Compound, preparation method therefor and use thereof

Abstract

The present invention provides a compound having a structure as represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotopic label thereof. The present invention further provides a preparation method for the compound or the pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotopic label thereof, and a use for preparing a ferroptosis inhibitor.

Description

A compound, its preparation method and uses Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a compound, its preparation method, and its use in the preparation of ferroptosis inhibitors. Background Technology

[0002] Ferroptosis is a programmed cell death process driven by iron-dependent lipid peroxidation. Morphologically, ferroptosis is characterized by reduced mitochondrial volume, increased mitochondrial membrane density, decreased or absent mitochondrial cristae, and rupture of the outer mitochondrial membrane, while the nucleus remains normal in size. This is the main morphological feature distinguishing ferroptosis from apoptosis, necrosis, and autophagy. Biochemically, ferroptosis is characterized by the accumulation of intracellular iron and reactive oxygen species (ROS), activation of the mitogen-activated protein kinase (MAPK) signaling system, inhibition of the cysteine / glutamate transporter system, and increased NADPH oxidation.

[0003] More and more studies have confirmed that ferroptosis is closely related to many symptoms, disorders and diseases. Dixon et al. first discovered in 2012 that this cell death pattern is associated with 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). Recent studies have further demonstrated the role of ferroptosis in cancer, organ damage, tissue ischemia-reperfusion injury, stroke, cardiovascular disease, and degenerative diseases (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 involves the occurrence and development of various cancers, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, immune-related diseases, liver and kidney failure, inflammation, and metabolic diseases, especially playing an important role in Alzheimer's disease, Parkinson's disease, tumors, stroke, ischemia-reperfusion injury, atherosclerosis, liver and kidney failure, inflammation, and diabetic complications. By stimulating or inhibiting ferroptosis, the occurrence and development of related diseases can be tolerated; therefore, ferroptosis inhibitors are considered potential drugs for treating these diseases.

[0004] Ferrostatin-1 (Fer-1) is a known, potent, and selective inhibitor of ferroptosis (Scott J Dixon 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] However, Ferrostatin-1 activity is not high, with IC50 values ​​exceeding 100 nM in various in vitro ferroptosis cell models. Therefore, discovering and preparing a more active ferroptosis inhibitor is an urgent problem to be solved. Summary of the Invention

[0006] To overcome the shortcomings of existing technologies, the purpose of this invention is to provide a compound with a novel structure that has shown excellent ferroptosis inhibitory activity in multiple cell models, and therefore can be used as a ferroptosis inhibitor for the prevention and / or treatment of various diseases.

[0007] The first aspect of the present invention provides a compound having the structure shown in formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, or isotopic label thereof.

[0008] In formula (Ⅰ), ring A is selected from C6 to C6. 12 The aryl group 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.

[0009] Ring B is selected from 5- to 12-membered heterocyclic groups or 5- to 12-membered heteroaryl groups, 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 substituents selected from halogen, hydroxyl, carboxyl, cyano, amino, C1- to C6 alkyl, C1- to C6 haloalkyl, C1- to C6 alkoxy or C1- to C6 haloalkoxy.

[0010] R1 and R2 are each independently selected from hydrogen, C1-C6 alkyl, or C3-C6 alkyl. 10 cycloalkyl;

[0011] 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, 5-12 membered heterocyclic, C6-C 12 The aryl or 5-12-membered heteroaryl group, wherein the hydroxyl, carboxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl group 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.

[0012] m is selected from 0, 1, 2, 3 or 4.

[0013] In some embodiments of the present invention, in formula (Ⅰ),

[0014] Ring A is selected from C6 to C6. 10 Aryl;

[0015] Ring B is selected from 5- to 8-membered heterocyclic groups, 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, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

[0016] R1 and R2 are each independently selected from hydrogen or C1 to C6 alkyl groups;

[0017] 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 heterocyclic or 5-8 membered heteroaryl, wherein the heterocyclic or heteroaryl is optionally substituted by one or more substituents selected from halogen, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0018] m is selected from 0, 1, 2 or 3.

[0019] In some preferred embodiments of the present invention, in formula (Ⅰ),

[0020] Ring A is selected from phenyl;

[0021] Ring B is selected from 5- to 6-membered heterocyclic groups, wherein the heterocyclic group contains 1 to 2 N atoms as ring atoms (e.g., piperidinyl or piperazine), and the heterocyclic group is optionally substituted by one or more substituents selected from C1- to C4 alkyl, C1- to C4 haloalkyl, C1- to C4 alkoxy or C1- to C4 haloalkoxy.

[0022] R1 and R2 are each independently selected from hydrogen or C1 to C4 alkyl groups;

[0023] 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, wherein the heterocyclic group contains at least one N atom as a ring atom (e.g., may be selected from piperidinyl, piperazine or morpholinyl), 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;

[0024] m is selected from 0, 1, or 2.

[0025] In some preferred embodiments of the present invention, in formula (Ⅰ), R3 may include, but is not limited to, the following groups: H, F, Cl, -OCH3, -CF3,

[0026] In some embodiments of the present invention, the compound has a structure as shown in formula (II):

[0027] In formula (II), Z1, Z2, and Z3 are each independently selected from -C(R4)2-, -NR4-, or bonds. Preferably, Z1, Z2, and Z3 are not simultaneously -NR4-.

[0028] Each R4 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. Preferably, the R4s are the same or different and are independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy.

[0029] R1, R2, R3, and m are each independently defined by any one of the above technical solutions.

[0030] In some embodiments of the present invention, the compound has a structure as shown in formula (Ⅲ):

[0031] In equation (Ⅲ), R1, R2, R3, R4, and m are each independently defined as in any of the above technical solutions.

[0032] In some preferred embodiments of the present invention, in formula (Ⅲ), R1 is selected from hydrogen, and R2 and R4 are each independently selected from methyl, ethyl, n-propyl or isopropyl;

[0033] Each R3 is independently selected from: hydrogen, F, Cl, methoxy, or trifluoromethyl;

[0034] m is selected from 0, 1, or 2.

[0035] In some embodiments of the invention, the compound has a structure as shown in formula (Ⅳ):

[0036] In formula (Ⅳ), Y is selected from -C(R6)2-, -NR6-, -O- or -S-;

[0037] 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, R5 and R6 are each independently selected from hydrogen, F, Cl, hydroxyl, carboxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy. More preferably, R5 and R6 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, carboxyl or trifluoromethyl.

[0038] n is selected from 0, 1, or 2;

[0039] R1, R2, and R4 are each independently defined as in any of the above technical solutions. Preferably, R1, R2, and R4 are each independently selected from hydrogen, methyl, ethyl, n-propyl, or isopropyl. More preferably, R1 is selected from hydrogen, and R2 and R4 are each independently selected from methyl, ethyl, n-propyl, or isopropyl.

[0040] In some embodiments of the invention, the compound has a structure as shown in formula (Ⅳ-1) or formula (Ⅳ-2):

[0041] In formula (Ⅳ-1) or formula (Ⅳ-2), Y, R1, R2, R4, R5, and n are each independently defined as in any of the above technical solutions.

[0042] In some preferred embodiments of the present invention, in formula (Ⅳ-1) or formula (Ⅳ-2), Y is selected from -C(R6)2-, -NR6- or -O-;

[0043] R1, R2, and R4 are each independently selected from hydrogen or C1-C4 alkyl groups (e.g., hydrogen, methyl, ethyl, n-propyl, isopropyl, etc.);

[0044] R5 and R6 are each independently selected from hydrogen, carboxyl, C1-C4 alkyl or C1-C4 haloalkyl (e.g., hydrogen, methyl, ethyl, n-propyl, isopropyl, carboxyl, trifluoromethyl, etc.).

[0045] In some preferred embodiments of the present invention, in formula (Ⅳ-1) or formula (Ⅳ-2), Y is selected from -C(R6)2-, -NH-, -N(CH3)- or -O-;

[0046] R1 is selected from hydrogen, and R2 and R4 are each independently selected from hydrogen, methyl, ethyl, n-propyl or isopropyl;

[0047] R5 and R6 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, carboxyl, or trifluoromethyl.

[0048] In some of the most preferred embodiments of the present invention, the compound may include the following compounds:

[0049] A second aspect of the present invention provides a method for preparing the compound or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope label as described in any of the above technical solutions, wherein the preparation method comprises: reacting an aniline compound with the structure shown in formula (I-1) with a halogenated compound with the structure shown in formula (I-2) to obtain a first intermediate with the structure shown in formula (I-3); reacting the first intermediate with p-toluenesulfonyl hydrazine to obtain a second intermediate with the structure shown in formula (I-4); and reacting the second intermediate with a boric acid compound with the structure shown in formula (I-5) to obtain the compound with the structure shown in formula (I).

[0050] Wherein, X is selected from halogens, for example, from Br;

[0051] Ring A, ring B, R1, R2, R3, and m are each independently defined as described in any of the above technical solutions.

[0052] In some embodiments of the present invention, the reaction raw materials with the structures shown in formulas (I-1), (I-2), (I-5), etc., can be commercially available products or synthesized with reference to existing literature.

[0053] A third aspect of the present invention provides a pharmaceutical composition comprising any one of the compounds described above, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, or isotope label thereof, and one or more pharmaceutically acceptable excipients.

[0054] The fourth aspect of the invention provides the use of any compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, or isotope label thereof, or any pharmaceutical composition thereof, as described in any of the above-described technical solutions, as a medicine (i.e., for therapeutic purposes).

[0055] The fifth aspect of the invention provides the use of any compound of the above-described technical solutions or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotopic label thereof, or a pharmaceutical composition of any of the above-described technical solutions in the preparation of ferroptosis inhibitors.

[0056] The compounds provided by this invention, or their pharmaceutically acceptable salts, stereoisomers, solvates, hydrates, or isotope-labeled derivatives, as well as the pharmaceutical compositions provided by this invention, can be used to prepare ferroptosis inhibitors (i.e., drugs for inhibiting cellular ferroptosis), thereby preventing and / or treating a variety of diseases, such as neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular diseases, renal failure, liver injury, diabetic complications, and cancer, by inhibiting cellular ferroptosis.

[0057] The sixth aspect of the present invention provides the use of any compound of the above-described technical solutions or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotopic label thereof, or any pharmaceutical composition of the above-described technical solutions in the preparation of a medicament for the prevention and / or treatment of neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular disease, renal failure, liver injury, diabetic complications or cancer.

[0058] A seventh aspect of the present invention provides a method for preventing and / or treating a disease, comprising administering to a patient a therapeutically effective dose of any of the above-described technical solutions a compound or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotope label thereof, or a pharmaceutical composition thereof, wherein the disease is a neurodegenerative disease, tissue ischemia-reperfusion injury, stroke, cardiovascular disease, renal failure, liver injury, diabetic complications, or cancer.

[0059] In some embodiments of the invention, the neurodegenerative disease may be Parkinson's syndrome or Alzheimer's disease.

[0060] In some embodiments of the present invention, the stroke may be ischemic stroke or hemorrhagic stroke.

[0061] In some embodiments of the present invention, the cancer may be pancreatic cancer.

[0062] The compounds provided by this invention, or their pharmaceutically acceptable salts, stereoisomers, solvates, hydrates, or isotopic labels, as well as the pharmaceutical compositions provided by this invention, prevent and / or treat the aforementioned diseases by inhibiting ferroptosis.

[0063] The technical solution provided by this invention has the following advantages:

[0064] (1) The compound provided by the present invention has significant differences in chemical structure compared with existing ferroptosis inhibitors, and also has superior cell ferroptosis inhibitory activity. Therefore, it can be used as a ferroptosis inhibitor with great application potential, expanding the types and applications of ferroptosis inhibitors, and thus has very important economic and social significance.

[0065] (2) The compound preparation process provided by the present invention is simple, the reaction conditions are mild, it is easy to operate and control, and the production cost is not high, so it is very suitable for industrial production. Detailed Implementation

[0066] the term

[0067] In this invention, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art.

[0068] Unless the context clearly requires otherwise, throughout the specification and claims, the words “comprising,” “having,” “including,” etc., should be understood to have an inclusive meaning, rather than an exclusive or exhaustive meaning; that is, the meaning of “including but not limited to.” Unless otherwise stated, “comprising” includes “consisting of.”

[0069] The term “and / or”, used alone or in combination in this document, 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.

[0070] The term "C1~C" is used in this article. n "Including C1~C2, C1~C3, ... C1~C n For example, the term "C1-C6" refers to a group having 1 to 6 carbon atoms, meaning the group contains 1, 2, 3, 4, 5, or 6 carbon atoms. Therefore, "C1-C4 alkyl" refers to an alkyl group containing 1 to 4 carbon atoms, where the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Numerical ranges used herein, such as "1-6", "6-12", etc., refer to integers within a given range.

[0071] The term "alkyl" as used alone or in combination herein refers to a saturated aliphatic hydrocarbon that is optionally substituted with a straight chain or optionally substituted with a branched chain. "alkyl" as used 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 to 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. When the term "alkyl" is used in this document and a numerical range is specified, for example, "C1 to C6 alkyl" refers to an alkyl group that can be composed of 1, 2, 3, 4, 5, or 6 carbon atoms. The term alkyl in this document also includes cases where no numerical range is specified. Alkyl groups can be substituted or unsubstituted.

[0072] The term "alkyl" as used in this article refers to an alkyl group linked to other groups, such as alkyl in alkoxy, haloalkyl, or haloalkoxy groups, and is defined in the same way as when used alone.

[0073] The term "haloalkyl" as used alone or in combination herein refers to an alkyl group in which one or more, or even all, of the hydrogen atoms are replaced by a halogen. C1-C6 haloalkyl includes, for example, C1-C4 or C1-C3 haloalkyl, preferably fluoroalkyl and chloroalkyl. Non-limiting examples of haloalkyl include fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, etc. Haloalkyl can be substituted or unsubstituted.

[0074] The term "alkoxy" as used alone or in combination herein refers to an alkyl group as defined above, which is attached to a parent molecule via an oxygen atom. C1-C6 alkoxy groups include, for example, C1-C4 or C1-C3 alkoxy groups. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, etc. Alkoxy groups may be substituted or unsubstituted.

[0075] The term "haloalkoxy" as used alone or in combination herein refers to an alkoxy group in which one or more, or even all, of the hydrogen atoms are replaced by a halogen. C1-C6 haloalkoxy groups include, for example, C1-C4 or C1-C3 haloalkoxy groups. Non-limiting examples of haloalkoxy groups include monofluoromethoxy, monochloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, etc. Haloalkoxy groups can be substituted or unsubstituted.

[0076] The term "cycloalkyl" as used alone or in combination herein refers to an optionally substituted non-aromatic saturated carbocyclic ring, which may include a monocyclic (having one ring), a bicyclic (having two rings), or a polycyclic (having more than two rings), and the ring type includes fused rings, bridged rings, and spirocyclic rings. Preferably, the cycloalkyl group may have 3 to 10 cyclic carbon atoms, for example, 3 to 8 or 3 to 6 cyclic carbon atoms. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The cycloalkyl group may be substituted or unsubstituted.

[0077] The term "heterocyclic group" as used alone or in combination herein refers to a non-aromatic, 5- to 12-membered monocyclic, bicyclic, or polycyclic ring, including fused, bridged, and spirocyclic rings, whose cyclic atoms may comprise 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Preferably, the heterocyclic group may have 5 to 10 cyclic atoms, for example, 5 to 8 cyclic atoms. Non-limiting examples of heterocyclic groups include, but are not limited to, morpholino, oxobutyryl, thiomorpholino, tetrahydrofurano, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidino, 2-oxo-piperidino, pyrrolyl, 2-oxo-pyrrolyl, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazine, hexahydropyrimidine, etc. The heterocyclic group may be substituted or unsubstituted.

[0078] The term "aryl" as used alone or in combination herein refers to an optionally substituted aromatic hydrocarbon group having 6 to 12, such as 6 to 10, cyclic carbon atoms, which can be monocyclic, bicyclic, or polycyclic. A bicyclic or multiple cyclic aryl group can be a monocyclic aryl group fused with other independent rings, such as alicyclic or aromatic rings. Non-limiting examples of monocyclic aryl groups include, but are not limited to, phenyl; non-limiting examples of bicyclic aryl groups include naphthyl, tetrahydronaphthyl, biphenyl, etc.; non-limiting examples of polycyclic aryl groups include, but are not limited to, phenanthryl, indene, anthracene, fluorenyl, azulel, etc. The aryl group can be substituted or unsubstituted.

[0079] The term "heteroaryl" as used alone or in combination herein refers to an optionally substituted aromatic 5- to 12-membered monocyclic, bicyclic, or polycyclic ring, including fused rings, bridged rings, and spirocyclic rings, wherein the cyclic atoms may comprise 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Preferably, the heteroaryl group may have 5 to 8 cyclic atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, inzolyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4 - Triazolyl, pyridyl, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl, etc. Heteroaryl groups can be substituted or unsubstituted.

[0080] The term “halogen” as used alone or in combination in this article refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0081] The term "hydroxyl group" as used alone or in combination in this article refers to -OH.

[0082] The term "carboxyl group" as used alone or in combination in this article refers to -COOH.

[0083] The term "cyano" as used alone or in combination in this article refers to -CN.

[0084] The term "amino" as used alone or in combination in this article refers to -NH2.

[0085] The term “bond” as used alone or in combination in this article refers to the absence of a substituent, where the two ends of the substituent are directly connected to form a bond.

[0086] The term "substituted" as used alone or in combination herein refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experiment or theory). For example, an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0087] The term “pharmaceutically acceptable” as used alone or in combination herein means 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 an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0088] As used alone or in combination herein, the term "pharmaceutically acceptable salt" means a salt obtained by reacting a compound of the present invention, which retains the bioavailability and properties of a free acid or free base, wherein the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base by reacting with a non-toxic inorganic or organic acid. It can be obtained using standard procedures well known in the art. Suitable salts are listed in Remingtong's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).

[0089] As used alone or in combination herein, the term "solvent" refers to a physical aggregate of the compound of the present invention with one or more solvent molecules formed by solvation, the physical aggregate including varying degrees of ions and covalent bonds, such as hydrogen bonds. "Hydrate" is a solvate with water (H₂O) molecules as a solvent.

[0090] The compounds of the present invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, sterically hindered isomers, and geometric (conformal) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention. Unless otherwise stated, the structures described in this invention also include all isomers of this structure, such as diastereomers, enantiomers, sterically hindered isomers, and geometric (conformal) isomers; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, sterically hindered isomers of biphenyl structures (see *Basic Organic Chemistry* (Second Edition), Vol. 1, Xing Qiyi et al., pp. 104-105); PAC, 1996, 68, 2193. (*Basic terminology of stereochemistry* (IUPAC Recommendations 1996, on page 2201)), and (Z) and (E) conformational isomers. Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereomers, sterically hindered isomers, and mixtures of geometric (conformal) isomers, are all within the scope of this invention.

[0091] The carbon, hydrogen, oxygen, sulfur, nitrogen, F, Cl, Br, I, etc. involved in the compounds of this invention include their isotopic forms. The carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the compounds of this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include... 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0092] The term "pharmaceutical composition" as used alone or in combination herein refers to a bioactive compound optionally mixed with at least one pharmaceutically acceptable chemical component (i.e., excipient), which includes, but is not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, excipients, solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, humectants, osmotic pressure regulators, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, antioxidants, chelating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoamers, encapsulating agents, humectants, absorbents, flocculants and anti-flocculators, filter aids, release inhibitors, etc.

[0093] The terms “independently” or “independently” as used alone or in combination herein mean that the definition of each group in the general formula is independent and unaffected by other groups, and that when two or more groups have the same options, the options they choose may be the same or different. For example, in formula (I), when there are two or more substituents R3 on the benzene ring, the optional substituents of each R3 may be the same or different.

[0094] The terms “optional” or “optionally” as used alone or in combination herein mean that an event or condition described below may or may not occur, including both cases in which the event or condition occurs and cases in which it does not occur. For example, “optionally alkyl-substituted heterocyclic group” means that the alkyl group may or may not be present, including both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group.

[0095] The terms “subject” or “patient” as used alone or in combination herein refer to animals, including human patients in need of treatment. In some respects, this document may also be applied in veterinary practice to any mammal or other animal in need of such immune-targeted therapy, including, but not limited to, non-human primates, dogs, felines, pigs, horses, and any other animals.

[0096] The term "treatment" and other similar synonyms, used alone or in combination herein, include relieving, reducing, or improving symptoms of a disease or condition; preventing other symptoms; improving or preventing the underlying metabolic causes of symptoms; inhibiting a disease or condition, such as preventing its progression; alleviating a disease or condition; improving a disease or condition; relieving symptoms caused by a disease or condition; or stopping the symptoms of a disease or condition. Furthermore, the term includes the purpose of prevention. The term also includes achieving therapeutic and / or preventative effects.

[0097] The term “room temperature” as used alone or in combination in this article refers to 25±5℃.

[0098] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0099] Unless otherwise specified, all raw materials or reagents used in the embodiments and comparative examples of this invention are commercially available products, and all percentages used are mass percentages unless otherwise specified.

[0100] In the embodiments and comparative examples of the present invention, the silica gel column chromatography used for compound purification uses 200-300 mesh silica gel as the carrier, and unless otherwise specified, the elution system is petroleum ether / ethyl acetate.

[0101] Example 1: Preparation of Compound 1

[0102] Formaldehyde aqueous solution (total 0.672 g, 37% concentration, 2.0 eq) and 1-(4-bromophenyl)piperazine (1 g, 1.0 eq) were added sequentially to the reaction vessel, and the mixture was stirred. Formic acid (0.381 g, 2.0 eq) was added dropwise. After the addition was complete, the temperature was raised to 80±5℃ and the reaction was maintained at this temperature for 1 h. TLC showed that the starting material was completely converted. The heating was turned off, and when the reaction temperature was lowered to 30℃, 20% NaOH aqueous solution was added to the reaction system to adjust the pH to 8-9. The mixture was extracted with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated until no obvious fractions were observed. The material was then transferred to a vacuum drying oven and dried at 40℃ to obtain 0.919 g of compound 1b, yield: 87%.

[0103] Tetrahydrofuran (10 mL) and compound 1b (900 mg, 1.0 eq) were added sequentially to the reaction flask. The temperature was lowered to below -60°C, and n-butyllithium (1.7 mL, 1.2 eq, 2.5 M) was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 2 h. Trimethyl borate (550 mg, 1.5 eq, diluted with an equal volume of tetrahydrofuran) was added dropwise, with the temperature controlled to not exceed -60°C during the addition. After the addition was complete, the mixture was kept at this temperature and stirred for 2 h, and then naturally warmed to room temperature and reacted for 16 h. Saturated ammonium chloride solution was added dropwise to adjust the pH of the system to approximately 8.3, and the mixture was stirred for 2 h. The mixture was filtered, and the filter cake was washed sequentially with water and n-heptane. The resulting filter cake was then slurried with a mixture of water and ethyl acetate (volume ratio 3:2) for 2 h. After filtration, the mixture was dried in a vacuum oven at 40°C to obtain 528 mg of compound 1c, with a yield of 68%.

[0104] 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 sequentially to the reaction flask, followed by DMF (50 mL). The mixture was stirred at room temperature for 24 h. TLC showed complete conversion of the starting material. Water (100 mL) was added to the reaction mixture, and the mixture was stirred for 1 h. The mixture was filtered, the filter cake was washed with water, and the filter cake was placed in a vacuum drying oven and dried at 55 °C for 16 h to obtain 3.78 g of compound 1d, yield: 96.85%.

[0105] Compound 1d (3.78 g, 1.0 eq) and methanol (75 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times, followed by the addition of a Pd / C catalyst (0.378 g, 10% w / w), and then purged with hydrogen three times. The reaction was carried out under hydrogen atmosphere with stirring at room temperature for 5 h. TLC showed complete conversion of the starting material. The reaction mixture was filtered through a diatomaceous earth filter, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to give 2.58 g of compound 1e, yield: 79.02%. MS m / z (ESI): 191.1544 (M+H) + .

[0106] Compound 1e (0.5 g, 1.0 eq), m-bromoacetophenone (0.523 g, 1.0 eq), tris(dibenzylacetone)dipalladium (120 mg, 0.05 eq), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (152 mg, 0.1 eq), cesium carbonate (1.284 g, 1.5 eq), and 1,4-dioxane (10 mL) were added sequentially to the reaction flask. The reaction was carried out at 105 °C for 16 h under nitrogen atmosphere. TLC showed complete conversion of the starting material. The mixture was cooled to room temperature, filtered through a diatomaceous earth sieve, concentrated, and purified by silica gel column chromatography to give 250 mg of compound 1f, yield: 30.84%. MS m / z (ESI): 309.1874 (M+H) + .

[0107] Compound 1f (250 mg, 1.0 eq), p-toluenesulfonyl hydrazine (181 mg, 1.2 eq), 3M HCl in MeOH (0.14 mL, 0.5 eq), and methanol (5 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 6 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 1 g of 250 mg compound, yield: 64.75%.

[0108] Compound 1 g (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 sequentially to the reaction flask. The reaction was carried out at 80 °C for 18 h under nitrogen atmosphere. TLC showed complete conversion of the starting material. The mixture was cooled to room temperature, extracted with 5% sodium hydroxide aqueous solution, and the organic phase was backwashed twice with water. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated, and purified by silica gel column chromatography using dichloromethane / methanol as the elution system, yielding 131 mg of compound 1 (yield: 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).

[0109] Example 2 Preparation of Compound 2

[0110] 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 sequentially to the reaction flask, followed by DMF (100 mL). The mixture was stirred at room temperature for 24 h. TLC showed complete conversion of the starting materials. Water (200 mL) was added to the reaction mixture, and the mixture was stirred for 1 h. The mixture was filtered, the filter cake was washed with water, and the filter cake was placed in a vacuum drying oven and dried at 55 °C for 16 h to obtain 8.482 g of compound 2a, yield: 87.28%.

[0111] Compound 2a (8.0 g, 1.0 eq) and methanol (160 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times, followed by the addition of a Pd / C catalyst (0.8 g, 10% w / w), and then purged with hydrogen three times. The reaction was carried out under hydrogen atmosphere and stirred at room temperature for 5 h. TLC showed complete conversion of the starting material. The reaction mixture was filtered through a diatomaceous earth liner, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to give 6.724 g of compound 2b, yield: 94.28%. MS m / z (ESI): 245.1263 (M+H) + .

[0112] Compound 2b (642 mg, 1.0 eq), m-bromoacetophenone (523 mg, 1.0 eq), tris(dibenzylacetone)dipalladium (120 mg, 0.05 eq), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (152 mg, 0.1 eq), cesium carbonate (1.284 g, 1.5 eq), and 1,4-dioxane (12 mL) were added sequentially to the reaction flask. The reaction was carried out at 105 °C for 24 h under nitrogen atmosphere. TLC showed complete conversion of the starting material. The mixture was cooled to room temperature, filtered through a diatomaceous earth sieve, and the filtrate was concentrated and purified by silica gel column chromatography to give 350 mg of compound 2c, yield: 36.75%. MS m / z (ESI): 363.1611 (M+H) + .

[0113] Compound 2c (350 mg, 1.0 eq), p-toluenesulfonyl hydrazine (216 mg, 1.2 eq), 3M HCl in MeOH (0.16 mL, 0.5 eq), and methanol (7 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 6 h under nitrogen atmosphere. TLC showed complete conversion of the starting material. The mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography to give 344 mg of compound 2d, yield: 66.84%.

[0114] 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 sequentially to a reaction flask. The reaction was carried out at 80 °C for 24 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution, and the organic phase was backwashed twice with water. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the elution system, yielding 148 mg of compound 2, yield: 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).

[0115] Example 3 Preparation of Compound 3

[0116] 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 sequentially to the reaction flask, followed by DMF (50 mL). The mixture was stirred at room temperature for 5 h. TLC showed complete conversion of the starting materials. Ice water (150 mL) was added to the reaction mixture, and the mixture was stirred for 1 h. The mixture was filtered, the filter cake was washed with water, and the filter cake was placed in a vacuum drying oven and dried at 55 °C for 16 h to obtain 3.56 g of compound 3a, yield: 96.49%.

[0117] Compound 3a (3.51 g, 1.0 eq) and methanol (70 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times, followed by the addition of Pd / C catalyst (0.35 g, 10% w / w). The mixture was then purged with hydrogen three times. The reaction was carried out under hydrogen atmosphere and stirred at room temperature for 5 h. TLC showed complete conversion of the starting material. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain 3.0 g of compound 3b, which was used directly in the next step. Yield: 99.85%.

[0118] 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-dimethyloxanthracene) (610 mg, 0.1 eq), cesium carbonate (5.11 g, 1.5 eq), and 1,4-dioxane (30 mL) were added sequentially to the reaction flask. The reaction was carried out at 105 °C for 15 h under nitrogen atmosphere. TLC showed complete conversion of the starting materials. The mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated, and purified by silica gel column chromatography to obtain 833 mg of compound 3c, yield: 26.88%.

[0119] Compound 3c (830 mg, 1.0 eq), p-toluenesulfonyl hydrazine (630 mg, 1.2 eq), 3M HCl in MeOH (0.47 mL, 0.5 eq), and methanol (16 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 6 h under nitrogen atmosphere. TLC showed complete conversion of the starting material. The mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography to give 505 mg of compound 3d, yield: 38.81%. MS m / z (ESI): 465.1887 (M+H) + .

[0120] 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 sequentially to a reaction flask. The reaction mixture was incubated at 80 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was then backwashed twice with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using dichloromethane / methanol as the elution system, yielding 256 mg of compound 3, with a yield of 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).

[0121] Example 4: Preparation of Compound 4

[0122] 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 sequentially to a reaction flask, followed by DMF (50 mL). The mixture was stirred at 110 °C for 50 h, cooled to room temperature, and water and ethyl acetate were added to the reaction solution. The mixture was extracted, separated, and the extract was backwashed twice with saturated NaCl aqueous solution. The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 2.74 g of compound 4a, yield: 70.2%.

[0123] Compound 4a (2.74 g, 1.0 eq) and methanol (30 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times, followed by the addition of Pd / C catalyst (0.274 g, 10% w / w). The mixture was then purged with hydrogen three times. The reaction was carried out under hydrogen atmosphere and stirred at room temperature for 6 h. TLC showed complete conversion of the starting material. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, and purified by silica gel column chromatography to give 1.32 g of compound 4b, yield: 55.7%.

[0124] 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'-bis(diphenylphosphine) (402 mg, 0.1 eq), cesium carbonate (3.13 g, 1.5 eq), and toluene (40 mL) were added sequentially to the reaction flask. The reaction was carried out at 110 °C for 24 h under nitrogen atmosphere. After cooling to room temperature, 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, yield: 33.0%.

[0125] Compound 4c (719 mg, 1.0 eq), p-toluenesulfonyl hydrazine (521 mg, 1.2 eq), 3M HCl in MeOH (0.4 mL, 0.5 eq), and methanol (15 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 12 h under nitrogen atmosphere. TLC showed that the starting material was basically completely converted. The mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography to obtain 384 mg of compound 4d, yield: 34.56%.

[0126] 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 sequentially to the reaction flask. The reaction was carried out at 80 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution, and the organic phase was backwashed twice with water. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the elution system, yielding 378 mg of compound 4, yield: 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).

[0127] Example 5: Preparation of Compound 5

[0128] 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'-bis(diphenylphosphine) (711 mg, 0.1 eq), cesium carbonate (7.44 g, 1.5 eq), and toluene (35 mL) were added sequentially to a reaction flask. The reaction mixture was incubated at 110 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and purified by silica gel column chromatography to give 1.02 g of compound 6a, yield: 42.29%. MS m / z (ESI): 212.1069 (M+H) + .

[0129] Compound 5a (1.02 g, 1.0 eq), p-toluenesulfonyl hydrazine (1.079 g, 1.2 eq), 3M HCl in MeOH (0.8 mL, 0.5 eq), and methanol (20.5 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 4 h under nitrogen atmosphere. TLC showed that the starting material was basically completely converted. The mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography to give 1.76 g of compound 5b, yield: 96.02%.

[0130] 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 sequentially to the reaction flask. The reaction was carried out at 80 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution, and the organic phase was backwashed twice with water. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the elution system, yielding 561 mg of compound 5, yield: 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).

[0131] Example 6: Preparation of Compound 6

[0132] 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'-bis(diphenylphosphine) (711 mg, 0.1 eq), cesium carbonate (7.44 g, 1.5 eq), and toluene (35 mL) were added sequentially to a reaction flask. The reaction mixture was incubated at 110 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and purified by silica gel column chromatography to give 1.37 g of compound 6a, yield: 42.96%. MS m / z (ESI): 280.0943 (M+H) + .

[0133] Compound 6a (0.7 g, 1.0 eq), p-toluenesulfonyl hydrazine (560 mg, 1.2 eq), 3M HCl in MeOH (0.43 mL, 0.5 eq), and methanol (14 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 6 h under nitrogen atmosphere. TLC showed that the starting material was basically completely converted. The mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography to give 0.706 g of compound 6b, yield: 62.92%.

[0134] 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 sequentially to a reaction flask. The reaction mixture was incubated at 80 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was then backwashed twice with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using dichloromethane / methanol as the elution system, yielding 320 mg of compound 6 (yield: 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).

[0135] Example 7 Preparation of Compound 7

[0136] 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 sequentially to the reaction flask, followed by DMF (50 mL). The mixture was stirred at 90 °C for 2 h. TLC showed complete conversion of the starting materials. Ice water (150 mL) was added to the reaction mixture, and the mixture was stirred for 1 h. The mixture was filtered, the filter cake was washed with water, and the filter cake was placed in a vacuum drying oven and dried at 55 °C for 16 h to obtain 3.065 g of compound 7a, yield: 78.19%.

[0137] Compound 7a (2.76 g, 1.0 eq) and methanol (55 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times, followed by the addition of Pd / C catalyst (0.275 g, 10% w / w). The mixture was then purged with hydrogen three times. The reaction was carried out under hydrogen atmosphere and stirred at room temperature for 5 h. TLC showed complete conversion of the starting material. The reaction mixture 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. Yield: 96.39%.

[0138] 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'-bis(diphenylphosphine) (600 mg, 0.1 eq), cesium carbonate (4.72 g, 1.5 eq), and toluene (15 mL) were added sequentially to a reaction flask. The reaction was carried out at 110 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, 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, yield: 44.63%.

[0139] Compound 7c (1.33 g, 1.0 eq), p-toluenesulfonyl hydrazine (0.969 g, 1.2 eq), 3M HCl in MeOH (0.72 mL, 0.5 eq), and methanol (27 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 16 h under nitrogen atmosphere. TLC showed that the starting material was basically completely converted. The mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography to give 1.607 g of compound 7d, yield: 78.21%.

[0140] 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 sequentially to the reaction flask. The reaction was carried out at 80 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution, and the organic phase was backwashed twice with water. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the elution system, yielding 345 mg of compound 7, yield: 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).

[0141] Example 8: Preparation of Compound 8

[0142] 1-tert-Butoxycarbonyl-4-methylpiperidine-4-carboxylic acid methyl ester (1.0 g, 1.0 eq) and ethyl acetate (20 mL) were added sequentially to the reaction flask and stirred until dissolved. Then, p-toluenesulfonic acid monohydrate (2.22 g, 3.0 eq) was added, and the mixture was stirred at 65 °C for 0.5 h. The reaction solution was concentrated to dryness to obtain compound 8a, which was used directly in the next step.

[0143] 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 sequentially to the reaction flask, and the mixture 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, with a yield of 91.36%.

[0144] Compound 8b (988 mg, 1.0 eq) and methanol (15 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times, followed by the addition of Pd / C catalyst (99 mg, 10% w / w). The mixture was then purged with hydrogen three times. The reaction was carried out under hydrogen atmosphere and stirred at room temperature for 2 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain 817 mg of compound 8c, yield: 92.84%.

[0145] 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'-bis(diphenylphosphine) (205 mg, 0.1 eq), cesium carbonate (1.61 g, 1.5 eq), and toluene (15 mL) were added sequentially to the reaction flask. The reaction was carried out at 110 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, 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, yield: 57.64%.

[0146] Compound 8d (695 mg, 1.0 eq), p-toluenesulfonyl hydrazine (425 mg, 1.2 eq), 3M HCl in MeOH (0.32 mL, 0.5 eq), and methanol (14 mL) were added sequentially to the reaction flask. The reaction was carried out at 45 °C for 6 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 707 mg of compound 8e, yield: 69.72%.

[0147] 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 sequentially to the reaction flask. The reaction was carried out at 80 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was backwashed twice with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the elution system, yielding 462 mg of compound 8f, yield: 67%.

[0148] Compound 8f (342 mg, 1.0 eq), tetrahydrofuran (4 mL), methanol (0.7 mL), and water (1 mL) were added sequentially to a reaction flask and dispersed thoroughly. Then, 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, dispersed in water, and the pH was adjusted to 6-7 with saturated citric acid solution. The mixture was then extracted with dichloromethane, and the organic phases were combined. The organic phase was backwashed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with a dichloromethane / methanol elution system, yielding 198 mg of compound 8, yield: 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).

[0149] Example 9: Preparation of Compound 9

[0150] 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 sequentially to a reaction flask, followed by DMF (50 mL). The mixture was stirred at 90 °C for 4 h. Ice water (150 mL) was added to the reaction mixture, and the mixture was stirred for 1 h. The mixture was filtered, the filter cake was washed with water, and the filter cake was placed in a 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%.

[0151] Compound 9a (3.95 g, 1.0 eq) and methanol (80 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times. Then, Pd / C catalyst (0.395 g, 10% w / w) was added, and the mixture was purged with hydrogen three times. The reaction was carried out under hydrogen atmosphere and stirred at room temperature for 4 h. 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.

[0152] 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'-bis(diphenylphosphine) (376 mg, 0.1 eq), cesium carbonate (2.836 g, 1.5 eq), and toluene (21 mL) were added sequentially to the reaction flask. The reaction was carried out at 110 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, 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, yield: 38.85%.

[0153] Compound 9c (729 mg, 1.0 eq), p-toluenesulfonyl hydrazine (502 mg, 1.2 eq), 3M HCl in MeOH (0.4 mL, 0.5 eq), and methanol (15 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 6 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 615 mg of compound 9d, yield: 55.56%.

[0154] 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 sequentially to the reaction flask. The reaction was carried out at 80 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution, and the organic phase was backwashed twice with water. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the eluent, yielding 77 mg of compound 9, yield: 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).

[0155] Example 10: Preparation of Compound 10

[0156] Compound 2-fluoro-4-chloroaniline (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'-bis(diphenylphosphine) (890 mg, 0.1 eq), cesium carbonate (6.715 g, 1.5 eq), and toluene (50 mL) were added sequentially to a reaction flask. The reaction was carried out at 110 °C for 24 h under nitrogen atmosphere. After cooling to room temperature, 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, yield: 27.19%.

[0157] Compound 10a (1.051 g, 1.0 eq), p-toluenesulfonyl hydrazine (891 mg, 1.2 eq), 3M HCl in MeOH (0.67 mL, 0.5 eq), and methanol (20 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 6 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 1.409 g of compound 10b, yield: 81.82%.

[0158] 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 sequentially to a reaction flask. The reaction was carried out at 80 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution, and the organic phase was backwashed twice with water. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the elution system, yielding 812 mg of compound 10, with a yield of 58.71%. MS m / z (ESI): 424.1947 (M+H) + . 1HNMR(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).

[0159] Example 11 Preparation of Compound 11

[0160] 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-dimethyloxanthracene) (800 mg, 0.1 eq), cesium carbonate (6.72 g, 1.5 eq), and 1,4-dioxane (40 mL) were added sequentially to a reaction flask. The reaction was carried out at 105 °C for 12 h under nitrogen atmosphere. TLC showed complete conversion of the starting materials. The mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated, and purified by silica gel column chromatography to give 1.93 g of compound 11a, yield: 58.29%.

[0161] Compound 11a (1.93 g, 1.0 eq), p-toluenesulfonyl hydrazine (1.79 g, 1.2 eq), 3M HCl in MeOH (1.33 mL, 0.5 eq), and methanol (38 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 6 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 1.0 g of compound 11b, yield: 30.53%.

[0162] 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 sequentially to a reaction flask. The reaction was carried out at 80 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution, and the organic phase was backwashed twice with water. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the eluent, yielding 420 mg of compound 11, with a yield of 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).

[0163] Example 12 Preparation of Compound 12

[0164] The following compounds were added sequentially to a 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'-bis(diphenylphosphine) (506 mg, 0.1 eq), cesium carbonate (3.97 g, 1.5 eq), and toluene (20 mL). The reaction was carried out at 110 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, 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, yield: 55.74%.

[0165] Compound 12a (1.092 g, 1.0 eq), p-toluenesulfonyl hydrazine (1.011 g, 1.2 eq), 3M HCl in MeOH (0.8 mL, 0.5 eq), and methanol (20 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 5 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 1.273 g of compound 12b, yield: 68.7%.

[0166] 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 sequentially to a reaction flask. The reaction was carried out at 80 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was then backwashed twice with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the elution system, yielding 626 mg of compound 12, yield: 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).

[0167] Example 13 Preparation of Compound 13

[0168] Compound o-methoxyaniline (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-dimethyloxanthracene) (470 mg, 0.1 eq), cesium carbonate (3.97 g, 1.5 eq), and 1,4-dioxane (20 mL) were added sequentially to a reaction flask. The reaction was carried out at 105 °C for 12 h under nitrogen atmosphere. TLC showed complete conversion of the starting materials. The mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated, and purified by silica gel column chromatography to give 0.924 g of compound 13a, yield: 47.17%.

[0169] Compound 13a (924 mg, 1.0 eq), p-toluenesulfonyl hydrazine (856 mg, 1.2 eq), 3M HCl in MeOH (0.7 mL, 0.5 eq), and methanol (20 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 5 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 0.719 g of compound 13b, yield: 45.85%.

[0170] 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 sequentially to the reaction flask. The reaction was carried out at 80 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution, and the organic phase was backwashed twice with water. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the elution system, yielding 543 mg of compound 13, yield: 77.02%. MS m / z (ESI): 402.2542 (M+H) + . 1HNMR (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).

[0171] Example 14 Preparation of Compound 14

[0172] Compounds 2,4-dimethoxyaniline (1.245 g, 1.0 eq), m-bromoacetophenone (2.1 g, 1.3 eq), tris(dibenzylacetone)dipalladium (370 mg, 0.05 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (470 mg, 0.1 eq), cesium carbonate (3.97 g, 1.5 eq), and 1,4-dioxane (25 mL) were added sequentially to a reaction flask. The reaction was carried out at 105 °C for 12 h under nitrogen atmosphere. TLC showed complete conversion of the starting materials. The mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated, and purified by silica gel column chromatography to obtain 400 mg of compound 14a, yield: 18.16%.

[0173] Compound 14a (400 mg, 1.0 eq), p-toluenesulfonyl hydrazine (329 mg, 1.2 eq), 3M HCl in MeOH (0.3 mL, 0.5 eq), and methanol (8 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 5 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 579 mg of compound 14b, yield: 89.35%.

[0174] 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 sequentially to the reaction flask. The reaction was carried out at 80 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution, and the organic phase was backwashed twice with water. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the elution system, yielding 364 mg of compound 14, yield: 64.03%. MS m / z (ESI): 432.2657 (M+H) + . 1HNMR(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).

[0175] Example 15 Preparation of Compound 15

[0176] 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 sequentially to a reaction flask, followed by DMSO (30 mL). The mixture was stirred at 120 °C for 50 h, cooled to room temperature, and water and ethyl acetate were added to the reaction solution. The mixture was extracted, separated, and the extract was backwashed twice with saturated NaCl aqueous solution. The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 1.275 g of compound 15a, yield: 32.8%.

[0177] Compound 15a (1.275 g, 1.0 eq) and methanol (30 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times, followed by the addition of Pd / C catalyst (0.127 g, 10% w / w). The mixture was then purged with hydrogen three times. The reaction mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain 1.071 g of compound 15b, yield: 94.31%.

[0178] 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'-bis(diphenylphosphine) (250 mg, 0.1 eq), cesium carbonate (2.0 g, 1.5 eq), and toluene (15 mL) were added sequentially to the reaction flask. The reaction was carried out at 110 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, 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, yield: 36.87%.

[0179] Compound 15c (547 mg, 1.0 eq), p-toluenesulfonyl hydrazine (337 mg, 1.2 eq), 3M HCl in MeOH (0.24 mL, 0.5 eq), and methanol (11 mL) were added sequentially to the reaction flask. The reaction was carried out at 50 °C for 6 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 480 mg of compound 15d, yield: 59.92%.

[0180] 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 sequentially to a reaction flask. The reaction mixture was incubated at 80 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was extracted with 5% sodium hydroxide aqueous solution. The organic phase was then backwashed twice with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using dichloromethane / methanol as the elution system, yielding 255 mg of compound 15, yield: 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).

[0181] Comparative Example 1 Compound Ferrostain-1

[0182] Compound Ferrostain-1 was purchased from Selleckchem, catalog number: S7243, lot number: S724303.

[0183] Preparation of compound ref-01 in Comparative Example 2

[0184] Phenyrazine (2.0 g, 1.0 eq) and toluene (20 mL) were added sequentially to the reaction flask, followed by acetyl chloride (1.714 g, 2.0 eq). The reaction was incubated at 50 °C for 1 h, then cooled to room temperature. The reaction solution was concentrated under reduced pressure to obtain compound ref-01a, which was used directly in the next step. MS m / z (ESI): 226.0870 (M+H) + .

[0185] Compound ref-01a (2.568 g, 1.0 eq) and dichloromethane (50 mL) were added sequentially to a reaction flask. The mixture was cooled to 0 °C, followed by the addition of acetyl chloride (0.895 g, 1.0 eq) and aluminum chloride (5.776 g, 3.8 eq). The mixture was stirred at 0 °C for 15 min, then heated to room temperature and reacted for another 0.5 h. The temperature was then raised to 40 °C and maintained for 3 h. The mixture was cooled to room temperature, and the reaction was quenched slowly with water. The mixture was extracted with dichloromethane, and the organic phase was backwashed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 2.01 g of compound ref-01b, yield: 65.97%. MS m / z (ESI): 290.0795 (M+Na). + .

[0186] Compound ref-01b (2.01 g, 1.0 eq), anhydrous ethanol (40 mL), and concentrated hydrochloric acid (7.5 mL) were added sequentially to a reaction flask. The reaction was maintained at 70 °C for 1 h under nitrogen atmosphere, cooled to room temperature, and the reaction was quenched with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, backwashed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.419 g of compound ref-01c, yield: 83.77%. MS m / z (ESI): 226.0849 (M+H) + .

[0187] Compound ref-01c (1.419 g, 1.0 eq), p-toluenesulfonyl hydrazine (1.408 g, 1.2 eq), 3M HCl in MeOH (1.05 mL, 0.5 eq), and methanol (28 mL) were added sequentially to the reaction flask. The reaction was carried out 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) + .

[0188] 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 sequentially to a reaction flask. The reaction was carried out at 110 °C for 3 h under nitrogen atmosphere. After cooling to room temperature, the reaction solution was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phase was backwashed twice with water. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the elution system, yielding 365 mg of compound ref-01, yield: 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).

[0189] Preparation of compound ref-02 in Comparative Example 3

[0190] Compound 1e (1 g, 1.0 eq), 4-bromobenzaldehyde (1.07 g, 1.1 eq), tris(dibenzylacetone)dipalladium (241 mg, 0.05 eq), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (304 mg, 0.1 eq), cesium carbonate (2.568 g, 1.5 eq), and 1,4-dioxane (20 mL) were added sequentially to the reaction flask. The reaction was carried out at 105 °C for 6 h under nitrogen atmosphere. TLC showed complete conversion of the starting materials. The mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated, and purified by silica gel column chromatography to obtain 460 mg of compound ref-02a, yield: 29.75%.

[0191] Compound ref-02a (460 mg, 1.0 eq), ethanol (11.5 mL), water (2.3 mL), and tetrahydrofuran (4.6 mL) were added sequentially to the reaction flask, followed by hydroxylamine hydrochloride (120 mg, 1.1 eq). The reaction was carried out at room temperature for 20 h. TLC showed that the starting material was completely converted. The reaction solution was concentrated to obtain compound ref-02b, which was used directly in the next step.

[0192] Compound ref-02b (484 mg, 1.0 eq), ethanol (15 mL), and borane-pyridine (290 mg, 2.0 eq) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and then 10% hydrochloric acid (3.1 mL) was added. The mixture was stirred at 0 °C for 10 min, then heated to room temperature and reacted for another 1 h at room temperature. TLC showed that the starting 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. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound ref-02c, which was used directly in the next step.

[0193] 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 sequentially to a reaction flask. The mixture was cooled to 0 °C, and then N,N-diisopropylethylamine (130 mg, 1.3 eq) was added. The mixture was stirred at 0 °C for 10 min, followed by the addition of DMT-MM (280 mg, 1.3 eq). The mixture was stirred at 0 °C for another 30 min, then heated to room temperature and reacted for 1.5 h. TLC showed complete conversion of the starting material. The reaction was quenched with water, and the mixture was extracted with dichloromethane. The organic phase was backwashed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane / methanol as the elution system, yielding 108 mg of compound ref-02, yield: 31.01%. MS m / z (ESI): 452.3025 (M+H) + . 1 HNMR (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).

[0194] Study on the inhibitory rate of experimental compound on Ferrottosis

[0195] To investigate the inhibitory rate of the compound of this invention on ferroptosis, a ferroptosis screening model was constructed in this experiment, as follows: The ferroptosis screening model mainly employed the CCK8 cell viability assay. First, human fibrosarcoma cells HT1080 (Chinese Academy of Sciences Cell Bank, TCHU170) and human neuroblastoma cells SH-SY5Y (Chinese Academy of Sciences Cell Bank, TCHU97) were cultured in dishes. The culture medium for HT1080 cells was MEM + 10% FBS + 2 mM L-Glutamine; the culture medium for SH-SY5Y cells was DMEM + 10% FBS. Cells in the logarithmic growth phase were seeded at a specific number (5000 cells / well), 80 μL per well, and then incubated at 37°C in a 5% CO2 environment to allow cell adhesion. After 24 hours, 10 μL of various concentrations of the compounds of this invention (starting at 10 μM or 1 μM, 3-fold dilution, 8 concentrations) prepared in cell culture medium and 10 μL of the ferroptosis inducer Erastin (Selleck, S7242) at a final concentration of 10 μM were added. Each compound was used in triplicate to ensure the accuracy of the results. Simultaneously, a positive control group (containing 10 μL of 1 μM of the compounds Ferrostain-1, ref-01, and ref-02 prepared in the same culture medium, starting at 1 μM, 3-fold dilution, 8 concentrations), a blank control group (containing the same volume of cell culture medium with the same concentration of DMSO, but without cells), and a solvent control group (containing the same volume of cell culture medium with the same concentration of DMSO, but with cells) were set up. Each group was also used in triplicate to ensure the accuracy of the results. After drug addition, the cells were placed in an incubator and cultured for 24 hours. Add 10 μL of CCK8 solution (Topscience, C0005) to each well, incubate for 2-4 hours, and then measure the absorbance at 450 nm using a microplate reader to calculate the inhibition rate of the compound against ferroptosis. The inhibition rate (IR) is calculated using the following formula: Inhibition rate % (IR) = [1 - (A experimental group - A blank) / (A solvent - A blank)] * 100%

[0196] The inhibition rate variation curve was fitted using GraphPadPrism6 software, and the IC was calculated. 50 value.

[0197] Experimental results show that compounds 1-15 of this invention have good inhibitory activity against ferroptosis in both HT1080 and SH-SY5Y cells, with an IC50 concentration of 100 mg / kg / dL. 50 The values ​​are all below 200 nM. The partial activity results of compounds 1 and other structures are shown in Table 1.

[0198] Table 1. Results of inhibitory activities of some compounds on ferroptosis in HT1080 and SH-SY5Y cells.

[0199] As shown in Table 1, the experimental results demonstrate that the compounds of this invention possess excellent ferroptosis inhibitory activity. Compound 1 and others exhibit significantly superior structures compared to existing control compounds Ferrostain-1, ref-01, and ref-02. For example, the inhibitory activity of compounds 1, 2, 3, and 4 in HT1080 cells is 11.6–31.4 times that of Ferrostain-1, 9.4–25.4 times that of ref-01, and 12.9–35.1 times that of ref-02. Similarly, the inhibitory activity of compounds 1, 2, 3, and 4 in SH-SY5Y cells is 6.9–12.2 times that of Ferrostain-1, 7.9–13.9 times that of ref-01, and 8.0–14.0 times that of ref-02. This indicates that the compounds of this invention can be used to prepare ferroptosis inhibitors for the prevention and / or treatment of various diseases related to ferroptosis, such as neurodegenerative diseases, Parkinson's syndrome, stroke, cardiovascular diseases, renal failure, diabetic complications, and cancer.

[0200] Unless otherwise specified, the terms used in this invention have the meanings commonly understood by those skilled in the art.

[0201] The embodiments described in this invention are for illustrative purposes only and are not intended to limit the scope of protection of this invention. Those skilled in the art can make various other substitutions, changes and improvements within the scope of this invention. Therefore, this invention is not limited to the above embodiments, but is only defined by the claims.

Claims

1. A compound having the structure shown in formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, or isotopic label thereof, In formula (Ⅰ), ring A is selected from C6 to C6. 12 The aryl group 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. Ring B is selected from 5- to 12-membered heterocyclic groups or 5- to 12-membered heteroaryl groups, 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 substituents selected from halogen, hydroxyl, carboxyl, cyano, amino, C1- to C6 alkyl, C1- to C6 haloalkyl, C1- to C6 alkoxy or C1- to C6 haloalkoxy. R1 and R2 are each independently selected from hydrogen, C1-C6 alkyl, or C3-C6 alkyl. 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, 5-12 membered heterocyclic, C6-C 12 The aryl or 5-12-membered heteroaryl group, wherein the hydroxyl, carboxyl, amino, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl group 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 form thereof, wherein, In formula (Ⅰ), Ring A is selected from C6 to C6. 10 Aryl; Ring B is selected from 5- to 8-membered heterocyclic groups, 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, hydroxyl, 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 to C6 alkyl groups; 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 heterocyclic or 5-8 membered heteroaryl, wherein the heterocyclic or heteroaryl is optionally substituted by 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 form thereof, wherein, In formula (Ⅰ), Ring A is selected from phenyl; Ring B is selected from 5- to 6-membered heterocyclic groups, 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- to C4 alkyl, C1- to C4 haloalkyl, C1- to C4 alkoxy or C1- to C4 haloalkoxy; the heterocyclic group is preferably selected from piperidinyl or piperazine. R1 and R2 are each independently selected from hydrogen or C1 to C4 alkyl groups; Each R3 is independently selected from hydrogen, F, Cl, hydroxyl, carboxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or a 5- or 6-membered heterocyclic group, wherein 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, piperazineyl, or morpholinyl. m is selected from 0, 1, or 2.

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

5. The compound according to claim 4, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, or isotope-labeled form thereof, wherein, The compound has the structure 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, and are 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, and R4 are each independently defined as described in claim 4; Preferably, the compound has a structure as shown in formula (Ⅳ-1) or formula (Ⅳ-2): In equation (Ⅳ-1) or equation (Ⅳ-2), Y, R1, R2, R4, R5, and n are each independently defined as in equation (Ⅳ); More preferably, R1, R2, and R4 are each independently selected from hydrogen, methyl, ethyl, n-propyl, or isopropyl.

6. A compound or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, or isotopic label, wherein, The compound includes:

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

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

9. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotopic label thereof, or the pharmaceutical composition of claim 8 in the preparation of an inhibitor of ferroptosis.

10. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate or isotopic label thereof, or the pharmaceutical composition of claim 8 in the preparation of a medicament for the prevention and / or treatment of neurodegenerative diseases, tissue ischemia-reperfusion injury, stroke, cardiovascular disease, renal failure, liver injury, diabetic complications or cancer. Preferably, the neurodegenerative disease is Parkinson's syndrome or Alzheimer's disease; Preferably, the stroke is an ischemic stroke or a hemorrhagic stroke; Preferably, the cancer is pancreatic cancer.

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