Compound as well as preparation method and application thereof

Abstract

The invention provides a compound with a structure as shown in a formula (I) or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate or an isotope label thereof. The invention also provides a preparation method of the compound or pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope label thereof, and application of the compound or pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope label in preparation of ferroptosis inhibitor, # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a compound, a preparation method thereof and use thereof in preparing a ferroptosis inhibitor. Background Art

[0002] Ferroptosis is a programmed cell death that is iron-dependent and lipid peroxidation-driven. The morphological characteristics of ferroptosis are mainly manifested in the reduction of mitochondrial volume, increase of mitochondrial membrane density, reduction or disappearance of mitochondrial cristae, rupture of mitochondrial outer membrane, and normal size of nucleus, which are the main morphological characteristics that distinguish ferroptosis from apoptosis, necrosis and autophagy. The biochemical characteristics of ferroptosis are mainly manifested in the accumulation of intracellular iron and ROS, activation of mitogen-activated protein kinase (MAPK) signal transduction system, inhibition of cystine / glutamate transporter system and increased NADPH oxidation.

[0003] More and more studies have confirmed that ferroptosis is closely related to many conditions, disorders and diseases. Dixon et al. first discovered in 2012 that this cell death mode is related to small molecule-induced RAS tumor cell death (Scott J Dixon et al., Cell. 2012 May 25; 149(5): 1060-72. doi: 10.1016 / j.cell.2012.03.042). Recently, a large number of studies have further demonstrated the role of ferroptosis in cancer, organ damage, tissue ischemia-reperfusion injury, stroke, cardiovascular disease, degenerative diseases, etc. (Bo Li et al., Frontiers in Pharmacology. 2020, vol. 11, doi: 10.3389 / fphar.2020.00239; Xuejun Jiang et al., Nat Rev Mol Cell Biol. 2021, vol. 22(4), pp. 266-282; Brent R. Stockwell, Cell. 2022, vol. 185, pp. 2401-2421, doi.org / 10.1016 / j.cell.2022.06.003; Xinhua Xia et al., Cell Death Discovery.2024,vol.10,pp.265-281,doi.org / 10.1038 / s41420-024-02037-9). Specifically, it is involved in the occurrence and development of various cancers, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, immune-related diseases, liver and kidney failure, inflammation, metabolic diseases, etc., especially in Alzheimer's disease, Parkinson's disease, tumors, stroke, ischemia-reperfusion injury, atherosclerosis, liver and kidney failure, inflammation, and diabetic complications. It plays an important role in diseases such as diabetes. By stimulating or inhibiting the occurrence of ferroptosis, the occurrence and development of related diseases can be tolerated. Therefore, ferroptosis inhibitors are considered to be potential drugs for the treatment of these diseases.

[0004] Ferrostatin-1 (Fer-1) is a known, effective, and selective ferroptosis inhibitor (Scott JDixon et al., Cell. 2012 May 25; 149(5): 1060-72. doi: 10.1016 / j.cell.2012.03.042), and its structural formula is shown below:

[0005]

[0006] However, the activity of Ferrostatin-1 is not high, and the IC50 values ​​in various in vitro ferroptosis cell models are all higher than 100nM. Therefore, how to discover and prepare a more active ferroptosis inhibitor is a difficult problem that needs to be solved urgently. Summary of the invention

[0007] In order to make up for the deficiencies in the prior art, the purpose of the present invention is to provide a compound with a completely new structure, which shows excellent ferroptosis inhibitory activity in multiple cell models and can therefore be used as a ferroptosis inhibitor for the prevention and / or treatment of various diseases.

[0008] The first aspect of the present invention provides a compound having a structure as shown in formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance thereof,

[0009]

[0010] In formula (I), ring A is selected from C 6 ~C 12 Aryl, the aryl group is optionally substituted by one or more selected from halogen, hydroxy, carboxyl, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy or C 1 ~C 6 substituted by a haloalkoxy substituent;

[0011] Ring B is selected from a 5- to 12-membered heterocyclic group or a 5- to 12-membered heteroaryl group, wherein the heterocyclic group or heteroaryl group contains at least one N atom as a ring atom, and the heterocyclic group or heteroaryl group is optionally substituted by one or more selected from halogen, hydroxyl, carboxyl, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy or C 1 ~C 6 substituted by a haloalkoxy substituent;

[0012] R 1 , R 2 are each independently selected from hydrogen, C 1 ~C 6 Alkyl or C 3 ~C 10 Cycloalkyl;

[0013] Each R 3are independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Halogenated alkoxy, C 3 ~C 10 Cycloalkyl, 5- to 12-membered heterocyclic group, C 6 ~C 12 The hydroxyl, carboxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted by one or more selected from halogen, hydroxyl, carboxyl, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy or C 1 ~C 6 substituted by a haloalkoxy substituent;

[0014] m is selected from 0, 1, 2, 3 or 4.

[0015] In some embodiments according to the present invention, in formula (I),

[0016] Ring A is selected from C 6 ~C 10 Aryl;

[0017] Ring B is selected from a 5- to 8-membered heterocyclic group, the heterocyclic group contains 1 to 3 N atoms as ring atoms, and the heterocyclic group is optionally substituted by one or more selected from halogen, hydroxyl, carboxyl, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy or C 1 ~C 6 substituted by a haloalkoxy substituent;

[0018] R 1 , R 2 are each independently selected from hydrogen or C 1 ~C 6 alkyl;

[0019] Each R 3 are independently selected from hydrogen, halogen, hydroxyl, carboxyl, C 1 ~C 6Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 A halogenated alkoxyl group, a 5- to 8-membered heterocyclic group or a 5- to 8-membered heteroaryl group, wherein the heterocyclic group or the heteroaryl group is optionally substituted by one or more selected from halogen, hydroxyl, carboxyl, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy or C 1 ~C 6 substituted by a haloalkoxy substituent;

[0020] m is selected from 0, 1, 2 or 3.

[0021] In some preferred embodiments according to the present invention, in formula (I),

[0022] Ring A is selected from phenyl;

[0023] Ring B is selected from a 5- to 6-membered heterocyclic group, the heterocyclic group contains 1 to 2 N atoms as ring atoms (for example, can be selected from piperidinyl or piperazinyl), and the heterocyclic group is optionally substituted by one or more selected from C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy or C 1 ~C 4 substituted by a haloalkoxy substituent;

[0024] R 1 , R 2 are each independently selected from hydrogen or C 1 ~C 4 alkyl;

[0025] Each R 3 Each independently selected from hydrogen, F, Cl, hydroxyl, carboxyl, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4A halogenated alkoxy or a 5- to 6-membered heterocyclic group, wherein the heterocyclic group contains at least one N atom as a ring atom (for example, can be selected from piperidinyl, piperazinyl or morpholinyl), and the heterocyclic group is optionally substituted by one or more selected from F, Cl, hydroxyl, carboxyl, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy or C 1 ~C 4 substituted by a haloalkoxy substituent;

[0026] m is selected from 0, 1 or 2.

[0027] In some more preferred embodiments according to the present invention, in formula (I), R 3 It may include but is not limited to the following groups: H, F, Cl, -OCH 3 , -CF 3 ,

[0028] In some embodiments according to the present invention, the compound has a structure as shown in formula (II):

[0029]

[0030] In formula (II), Z 1 , Z 2 , Z 3 Each independently selected from -C(R 4 ) 2 -、-NR 4 - or a bond, preferably, Z 1 , Z 2 , Z 3 Different from -NR 4 -;

[0031] Each R 4 are each independently selected from hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy or C 1 ~C 6 Preferably, R 4 are the same or different, each independently selected from hydrogen, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C1 ~C 4 Alkoxy or C 1 ~C 4 Haloalkoxy;

[0032] R 1 , R 2 , R 3 , m are each independently defined in any one of the above technical solutions.

[0033] In some embodiments according to the present invention, the compound has a structure as shown in formula (III):

[0034]

[0035] In formula (III), R 1 , R 2 , R 3 , R 4 , m are each independently defined as in any one of the above technical solutions.

[0036] In some preferred embodiments according to the present invention, in formula (III), R 1 Selected from hydrogen, R 2 , R 4 Each is independently selected from methyl, ethyl, n-propyl or isopropyl;

[0037] Each R 3 Each independently selected from: hydrogen, F, Cl, methoxy or trifluoromethyl;

[0038] m is selected from 0, 1 or 2.

[0039] In some embodiments according to the present invention, the compound has a structure as shown in formula (IV):

[0040]

[0041] In formula (IV), Y is selected from -C(R 6 ) 2 -、-NR 6 -, -O-, or -S-;

[0042] R 5 , R 6 are independently selected from hydrogen, halogen, hydroxyl, carboxyl, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy or C 1 ~C 6 Preferably, R 5, R 6 Each independently selected from hydrogen, F, Cl, hydroxyl, carboxyl, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Alkoxy or C 1 ~C 4 Haloalkoxy, more preferably, R 5 , R 6 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, carboxyl or trifluoromethyl;

[0043] n is selected from 0, 1 or 2;

[0044] R 1 , R 2 , R 4 Each independently as defined in any one of the above technical solutions, preferably, R 1 , R 2 , R 4 are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl, more preferably, R 1 Selected from hydrogen, R 2 , R 4 Each is independently selected from methyl, ethyl, n-propyl or isopropyl.

[0045] In some embodiments according to the present invention, the compound has a structure as shown in formula (IV-1) or formula (IV-2):

[0046]

[0047] In formula (IV-1) or formula (IV-2), Y, R 1 , R 2 , R 4 , R 5 , n are each independently defined as in any one of the above technical solutions.

[0048] In some preferred embodiments according to the present invention, in formula (IV-1) or formula (IV-2), Y is selected from -C(R 6 ) 2 -、-NR 6 -or-O-;

[0049] R 1 , R 2 , R 4 are each independently selected from hydrogen or C 1 ~C 4 Alkyl (e.g., hydrogen, methyl, ethyl, n-propyl, isopropyl, etc.);

[0050] R 5 , R 6 Each independently selected from hydrogen, carboxyl, C 1 ~C 4 Alkyl or C 1 ~C 4 Haloalkyl (eg, hydrogen, methyl, ethyl, n-propyl, isopropyl, carboxyl, trifluoromethyl, etc.).

[0051] In some more preferred embodiments according to the present invention, in formula (IV-1) or formula (IV-2), Y is selected from -C(R 6 ) 2 -、-NH-、-N(CH 3 )-or-O-;

[0052] R 1 Selected from hydrogen, R 2 , R 4 are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl;

[0053] R 5 , R 6 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, carboxyl or trifluoromethyl.

[0054] In some most preferred embodiments according to the present invention, the compound may include the following compounds:

[0055]

[0056]

[0057] The second aspect of the present invention provides a method for preparing the compound or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled product according to any one of the above technical schemes, wherein the preparation method comprises: reacting an aniline compound with a structure as shown in formula (I-1) with a halide with a structure as shown in formula (I-2) to obtain a first intermediate with a structure as shown in formula (I-3), reacting the first intermediate with p-toluenesulfonylhydrazine to obtain a second intermediate with a structure as shown in formula (I-4), and reacting the second intermediate with a boric acid compound with a structure as shown in formula (I-5) to obtain a compound with a structure as shown in formula (I);

[0058]

[0059] wherein X is selected from halogen, for example, selected from Br;

[0060] Ring A, Ring B, R 1 , R 2 , R 3, m are each independently defined as in any one of the above technical solutions.

[0061] In some embodiments according to the present invention, the reaction raw materials of the structures represented by formula (I-1), formula (I-2), formula (I-5), etc. can be commercially available products or synthesized with reference to existing literature.

[0062] The third aspect of the present invention provides a pharmaceutical composition comprising the compound described in any one of the above technical solutions or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance, and one or more pharmaceutically acceptable excipients.

[0063] The fourth aspect of the present invention provides the use of the compound described in any one of the above technical schemes or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance, or the pharmaceutical composition described in any one of the above technical schemes in the preparation of a ferroptosis inhibitor.

[0064] The compounds provided by the present invention or their pharmaceutically acceptable salts, stereoisomers, solvates, hydrates or isotope-labeled substances, and the pharmaceutical compositions provided by the present invention can be used to prepare ferroptosis inhibitors (i.e., drugs for inhibiting cellular ferroptosis), and prevent and / or treat various diseases by inhibiting cellular ferroptosis, such as neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular diseases, renal failure, liver damage, diabetic complications, cancer, etc.

[0065] A fifth aspect of the present invention provides the use of the compound described in any one of the above technical schemes or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope label, or the pharmaceutical composition described in any one of the above technical schemes in the preparation of a medicament for preventing and / or treating neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular disease, renal failure, liver damage, diabetic complications or cancer.

[0066] In some embodiments according to the present invention, the neurodegenerative disease may be Parkinson's syndrome or Alzheimer's disease.

[0067] In some embodiments of the present invention, the stroke may be ischemic stroke or hemorrhagic stroke.

[0068] In some embodiments according to the present invention, the cancer may be pancreatic cancer.

[0069] The compound provided by the present invention or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance, and the pharmaceutical composition provided by the present invention prevent and / or treat the above-mentioned diseases by inhibiting cell ferroptosis.

[0070] The technical solution provided by the present invention has the following advantages:

[0071] (1) Compared with existing ferroptosis inhibitors, the compounds provided by the present invention have obvious chemical structure differences and also have more excellent cell ferroptosis inhibitory activity. Therefore, they can be used as a ferroptosis inhibitor with great application potential, expanding the types and applications of ferroptosis inhibitors, and thus have very important economic and social significance.

[0072] (2) The compound provided by the present invention has a simple preparation process, mild reaction conditions, is easy to operate and control, and has a low production cost, and is therefore very suitable for industrial production. DETAILED DESCRIPTION

[0073] the term

[0074] In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art.

[0075] Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "having," "including," etc. should be understood to have an inclusive sense, rather than an exclusive or exhaustive sense; that is, in the sense of "including but not limited to." Unless otherwise specified, "comprising" includes "consisting of.

[0076] The term "and / or" used herein, alone or in combination, such as "X and / or Y," should be understood to mean "X and Y" or "X or Y" and should be used to provide clear support for both meanings or either meaning.

[0077] The “C 1 ~C n "Including C 1 ~C 2 , C 1 ~C 3 , ...C 1 ~C n For example, the “C 1 ~C 6 " means that the part has 1 to 6 carbon atoms, that is, the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. Therefore, for example, "C 1 ~C 4 The term "alkyl" refers to an alkyl group containing 1 to 4 carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The numerical ranges herein, such as "1 to 6", "6 to 12", etc., refer to each integer in the given range.

[0078] The term "alkyl" used herein alone or in combination refers to an optionally substituted straight chain or optionally substituted branched saturated aliphatic hydrocarbon. The "alkyl" herein preferably has 1 to 6 carbon atoms, for example, 1 to 6 carbon atoms, or 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1-3 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, etc. As used herein, when a numeric range is present for a group such as "alkyl", for example, "C 1 ~C 6 The term "alkyl" refers to an alkyl group which may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The alkyl group herein also includes the case where no numerical range is specified. The alkyl group may be substituted or unsubstituted.

[0079] As used herein, "alkyl" refers to an alkyl group attached to another group, for example, alkoxy, haloalkyl, alkyl in haloalkoxy, and has the same definition as when used alone.

[0080] The term "haloalkyl" as used herein, alone or in combination, refers to an alkyl group in which one or more, or even all, hydrogen atoms are replaced by halogen atoms. 1 ~C 6 Haloalkyl groups include, for example, C 1 ~C 4 Haloalkyl or C 1 ~C 3 The haloalkyl group is preferably a fluoroalkyl group and a chloroalkyl group, and non-limiting examples of the haloalkyl group include fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, etc. The haloalkyl group may be substituted or unsubstituted.

[0081] The term "alkoxy" as used herein, alone or in combination, refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. 1 ~C 6 Alkoxy groups include, for example, C 1 ~C 4 Alkoxy or C 1 ~C 3Alkoxy, non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc. Alkoxy can be substituted or unsubstituted.

[0082] The term "haloalkoxy" as used herein, alone or in combination, refers to an alkoxy group in which one or more, or even all, hydrogen atoms are replaced by halogen atoms. 1 ~C 6 Haloalkoxy includes, for example, C 1 ~C 4 Haloalkoxy or C 1 ~C 3 Haloalkoxy, non-limiting examples of haloalkoxy include monofluoromethoxy, monochloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, etc. The haloalkoxy group may be substituted or unsubstituted.

[0083] The term "cycloalkyl" used herein alone or in combination refers to an optionally substituted non-aromatic saturated carbocyclic ring, which may include a monocyclic ring (having one ring), a bicyclic ring (having two rings) or a polycyclic ring (having more than two rings), and the ring types include fused rings, bridged rings and spiro rings. Preferably, the cycloalkyl group may have 3 to 10 ring-forming carbon atoms, for example, 3 to 8 ring-forming carbon atoms or 3 to 6 ring-forming carbon atoms. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The cycloalkyl group may be substituted or unsubstituted.

[0084] The term "heterocyclyl" used herein alone or in combination refers to an optionally substituted non-aromatic 5 to 12-membered monocyclic, bicyclic or polycyclic ring, the ring types include fused rings, bridged rings and spirocyclic rings, and the ring atoms may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Preferably, the heterocyclyl may have 5 to 10 ring atoms, for example, 5 to 8 ring atoms. Non-limiting examples of heterocyclyl include, but are not limited to, morpholinyl, oxetane, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidine, etc. The heterocyclyl may be substituted or unsubstituted.

[0085] The term "aryl" used herein alone or in combination refers to an optionally substituted aromatic hydrocarbon group having 6 to 12, such as 6 to 10, ring-forming carbon atoms, which may be a monocyclic aryl, a bicyclic aryl or a polycyclic aryl. A bicyclic aryl or a polycyclic aryl may be a monocyclic aryl fused with other independent rings, such as an alicyclic ring or an aromatic ring. Non-limiting examples of monocyclic aryl groups include, but are not limited to, phenyl, etc.; non-limiting examples of bicyclic aryl groups include, but are not limited to, naphthyl, tetrahydronaphthyl, biphenyl, etc.; non-limiting examples of polycyclic aryl groups include, but are not limited to, phenanthrenyl, indenyl, anthracenyl, fluorenyl, azulenyl, etc. Aryl groups may be substituted or unsubstituted.

[0086] The term "heteroaryl" used herein alone or in combination refers to an optionally substituted aromatic 5- to 12-membered monocyclic, bicyclic or polycyclic ring, the ring types of which include fused rings, bridged rings and spiro rings, and the ring atoms thereof may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Preferably, the heteroaryl may have 5 to 8 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4 The heteroaryl group may be substituted or unsubstituted.

[0087] The term "halogen" as used herein, alone or in combination, refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0088] The term "hydroxy," as used herein, alone or in combination, refers to -OH.

[0089] The term "carboxy," as used herein, alone or in combination, refers to -COOH.

[0090] The term "cyano," as used herein, alone or in combination, refers to -CN.

[0091] The term "amino" as used herein, alone or in combination, refers to -NH 2 .

[0092] The term "bond" as used herein, alone or in combination, means that the indicated substituent is absent and both end portions of the substituent are directly linked to form a bond.

[0093] The term "substituted" as used herein, alone or in combination, refers to one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in a group, which are replaced independently of one another by a corresponding number of substituents. Those skilled in the art will be able to determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0094] The term "pharmaceutically acceptable" as used herein, alone or in combination, refers to a substance that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0095] The term "pharmaceutically acceptable salt" used herein, alone or in combination, refers to a compound of the present invention that retains the biological effectiveness and properties of a free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid. Standard procedures well known in the art can be used to obtain. Suitable salts are listed in Remingtong's Pharmaceutical Scicences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).

[0096] The term "solvate" as used herein, alone or in combination, refers to a physical aggregate of a compound of the invention and one or more solvent molecules formed by solvation, which includes varying degrees of ionic and covalent bonding, such as hydrogen bonding. "Hydrate" is a physical aggregate formed by the reaction of water (H 2 O) The molecule is a solvate of a solvent.

[0097] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, hindered isomers and geometric (conformation) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention. Unless otherwise indicated, the structure described in the present invention also includes all isomers of the structure, such as diastereomers, enantiomers, steric isomers and geometric (conformation) isomer forms; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, steric isomers of biphenyl structures (see "Basic Organic Chemistry" (Second Edition), Volume 1, Xing Qiyi et al., p104-105); PAC, 1996, 68, 2193. (Basic terminology of stereochemistry (IUPAC Recommendations 1996, on page 2201)), (Z) and (E) conformational isomers. Therefore, single stereoisomers of the compounds of the present invention as well as enantiomeric mixtures, diastereomeric mixtures, steric isomers and geometric (conformation) isomer mixtures are all within the scope of the present invention.

[0098] The carbon, hydrogen, oxygen, sulfur, nitrogen, F, Cl, Br, I, etc. involved in the compounds of the present invention include their isotopes. The carbon, hydrogen, oxygen, sulfur or nitrogen involved in the compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0099] The term "pharmaceutical composition" as used herein, alone or in combination, refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component (i.e., excipient), wherein the pharmaceutically acceptable chemical component (excipient) includes but is not limited to carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, excipients, solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoaming agents, inclusion agents, humectants, absorbents, flocculants and deflocculating agents, filter aids, release retardants, etc.

[0100] The term "independent" or "independently" used herein alone or in combination means that the definition of each group in the general formula is independent and is not affected by other groups. When two or more groups have the same optional items, the optional items they choose can be the same or different. For example, in formula (I), the substituent R on the benzene ring 3 When the number is two or more, each R 3 The optional substituents of may be the same or different.

[0101] The term "optional" or "optionally" as used herein, alone or in combination, means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl may but need not be present, and the description includes instances where the heterocyclyl is substituted with alkyl and instances where the heterocyclyl is not substituted with alkyl.

[0102] The term "subject" or "patient" used herein, alone or in combination, refers to an animal, including a human patient in need of treatment. In certain aspects, this article can also be applied to any mammal or other animal in need of such immune-targeted therapy in veterinary practice, including but not limited to non-human primates, canines, felines, pigs, horses, and any other animals.

[0103] The term "treat" and other similar synonyms used herein, alone or in combination, include alleviating, alleviating or ameliorating symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing potential metabolic causes of symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, making a disease or condition better, alleviating symptoms caused by a disease or condition, or stopping symptoms of a disease or condition, and in addition, the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and / or a preventive effect.

[0104] The term "room temperature" as used herein, alone or in combination, refers to 25±5°C.

[0105] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments.

[0106] In the embodiments and comparative examples of the present invention, the raw materials or reagents used are all commercially available products unless otherwise specified, and the percentages used are all mass percentages unless otherwise specified.

[0107] In the examples and comparative examples of the present invention, the silica gel column chromatography used for compound purification uses 200-300 mesh silica gel as a carrier, and unless otherwise specified, the elution system is petroleum ether / ethyl acetate.

[0108] Example 1 Preparation of Compound 1

[0109]

[0110] Add formaldehyde aqueous solution (total 0.672g, concentration 37%, 2.0eq) and 1-(4-bromophenyl)piperazine (1g, 1.0eq) to the reaction kettle in sequence and stir. Add formic acid (0.381g, 2.0eq) dropwise, raise the temperature to 80±5℃, keep the temperature for 1h, TLC shows that the raw material is completely converted. Turn off the heating, when the reaction temperature drops to 30℃, add 20% NaOH aqueous solution to the reaction system to make the system pH=8-9. Extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, concentrate until there is no obvious fraction, transfer the material to a vacuum drying oven at 40℃ for drying, and obtain 0.919g of compound 1b, yield: 87%.

[0111] Tetrahydrofuran (10 mL) and compound 1b (900 mg, 1.0 eq) were added to the reaction bottle in sequence, cooled to below -60°C, n-butyl lithium (1.7 mL, 1.2 eq, 2.5 M) was added dropwise, and the mixture was stirred for 2 h. Trimethyl borate (550 mg, 1.5 eq, diluted with an equal volume of tetrahydrofuran) was added dropwise, and the temperature was controlled not to exceed -60°C during the addition process. After the addition was completed, the mixture was stirred for 2 h and then naturally heated to room temperature for 16 h. Saturated ammonium chloride solution was added dropwise to make the pH value of the system about 8.3, stirred for 2 h, filtered, and the filter cake was rinsed with water and n-heptane in sequence. The obtained filter cake was slurried with a mixed solvent of water and ethyl acetate (volume ratio of 3:2) for 2 h, filtered, and dried in a vacuum oven at 40°C to obtain 528 mg of compound 1c, with a yield of 68%.

[0112]

[0113] To the reaction flask, p-fluoronitrobenzene (2.50 g, 1.0 eq), 4-methylpiperidine (1.76 g, 1.0 eq) and potassium carbonate (3.67 g, 1.5 eq) were added in sequence, and then DMF (50 mL) was added, and the reaction was stirred at room temperature for 24 h; TLC showed that the raw materials were completely converted, and water (100 mL) was added to the reaction solution, and stirred for 1 h; the solution was filtered, and the filter cake was washed with water, and the filter cake was placed in a reduced pressure vacuum drying oven and dried at 55°C for 16 h to obtain 3.78 g of compound 1d, with a yield of 96.85%.

[0114] Compound 1d (3.78 g, 1.0 eq) and methanol (75 mL) were added to the reaction flask in sequence, and the atmosphere was replaced with nitrogen three times. Pd / C catalyst (0.378 g, 10% w / w) was then added, and the atmosphere was replaced with hydrogen three times. The reaction was stirred at room temperature for 5 h under a hydrogen atmosphere. TLC showed that the raw material was completely converted. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain 2.58 g of compound 1e, with a yield of 79.02%. MS m / z (ESI): 191.1544 (M+H) + .

[0115] Compound 1e (0.5 g, 1.0 eq), m-bromoacetophenone (0.523 g, 1.0 eq), tris(dibenzylideneacetone)dipalladium (120 mg, 0.05 eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (152 mg, 0.1 eq), cesium carbonate (1.284 g, 1.5 eq) and 1,4-dioxane (10 mL) were added to the reaction flask in sequence. The mixture was kept at 105°C for 16 h under nitrogen atmosphere. TLC showed that the raw materials were completely converted. The mixture was cooled to room temperature, filtered through a pad of diatomaceous earth, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 250 mg of compound 1f with a yield of 30.84%. MS m / z (ESI): 309.1874 (M+H) + .

[0116] Compound 1f (250 mg, 1.0 eq), p-toluenesulfonyl hydrazide (181 mg, 1.2 eq), 3 M HCl in MeOH (0.14 mL, 0.5 eq) and methanol (5 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 6 h under nitrogen atmosphere. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 250 mg of compound 1g. The yield was 64.75%.

[0117] Compound 1g (250 mg, 1.0 eq), compound 1c (174 mg, 1.5 eq), potassium carbonate (116 mg, 1.6 eq), 2-methyltetrahydrofuran (3.75 mL) and 1,4-dioxane (1.25 mL) were added to the reaction bottle in sequence. The mixture was kept at 80°C for 18 h under nitrogen atmosphere. TLC showed that the raw materials were completely converted. The mixture was cooled to room temperature and the reaction solution was extracted with 5% aqueous sodium hydroxide solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography. The elution system was dichloromethane / methanol. 131 mg of compound 1 was obtained. The yield was 53.34%. MS m / z (ESI): 469.3323 (M+H) + . 1 HNMR (400MHz, DMSO-d6) δ = 7.70 (s, 1H), 7.08-7.02 (m, 3H), 6.93 (d, J = 8.4Hz, 2H), 6.86-6. 82(m,4H),6.76(s,1H),6.71(d,J=8.0Hz,1H),6.59(d,J=7.6Hz,1H),3.95-3.90(m,1H),3. 49(d,J=12.0Hz,2H),3.07-3.05(m,4H),2.56(d,J=12.0Hz,2H),2.44-2.42(m,4H),2.21(s ,3H),1.68(d,J=12.8Hz,2H),1.50-1.43(m,4H),1.29-1.22(m,2H),0.94(d,J=6.4Hz,3H).

[0118] Example 2 Preparation of Compound 2

[0119]

[0120] To the reaction flask, p-fluoronitrobenzene (5.0 g, 1.0 eq), 4-trifluoromethylpiperidine (5.426 g, 1.0 eq) and potassium carbonate (7.345 g, 1.5 eq) were added in sequence, and then DMF (100 mL) was added, and the reaction was stirred at room temperature for 24 h; TLC showed that the raw materials were completely converted, water (200 mL) was added to the reaction solution, and stirred for 1 h; the solution was filtered, the filter cake was washed with water, and the filter cake was placed in a reduced pressure vacuum drying oven and dried at 55 ° C for 16 h to obtain 8.482 g of compound 2a, with a yield of 87.28%.

[0121] Compound 2a (8.0 g, 1.0 eq) and methanol (160 mL) were added to the reaction flask in sequence, and the atmosphere was replaced with nitrogen three times. Pd / C catalyst (0.8 g, 10% w / w) was then added, and the atmosphere was replaced with hydrogen three times. The reaction was stirred at room temperature for 5 h under a hydrogen atmosphere. TLC showed that the raw material was completely converted. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain 6.724 g of compound 2b, with a yield of 94.28%. MS m / z (ESI): 245.1263 (M+H) + .

[0122] Compound 2b (642 mg, 1.0 eq), m-bromoacetophenone (523 mg, 1.0 eq), tris(dibenzylideneacetone)dipalladium (120 mg, 0.05 eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (152 mg, 0.1 eq), cesium carbonate (1.284 g, 1.5 eq) and 1,4-dioxane (12 mL) were added to the reaction flask in sequence. The mixture was kept at 105°C for 24 h under nitrogen atmosphere. TLC showed that the raw materials were completely converted. The mixture was cooled to room temperature, the reaction solution was filtered with diatomaceous earth pad, the filtrate was concentrated, and the mixture was purified by silica gel column chromatography to obtain 350 mg of compound 2c, with a yield of 36.75%. MS m / z (ESI): 363.1611 (M+H) + .

[0123] Compound 2c (350 mg, 1.0 eq), p-toluenesulfonyl hydrazide (216 mg, 1.2 eq), 3 M HCl in MeOH (0.16 mL, 0.5 eq) and methanol (7 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 6 h under nitrogen. TLC showed that the raw material was completely converted. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 344 mg of compound 2d. The yield was 66.84%.

[0124] Compound 2d (340 mg, 1.0 eq), compound 1c (212 mg, 1.5 eq), potassium carbonate (142 mg, 1.6 eq), 2-methyltetrahydrofuran (5.1 mL) and 1,4-dioxane (1.7 mL) were added to the reaction bottle in sequence. The mixture was kept at 80°C for 24 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography. The elution system was dichloromethane / methanol. 148 mg of compound 2 was obtained. The yield was 44.17%. MS m / z (ESI): 523.2964 (M+H) + . 1HNMR (400MHz, DMSO-d6) δ = 7.76 (s, 1H), 7.24 (d, J = 8.0Hz, 2H), 7.06-7.02 (m, 2H ),6.94(d,J=8.8Hz,2H),6.85(t,J=9.2Hz,4H),6.74(d,J=7.6Hz,2H),5.40(s,1 H),3.61(d,J=12.0Hz,2H),3.09-3.07(m,4H),2.62(t,J=12.0Hz,2H),2.45-2. 43(m,5H),2.21(s,3H),1.88(d,J=12.8Hz,2H),1.75(s,3H),1.63-1.53(m,2H).

[0125]

[0126] To the reaction flask, p-fluoronitrobenzene (2.5 g, 1.0 eq), morpholine (1.544 g, 1.0 eq) and potassium carbonate (3.674 g, 1.5 eq) were added in sequence, and then DMF (50 mL) was added, and the reaction was stirred at room temperature for 5 h. TLC showed that the raw materials were completely converted. Ice water (150 mL) was added to the reaction solution, and stirred for 1 h. Filter, wash the filter cake with water, place the filter cake in a reduced pressure vacuum drying oven, and dry it at 55°C for 16 h to obtain 3.56 g of compound 3a. The yield was 96.49%.

[0127] Compound 3a (3.51 g, 1.0 eq) and methanol (70 mL) were added to the reaction bottle in sequence, and the atmosphere was replaced with nitrogen three times. Pd / C catalyst (0.35 g, 10% w / w) was then added, and the atmosphere was replaced with hydrogen three times. The reaction was stirred at room temperature for 5 h under a hydrogen environment. TLC showed that the raw material was completely converted. The reaction solution was filtered through diatomaceous earth and the filtrate was concentrated to obtain 3.0 g of compound 3b, which was directly used in the next step. The yield was 99.85%.

[0128] Compound 3b (1.864 g, 1.0 eq), m-bromoacetophenone (2.5 g, 1.2 eq), tris(dibenzylideneacetone)dipalladium (480 mg, 0.05 eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (610 mg, 0.1 eq), cesium carbonate (5.11 g, 1.5 eq) and 1,4-dioxane (30 mL) were added to the reaction flask in sequence. The reaction was carried out at 105 °C for 15 h under nitrogen atmosphere. TLC showed that the raw material was completely converted. The mixture was cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain 833 mg of compound 3c with a yield of 26.88%.

[0129] Compound 3c (830 mg, 1.0 eq), p-toluenesulfonyl hydrazide (630 mg, 1.2 eq), 3M HCl in MeOH (0.47 mL, 0.5 eq) and methanol (16 mL) were added to the reaction flask in sequence. The mixture was kept at 50°C for 6 h under nitrogen atmosphere. TLC showed that the raw materials were completely converted. The mixture was cooled to room temperature, concentrated and purified by silica gel column chromatography to obtain 505 mg of compound 3d with a yield of 38.81%. MS m / z (ESI): 465.1887 (M+H) + .

[0130] Compound 3d (500 mg, 1.0 eq), compound 1c (360 mg, 1.5 eq), potassium carbonate (240 mg, 1.6 eq), 2-methyltetrahydrofuran (7.5 mL) and 1,4-dioxane (2.5 mL) were added to the reaction bottle in sequence. The mixture was kept at 80°C for 16 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography. The elution system was dichloromethane / methanol. 256 mg of compound 3 was obtained. The yield was 52.09%. MS m / z (ESI): 457.2961 (M+H) + . 1 HNMR(400MHz, DMSO-d6)δ=7.78(s,1H),7.07(t,J=8.0Hz,3H),6.99(d,J=8.4Hz,2H),6.86-6.83(m,4H),6.78–6.72(m,2H),6.61(d,J=7.6H z,1H),3.93(q,J=7.2Hz,1H),3.71(s,3H),3.37(s,4H),3.06(t,J=4.8Hz,4H),2.45-2.42(m,4H),2.22-2.20(m,4H),1.49(d,J=7.2Hz,3H).

[0131] Example 4 Preparation of Compound 4

[0132]

[0133] m-Fluoronitrobenzene (2.5 g, 1.0 eq), 4-methylpiperidine (1.76 g, 1.0 eq) and potassium carbonate (3.674 g, 1.5 eq) were added to the reaction flask in sequence, and then DMF (50 mL) was added. The reaction was stirred at 110°C for 50 h, and then cooled to room temperature. Water and ethyl acetate were added to the reaction solution, extracted, and separated. The extract was backwashed twice with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography to obtain 2.74 g of compound 4a. The yield was 70.2%.

[0134] Compound 4a (2.74 g, 1.0 eq) and methanol (30 mL) were added to the reaction flask in sequence, and the atmosphere was replaced with nitrogen three times. Pd / C catalyst (0.274 g, 10% w / w) was then added, and the atmosphere was replaced with hydrogen three times. The reaction was stirred at room temperature for 6 h under a hydrogen environment. TLC showed that the raw material was completely converted. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and purified by silica gel column chromatography to obtain 1.32 g of compound 4b. The yield was 55.7%.

[0135] Compound 4b (1.219 g, 1.0 eq), m-bromoacetophenone (1.536 g, 1.2 eq), palladium acetate (72 mg, 0.05 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (402 mg, 0.1 eq), cesium carbonate (3.13 g, 1.5 eq) and toluene (40 mL) were added to the reaction flask in sequence. The mixture was kept at 110 °C for 24 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain 652 mg of compound 4c with a yield of 33.0%.

[0136] Compound 4c (719 mg, 1.0 eq), p-toluenesulfonyl hydrazide (521 mg, 1.2 eq), 3 M HCl in MeOH (0.4 mL, 0.5 eq) and methanol (15 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 12 h under nitrogen. TLC showed that the raw material was basically converted. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 384 mg of compound 4d. The yield was 34.56%.

[0137] Compound 4d (384 mg, 1.0 eq), compound 1c (266 mg, 1.5 eq), potassium carbonate (178 mg, 1.6 eq), 2-methyltetrahydrofuran (6 mL) and 1,4-dioxane (2 mL) were added to the reaction bottle in sequence. The mixture was kept at 80°C for 12 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% aqueous sodium hydroxide solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography. The elution system was dichloromethane / methanol. 378 mg of compound 4 was obtained. The yield was 31.22%. MS m / z (ESI): 469.3319 (M+H) + . 1HNMR (400MHz, DMSO-d6) δ = 7.94 (s, 1H), 7.13–7.07 (m, 3H), 7.01 (t, J = 8.0Hz, 1H), 6.92 (s, 1H), 6.8 4(d,J=8.0Hz,3H),6.69(d,J=8.0Hz,1H),6.56(s,1H),6.44-6.38(m,2H),3.95(q,J=7.2Hz,1H),3 .52(d,J=12.4Hz,2H),3.07-3.05(m,4H),2.58(t,J=12.0Hz,2H),2.45-2.42(t,J=4.9Hz,4H),2.2 1(s,3H),1.64(d,J=13.2Hz,2H),1.50(d,J=7.2Hz,4H),1.26–1.17(m,3H),0.92(d,J=6.4Hz,2H).

[0138] Example 5 Preparation of Compound 5

[0139]

[0140] Aniline (1.064 g, 1.0 eq), m-bromoacetophenone (2.5 g, 1.2 eq), palladium acetate (128 mg, 0.05 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (711 mg, 0.1 eq), cesium carbonate (7.44 g, 1.5 eq) and toluene (35 mL) were added to the reaction bottle in sequence. The mixture was kept at 110°C for 12 h under nitrogen atmosphere, cooled to room temperature, filtered through diatomaceous earth pad, the filtrate was concentrated, and purified by silica gel column chromatography to obtain 1.02 g of compound 6a, with a yield of 42.29%. MS m / z (ESI): 212.1069 (M+H) + .

[0141] Compound 5a (1.02 g, 1.0 eq), p-toluenesulfonyl hydrazide (1.079 g, 1.2 eq), 3 M HCl in MeOH (0.8 mL, 0.5 eq) and methanol (20.5 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 4 h under nitrogen. TLC showed that the raw material was basically converted. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 1.76 g of compound 5b with a yield of 96.02%.

[0142] Compound 5b (1.0 g, 1.0 eq), compound 1c (0.87 g, 1.5 eq), potassium carbonate (583 mg, 1.6 eq), 2-methyltetrahydrofuran (15 mL) and 1,4-dioxane (5 mL) were added to the reaction flask in sequence. The mixture was kept at 80°C for 16 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the eluent system to obtain 561 mg of compound 5 with a yield of 31.22%. MS m / z (ESI): 372.2437 (M+H) + . 1 HNMR (400MHz, DMSO-d6) δ = 8.10 (s, 1H), 7.20 (t, J = 7.6Hz, 2H), 7.14-7.08 (m, 3H), 7.02 (d, J = 8.0Hz, 2H), 6.90–6.84 (m, 4H), 6.79 (t, J = 7. 3Hz,1H),6.72(d,J=7.2Hz,1H),3.97(q,J=7.2Hz,1H),3.06(t,J=5.2Hz,4H),2.43(t,J=5.2Hz,4H),2.21(s,3H),1.51(d,J=7.2Hz,3H).

[0143] Example 6 Preparation of Compound 6

[0144]

[0145] To the reaction flask, p-fluoroaniline (1.84 g, 1.0 eq), m-bromoacetophenone (2.5 g, 1.2 eq), palladium acetate (128 mg, 0.05 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (711 mg, 0.1 eq), cesium carbonate (7.44 g, 1.5 eq) and toluene (35 mL) were added in sequence. The mixture was kept at 110°C for 12 h under nitrogen atmosphere, cooled to room temperature, filtered through diatomaceous earth pad, the filtrate was concentrated, and purified by silica gel column chromatography to obtain 1.37 g of compound 6a, with a yield of 42.96%. MS m / z (ESI): 280.0943 (M+H) + .

[0146] Compound 6a (0.7 g, 1.0 eq), p-toluenesulfonyl hydrazide (560 mg, 1.2 eq), 3 M HCl in MeOH (0.43 mL, 0.5 eq) and methanol (14 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 6 h under nitrogen. TLC showed that the raw material was basically converted. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 0.706 g of compound 6b. The yield was 62.92%.

[0147] Compound 6b (600 mg, 1.0 eq), compound 1c (443 mg, 1.5 eq), potassium carbonate (287 mg, 1.6 eq), 2-methyltetrahydrofuran (9 mL) and 1,4-dioxane (3 mL) were added to the reaction bottle in sequence. The mixture was kept at 80°C for 16 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% aqueous sodium hydroxide solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography with an elution system of dichloromethane / methanol to obtain 320 mg of compound 6 with a yield of 56%. MS m / z (ESI): 440.2307 (M+H) + . 1 HNMR (400MHz, DMSO-d6) δ = 8.65 (s, 1H), 7.48 (d, J = 8.4Hz, 2H), 7.21 (t, J = 8.0Hz, 1H), 7.09 (t, J = 8.8Hz, 4H), 7.00–6.96 (m, 2 H),6.88-6.85(m,3H),4.06-3.99(m,1H),3.07(t,J=4.8Hz,4H),2.44(t,J=4.8Hz,4H),2.22(s,3H),1.53(d,J=7.2Hz,3H).

[0148] Example 7 Preparation of Compound 7

[0149]

[0150] To the reaction flask, p-fluoronitrobenzene (2.5 g, 1.0 eq), N-methylpiperazine (1.775 g, 1.0 eq) and potassium carbonate (3.674 g, 1.5 eq) were added in sequence, and then DMF (50 mL) was added, and the reaction was stirred at 90°C for 2 h. TLC showed that the raw materials were completely converted. Ice water (150 mL) was added to the reaction solution, and the mixture was stirred for 1 h. The mixture was filtered, and the filter cake was washed with water. The filter cake was placed in a reduced pressure vacuum drying oven and dried at 55°C for 16 h to obtain 3.065 g of compound 7a. The yield was 78.19%.

[0151] Compound 7a (2.76 g, 1.0 eq) and methanol (55 mL) were added to the reaction bottle in sequence, and the atmosphere was replaced with nitrogen three times. Pd / C catalyst (0.275 g, 10% w / w) was then added, and the atmosphere was replaced with hydrogen three times. The reaction was stirred at room temperature for 5 h under a hydrogen environment. TLC showed that the raw material was completely converted. The reaction solution was filtered through diatomaceous earth and the filtrate was concentrated to obtain 2.3 g of compound 7b, which was directly used in the next step. The yield was 96.39%.

[0152] Compound 7b (1.845 g, 1.0 eq), m-bromoacetophenone (2.3 g, 1.2 eq), palladium acetate (110 mg, 0.05 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (600 mg, 0.1 eq), cesium carbonate (4.72 g, 1.5 eq) and toluene (15 mL) were added to the reaction flask in sequence. The mixture was kept at 110 °C for 16 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain 1.33 g of compound 7c with a yield of 44.63%.

[0153] Compound 7c (1.33 g, 1.0 eq), p-toluenesulfonyl hydrazide (0.969 g, 1.2 eq), 3 M HCl in MeOH (0.72 mL, 0.5 eq) and methanol (27 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 16 h under nitrogen. TLC showed that the raw material was basically converted. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 1.607 g of compound 7d. The yield was 78.21%.

[0154] Compound 7d (1.0 g, 1.0 eq), compound 1c (0.69 g, 1.5 eq), potassium carbonate (0.46 g, 1.6 eq), 2-methyltetrahydrofuran (15 mL) and 1,4-dioxane (6 mL) were added to the reaction bottle in sequence. The mixture was kept at 80°C for 16 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the eluent system to obtain 345 mg of compound 7 with a yield of 35.08%. MS m / z (ESI): 470.3248 (M+H) + . 1 HNMR(400MHz, DMSO-d6)δ=7.72(s,1H),7.08–7.02(m,3H),6.94(d,J=8.8Hz,2H),6.86–6.83(m,4H),6.76-6.75(m,1H),6.73-6.70(m, 1H), 6.59 (d, J = 7.2Hz, 1H), 3.92 (q, J = 7.2Hz, 1H), 3.08-3.02 (m, 7H), 2.46-2.42 (m, 9H), 2.22 (d, J = 4.4Hz, 6H), 1.49 (d, J = 7.2Hz, 3H).

[0155] Example 8 Preparation of Compound 8

[0156]

[0157] To the reaction bottle, 1-tert-butoxycarbonyl-4-methylpiperidine-4-carboxylic acid methyl ester (1.0 g, 1.0 eq) and ethyl acetate (20 mL) were added in sequence. After stirring to dissolve, p-toluenesulfonic acid monohydrate (2.22 g, 3.0 eq) was added. The reaction was stirred at 65°C for 0.5 h. The reaction solution was concentrated to dryness to obtain compound 8a, which was directly used in the next step.

[0158] To the reaction flask, the unpurified compound 8a obtained in the previous step, DMF (25 mL), p-fluoronitrobenzene (550 mg, 1.0 eq) and potassium carbonate (2.69 g, 5 eq) were added in sequence, and the reaction was stirred at room temperature for 24 h. Water (75 mL) was added and stirring was continued for 0.5 h. The mixture was filtered, the filter cake was washed with water, and dried under reduced pressure at 50°C to obtain 988 mg of compound 8b. The yield was 91.36%.

[0159] Compound 8b (988 mg, 1.0 eq) and methanol (15 mL) were added to the reaction bottle in sequence, and the atmosphere was replaced with nitrogen three times. Pd / C catalyst (99 mg, 10% w / w) was then added, and the atmosphere was replaced with hydrogen three times. The reaction was stirred at room temperature for 2 h under a hydrogen environment. The reaction solution was filtered through diatomaceous earth and the filtrate was concentrated to give 817 mg of compound 8c. The yield was 92.84%.

[0160] Compound 8c (817 mg, 1.0 eq), m-bromoacetophenone (786 mg, 1.2 eq), palladium acetate (37 mg, 0.05 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (205 mg, 0.1 eq), cesium carbonate (1.61 g, 1.5 eq) and toluene (15 mL) were added to the reaction flask in sequence. The mixture was kept at 110 °C for 16 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain 695 mg of compound 8d in a yield of 57.64%.

[0161] Compound 8d (695 mg, 1.0 eq), p-toluenesulfonyl hydrazide (425 mg, 1.2 eq), 3 M HCl in MeOH (0.32 mL, 0.5 eq) and methanol (14 mL) were added to the reaction flask in sequence. The mixture was kept at 45 °C for 6 h under nitrogen atmosphere. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 707 mg of compound 8e with a yield of 69.72%.

[0162] Compound 8e (700 mg, 1.0 eq), compound 1c (430 mg, 1.5 eq), potassium carbonate (290 mg, 1.6 eq), 2-methyltetrahydrofuran (10.5 mL) and 1,4-dioxane (3.5 mL) were added to the reaction flask in sequence. The mixture was kept at 80 °C for 16 h under nitrogen environment, cooled to room temperature, and the reaction solution was extracted with 5% aqueous sodium hydroxide solution. The organic phase was backwashed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography with an elution system of dichloromethane / methanol to obtain 462 mg of compound 8f with a yield of 67%.

[0163] Compound 8f (342 mg, 1.0 eq), tetrahydrofuran (4 mL), methanol (0.7 mL) and water (1 mL) were added to the reaction bottle in sequence. After uniform dispersion, lithium hydroxide monohydrate (82 mg, 3.0 eq) was added, and the mixture was stirred at 50°C for 5 h. The mixture was concentrated to dryness, and water was added to disperse the mixture. The pH was adjusted to 6-7 with a saturated aqueous citric acid solution. The mixture was extracted with dichloromethane, and the organic phases were combined. The organic phases were backwashed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography. The elution system was dichloromethane / methanol. 198 mg of compound 8 was obtained. The yield was 59.48%. MS m / z (ESI): 513.3230 (M+H) + . 1 HNMR (400MHz, DMSO-d6) δ=7.72(s,1H),7.08-7.02(m,3H),6.92-6.81(m,6H),6.73-6.69(m,2H),6.60(d,J=7.6Hz,1H),3.95-3.90(m,1H),3.27-3 .22(m,2H),3.08-3.06(m,4H),2.76(t,J=10.8Hz,2H),2.48-2.45(m,4H) ,2.23(s,3H),2.06(d,J=13.2Hz,2H),1.49(d,J=6.8Hz,5H),1.16(s,3H).

[0164] Example 9 Preparation of Compound 9

[0165]

[0166] To the reaction flask, p-fluoronitrobenzene (2.5 g, 1.0 eq), 2,6-dimethylmorpholine (2.041 g, 1.0 eq) and potassium carbonate (3.674 g, 1.5 eq) were added in sequence, and then DMF (50 mL) was added, and the reaction was stirred at 90°C for 4 h; ice water (150 mL) was added to the reaction solution, and stirred for 1 h; the mixture was filtered, and the filter cake was washed with water. The filter cake was placed in a reduced pressure vacuum drying oven and dried at 55°C for 16 h to obtain 4.006 g of compound 9a, with a yield of 96.49%.

[0167] Compound 9a (3.95 g, 1.0 eq) and methanol (80 mL) were added to the reaction bottle in sequence. The atmosphere was replaced with nitrogen three times. Pd / C catalyst (0.395 g, 10% w / w) was added and the atmosphere was replaced with hydrogen three times. The reaction was stirred at room temperature for 4 h under hydrogen environment. The reaction solution was filtered through diatomaceous earth and the filtrate was concentrated to obtain 3.57 g of compound 9b, which was used directly in the next step.

[0168] Compound 9b (1.193 g, 1.0 eq), m-bromoacetophenone (1.382 g, 1.2 eq), palladium acetate (65 mg, 0.05 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (376 mg, 0.1 eq), cesium carbonate (2.836 g, 1.5 eq) and toluene (21 mL) were added to the reaction flask in sequence. The mixture was kept at 110 °C for 16 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain 729 mg of compound 9c. The yield was 38.85%.

[0169] Compound 9c (729 mg, 1.0 eq), p-toluenesulfonyl hydrazide (502 mg, 1.2 eq), 3 M HCl in MeOH (0.4 mL, 0.5 eq) and methanol (15 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 6 h under nitrogen atmosphere. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 615 mg of compound 9d in a yield of 55.56%.

[0170] Compound 9d (615 mg, 1.0 eq), compound 1c (412 mg, 1.5 eq), potassium carbonate (276 mg, 1.6 eq), 2-methyltetrahydrofuran (10 mL) and 1,4-dioxane (3 mL) were added to the reaction bottle in sequence. The mixture was kept at 80°C for 16 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography. The elution system was dichloromethane / methanol. 77 mg of compound 9 was obtained. The yield was 12.73%. MS m / z (ESI): 485.3277 (M+H) + . 1HNMR(400MHz, DMSO-d6)δ=7.73(s,1H),7.20(t,J=7.6Hz,1H),7.08–7.02(m,3H ),6.93(t,J=9.6Hz,3H),6.84(d,J=8.4Hz,3H),6.79–6.71(m,2H),6.59(d,J=7 .6Hz,1H),3.73-3.65(m,2H),3.11(t,J=4.8Hz,2H),3.06(t,J=4.8Hz,3H),2.4 6-2.42(m,6H),2.22–2.15(m,6H),1.49(d,J=7.2Hz,3H),1.14(d,J=6.0Hz,4H).

[0171] Example 10 Preparation of Compound 10

[0172]

[0173] Compound 2-fluoro-4-chloro-aniline (2.0 g, 1.0 eq), m-bromoacetophenone (3.271 g, 1.2 eq), palladium acetate (154 mg, 0.05 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (890 mg, 0.1 eq), cesium carbonate (6.715 g, 1.5 eq) and toluene (50 mL) were added to the reaction flask in sequence. The mixture was kept at 110 ° C for 24 h under nitrogen environment, cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain 985 mg of compound 10a. The yield was 27.19%.

[0174] Compound 10a (1.051 g, 1.0 eq), p-toluenesulfonyl hydrazide (891 mg, 1.2 eq), 3 M HCl in MeOH (0.67 mL, 0.5 eq) and methanol (20 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 6 h under nitrogen atmosphere. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 1.409 g of compound 10b. The yield was 81.82%.

[0175] Compound 10b (1.409 g, 1.0 eq), compound 1c (1.077 g, 1.5 eq), potassium carbonate (721 mg, 1.6 eq), 2-methyltetrahydrofuran (21 mL) and 1,4-dioxane (7 mL) were added to the reaction bottle in sequence. The mixture was kept at 80°C for 12 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the eluent system to obtain 812 mg of compound 10 with a yield of 58.71%. MS m / z (ESI): 424.1947 (M+H)+ . 1 HNMR(400MHz,DMSO-d6)δ=7.99(s,1H),7.38-7.35(m,1H),7.22–7.07(m,5H),6.89–6.76(m,5H),3 .97(q,J=7.2Hz,1H),3.08-3.05(m,4H),2.43(t,J=4.8Hz,4H),2.21(s,3H),1.51(d,J=7.2Hz,3H).

[0176] Example 11 Preparation of Compound 11

[0177]

[0178] Compound p-methoxyaniline (1.69 g, 1.0 eq), m-bromoacetophenone (3.28 g, 1.2 eq), tris(dibenzylideneacetone)dipalladium (630 mg, 0.05 eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (800 mg, 0.1 eq), cesium carbonate (6.72 g, 1.5 eq) and 1,4-dioxane (40 mL) were added to the reaction flask in sequence. The reaction was kept at 105 ° C for 12 h under nitrogen environment. TLC showed that the raw material was completely converted. The mixture was cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain 1.93 g of compound 11a. The yield was 58.29%.

[0179] Compound 11a (1.93 g, 1.0 eq), p-toluenesulfonyl hydrazide (1.79 g, 1.2 eq), 3 M HCl in MeOH (1.33 mL, 0.5 eq) and methanol (38 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 6 h under nitrogen atmosphere. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 1.0 g of compound 11b with a yield of 30.53%.

[0180] Compound 11b (1.0 g, 1.0 eq), compound 1c (0.81 g, 1.5 eq), potassium carbonate (540 mg, 1.6 eq), 2-methyltetrahydrofuran (15 mL) and 1,4-dioxane (5 mL) were added to the reaction bottle in sequence. The reaction was kept at 80°C for 16 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography. The elution system was dichloromethane / methanol, and 420 mg of compound 11 was obtained. The yield was 42.83%. MS m / z (ESI): 402.2539 (M+H) + . 1HNMR (400MHz, DMSO-d6) δ=7.78(s,1H),7.08–6.98(m,5H),6.85–6.82(m,4H),6.77(s,1H),6.73(d,J=8.4Hz,1H),6.60(d,J =7.6Hz,1H),3.93(q,J=7.2Hz,1H),3.70(s,3H),3.07-3.45(m,4H),2.45-2.41(m,4H),2.20(s,3H),1.49(d,J=7.2Hz,3H).

[0181] Example 12 Preparation of Compound 12

[0182]

[0183] To the reaction flask, m-methoxyaniline (1.0 g, 1.0 eq), m-bromoacetophenone (1.94 g, 1.2 eq), palladium acetate (91 mg, 0.05 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (506 mg, 0.1 eq), cesium carbonate (3.97 g, 1.5 eq) and toluene (20 mL) were added in sequence. Under a nitrogen environment, the mixture was kept at 110 °C for 12 h, cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain 1.092 g of compound 12a. The yield was 55.74%.

[0184] Compound 12a (1.092 g, 1.0 eq), p-toluenesulfonyl hydrazide (1.011 g, 1.2 eq), 3 M HCl in MeOH (0.8 mL, 0.5 eq) and methanol (20 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 5 h under nitrogen atmosphere. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 1.273 g of compound 12b with a yield of 68.7%.

[0185] Compound 12b (1.273 g, 1.0 eq), compound 1c (1.03 g, 1.5 eq), potassium carbonate (690 mg, 1.6 eq), 2-methyltetrahydrofuran (15 mL) and 1,4-dioxane (5 mL) were added to the reaction bottle in sequence. The mixture was kept at 80°C for 12 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography with an elution system of dichloromethane / methanol to obtain 626 mg of compound 12 with a yield of 50.15%. MS m / z (ESI): 402.2553 (M+H) + . 1HNMR (400MHz, DMSO-d6) δ = 8.11 (s, 1H), 7.15–7.07 (m, 4H), 6.93–6.88 (m, 2H), 6.85 (d, J = 8.4Hz, 2H), 6.74 (d, J = 7.6Hz, 1H), 6.60–6.55 (m, 2H), 6.36(dd,J=8.4,2.4Hz,1H),3.98(q,J=7.2Hz,1H),3.66(s,3H),3.06(t,J=4.8Hz,4H),2.44–2.42(m,4H),2.21(s,3H),1.51(d,J=7.2Hz,3H).

[0186] Example 13 Preparation of Compound 13

[0187]

[0188] Compound o-anisidine (1.0 g, 1.0 eq), m-bromoacetophenone (2.1 g, 1.3 eq), tris(dibenzylideneacetone)dipalladium (370 mg, 0.05 eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (470 mg, 0.1 eq), cesium carbonate (3.97 g, 1.5 eq) and 1,4-dioxane (20 mL) were added to the reaction flask in sequence. The reaction was carried out at 105 °C under nitrogen for 12 h. TLC showed that the raw material was completely converted. The mixture was cooled to room temperature and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain 0.924 g of compound 13a with a yield of 47.17%.

[0189] Compound 13a (924 mg, 1.0 eq), p-toluenesulfonyl hydrazide (856 mg, 1.2 eq), 3 M HCl in MeOH (0.7 mL, 0.5 eq) and methanol (20 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 5 h under nitrogen atmosphere. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 0.719 g of compound 13b. The yield was 45.85%.

[0190] Compound 13b (719 mg, 1.0 eq), compound 1c (580 mg, 1.5 eq), potassium carbonate (390 mg, 1.6 eq), 2-methyltetrahydrofuran (10.8 mL) and 1,4-dioxane (3.6 mL) were added to the reaction bottle in sequence. The mixture was kept at 80°C for 12 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography. The elution system was dichloromethane / methanol. 543 mg of compound 13 was obtained. The yield was 77.02%. MS m / z (ESI): 402.2542 (M+H) +. 1 HNMR (400MHz, DMSO-d6) δ = 7.23 (s, 1H), 7.14 (dd, J = 7.6, 2.0Hz, 1H), 7.10-7.06 (m, 3H), 6.98 (dd, J = 7.6, 2.0Hz, 1H), 6.93-6.91 (m, 1H), 6.88-6.7 9(m,5H),6.68(d,J=7.6Hz,1H),3.95(q,J=7.2Hz,1H),3.79(s,3H),3.06 (t,J=6.0Hz,4H),2.44–2.42(m,4H),2.21(s,3H),1.50(d,J=7.2Hz,3H).

[0191] Example 14 Preparation of Compound 14

[0192]

[0193] Compound 2,4-dimethoxyaniline (1.245 g, 1.0 eq), m-bromoacetophenone (2.1 g, 1.3 eq), tris(dibenzylideneacetone)dipalladium (370 mg, 0.05 eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (470 mg, 0.1 eq), cesium carbonate (3.97 g, 1.5 eq) and 1,4-dioxane (25 mL) were added to the reaction flask in sequence. The reaction was carried out at 105 °C for 12 h under nitrogen environment. TLC showed that the raw material was completely converted. The mixture was cooled to room temperature and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain 400 mg of compound 14a with a yield of 18.16%.

[0194] Compound 14a (400 mg, 1.0 eq), p-toluenesulfonyl hydrazide (329 mg, 1.2 eq), 3M HCl in MeOH (0.3 mL, 0.5 eq) and methanol (8 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 5 h under nitrogen atmosphere. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 579 mg of compound 14b. The yield was 89.35%.

[0195] Compound 14b (579 mg, 1.0 eq), compound 1c (440 mg, 1.5 eq), potassium carbonate (290 mg, 1.6 eq), 2-methyltetrahydrofuran (8.7 mL) and 1,4-dioxane (2.9 mL) were added to the reaction bottle in sequence. The mixture was kept at 80°C for 12 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography with an elution system of dichloromethane / methanol to obtain 364 mg of compound 14 with a yield of 64.03%. MS m / z (ESI): 432.2657 (M+H) + . 1 HNMR(400MHz, DMSO-d6)δ=7.08-7.04(m,3H),7.01–6.97(m,2H),6.84(d,J=8.8Hz,2H),6.70(t,J=2.0Hz,1H),6.61(d,J=2.8Hz,1H),6.57–6.53(m,2 H),6.45(dd,J=8.8,2.8Hz,1H),3.89(q,J=7.2Hz,1H),3.74(s,6H),3.06( t,J=4.8Hz,4H),2.43(t,J=4.8Hz,4H),2.21(s,3H),1.48(d,J=7.2Hz,3H).

[0196] Example 15 Preparation of Compound 15

[0197]

[0198] m-Fluoronitrobenzene (2.0 g, 1.0 eq), 4-trifluoromethylpiperidine (2.17 g, 1.0 eq) and potassium carbonate (2.94 g, 1.5 eq) were added to the reaction bottle in sequence, and DMSO (30 mL) was added. The reaction was stirred at 120°C for 50 h, and the mixture was cooled to room temperature. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted and separated. The extract was backwashed twice with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography to obtain 1.275 g of compound 15a. The yield was 32.8%.

[0199] Compound 15a (1.275 g, 1.0 eq) and methanol (30 mL) were added to the reaction flask in sequence, and the atmosphere was replaced with nitrogen three times. Pd / C catalyst (0.127 g, 10% w / w) was then added, and the atmosphere was replaced with hydrogen three times. The reaction was stirred at room temperature for 2 h under hydrogen environment. The reaction solution was filtered through diatomaceous earth and the filtrate was concentrated to obtain 1.071 g of compound 15b. The yield was 94.31%.

[0200] Compound 15b (1.0 g, 1.0 eq), m-bromoacetophenone (1.22 g, 1.5 eq), palladium acetate (46 mg, 0.05 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (250 mg, 0.1 eq), cesium carbonate (2.0 g, 1.5 eq) and toluene (15 mL) were added to the reaction flask in sequence. The mixture was kept at 110 °C for 12 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain 547 mg of compound 15c. The yield was 36.87%.

[0201] Compound 15c (547 mg, 1.0 eq), p-toluenesulfonyl hydrazide (337 mg, 1.2 eq), 3M HCl in MeOH (0.24 mL, 0.5 eq) and methanol (11 mL) were added to the reaction flask in sequence. The mixture was kept at 50 °C for 6 h under nitrogen atmosphere. The mixture was cooled to room temperature, and the reaction solution was concentrated and purified by silica gel column chromatography to obtain 480 mg of compound 15d. The yield was 59.92%.

[0202] Compound 15d (480 mg, 1.0 eq), compound 1c (298 mg, 1.5 eq), potassium carbonate (199 mg, 1.6 eq), 2-methyltetrahydrofuran (7.2 mL) and 1,4-dioxane (2.4 mL) were added to the reaction bottle in sequence. The mixture was kept at 80°C for 12 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography with an elution system of dichloromethane / methanol to obtain 255 mg of compound 15 with a yield of 53.91%. MS m / z (ESI): 523.3012 (M+H) + . 1 HNMR (400MHz, DMSO-d6) δ = 7.97 (s, 1H), 7.14-7.02 (m, 4H), 6.92-6.91 (m, 1H), 6. 85–6.83(m,3H),6.71(d,J=8.0Hz,1H),6.57(t,J=2.4Hz,1H),6.48-6.41(m,2H), 3.96(q,J=7.2Hz,1H),3.64(d,J=12.4Hz,2H),3.06(t,J=4.8Hz,4H),2.69-2.62( m,2H),2.43(t,J=4.8Hz,5H),2.21(s,3H),1.87–1.82(m,2H),1.57–1.47(m,5H).

[0203] Comparative Example 1 Compound Ferrostain-1

[0204]

[0205] The compound Ferrostain-1 was purchased from Selleckchem, product number: S7243, batch number: S724303.

[0206] Comparative Example 2 Preparation of Compound ref-01

[0207]

[0208] Phenoxazine (2.0 g, 1.0 eq) and toluene (20 mL) were added to the reaction flask in sequence, and then acetyl chloride (1.714 g, 2.0 eq) was added. The reaction was kept at 50°C for 1 h, cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain compound ref-01a, which was directly used in the next step. MS m / z (ESI): 226.0870 (M+H) + .

[0209] Compound ref-01a (2.568 g, 1.0 eq) and dichloromethane (50 mL) were added to the reaction flask in sequence, the temperature was lowered to 0°C, acetyl chloride (0.895 g, 1.0 eq) and aluminum chloride (5.776 g, 3.8 eq) were added, the reaction was stirred at 0°C for 15 min, the temperature was raised to room temperature, the reaction was continued at room temperature for 0.5 h, the temperature was raised to 40°C and the reaction was kept for 3 h, the temperature was lowered to room temperature, water was slowly added to quench the reaction, dichloromethane was added to extract, the organic phase was backwashed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography to obtain 2.01 g of compound ref-01b, yield: 65.97%. MS m / z (ESI): 290.0795 (M+Na) + .

[0210] Compound ref-01b (2.01 g, 1.0 eq), anhydrous ethanol (40 mL) and concentrated hydrochloric acid (7.5 mL) were added to the reaction flask in sequence. The mixture was kept at 70°C for 1 h under nitrogen atmosphere, cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was backwashed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 1.419 g of compound ref-01c, with a yield of 83.77%. MS m / z (ESI): 226.0849 (M+H) + .

[0211] Compound ref-01c (1.419 g, 1.0 eq), p-toluenesulfonyl hydrazide (1.408 g, 1.2 eq), 3M HCl in MeOH (1.05 mL, 0.5 eq) and methanol (28 mL) were added to the reaction flask in sequence. The mixture was kept at 45 °C for 3 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was concentrated to obtain compound ref-01d, which was used directly in the next step. MS m / z (ESI): 394.1204 (M+H) + .

[0212] Compound ref-01d (500 mg, 1.0 eq), compound 1c (420 mg, 1.5 eq), potassium carbonate (270 mg, 1.5 eq) and 1,4-dioxane (25 mL) were added to the reaction bottle in sequence. The mixture was kept at 110°C for 3 h under nitrogen atmosphere, cooled to room temperature, and the reaction solution was quenched with saturated sodium bicarbonate aqueous solution. Dichloromethane was added for extraction, and the organic phase was backwashed with water twice, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography. The elution system was dichloromethane / methanol. 365 mg of compound ref-01 was obtained. The yield was 74.55%. MS m / z (ESI): 386.2234 (M+H) + . 1 HNMR (400MHz, DMSO-d6) δ = 8.10 (s, 1H), 7.05 (d, J = 8.4Hz, 2H), 6.85 (d, J = 8.4 Hz,2H),6.70(td,J=7.4,2.0Hz,1H),6.59–6.50(m,3H),6.45(dd,J=8.0,2.0H z,1H),6.41(dd,J=7.6,1.6Hz,1H),6.24(d,J=2.0Hz,1H),3.83(q,J=7.2Hz,1 H),3.08–3.05(m,4H),2.44–2.42(m,4H),2.21(s,3H),1.44(d,J=7.2Hz,3H).

[0213] Comparative Example 3 Preparation of Compound ref-02

[0214]

[0215] Compound 1e (1 g, 1.0 eq), 4-bromobenzaldehyde (1.07 g, 1.1 eq), tris(dibenzylideneacetone)dipalladium (241 mg, 0.05 eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (304 mg, 0.1 eq), cesium carbonate (2.568 g, 1.5 eq) and 1,4-dioxane (20 mL) were added to the reaction flask in sequence. The reaction was carried out at 105° C. for 6 h under nitrogen atmosphere. TLC showed that the raw materials were completely converted. The mixture was cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain 460 mg of compound ref-02a. The yield was 29.75%.

[0216] Compound ref-02a (460 mg, 1.0 eq), ethanol (11.5 mL), water (2.3 mL) and tetrahydrofuran (4.6 mL) were added to the reaction flask in sequence, and then hydroxylamine hydrochloride (120 mg, 1.1 eq) was added. The reaction was carried out at room temperature for 20 h. TLC showed that the raw material was completely converted. The reaction solution was concentrated to obtain compound ref-02b, which was directly used in the next step.

[0217] Compound ref-02b (484 mg, 1.0 eq), ethanol (15 mL) and borane-pyridine (290 mg, 2.0 eq) were added to the reaction bottle in sequence, the temperature was lowered to 0°C, 10% hydrochloric acid (3.1 mL) was added, the reaction was stirred at 0°C for 10 min, the temperature was raised to room temperature, and the reaction was continued at room temperature for 1 h. TLC showed that the raw material was completely converted. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phase was backwashed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound ref-02c, which was directly used in the next step.

[0218] Compound ref-02c (240 mg, 1.0 eq), 2-(4-methylpiperazin-1-yl)acetic acid (160 mg, 1.3 eq) and N,N-dimethylformamide (2.5 mL) were added to the reaction bottle in sequence, the temperature was lowered to 0°C, N,N-diisopropylethylamine (130 mg, 1.3 eq) was added, the reaction was stirred at 0°C for 10 min, DMT-MM (280 mg, 1.3 eq) was added, the reaction was stirred at 0°C for 30 min, the temperature was raised to room temperature, and the reaction was continued at room temperature for 1.5 h. TLC showed that the raw material was completely converted, water was added to quench the reaction, dichloromethane was added to extract, the organic phase was backwashed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography, the elution system was dichloromethane / methanol, and 108 mg of compound ref-02 was obtained, the yield: 31.01%. MS m / z (ESI): 452.3025 (M+H) + . 1HNMR (400MHz, MeOH-d4) δ = 7.16–6.92 (m, 8H), 4.65 (s, 2H), 3.16 (d, J = 11.2Hz, 3H), 2. 67–2.59(m,9H),2.33(s,3H),1.78(d,J=12.4Hz,2H),1.50–1.24(m,5H),1.01(s,3H).

[0219] Study on the Inhibition Rate of Ferroptosis by Experimental Example Compounds

[0220] In order to study the inhibition rate of the compounds of the present invention on Ferroptosis, a Ferroptosis screening model was constructed in this experimental example, as follows: The Ferroptosis screening model mainly uses the CCK8 cell viability detection method. First, human fibrosarcoma cells HT1080 (Cell Bank of the Chinese Academy of Sciences, TCHu170) and human neuroblastoma cells SH-SY5Y (Cell Bank of the Chinese Academy of Sciences, TCHu97) were cultured in a dish. The HT1080 cell culture medium was MEM+10% FBS+2mM L-Glutamine; the SH-SY5Y cell culture medium was DMEM+10% FBS. Cells in the logarithmic growth phase were inoculated in a specific number in a 96-well plate (5000 cells / well), 80 μL per well, and then placed in a 37°C, 5% CO 2 Culture in an incubator with an environment to allow the cells to adhere to the wall. After 24 hours, add 10 μL of various concentrations of the compound of the present invention prepared using cell culture medium (starting at 10 μM or 1 μM concentration, 3-fold dilution, 8 concentrations) and 10 μL of the Ferroptosis inducer Erastin (Selleck, S7242) with a final concentration of 10 μM, and set 3 replicates for each compound to ensure the accuracy of the results. At the same time, set a positive control group (add 10 μL of the same culture medium prepared with a 1 μM concentration starting, 3-fold dilution, 8 concentrations of compounds Ferrostain-1, ref-01, ref-02), a blank control group (add the above-specified cell culture medium with the same DMSO concentration, without cells) and a solvent control group (add the above-specified cell culture medium with the same DMSO concentration, containing cells), and each group also sets 3 replicates to ensure the accuracy of the results. After adding the drug, put it in an incubator and culture it for 24 hours. 10 μL CCK8 solution (Topscience, C0005) was added to each well, and the cells were placed in an incubator for 2-4 hours. The absorbance at 450 nm was then measured with an ELISA reader to calculate the inhibition rate of the compound on Ferroptosis. The inhibition rate was calculated using the following formula: Inhibition rate (IR) = [1-(A experimental group-A blank) / (A solvent-A blank)]*100%

[0221] GraphPad Prism 6 software was used to fit the inhibition rate curve and calculate the IC 50 value.

[0222] The experimental results show that compounds 1-15 of the present invention have good inhibitory activity against ferroptosis of HT1080 cells and SH-SY5Y cells, IC 50 The values ​​were all lower than 200 nM. Some activity results of compound 1 and other structures are shown in Table 1.

[0223] Table 1 Results of the inhibitory activity of some compounds on ferroptosis of HT1080 cells and SH-SY5Y cells

[0224]

[0225] From the experimental results shown in Table 1, it can be seen that the compounds of the present invention have excellent ferroptosis inhibitory activity, and the structures of compound 1 and the like are significantly superior to the existing reference compounds Ferrostain-1, ref-01 and ref-02. For example, the inhibitory activity of compound 1, compound 2, compound 3 and compound 4 in HT1080 cells is 11.6 to 31.4 times that of Ferrostain-1, 9.4 to 25.4 times that of ref-01, and 12.9 to 35.1 times that of ref-02; the inhibitory activity of compound 1, compound 2, compound 3 and compound 4 in SH-SY5Y cells is 6.9 to 12.2 times that of Ferrostain-1, 7.9 to 13.9 times that of ref-01, and 8.0 to 14.0 times that of ref-02. This shows that the compounds of the present invention can be used to prepare ferroptosis inhibitors to prevent and / or treat a variety of diseases related to ferroptosis, such as neurodegenerative diseases, Parkinson's syndrome, stroke, cardiovascular disease, renal failure, diabetic complications, cancer, etc.

[0226] Unless otherwise defined, the terms used in the present invention have the meanings commonly understood by those skilled in the art.

[0227] The embodiments described in the present invention are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Those skilled in the art may make various other substitutions, changes and improvements within the scope of the present invention. Therefore, the present invention is not limited to the above embodiments, but is only limited by the claims.

Claims

1. A compound having a structure as shown in formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance thereof, In formula (I), ring A is selected from C6 to C 12 Aryl, which is optionally substituted by one or more substituents selected from halogen, hydroxy, carboxyl, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; Ring B is selected from a 5- to 12-membered heterocyclyl or a 5- to 12-membered heteroaryl, wherein the heterocyclyl or heteroaryl contains at least one N atom as a ring atom, and the heterocyclyl or heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxy, carboxyl, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R1 and R2 are each independently selected from hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl; Each R3 is independently selected from hydrogen, halogen, hydroxyl, carboxyl, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C 10 Cycloalkyl, 5- to 12-membered heterocyclic group, C6-C 12 Aryl or 5-12 membered heteroaryl, wherein the hydroxyl, carboxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxyl, carboxyl, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; m is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance thereof, wherein: In formula (I), Ring A is selected from C6~C 10 Aryl; Ring B is selected from a 5- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 N atoms as ring atoms, and the heterocyclic group is optionally substituted by one or more substituents selected from halogen, hydroxy, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R1 and R2 are each independently selected from hydrogen or C1-C6 alkyl; Each R3 is independently selected from hydrogen, halogen, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 5-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from halogen, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; m is selected from 0, 1, 2 or 3.

3. The compound according to claim 2 or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance thereof, wherein: In formula (I), Ring A is selected from phenyl; Ring B is selected from a 5- to 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 N atoms as ring atoms, and the heterocyclic group is optionally substituted by one or more substituents selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy; the heterocyclic group is preferably selected from piperidinyl or piperazinyl; R1 and R2 are each independently selected from hydrogen or C1-C4 alkyl; Each R3 is independently selected from hydrogen, F, Cl, hydroxyl, carboxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or 5-6 membered heterocyclic group, the heterocyclic group contains at least one N atom as a ring atom, and the heterocyclic group is optionally substituted by one or more substituents selected from F, Cl, hydroxyl, carboxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy; the heterocyclic group is preferably selected from piperidinyl, piperazinyl or morpholinyl; m is selected from 0, 1 or 2.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance thereof, wherein: The compound has a structure as shown in formula (II): In formula (II), Z1, Z2, and Z3 are each independently selected from -C(R4)2-, -NR4- or a bond; Each R4 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy, preferably selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy; R1, R2, R3, and m are each independently as defined in any one of claims 1 to 3; Preferably, the compound has a structure as shown in formula (III): In formula (III), R1, R2, R3, R4 and m are each independently as defined in formula (II).

5. The compound according to claim 4 or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance thereof, wherein: The compound has a structure as shown in formula (IV): In formula (IV), Y is selected from -C(R6)2-, -NR6-, -O- or -S-; R5 and R6 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy, preferably selected from hydrogen, F, Cl, hydroxyl, carboxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy; n is selected from 0, 1 or 2; R1, R2, R4 are each independently as defined in claim 4; Preferably, the compound has a structure as shown in formula (IV-1) or formula (IV-2): In formula (IV-1) or formula (IV-2), Y, R1, R2, R4, R5, and n are each independently defined as in formula (IV); More preferably, R1, R2, R4 are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl.

6. A compound or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance thereof, wherein: The compounds include:

7. A method for preparing the compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled product thereof, wherein: The preparation method comprises: reacting an aniline compound of the structure shown in formula (I-1) with a halide of the structure shown in formula (I-2) to obtain a first intermediate of the structure shown in formula (I-3); reacting the first intermediate with p-toluenesulfonyl hydrazide to obtain a second intermediate of the structure shown in formula (I-4); reacting the second intermediate with a boric acid compound of the structure shown in formula (I-5) to obtain a compound of the structure shown in formula (I); Wherein, X is selected from halogen, preferably selected from Br; Ring A, ring B, R1, R2, R3 and m are each independently as defined in claim 1.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance thereof, and one or more pharmaceutically acceptable excipients.

9. Use of the compound according to any one of claims 1 to 6 or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance, or the pharmaceutical composition according to claim 8 in the preparation of a ferroptosis inhibitor.

10. Use of the compound according to any one of claims 1 to 6 or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope-labeled substance, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular disease, renal failure, liver damage, diabetic complications or cancer; Preferably, the neurodegenerative disease is Parkinson's syndrome or Alzheimer's disease; Preferably, the stroke is ischemic stroke or hemorrhagic stroke; Preferably, the cancer is pancreatic cancer.

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