(dd,J=8.7,7.1Hz,1H),8.07(m,2H),7.09(dt,J=3.9,2.2Hz,1H),6.92(m,1H),6.30(m,1H).

[0166] HRMS m / z(ESI) Calculated value: C 18 H 10 N4O2[M+H] + 315.0877; Actual value: 315.0875; HPLC purity = 97.6%.

[0167] Example 13. Synthesis of Compound 13

[0168]

[0169] Compound 13 was prepared by a synthetic method similar to that of Example 1 with a yield of 77%.

[0170] Compound 13 1 H NMR and HRMS data are as follows:

[0171] 1 H NMR (400MHz, DMSO) δ8.70(dd,J=7.1,1.4Hz,1H),8.55(dd,J=8.7,1.4Hz,1H),8.40–8.32(m,1H),8.30–8.22( m,1H),8.11(ddt,J=19.5,17.1,11.0Hz,3H),7.28(dt,J=29.2,14.6Hz,2H),7.05–6.93(m,3H),5.19(s,2H).

[0172] HRMS m / z(ESI) Calculated value: C 21 H 14 N4O2[M+H] + 355.1190; Actual value: 355.1188; HPLC purity = 98.3%.

[0173] Example 14. Synthesis of Compound 14

[0174]

[0175] Compound 14 was prepared by a synthetic method similar to that of Example 1 with a yield of 40%.

[0176] Compound 14 1 H NMR and HRMS data are as follows:

[0177] 1 H NMR (400MHz, DMSO) δ 8.80 (d, J = 7.0 Hz, 1H), 8.63 (d, J = 8.7 Hz, 1H), 8.35 (s, 2H), 8.21 (d, J = 8.9 Hz, 2H), 8.08 (d, J = 10.0 Hz, 2H), 7.38 (s, 2H), 2.74 (s, 3H).

[0178] HRMS m / z(ESI) Calculated value: C 21 H 13 FN4O[M+H] + 357.1146; Actual value: 357.1145; HPLC purity = 98.2%.

[0179] Example 15. Synthesis of Compound 15

[0180] The synthetic route of compound 15 is as follows:

[0181]

[0182] p-Toluonitrile (1 g, 1.56 mmol, 1.00 eq), hydroxylamine hydrochloride (2.37 g, 6.24 mmol, 4.00 eq) and sodium carbonate (1.81 g, 3.12 mmol, 2.00 eq) were dissolved in a mixed solution of ethanol: water = 2: 1 (20 mL: 10 mL). The reaction was stirred at 80 ° C for 12 hours until the solution gradually clarified. After the reaction was completed, the reaction was cooled to room temperature. After filtration, the combined organic solution was concentrated in vacuo, and the residue was purified by column chromatography to obtain intermediate b (1.08 g, 1.32 mmol, 84%).

[0183] Intermediate b (1.08 g, 1.32 mmol, 1.00 eq), phenazine-1-carboxylic acid (1.61 g, 1.32 mmol, 1.00 eq) and HATU (2.79 g, 1.45 mmol, 1.10 eq) were dissolved in 50 mL DCM, and N,N-diisopropylethylamine (3.83 ml, 3.96 mmol, 3.00 eq) was added and reacted for 8 h. After the reaction was completed by TLC monitoring, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to obtain intermediate c (1.21 g, 0.99 mmol, 75%).

[0184] Intermediate c was dissolved in 3.5 mL of 1,4-dioxane, heated to 120°C, and reacted for 12 hours. After the reaction was completed (TLC monitoring), the solvent was removed under reduced pressure and purified by thin layer chromatography to obtain yellow solid compound 15 (0.41 g, 0.34 mmmol, 35%).

[0185] Compound 15 1 H NMR and HRMS data are as follows:

[0186] 1 H NMR (400MHz, CDCl3) δ8.70(d,J=6.0Hz,1H),8.51(d,J=8.7Hz,1H),8.38(dd,J=6.9,3.1Hz,1H),8.28(m,1H),8.1 7(d,J=8.1Hz,2H), 7.99(dd,J=8.6,7.2Hz,1H), 7.91(dd,J=6.8,3.4Hz,2H), 7.36(d,J=7.9Hz,2H), 2.46(s,3H).

[0187] HRMS m / z(ESI) Calculated value: C 21 H 14 N4O[M+H] + 339.1240; Actual value: 339.1241; HPLC purity = 95.1%.

[0188] Example 16. Synthesis of Compound 16

[0189]

[0190] Using a synthetic method similar to Example 15, compound 16 was prepared with a yield of 35%.

[0191] Compound 16 1 H NMR and HRMS data are as follows:

[0192] 1 H NMR (400MHz, CDCl3) δ8.70 (d, J = 6.1 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.29 (s, 3H), 7.98 (dd, J = 22.1, 13.9 Hz, 3H), 7.24 (m, 2H).

[0193] HRMS m / z(ESI) Calculated value: C 20 H 11 FN4O[M+H] + 343.0990; Actual value: 343.0988; HPLC purity = 95.3%.

[0194] Example 17. Synthesis of Compound 17

[0195]

[0196] Using a synthetic method similar to Example 15, compound 17 was prepared with a yield of 31%.

[0197] Compound 17 1 H NMR and HRMS data are as follows:

[0198] 1H NMR(400MHz, CDCl3)δ8.71(dd,J=7.0,1.1Hz,1H),8.50(dd,J=8.7,1.1Hz,1H),8.38(m,1H),8.28(m,1H),8.21 (d,J=8.4Hz,2H),7.99(dd,J=8.6,7.1Hz,1H),7.91(dd,J=6.7,3.5Hz,2H),7.57(d,J=8.4Hz,2H),1.40(s,9H).

[0199] HRMS m / z(ESI) Calculated value: C 24 H 20 N4O[M+H] + 381.1710; Actual value: 381.1709; HPLC purity = 95.6%.

[0200] Example 18, Synthesis of Compound 18

[0201]

[0202] Using a synthetic method similar to Example 15, compound 18 was prepared with a yield of 30%.

[0203] Compound 18 1 H NMR and HRMS data are as follows:

[0204] 1 H NMR (400MHz, CDCl3) δ8.69(dd,J=7.0,1.1Hz,1H),8.51(m,1H),8.38(m,1H),8.28(m,1H),8.18(d,J=8.8Hz,2 H), 7.99 (dd, J = 8.7, 7.1Hz, 1H), 7.91 (dd, J = 6.3, 3.9Hz, 2H), 7.03 (d, J = 8.9Hz, 2H), 3.90 (m, 4H), 3.31 (m, 4H).

[0205] HRMS m / z(ESI) Calculated value: C 24 H 19 N5O2[M+H] + 410.1612; Actual value: 410.1611; HPLC purity = 95.1%.

[0206] Example 19, Synthesis of Compound 19

[0207]

[0208] Using a synthetic method similar to Example 15, compound 19 was prepared with a yield of 32%.

[0209] Compound 19 1 H NMR and HRMS data are as follows:

[0210] 1 H NMR (400MHz, CDCl3) δ8.71(d,J=6.7Hz,1H),8.52(d,J=8.7Hz,1H),8.39(dd,J=15.1,5.7Hz,3H),8. 28(dd,J=6.6,3.3Hz,1H), 8.00(t,J=7.6Hz,1H), 7.92(dd,J=6.6,3.2Hz,2H), 7.82(d,J=8.1Hz,2H).

[0211] HRMS m / z(ESI) Calculated value: C 21 H 11 F3N4O[M+H] + 393.0958; Actual value: 393.0956; HPLC purity = 100.0%.

[0212] Example 20, Synthesis of Compound 20

[0213]

[0214] Using a similar synthesis method to Example 15, compound 20 was prepared with a yield of 32%.

[0215] Compound 20 1 H NMR and HRMS data are as follows:

[0216] 1 H NMR (400MHz, DMSO) δ8.82(d,J=8.5Hz,1H),8.67-8.61(m,1H),8.46(d,J=8.7Hz,2H),8.35(d d, J=14.3, 6.7Hz, 2H), 8.21 (dd, J=8.6, 6.8Hz, 3H), 8.08 (dd, J=6.1, 4.2Hz, 2H), 3.34 (s, 3H).

[0217] HRMS m / z(ESI) Calculated value: C 21 H 14 N4O3S[M+H] + 403.0859; Actual value: 403.0858; HPLC purity = 99.2%.

[0218] Example 21. Synthesis of Compound 21

[0219]

[0220] Using a synthetic method similar to Example 15, compound 21 was prepared with a yield of 28%.

[0221] Compound 21 1 H NMR and HRMS data are as follows:

[0222] 1 H NMR (400MHz, DMSO) δ8.98(d,J=5.9Hz,1H),8.73(d,J=7.3Hz,1H),8.42(d,J=8.5Hz,1H),8.32(d,J=8.5Hz,2H),8.30-8.24 (m,1H),8.20(d,J=8.4Hz,3H),8.13(t,J=9.0Hz,2H),7.92(d,J=7.3Hz,2H),7.60(t,J=7.4Hz,2H),7.53(t,J=7.3Hz,1H).

[0223] HRMS m / z(ESI) Calculated value: C 25 H22N6O[M+H] + 401.1397; Actual value: 401.1397; HPLC purity = 96.2%.

[0224] Example 22, Synthesis of Compound 22

[0225]

[0226] Using a synthetic method similar to Example 15, compound 22 was prepared with a yield of 35%.

[0227] Compound 22 1 H NMR and HRMS data are as follows:

[0228] 1 H NMR (400MHz, CDCl3) δ9.06(d,J=7.1Hz,1H),8.44(d,J=8.7Hz,1H),8.26(d,J=9.5H z,1H),8.17(m,4H),7.97(m,1H),7.91(m,2H),7.05(d,J=8.6Hz,2H),3.90(s,3H).

[0229] HRMS m / z(ESI) Calculated value: C 21 H 14 N4O2[M+H] + 355.1190; Actual value: 355.1189; HPLC purity = 95.9%.

[0230] Example 23. Synthesis of Compound 23

[0231]

[0232] Using a synthetic method similar to Example 15, compound 23 was prepared with a yield of 39%.

[0233] Compound 23 1 H NMR and HRMS data are as follows:

[0234] 1 H NMR (400MHz, DMSO) δ8.82 (d, J = 5.7 Hz, 1H), 8.64 (d, J = 8.7 Hz, 1H), 8.48 (t, J = 7.8 Hz, 4H), 8.35 (s, 2H), 8.20 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 10.1 Hz, 2H).

[0235] HRMS m / z(ESI) Calculated value: C 20 H 11 N5O3[M+H] + 370.0935; Actual value: 370.0933; HPLC purity = 96.5%.

[0236] Example 24. Synthesis of Compound 24

[0237]

[0238] Using a synthetic method similar to Example 15, compound 24 was prepared with a yield of 40%.

[0239] Compound 24 1 H NMR and HRMS data are as follows:

[0240] 1 H NMR (400MHz, CDCl3) δ8.71(dd,J=7.0,1.2Hz,1H),8.52(dd,J=8.7,1.2Hz,1H),8.39(m,1H),8.29(m,1H),8.09(m,2H) ,8.00(dd,J=8.7,7.1Hz,1H),7.92(dd,J=6.8,3.4Hz,2H),7.44(t,J=7.6Hz,1H),7.37(d,J=7.7Hz,1H),2.48(s,3H).

[0241] HRMS m / z(ESI) Calculated value: C 21 H 14 N4O[M+H] +339.1240; Actual value: 339.1239; HPLC purity = 99.4%.

[0242] Example 25. Synthesis of Compound 25

[0243]

[0244] Using a synthetic method similar to Example 15, compound 25 was prepared with a yield of 42%.

[0245] Compound 25 1 H NMR and HRMS data are as follows:

[0246] 1 H NMR (400MHz, CDCl3) δ8.71(d,J=7.0Hz,1H),8.52(d,J=8.8Hz,1H),8.38(dd,J=6.8,3.3Hz,1H),8.29(m,1H),8.0 8(d,J=7.7Hz,1H), 8.00(t,J=7.9Hz,2H), 7.92(dd,J=6.7,3.3Hz,2H), 7.53(dd,J=13.8,7.9Hz,1H), 7.26(m,1H).

[0247] HRMS m / z(ESI) Calculated value: C 20 H 11 FN4O[M+H] + 343.0990; Actual value: 343.0989; HPLC purity = 95.8%.

[0248] Example 26. Synthesis of Compound 26

[0249]

[0250] Using a synthetic method similar to Example 15, compound 26 was prepared with a yield of 32%.

[0251] Compound 26 1 H NMR and HRMS data are as follows:

[0252] 1H NMR (400MHz, CDCl3) δ8.72(d,J=6.9Hz,1H),8.56(s,1H),8.51(d,J=8.7Hz,1H),8.46(d,J=7.8Hz,1H),8.37(dd,J=6.7,3.4 Hz,1H),8.27(dd,J=6.7,3.4Hz,1H),7.99(m,1H),7.91(dd,J=6.8,3.4Hz,2H),7.81(d,J=7.8Hz,1H),7.68(t,J=7.8Hz,1H).

[0253] HRMS m / z(ESI) Calculated value: C 21 H 11 F3N4O[M+H] + 393.0958; Actual value: 393.0957; HPLC purity = 98.4%.

[0254] Example 27. Synthesis of Compound 27

[0255]

[0256] Using a synthetic method similar to Example 16, compound 29 was prepared with a yield of 25%.

[0257] Compound 27 1 H NMR and HRMS data are as follows:

[0258] 1 H NMR (400MHz, CDCl3) δ8.71(dd,J=7.0,1.3Hz,1H),8.52(dd,J=8.7,1.3Hz,1H),8.37(dd,J=6.7,3.4Hz,1H),8.28(dd,J=6.8,3.3Hz,1 H), 8.23 ​​(d, J = 7.8Hz, 1H), 8.16 (s, 1H), 8.00 (dd, J = 8.7, 7.1Hz, 1H), 7.93 (dt, J = 6.8, 3.3Hz, 2H), 7.59 (t, J = 8.0Hz, 1H), 7.42 (m, 1H).

[0259] HRMS m / z(ESI) Calculated value: C 21 H 11 F3N4O2[M+H] + 409.0907; Actual value: 409.0906; HPLC purity = 95.4%.

[0260] Example 28. Synthesis of Compound 28

[0261]

[0262] Using a synthetic method similar to Example 15, compound 28 was prepared with a yield of 38%.

[0263] Compound 28 1 H NMR and HRMS data are as follows:

[0264] 1 H NMR (400MHz, CDCl3) δ8.71(dd,J=7.0,1.1Hz,1H),8.50(m,1H),8.37(m,1H),8.27(m,1H),7.99(dd,J=8.6,7. 2Hz, 1H), 7.91 (dd, J = 6.8, 3.4Hz, 2H), 7.62 (d, J = 7.8Hz, 2H), 7.40 (t, J = 8.1Hz, 1H), 6.91 (m, 1H), 3.06 (s, 6H).

[0265] HRMS m / z(ESI) Calculated value: C 22 H 17 N5O[M+H] + 368.1506; Actual value: 368.1503; HPLC purity = 95.4%.

[0266] Example 29, Synthesis of Compound 29

[0267]

[0268] Using a synthetic method similar to Example 15, compound 29 was prepared with a yield of 35%.

[0269] Compound 29 1 H NMR and HRMS data are as follows:

[0270] 1 H NMR (400MHz, CDCl3) δ8.72(dd,J=7.0,1.2Hz,1H),8.53(dd,J=8.8,1.2Hz,1H),8.45(s,1H),8.39(dd,J=6.7,3.4Hz,1H),8.29(dd,J=6.6, 3.5Hz, 1H), 8.22 (d, J = 7.8Hz, 1H), 8.01 (dd, J = 8.7, 7.1Hz, 1H), 7.93 (dq, J = 6.5, 3.1Hz, 2H), 7.69 (d, J = 8.8Hz, 1H), 7.43 (t, J = 7.9Hz, 1H).

[0271] HRMS m / z(ESI) Calculated value: C20 H 11 BrN4O[M+H] + 403.0189; Actual value: 403.0188; HPLC purity = 99.9%.

[0272] Example 30, Synthesis of Compound 30

[0273]

[0274] Using a synthetic method similar to Example 15, compound 30 was prepared with a yield of 38%.

[0275] Compound 30 1 H NMR and HRMS data are as follows:

[0276] 1 H NMR (400MHz, CDCl3) δ8.71(dd,J=7.0,1.1Hz,1H),8.50(dd,J=8.7,1.1Hz,1H),8.37(dd,J=6.5,3.6Hz,1H),8.31(s,1H),8.27(m,1H),8. 10(d,J=7.6Hz,1H),7.99(dd,J=8.6,7.2Hz,1H),7.91(dd,J=6.8,3.4Hz,2H),7.60(d,J=8.4Hz,1H),7.49(t,J=7.7Hz,1H),1.43(s,9H).

[0277] HRMS m / z(ESI) Calculated value: C 24 H 20 N4O[M+H] + 381.1710; Actual value: 381.1709; HPLC purity = 96.8%.

[0278] Example 31, Synthesis of Compound 31

[0279]

[0280] Using a synthetic method similar to Example 15, compound 31 was prepared with a yield of 37%.

[0281] Compound 31 1 H NMR and HRMS data are as follows:

[0282] 1H NMR (400MHz, CDCl3) δ8.71 (d, J = 7.0 Hz, 1H), 8.51 (m, 1H), 8.38 (dd, J = 6.9, 3. 1Hz,1H),8.28(m,1H),8.22(s,1H),8.17(d,J=7.5Hz,1H),7.99(dd,J=8.6,7 .1Hz,1H),7.91(dd,J=6.8,3.4Hz,2H),7.57(d,J=7.6Hz,1H),7.50(t,J=7.6 Hz, 1H), 3.62 (s, 2H), 2.47 (s, 4H), 1.62 (dt, J = 11.0, 5.6Hz, 4H), 1.45 (m, 2H).

[0283] HRMS m / z(ESI) Calculated value: C 26 H 23 N5O[M+H] + 422.1975; Actual value: 422.1974; HPLC purity = 98.6%.

[0284] Example 32, Synthesis of Compound 32

[0285]

[0286] Using a synthetic method similar to Example 15, compound 32 was prepared with a yield of 32%.

[0287] Compound 32 1 H NMR and HRMS data are as follows:

[0288] 1 H NMR (400MHz, CDCl3) δ8.73(d,J=6.2Hz,1H),8.50(dd,J=8.4,3.2Hz,1H),8.38(m,1H),8.28(d,J=3.2Hz,1H),8.20(d ,J=7.6Hz,1H),7.99(dt,J=11.6,5.9Hz,1H),7.90(dd,J=6.6,3.3Hz,2H),7.41(dq,J=14.3,7.1Hz,3H),2.79(s,3H).

[0289] HRMS m / z(ESI) Calculated value: C 21 H 14 N4O[M+H] + 339.1240; Actual value: 339.1239; HPLC purity = 99.2%.

[0290] Example 33. Synthesis of Compound 33

[0291]

[0292] Using a synthetic method similar to Example 15, compound 33 was prepared with a yield of 40%.

[0293] Compound 33 1 H NMR and HRMS data are as follows:

[0294] 1 H NMR(400MHz, CDCl3) δ8.72(dd,J=7.0,1.1Hz,1H),8.52(dd,J=8.8,1.1Hz,1H),8.38(m,1H),8.28 (m,2H),8.00(dd,J=8.7,7.1Hz,1H),7.92(m,2H),7.55(ddd,J=7.1,5.0,1.6Hz,1H),7.33(m,2H).

[0295] HRMS m / z(ESI) Calculated value: C 20 H 11 FN4O[M+H] + 343.0990; Actual value: 343.0987; HPLC purity = 95.8%.

[0296] Example 34. Synthesis of Compound 34

[0297]

[0298] Using a synthetic method similar to Example 15, compound 34 was prepared with a yield of 40%.

[0299] Compound 34 1 H NMR and HRMS data are as follows:

[0300] 1 H NMR (400MHz, CDCl3) δ8.69(d,J=7.0Hz,1H),8.50(d,J=8.7Hz,1H),8.37(m,1H),8.26(ddd,J=9.3,7.6,2.6Hz,2H) ,7.98(dd,J=8.5,7.3Hz,1H),7.91(dd,J=6.8,3.4Hz,2H),7.53(m,1H),7.14(dd,J=14.3,7.8Hz,2H),4.06(s,3H).

[0301] HRMS m / z(ESI) Calculated value: C 21 H 14 N4O2[M+H] +355.1190; Actual value: 355.1189; HPLC purity = 98.4%.

[0302] Example 35. Synthesis of Compound 35

[0303]

[0304] Using a synthetic method similar to Example 15, compound 35 was prepared with a yield of 33%.

[0305] Compound 35 1 H NMR and HRMS data are as follows:

[0306] 1 H NMR (400MHz, CDCl3) δ8.70(d,J=6.9Hz,1H),8.50(d,J=8.7Hz,1H),8.39(m,1H),8.28(m,1H),8.20(d,J=7.5Hz,1 H), 7.99 (m, 1H), 7.91 (dd, J = 6.7, 3.4Hz, 2H), 7.50 (t, J = 7.7Hz, 1H), 4.29 (q, J = 7.0Hz, 2H), 1.57 (t, J = 7.0Hz, 3H).

[0307] HRMS m / z(ESI) Calculated value: C 22 H 16 N4O2[M+H] + 369.1346; Actual value: 369.1343; HPLC purity = 99.3%.

[0308] Example 36. Synthesis of Compound 36

[0309]

[0310] Using a synthetic method similar to Example 15, compound 36 was prepared with a yield of 35%.

[0311] Compound 36 1 H NMR and HRMS data are as follows:

[0312] 1H NMR (400MHz, CDCl3) δ8.71 (d, J = 7.0 Hz, 1H), 8.51 (m, 1H), 8.38 (dd, J = 6.9, 3. 1Hz,1H),8.28(m,1H),8.22(s,1H),8.17(d,J=7.5Hz,1H),7.99(dd,J=8.6,7 .1Hz,1H),7.91(dd,J=6.8,3.4Hz,2H),7.57(d,J=7.6Hz,1H),7.50(t,J=7.6 Hz, 1H), 3.62 (s, 2H), 2.47 (s, 4H), 1.62 (dt, J = 11.0, 5.6Hz, 4H), 1.45 (m, 2H).

[0313] HRMS m / z(ESI) Calculated value: C 21 H 11 F3N4O[M+H] + 393.0958; Actual value: 393.0957; HPLC purity = 98.5%.

[0314] Example 37. Synthesis of Compound 37

[0315]

[0316] Using a synthetic method similar to Example 15, compound 37 was prepared with a yield of 35%.

[0317] Compound 37 1 H NMR and HRMS data are as follows:

[0318] 1 H NMR (400MHz, DMSO) δ8.74(dd,J=7.0,1.3Hz,1H),8.61(dd,J=8.8,1.3Hz,1H),8.41-8.30(m,2H),8.18(d d,J=8.8,7.1Hz,1H),8.09-8.00(m,3H),7.67-7.59(m,1H),7.31(d,J=8.4Hz,1H),7.19(t,J=7.5Hz,1H).

[0319] HRMS m / z(ESI) Calculated value: C 26 H 23 N5O[M+H] + 409.0907; Actual value: 409.0905; HPLC purity = 96.7%.

[0320] Example 38, Synthesis of Compound 38

[0321]

[0322] Using a synthetic method similar to Example 15, compound 38 was prepared with a yield of 34%.

[0323] Compound 38 1 H NMR and HRMS data are as follows:

[0324] 1 H NMR (400MHz, CDCl3) δ8.72(d,J=6.7Hz,1H),8.51(d,J=8.7Hz,1H),8.39(dd,J=6.3,3.8Hz,1H),8.28(dd,J=7.0,3.0Hz,1H),7.99( m,1H),7.91(dd,J=6.7,3.4Hz,2H),7.74(d,J=7.8Hz,1H),7.23(d,J=8.0Hz,1H),7.12(d,J=8.1Hz,1H),4.08(s,3H),3.96(s,3H).

[0325] HRMS m / z(ESI) Calculated value: C 22 H 16 FN4O3[M+H] + 385.1295; Actual value: 385.1295; HPLC purity = 97.1%.

[0326] Example 39, Synthesis of Compound 39

[0327]

[0328] Using a synthetic method similar to Example 15, compound 39 was prepared with a yield of 30%.

[0329] Compound 39 1 H NMR and HRMS data are as follows:

[0330] 1 H NMR (400MHz, CDCl3) δ8.70(d,J=7.0Hz,1H),8.53(d,J=8.7Hz,1H),8.38(dd,J=6.6,3.5Hz,1H),8.29(dd,J=6.9,3.3Hz ,1H),8.12(m,1H),8.06(m,1H),8.00(dd,J=8.6,7.2Hz,1H),7.93(dd,J=6.8,3.4Hz,2H),7.35(dd,J=18.0,8.4Hz,1H).

[0331] HRMS m / z(ESI) Calculated value: C20 H 10 F2N4O[M+H] + 361.0895; Actual value: 361.0893; HPLC purity = 95.5%.

[0332] Example 40, Synthesis of Compound 40

[0333]

[0334] Using a synthetic method similar to Example 15, compound 40 was prepared with a yield of 36%.

[0335] Compound 40 1 H NMR and HRMS data are as follows:

[0336] 1 H NMR (400MHz, CDCl3) δ8.72(m,1H),8.53(dd,J=8.8,1.2Hz,1H),8.38(dd,J=6.8,3.3Hz,1H),8.29(dd,J=6 .5,3.6Hz,1H),8.17(m,1H),8.00(dd,J=8.7,7.1Hz,1H),7.92(m,2H),7.61(m,1H),7.30(t,J=7.9Hz,1H).

[0337] HRMS m / z(ESI) Calculated value: C 20 H 10 FN5O2[M+H] + 388.0840; Actual value: 388.0838; HPLC purity = 96.1%.

[0338] Example 41, Synthesis of Compound 41

[0339]

[0340] Using a similar synthesis method to Example 15, compound 41 was prepared with a yield of 36%.

[0341] Compound 41 1 H NMR and HRMS data are as follows:

[0342] 1H NMR (400MHz, CDCl3) δ8.71(dd,J=7.0,1.3Hz,1H),8.52(dd,J=8.7,1.3Hz,1H),8.38(m,1H),8.29(dd,J= 7.0, 3.1Hz, 1H), 7.98 (m, 2H), 7.92 (dd, J = 6.8, 3.4Hz, 3H), 7.36 (t, J = 7.7Hz, 1H), 2.39 (d, J = 1.5Hz, 3H).

[0343] HRMS m / z(ESI) Calculated value: C 21 H 13 FN4O[M+H] + 357.1146; Actual value: 357.1145; HPLC purity = 98.1%.

[0344] Example 42, Synthesis of Compound 42

[0345]

[0346] Using a similar synthesis method to Example 15, compound 42 was prepared with a yield of 38%.

[0347] Compound 42 1 H NMR and HRMS data are as follows:

[0348] 1 H NMR (400MHz, DMSO) δ8.80(d,J=5.8Hz,1H),8.63(d,J=7.5Hz,1H),8.34(dd,J=13.0,7.3Hz ,2H),8.24-8.16(m,1H),8.11-8.05(m,2H),7.85(d,J=5.5Hz,2H),7.62(d,J=9.4Hz,1H).

[0349] HRMS m / z(ESI) Calculated value: C 20 H 10 F2N4O[M+H] + 361.0895; Actual value: 361.0894; HPLC purity = 98.8%.

[0350] Example 43. Synthesis of Compound 43

[0351]

[0352] Using a similar synthesis method to Example 15, compound 43 was prepared with a yield of 33%.

[0353] Compound 43 1H NMR and HRMS data are as follows:

[0354] 1 H NMR(400MHz,DMSO)δ8.79(d,J=7.0Hz,1H),8.63(d,J=8.9Hz,1H),8.41-8.30(m,2H ),8.28-8.16(m,2H),8.12-8.03(m,2H),7.85-7.77(m,1H),7.62(d,J=8.5Hz,1H).

[0355] HRMS m / z(ESI) Calculated value: C 20 H 10 ClFN4O[M+H] + 377.0600; Actual value: 377.0658; HPLC purity = 98.2%.

[0356] Example 44. Synthesis of Compound 44

[0357]

[0358] Using a similar synthesis method to Example 15, compound 44 was prepared with a yield of 35%.

[0359] Compound 44 1 H NMR and HRMS data are as follows:

[0360] 1 H NMR (400MHz, DMSO) δ8.49(d,J=7.6Hz,1H),8.42(d,J=6.9Hz,1H),8.37-8.31(m ,1H),8.26-8.20(m,1H),8.12-8.02(m,3H),7.62(s,1H),7.41(d,J=9.4Hz,1H).

[0361] HRMS m / z(ESI) Calculated value: C 20 H9F3N4O[M+H] + 379.0801; Actual value: 379.0800; HPLC purity = 97.5%.

[0362] Example 45. Synthesis of Compound 45

[0363]

[0364] Using a similar synthesis method to Example 15, compound 45 was prepared with a yield of 33%.

[0365] Compound 45 1H NMR and HRMS data are as follows:

[0366] 1 H NMR (400MHz, DMSO) δ8.80(dd,J=7.0,1.2Hz,1H),8.63(dd,J=8.8,1.3Hz,1H),8.35(m,2H),8.31(dd,J=6.6,3.8Hz,1H),8.20(dd,J=8.7,7.1Hz,1H),8.08( m,2H),7.46(s,1H),7.26(d,J=5.1Hz,1H),4.40(dd,J=12.8,3.0Hz,2H),2.39 (t, J = 11.9 Hz, 2H), 1.64 (ddd, J = 10.4, 8.6, 4.3 Hz, 2H), 0.95 (d, J = 6.5 Hz, 6H).

[0367] HRMS m / z(ESI) Calculated value: C 26 H 24 N6O[M+H] + 437.2084; Actual value: 437.2084; HPLC purity = 99.1%.

[0368] Example 46. Synthesis of Compound 46

[0369]

[0370] Using a similar synthesis method to Example 15, compound 46 was prepared with a yield of 36%.

[0371] Compound 46 1 H NMR and HRMS data are as follows:

[0372] 1 H NMR (400MHz, DMSO) δ8.78(d,J=7.0Hz,1H),8.62(d,J=8.7Hz,1H),8.39-8.28(m,3H),8.22-8.13(m,1 H), 8.08 (d, J = 10.0Hz, 2H), 7.34 (d, J = 4.4Hz, 1H), 7.03 (s, 1H), 4.17 (s, 4H), 2.92 (t, J = 12.5Hz, 4H).

[0373] HRMS m / z(ESI) Calculated value: C 25 H 18 F2N6O[M+H] + 457.1583; Actual value: 457.1581; HPLC purity = 97.9%.

[0374] Example 47, Synthesis of Compound 47

[0375] The synthetic route of compound 47 is as follows:

[0376]

[0377] Phenazine-1-carboxylic acid (1g, 1.04mmol, 1.00eq), 3-pyridine carboxylic acid hydrazide (0.61g, 1.04mmol, 1.00eq) and O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (1.43g, 1.04mmol, 1.00eq) were dissolved in 50mL acetonitrile, and N,N-diisopropylethylamine (2.38ml, 3.12mmol, 3.00eq) was added, and the reaction was carried out at room temperature for 8h. After the reaction was completed by TLC monitoring, the reaction did not require further treatment. Toluenesulfonyl chloride (0.09g, 0.10mmol, 0.10eq) and N,N-diisopropylethylamine (2.83ml, 3.12mmol, 3.00eq) were added to the reaction system, and the reaction was continued to stir at room temperature for 12 hours. After the reaction was completed as monitored by TLC, the solvent was removed under reduced pressure and the residue was purified by column chromatography to obtain yellow solid powder Compound 47 (0.89 g, 0.62 mmol, 59%).

[0378] Compound 47 1 H NMR and HRMS data are as follows:

[0379] 1 H NMR (400MHz, DMSO) δ9.38(s,1H),8.89(d,J=3.4Hz,1H),8.72(d,J=6.0Hz,1H),8.57(dd,J=8.2,6.0Hz ,2H),8.35(dd,J=9.9,2.3Hz,2H),8.24-8.12(m,1H),8.12–8.02(m,2H),7.74(dd,J=7.8,4.6Hz,1H).

[0380] HRMS m / z(ESI) Calculated value: C 19 H 11 N5O[M+H] + 326.1036; Actual value: 326.1035; HPLC purity = 96.3%.

[0381] Example 48, Synthesis of Compound 48

[0382]

[0383] Using a similar synthesis method to Example 47, compound 48 was prepared with a yield of 46%.

[0384] Compound 48 1 H NMR and HRMS data are as follows:

[0385] 1 H NMR (400MHz, DMSO) δ8.68 (d, J = 6.8 Hz, 1H), 8.56 (d, J = 8.5 Hz, 1H), 8.33 (m, 2H), 8.18 (dd, J = 19.6, 5.7 Hz, 3H), 8.06 (m, 2H), 7.70 (d, J = 5.1 Hz, 3H).

[0386] HRMS m / z(ESI) Calculated value: C 20 H 12 N4O[M+H] + 325.1084; Actual value: 325.1083; HPLC purity = 96.8%.

[0387] Example 49, Synthesis of Compound 49

[0388]

[0389] Using a similar synthetic method to Example 47, compound 49 was prepared with a yield of 55%.

[0390] Compound 49 1 H NMR and HRMS data are as follows:

[0391] 1 H NMR (400MHz, DMSO) δ9.37(d,J=1.6Hz,1H),8.89(dd,J=4.9,1.5Hz,1H),8.72(dd,J=7.0,1.1Hz,1H ),8.57(m,2H),8.35(m,2H),8.18(dd,J=8.7,7.1Hz,1H),8.07(m,2H),7.74(dd,J=7.8,4.6Hz,1H).

[0392] HRMS m / z(ESI) Calculated value: C 19 H 11 N5O[M+H] + 326.1036; Actual value: 326.1036; HPLC purity = 97.2%.

[0393] The beneficial effects of the present invention are demonstrated by experimental examples below.

[0394] Experimental Example 1: Study on the Inhibition Rate of Ferroptosis by the Compounds of the Invention

[0395] 1. Experimental methods

[0396] The Ferroptosis screening model mainly uses the MTT cell viability assay. First, the ovarian cancer cell line ES2 is cultured in a dish, and the cells in the logarithmic growth phase are inoculated into a 96-well plate at 3000-4000 cells per well (3000-10000 cells / well), 100 μL per well, and then placed in an incubator at 37°C and 5% CO2 to allow the cells to adhere to the wall. After 24 hours, 100 μL of the compound diluted in a concentration gradient prepared with complete culture medium and the Ferroptosis inducer Erastin (final concentration 10 μM) are added. Three replicate wells are set for each compound to ensure the accuracy of the results, and a negative control group, a positive control group, a blank control group and a solvent control group are set. After adding the drug, place it in an incubator and culture it for 48 hours. On the day of the MTT experiment, the MTT test solution (5 mg / mL MTT solution dissolved in physiological saline, stored at 4°C away from light) was prepared in advance, 20 μL of MTT solution was added to each well, and the wells were placed in the incubator for 2-4 hours. Then, 50 μL of 20% SDS solution (dissolved in MiliiQ water, 1% concentrated hydrochloric acid) was added to each well, and the wells were placed in the incubator overnight. The absorbance value at 570 nm was detected with an ELISA reader the next day to calculate the drug's inhibition rate on Ferroptosis. The absorbance value of the general control group should be between 0.8-1.2 as a normal value. After obtaining the absorbance value (represented by A) data, the average value of the three replicate wells was calculated, and the inhibition rate was calculated using the following formula:

[0397] Inhibition rate (IR) = [1-(A 实验组 -A 空白对照组 ) / (A 溶剂对照组 -A 空白对照组 )]*100%.

[0398] GraphPad Prism 5 software was used to fit the inhibition rate curve and calculate the EC 50 .

[0399] 2. Experimental results

[0400] EC analysis was performed on 49 compounds of the present invention. 50 The test results are shown in the following table:

[0401] Table 1 EC of compounds 50 value

[0402] Compound <![CDATA[EC 50 (μM)]]> Compound <![CDATA[EC 50 (μM)]]> 1 0.004 2 0.268 3 0.136 4 0.214 5 0.604 6 0.006 7 0.143 8 0.131 9 0.240 10 0.007 11 0.334 12 0.009 13 0.983 14 0.041 15 0.130 16 0.002 17 0.011 18 0.001 19 0.003 20 0.002 21 0.003 22 0.132 23 0.006 24 0.007 25 0.006 26 0.002 27 0.085 28 0.001 29 0.002 30 0.003 31 0.0007 32 0.013 33 0.005 34 0.013 35 0.023 36 0.039 37 0.043 38 0.013 39 0.009 40 0.013 41 0.007 42 0.019 43 0.039 44 0.065 45 0.005 46 0.023 47 0.003 48 0.001 49 0.002 Fer-1 0.070

[0403] It can be seen from Table 1 that the compounds prepared in the present invention have a good inhibitory effect on ferroptosis and can be used to prepare ferroptosis inhibitors.

[0404] Experimental Example 2: The compounds of the present invention do not have chelating and reducing properties

[0405] This experiment takes compounds 31 and 48 as examples to study the chelating and reducing properties of the compounds of the present invention.

[0406] 1. Experimental methods

[0407] The chelation of compounds was studied by using the property of iron and phenanthroline to form a colored complex. The test compound solution, FeSO4 solution and phenanthroline solution were added to 100 μL of distilled water and incubated at room temperature for 5 minutes. Finally, the sample was measured at a wavelength of 562 nm using a CLARIOstar multifunctional microplate reader (BMG Labtech, Germany). At the same time, deferoxamine (DFO) was selected as a positive control and DMSO as a blank control. The A of the blank control well was 562 Calculate sample well A as the standard value (100%) 562 The relative amount of .

[0408] The 2,2-diphenyl-1-picrylhydrazyl (DPPH) method was used to study the reducibility. The stable free radical 1,1-diphenyl-2-pyridylhydrazine (DPPH) was dissolved in methanol at a concentration of 0.05mM and added to each well of a 96-well plate in a volume of 0.2mL. The test compounds (Compound 31, Compound 48) were dissolved in DMSO to prepare a 10mM solution, and 1μL was added to each well to a final concentration of 0.05mM. After thorough mixing, the plate was incubated at room temperature for 10 minutes, and the absorbance at 517nm was measured using a multifunctional microplate reader. The experiment was repeated 3 times, and the mean and standard deviation were calculated based on the results.

[0409] 2. Experimental results

[0410] result( Figure 1 A, B) show that the compounds 31 and 48 prepared by the present invention inhibit ferroptosis not through reduction mechanism and chelation mechanism. Therefore, the compounds 31 and 48 of the present invention do not have chelation and reduction properties and can be used to prepare non-chelating, non-reducing non-classical ferroptosis inhibitors.

[0411] Experimental Example 3: Study on the protection of cells from ferroptosis by the compounds of the present invention in vitro

[0412] This experiment took compound 31 as an example to study the activity of the compound of the present invention in protecting cells from ferroptosis in vitro.

[0413] 1 Experimental methods

[0414] The cell viability was detected by MTT method. First, cells ES2 and LX-2 were collected and seeded into 96-well plates at a concentration of 3000 cells per well. The plates were incubated at 37°C and 5% carbon dioxide until the cells adhered. After adhesion, the cells were treated with the specified concentration of compounds for 72 hours. Then 20 μL of 5 mg / mL MTT solution (dissolved in physiological saline) was added to each well and incubated for another 2-4 hours. Subsequently, 50 μL of 20% (w / v) acidified sodium dodecyl sulfate was added to each well and incubated for at least 8 hours. Finally, the absorbance was measured at a wavelength of 560 nm using a multifunctional microplate reader. All data were calculated using GraphPad Prism software. All experiments were repeated 3 times.

[0415] 2 Experimental results

[0416] In vitro, compound 31 can protect ES-2 (ovarian cancer cells) ( Figure 3 ) and LX-2 (human hepatic stellate cells) are protected from ferroptosis ( Figure 2 A).

[0417] The above results indicate that the compounds of the present invention can effectively protect cells from ferroptosis and can be used to treat ferroptosis-related diseases.

[0418] Experimental Example 4: Study of the compounds of the present invention in animal models of liver injury

[0419] Overdose of acetaminophen (APAP) is an important cause of drug-induced liver injury (DILI) and acute liver failure. Many studies have found that ferroptosis is involved in DILI. This experiment uses compound 31 as an example to study the therapeutic effect of the compound of the present invention on liver injury.

[0420] 1 Experimental methods

[0421] The APAP-induced acute liver injury model was used to evaluate the in vivo effect of compound 31.

[0422] The experimental groups were treated as follows:

[0423] Experimental (APAP+31 3 mg / kg) group: male mice were administered with 3 mg / kg of compound 31 and then with 500 mg / kg of APAP.

[0424] Experimental (APAP+31 10 mg / kg) group: male mice were given 10 mg / kg of compound 31 and then 500 mg / kg of APAP.

[0425] Experimental (APAP+Fer-1 10 mg / kg) group: Male mice were given 10 mg / kg of Fer-1 and then 500 mg / kg of APAP.

[0426] Blank group: no treatment was given.

[0427] Control (APAP+Vehicle, denoted as APAP+Vehicle) group: male mice were given a corresponding volume of solvent and then given a 500 mg / kg dose of APAP.

[0428] The solvent used in this experiment is: 10% DMSO + 40% PEG400 + 5% HS15 + 45% normal saline.

[0429] After 6 h of APAP treatment, liver tissues and blood were collected for hematoxylin and eosin (H&E) staining or biochemical testing.

[0430] 2 Experimental results

[0431] The mice in the control group showed severe liver tissue lesions ( Figure 2 B), serum aspartate aminotransferase (ALT), alanine aminotransferase (AST) ( Figure 2 C) and elevated liver MDA levels ( Figure 2 D), indicating that the acute liver injury model was successfully established. In contrast, administration of 3 mg / kg of compound 31 can reduce liver tissue damage, as shown by inhibiting liver cell death and reducing serum ALT, AST and liver MDA levels ( Figure 2 BD).

[0432] These results indicate that the compounds of the present invention are useful in the treatment of liver damage.

[0433] Experimental Example 5: Study on the Compound of the Invention in a Chronic Atrophic Gastritis Model

[0434] This experiment takes compound 48 as an example to study the therapeutic effect of the compound of the present invention on chronic atrophic gastritis.

[0435] 1. Experimental methods

[0436] The in vivo effect of compound 48 was evaluated using the chronic atrophic gastritis model.

[0437] The experimental groups and treatments are as follows:

[0438] Experimental (HSD+48) group: mice were orally administered 20 mg / kg of compound 48 and then continuously given a high-salt diet for four weeks;

[0439] Experimental (HSD+Fer-1) group: Mice were orally administered 20 mg / kg of Fer-1 and then continuously given a high-salt diet for four weeks.

[0440] Blank (Control+solvent) group: mice were given corresponding volume of solvent.

[0441] Control (HSD+solvent) group: mice were given a corresponding volume of solvent and then given a high-salt diet for four consecutive weeks.

[0442] The solvent used in this experiment is: 10% DMSO + 40% PEG400 + 5% HS15 + 45% normal saline.

[0443] After 4 weeks of administration, gastric tissues were obtained for hematoxylin and eosin (H&E) staining.

[0444] 2. Experimental results

[0445] Mice in the control group developed severe lesions ( Figure 4 AB), gastric inflammation, atrophy, and mucus hyperplasia indicators increased significantly ( Figure 4 CD), indicating that the chronic atrophic gastritis model was successfully established. In contrast, administration of 20 mg / kg of compound 48 reduced gastric corpus damage, manifested as inhibition of atrophy, reduction of inflammation and mucus hyperplasia ( Figure 4 These results show that the compounds of the present invention can be used to treat chronic atrophic gastritis.

[0446] In summary, the present invention provides a non-classical ferroptosis inhibitor and its preparation method and use. The compound prepared by the present invention has a good inhibitory effect on Ferroptosis, and inhibits Ferroptosis without reduction mechanism and chelation mechanism, and can be used to prepare non-chelated, non-reduced non-classical ferroptosis inhibitors. Therefore, the compound of the present invention can be used to prepare drugs for the prevention and / or treatment of diseases such as neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular, renal failure, inflammation, cardiotoxicity, acute organ damage, chronic atrophic gastritis or diabetic complications related to ferroptosis, and has broad market prospects. The experimental results also further verified that the compound of the present invention can be used to treat chronic atrophic gastritis and can alleviate acute liver damage induced by acetaminophen.

Claims

1. A compound represented by formula I, or a salt thereof, or a stereoisomer thereof: in, Ring A is a 3- to 8-membered heteroaromatic ring; R1 is LXB1; L is selected from none, C 1～6 Alkylene; X is selected from none, O; B1 is selected from the following groups which are unsubstituted or substituted by one or more B': phenyl, C 1～6 Alkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl, 3-8 membered heteroaryl; B' is independently selected from halogen, SO2B4, nitro, C 1～6 Alkyl, C 1～6 Alkoxy, halogen substituted C 1～6 Alkyl, halogen substituted C 1～6 Alkoxy, NB2B3, phenyl which is unsubstituted or substituted by one or more B", 3-8-membered heterocycloalkyl which is unsubstituted or substituted by one or more B", 3-8-membered heteroaryl which is unsubstituted or substituted by one or more B"; B4 is selected from C 1～3 alkyl; B2 and B3 are each independently selected from C 1～6 Alkyl; or B2 and B3 are connected to form a spiro ring; B" are each independently selected from halogen, C 1～6 alkyl.

2. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, characterized in that: The ring A is a 5- to 6-membered heteroaromatic ring; R1 is LXB1; L is selected from none, C 1～3 Alkylene; X is selected from none, O; B1 is selected from the following groups which are unsubstituted or substituted by one or more B': phenyl, C 1～4 Alkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heteroaryl; B' is independently selected from halogen, SO2B4, nitro, C 1～4 Alkyl, C 1～3 Alkoxy, halogen substituted C 1～3 Alkyl, halogen substituted C 1～3 Alkoxy, NB2B3, phenyl which is unsubstituted or substituted by one or more B", 5-6-membered heterocycloalkyl which is unsubstituted or substituted by one or more B", 5-6-membered heteroaryl which is unsubstituted or substituted by one or more B"; B2 and B3 are each independently selected from C 1～3 Alkyl; or B2 and B3 are connected to form a spiro ring; B" are each independently selected from halogen, C 1～3 alkyl.

3. The compound according to claim 2, or a salt thereof, or a stereoisomer thereof, characterized in that: The compound is shown in formula II: wherein D is selected from N and CR1, E is selected from N and CR1, and one of D and E is N; R1 is LXB1; L is selected from none, C 1～3 Alkylene; X is selected from none, O; B1 is selected from the following groups which are unsubstituted or substituted by one or more B': phenyl, C 1～4 Alkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heteroaryl; B' is independently selected from halogen, SO2B4, nitro, C 1～4 Alkyl, C 1～3 Alkoxy, halogen substituted C 1～3 Alkyl, halogen substituted C 1～3 Alkoxy, NB2B3, phenyl which is unsubstituted or substituted by one or more B", 5-6-membered heterocycloalkyl which is unsubstituted or substituted by one or more B", 5-6-membered heteroaryl which is unsubstituted or substituted by one or more B"; B2 and B3 are each independently selected from C 1～3 Alkyl; or B2 and B3 are connected to form a spiro ring; B" are each independently selected from halogen, C 1～3 alkyl.

4. The compound according to claim 3, or a salt thereof, or a stereoisomer thereof, characterized in that: The compound is represented by formula III or formula IV: Among them, R1 is LXB1; L is selected from none, C 1～3 Alkylene; X is selected from none, O; B1 is selected from the following groups which are unsubstituted or substituted by one or more B': phenyl, C 1～4 Alkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heteroaryl; B' is independently selected from halogen, SO2B4, nitro, C 1～4 Alkyl, C 1～3 Alkoxy, halogen substituted C 1～3 Alkyl, halogen substituted C 1～3 Alkoxy, NB2B3, phenyl which is unsubstituted or substituted by one or more B", 5-6-membered heterocycloalkyl which is unsubstituted or substituted by one or more B", 5-6-membered heteroaryl which is unsubstituted or substituted by one or more B"; B4 is selected from C 1～3 alkyl; B2 and B3 are each independently selected from C 1～3 or B2 and B3 are connected to form a spiro ring, which is unsubstituted or substituted by one or more B5 B5 are each independently selected from C 1～3 Alkyl, halogen; B" are each independently selected from halogen, C 1～3 alkyl; The heteroatom in the heterocycloalkyl group is one or more than two of O, N, and S, and the heteroatom in the heteroaryl group is one or more than two of O, N, and S.

5. The compound according to any one of claims 1 to 4, or a salt thereof, or a stereoisomer thereof, characterized in that: The compound is one of the following compounds:

6. A method for preparing the compound according to any one of claims 4 to 5, or a salt thereof, or a stereoisomer thereof, characterized in that: The method comprises the following steps: Phenazine-1-carboxylic acid reacts with compound A to obtain intermediate a; intermediate a undergoes condensation reaction to obtain; Alternatively, the method comprises the following steps: Phenazine-1-carboxylic acid reacts with compound B to obtain intermediate b; intermediate b undergoes condensation reaction to obtain; or, phenazine-1-carboxylic acid reacts with compound B to obtain intermediate c; intermediate c undergoes condensation reaction to obtain; Wherein, R1 is as described in any one of claims 4 to 5.

7. The method according to claim 6, characterized in that The method comprises the following steps: the phenazine-1-carboxylic acid and compound A are reacted under the action of a condensing agent and a catalyst; the molar ratio of the phenazine-1-carboxylic acid, compound A, condensing agent and catalyst is 1:0.5-1.5:1-1.5:2-4; the solvent of the reaction is an organic solvent; the temperature of the reaction is 10-40°C and the time is 6-10 hours; The condensation reaction of the intermediate a comprises the following steps: a condensation reaction is carried out under the action of a halogenating agent and a base; the molar ratio of the intermediate a, the brominating agent and the base is 1:1-1.5:1-1.5; the solvent of the reaction is an organic solvent; the temperature of the reaction is 10-40°C and the time is 2-6 hours; Alternatively, the condensation reaction of the intermediate a comprises the following steps: the solvent for the reaction of the intermediate a is an organic solvent; the reaction temperature is 110 to 130° C., and the reaction time is 10 to 14 hours; Alternatively, the method comprises the following steps: The phenazine-1-carboxylic acid and compound B react under the action of a condensing agent and a catalyst; the molar ratio of the phenazine-1-carboxylic acid, compound B, condensing agent and catalyst is 1:0.5-1.5:0.5-1.5:2-4; the solvent of the reaction is an organic solvent; the reaction temperature is 10-40°C and the reaction time is 6-10 hours; The condensation reaction of the intermediates b and c comprises the following steps: a condensation reaction is carried out under the action of a halogenating agent and a catalyst; the molar ratio of the halogenating agent and the catalyst is 0.05-0.15:2-4; the reaction temperature is 10-40°C and the reaction time is 10-14 hours.

8. A pharmaceutical composition, characterized in that The invention is a preparation prepared by using the compound described in any one of claims 1 to 5, or its salt, or its stereoisomer as an active ingredient and adding auxiliary agents commonly used in pharmacy.

9. Use of the compound according to any one of claims 1 to 5, or a salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to claim 8 in the preparation of a ferroptosis inhibitor.

10. The use according to claim 9, characterized in that The ferroptosis inhibitor is a drug for preventing and / or treating neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular disease, renal failure, inflammation, cardiotoxicity, acute organ damage, chronic atrophic gastritis or diabetic complications; preferably, the acute organ damage is acute liver damage.

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