Fused ring heterocyclic compounds and uses thereof, pharmaceutical compositions containing the same and uses thereof

Abstract

The application discloses a fused ring heterocyclic compound and application, a pharmaceutical composition containing the same and application. In the application, the fused ring heterocyclic compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof has a structure shown in general formula (I), and can be used as a TRPM2 inhibitor and applied to preparation of a medicine for treating a TRPM2 function abnormality disease.

Description

Technical Field

[0001] The embodiments of the present invention relate to the field of medicinal chemistry, and particularly to fused-ring heterocyclic compounds and their applications, and pharmaceutical compositions containing them and their applications. Background Technology

[0002] TRPM2 (Transient Receptor Potential Melastatin 2) is a permeable homotetrameric nonselective cation channel in the transient receptor potential ion channel family, widely expressed in cells throughout the human body, such as those in the brain, heart, blood vessels, kidneys, endothelial cells, smooth muscle cells, and immune cells. Extracellular signals such as oxidative stress, tumor necrosis factor-α (TNF-α), amyloid β-peptide (Aβ), and concanavalin A (ConA) can all lead to the production of intracellular adenosine diphosphate ribose (ADPR). As a proven endogenous ligand of TRPM2, increased levels of ADPR activate TRPM2 channels, causing an influx of cations such as Na+, K+, Zn2+, and Ca+ into the cell, thus affecting intracellular ion homeostasis.

[0003] In recent years, in-depth research on the function of TRPM2 channels has revealed that they mediate many important physiological and pathological functions: 1) participating in the regulation of fever reduction and the regulation of mouse adaptation to external temperature (Song K et al., Science, 2016; Tan CH et al., Nature, 2016); 2) mediating various important immune and inflammatory responses, such as mediating lung inflammation induced by antitumor drugs (Yonezawa R et al., Free Radic Biol Med, 2016); 3) regulating calcium ion influx, cytokine and chemokine release, and reactive oxygen species (ROS) levels, mediating the development of neurological diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, spinal cord injury, and pain (Hermosura MC et al., Proc Natl Acad Sci USA, 2008). M et al., J Recept Signal Transduct Res, 2012; Ostapchenko VG et al., J Neurosci, 2015); 4) It participates in regulating insulin secretion and blood glucose levels, mediating the occurrence of diabetes (Uchida K et al., Diabetes, 2011); 5) It plays a role in the occurrence and development of various malignant tumors such as breast cancer, bladder cancer, neuroblastoma, and prostate cancer through the regulation of its own expression level (Hopkins MM et al., Int J Oncol, 2015; Cao QF et al., Cancer Biother Radiopharm, 2015; Chen SJ et al., Am J Physiol Cell Physiol, 2013; Zeng X et al., Prostate Cancer Prostatic Dis, 2010).

[0004] In summary, the TRPM2 channel participates in the regulation of various pathophysiological functions and is a potential therapeutic target for many diseases. Moreover, studies have shown that many diseases involving this channel are caused by its overactivation. Therefore, the development of inhibitors of this channel is of great importance for further elucidating its function, confirming its role as a therapeutic target for various diseases, and developing drugs targeting this target. Summary of the Invention

[0005] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound. Such salts include: salts formed by addition to an inorganic acid or an organic acid, such as nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, mucoacinic acid, etc.; or salts formed when an acidic proton present on the parent compound is replaced by a metal ion, such as an alkali metal ion or an alkaline earth metal ion; or coordination compounds formed with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing an acid radical or a base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in their free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0006] As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers primarily include cis-trans isomers and optical isomers. The compounds described in this invention can exist in stereoisomer form and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers, and transisomers. The compounds described in this invention can also exist in any combination or mixture of the aforementioned stereoisomers, such as meso compounds, racemic compounds, and equal mixtures of transisomers. Examples include a single enantiomer, a single diastereomer or a mixture of more than one, or a single transisomer or a mixture thereof.

[0007] As used herein, the term "solvent compound" refers to a substance formed by combining the compounds of the present invention with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include water, ethanol, acetic acid, etc. Solvent compounds include stoichiometric solvent compounds and non-stoichiometric solvent compounds, preferably hydrates. Some compounds of the present invention may exist in a non-solventized or solvated form, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of the present invention.

[0008] As used herein, the terms “heteroaryl,” “heteroaryl ring,” and “heteroaryl ring” are used interchangeably to refer to a monocyclic or fused polycyclic (i.e., sharing adjacent ring atom pairs, which may be CC or NC) group in which the ring atoms are substituted by at least one heteroatom independently selected from nitrogen, oxygen, or sulfur, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The term “five-membered heteroaryl” as used herein refers to a heteroaryl having five ring atoms, and the term “six-membered heteroaryl” refers to a heteroaryl having six ring atoms. The terms “five-membered heteroaryl” and “six-membered heteroaryl” as used herein do not limit the inclusion of the following forms:

[0009]

[0010] As used herein, the term "heterocyclic group" is a cyclic group in which at least one carbon atom of a monocyclic ring is replaced by a heteroatom, which is a non-carbon atom, preferably an N, O, or S atom.

[0011] The purpose of this invention is to provide a fused-ring heterocyclic compound that can be used as a TRPM2 inhibitor in the preparation of drugs for treating TRPM2 dysfunction.

[0012] To address the aforementioned technical problems, a first aspect of the present invention provides a fused-ring heterocyclic compound, or a pharmaceutically acceptable salt, stereoisomer, solvent compound, or prodrug thereof, wherein the fused-ring heterocyclic compound has the structure shown in general formula (I):

[0013]

[0014] In the formula, R 1 For unsubstituted or at least one hydrogen atom is R 1-1 Substituted heteroaryl, unsubstituted, or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-1 Halogen or C 1～6 Alkyl, R 1-2 Halogen, cyano, nitro, C 2～8 Ester group, C 1～6 Alkyl or C 1～6 Alkoxy;

[0015] Indicates a single bond or a double bond, when When it is a single bond, R 2 Hydroxyl group, C 2～12 Acyloxy or C 1～6 alkoxy; when When it is a double bond, R 2 It is an oxygen atom;

[0016] R 3 Hydroxyl group, C 1～4 Alkyl, C 1～6 Alkoxy, Or a heterocyclic group containing at least one N, O, and / or S atom, wherein Ra and Rb are independently selected from hydrogen, C, and C, respectively. 1～4 Alkyl or C 1～4 Alkoxy;

[0017] X is a carbon atom or a nitrogen atom.

[0018] To achieve better technical results, the fused-ring heterocyclic compounds of the present invention do not include the following structures:

[0019]

[0020] In some preferred embodiments, the R 1 For unsubstituted or at least one hydrogen atom is R 1-1 Substituted heteroaryl groups, wherein the unsubstituted or at least one hydrogen atom is R 1-1 The substituted heteroaryl group is either unsubstituted or has at least one hydrogen atom replaced by R. 1-1 The substituted five-membered heteroaryl group or the unsubstituted or at least one hydrogen atom is R 1-1 Substituted six-membered heteroaryl; wherein, the R 1-1 Halogen or C 1～6 Alkyl group, wherein the halogen is preferably fluorine, chlorine, bromine or iodine, and the C 1～6 Alkyl groups are preferably C 1～4Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl);

[0021] The unsubstituted or at least one hydrogen atom is R 1-1 The substituted five-membered heteroaryl group is preferably an unsubstituted group containing at least one N, O, or S atom, or at least one hydrogen atom is replaced by R. 1-1 The substituted five-membered heteroaryl group is more preferably an unsubstituted group containing one O or S atom or at least one hydrogen atom replaced by R. 1-1 The substituted five-membered heteroaryl group is most preferably furanyl or thiophene, wherein the furanyl group is preferably... The thiophene group is preferably... (the R mentioned above) 1-1 The number of R can be one or more, when there are multiple R 1-1 At that time, the R mentioned 1-1 (Same or different);

[0022] The unsubstituted or at least one hydrogen atom is R 1-1 The substituted six-membered heteroaryl group is preferably an unsubstituted group containing at least one N, O, or S atom, or at least one hydrogen atom is replaced by R. 1-1 The substituted six-membered heteroaryl group is more preferably unsubstituted or has at least one hydrogen atom replaced by R. 1-1 The substituted pyridinyl group, preferably... (the R mentioned above) 1-1 The number of R can be one or more, when there are multiple R 1-1 At that time, the R mentioned 1-1 (Same or different);

[0023] Or, the R 1 For unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl (R) 1-2 The number of R can be one or more, when there are multiple R 1-2 At that time, the R mentioned 1-2 (Same or different), the R 1-2 Halogen, cyano, nitro, C 1～6 Alkyl or C 1～6 alkoxy group; the halogen is preferably fluorine, chlorine, bromine or iodine; the C 1～6 Alkyl groups are preferably C 1～4 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl); the C 1～6 Alkoxy groups are preferably C 1～4 Alkoxy groups (e.g., methoxy or ethoxy groups).

[0024] In some preferred solutions, Indicates a single bond, R 2 Hydroxyl group, C2～12 Acyloxy or C 1～6 Alkoxy; the C 2～12 Acyloxy group is preferably C 2～8 Acyloxy group, the C 2～8 Acyloxy group is Where Re is C 1～7 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, or heptyl); the C 1～6 Alkoxy groups are preferably C 1～4 Alkyl groups (e.g., methoxy, ethoxy, or propoxy);

[0025] or, It is a double bond, R 2 It is an oxygen atom.

[0026] In some preferred solutions, R 3 Hydroxyl group, C 1～4 Alkyl, C 1～6 Alkoxy, Or a heterocyclic group containing at least one N, O, or S atom, wherein Ra and Rb are independently selected from hydrogen, C, and S, respectively. 1～4 Alkyl or C 1～4 Alkoxy; the C 1～4 The alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; the C 1～6 Alkoxy groups are preferably C 1～4 Alkyl groups (e.g., methoxy, ethoxy, or propoxy); the In this context, Ra and Rb are each preferably hydrogen, methyl, ethyl, methoxy, or ethoxy (e.g., ...). The heterocyclic group containing at least one N, O, and / or S atom is preferably a three-membered heterocyclic group containing at least one N, O, and / or S atom, a four-membered heterocyclic group containing at least one N, O, and / or S atom, a five-membered heterocyclic group containing at least one N, O, and / or S atom, or a six-membered heterocyclic group containing at least one N, O, and / or S atom. More preferably, it is a four-membered heterocyclic group containing at least one N and / or O atom, a five-membered heterocyclic group containing at least one N and / or O atom, or a six-membered heterocyclic group containing at least one N and / or O atom. Further preferably, it is a four-membered heterocyclic group containing one or two N and / or O atoms, a five-membered heterocyclic group containing one or two N and / or O atoms, or a six-membered heterocyclic group containing one or two N and / or O atoms. Most preferably, it is a four- to six-membered cyclic imine group (e.g., A six-membered heterocyclic group containing two nitrogen atoms, preferably Rc is selected from hydrogen or C. 1～4 Alkoxy groups, (e.g.: Or a six-membered heterocyclic group containing one nitrogen atom and one oxygen atom (e.g.: ).

[0027] In some preferred embodiments, X is a carbon atom, and the fused-ring heterocyclic compound has the structure shown in general formula (II):

[0028]

[0029] In the formula, R 1 For unsubstituted or at least one hydrogen atom is R 1-1 Substituted heteroaryl, unsubstituted, or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-1 Halogen or C 1～6 Alkyl, R 1-2 Halogen, cyano, nitro, C 1～6 Alkyl, C 1～6 alkoxy group; the halogen is preferably fluorine, chlorine, bromine or iodine, and the C 1～6 Alkyl groups are preferably C 1～4 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl); the C 1～6 The alkoxy group is preferably the C 1～6 Alkoxy groups are preferably C 1～4 Alkyl groups (e.g., methoxy or ethoxy);

[0030] Indicates a single bond or a double bond, when When it is a single bond, R 2 Hydroxyl group, C 2～12 Acyloxy or C 1～6 alkoxy; when When it is a double bond, R 2 The C is an oxygen atom; 2～12 Acyloxy group is preferably C 2～8 Acyloxy group, the C 2～8 Acyloxy group is Where Re is C 1～7 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, or heptyl); the C 1～6 Alkoxy groups are preferably C 1～4 Alkyl groups (e.g., methoxy, ethoxy, or propoxy);

[0031] R 3 Hydroxyl group, C 1～4 Alkyl, C 1～6 Alkoxy, Or a heterocyclic group containing at least one N, O, and / or S atom, wherein Ra and Rb are independently selected from hydrogen, C, and C, respectively. 1～4 Alkyl or C 1～4 Alkoxy; the C 1～4The alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; the C 1～6 Alkoxy groups are preferably C 1～4 Alkyl groups (e.g., methoxy, ethoxy, or propoxy); the In this context, Ra and Rb are each preferably hydrogen, methyl, ethyl, methoxy, or ethoxy (e.g., ...). The heterocyclic group containing at least one N, O, and / or S atom is preferably a three-membered heterocyclic group containing at least one N, O, and / or S atom, a four-membered heterocyclic group containing at least one N, O, and / or S atom, a five-membered heterocyclic group containing at least one N, O, and / or S atom, or a six-membered heterocyclic group containing at least one N, O, and / or S atom, more preferably a four-membered heterocyclic group containing at least one N and / or O atom, a five-membered heterocyclic group containing at least one N and / or O atom, or a six-membered heterocyclic group containing at least one N and / or O atom, further preferably a four-membered heterocyclic group containing one or two N and / or O atom, a five-membered heterocyclic group containing one or two N and / or O atom, or a six-membered heterocyclic group containing one or two N and / or O atom, most preferably: a four- to six-membered cyclic imine group (e.g.: A six-membered heterocyclic group containing two nitrogen atoms, preferably Rc is selected from hydrogen or C. 1～4 Alkoxy groups, (e.g.: Or a six-membered heterocyclic group containing one nitrogen atom and one oxygen atom (e.g.: ).

[0032] In some preferred embodiments, X is a carbon atom. The fused-ring heterocyclic compound has a structure represented by general formula (III), consisting of a single bond.

[0033]

[0034] In the formula, R 1 For unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-2 Halogen, cyano, nitro, C 1～6 Alkyl, C 1～6 Alkoxy; preferably, R 1 It is an unsubstituted phenyl group;

[0035] R 2 Hydroxyl group, C 2～12 Acyloxy or C 1～6 Alkoxy; preferably, R 2 Hydroxyl group, C 2～8 Acyloxy or C 1～4 Alkoxy, the C 2～8 Acyloxy group is Where Re is C 1～7 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, or heptyl); the C 1～4 The alkoxy group is preferably methoxy, ethoxy, or propoxy;

[0036] R 3 Hydroxyl group, C 1～4 Alkyl, C 1～6 alkoxy or Ra and Rb are independently selected from hydrogen and C, respectively. 1～4 Alkyl or C 1～4 Alkoxy; preferably, R 3 Hydroxyl group, C 1～4 alkoxy or Ra and Rb are independently selected from hydrogen or C, respectively. 1～4 Alkyl; more preferably, R 3 Hydroxyl, methoxy, ethoxy

[0037] In some preferred embodiments, X is a carbon atom. The fused-ring heterocyclic compound has a double bond and the structure shown in general formula (Ⅳ):

[0038]

[0039] In the formula, R 1 For unsubstituted or at least one hydrogen atom is R 1-1 Substituted heteroaryl, unsubstituted, or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-1 Halogen or C 1～6 Alkyl, R 1-2 Halogen, cyano, nitro, C 1～6 Alkyl, C 1～6 Alkoxy;

[0040] R 3 Hydroxyl group, C 1～4 Alkyl, C 1～6 alkoxy groups, heterocyclic groups containing at least one N, O, and / or S atom, or Ra and Rb are independently selected from hydrogen and C, respectively. 1～4 Alkyl or C 1～4 Alkoxy; preferably, R 3 Hydroxyl group, C 1～4 Alkoxy groups, four-membered heterocyclic groups containing at least one N and / or O atom, five-membered heterocyclic groups containing at least one N and / or O atom, six-membered heterocyclic groups containing at least one N and / or O atom, or Ra and Rb are each independently selected from hydrogen, hydrogen, methyl, ethyl, methoxy, or ethoxy; more preferably, R 3 Hydroxyl, methoxy, ethoxy, propoxy, four- to six-membered cyclic imino groups (e.g.: ), six-membered heterocyclic groups containing two nitrogen atoms (e.g.: ) or a six-membered heterocyclic group containing one nitrogen atom and one oxygen atom (e.g.: ).

[0041] In some preferred embodiments, X is a carbon atom. The fused-ring heterocyclic compound has a double bond and the structure shown in general formula (Ⅳ):

[0042]

[0043] In the formula, R 1 It is an unsubstituted five-membered heteroaryl, an unsubstituted six-membered heteroaryl, or an unsubstituted or at least one hydrogen atom surrounded by R. 1-2 Substituted phenyl, wherein R 1-2 Halogen, C 1～6 Alkyl, C 1～6 alkoxy group; the halogen is preferably fluorine, chlorine or bromine; the C 1～6 Alkyl groups are preferably C 1～4 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl); the C 1～6 Alkoxy C 1～4 Alkyl groups (e.g., methoxy groups);

[0044] R 3 C 1～4 Alkyl, C 1～6 alkoxy; wherein, the C 1～4 The alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl (e.g., methyl); the C 1～6 Alkoxy groups are preferably C 1～4 Alkyl groups (e.g., methoxy, ethoxy, or propoxy).

[0045] In some preferred embodiments, X is a carbon atom. The fused-ring heterocyclic compound has a double bond and the structure shown in general formula (Ⅳ):

[0046]

[0047] In the formula, R 1 For an unsubstituted six-membered heteroaryl group, unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-2 Halogens (e.g., fluorine);

[0048] R 3 It is a hydroxyl group.

[0049] In some preferred embodiments, X is a carbon atom. The fused-ring heterocyclic compound has a double bond and the structure shown in general formula (Ⅳ):

[0050]

[0051] In the formula, R 1 For an unsubstituted six-membered heteroaryl group, unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-2 Halogens (e.g., fluorine);

[0052] R 3 for Or a heterocyclic group containing at least one N, O, and / or S atom, wherein Ra and Rb are independently selected from hydrogen, C, and C, respectively. 1～4 Alkyl or C 1～4 alkoxy; the In this context, Ra and Rb are each preferably hydrogen, methyl, ethyl, methoxy, or ethoxy (e.g., ...). The heterocyclic group containing at least one N, O, and / or S atom is preferably a four- to six-membered cyclic imine group (e.g.: ), Rc is selected from hydrogen or C. 1～4 Alkoxy groups, (e.g.: Or a six-membered heterocyclic group containing one nitrogen atom and one oxygen atom (e.g.: ).

[0053] In some preferred embodiments, X is a carbon atom. The fused-ring heterocyclic compound has a double bond and the structure shown in general formula (Ⅳ):

[0054]

[0055] In the formula, R 1 for

[0056] R 3 for

[0057] In some preferred embodiments, the fused-ring heterocyclic compound is selected from any of the following structures:

[0058]

[0059] In some preferred embodiments, X is a nitrogen atom. The fused-ring heterocyclic compound has a structure represented by general formula (V), consisting of a single bond.

[0060]

[0061] In the formula, R 1 For unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-2 Halogen, cyano, nitro, C 1～6 Alkyl, C 1～6 Alkoxy; preferably, R 1 An unsubstituted phenyl group or at least one hydrogen atom is halogenated or C 1～4 Alkyl-substituted phenyl; more preferably, R 1 It is an unsubstituted phenyl group;

[0062] R 2 Hydroxyl or C 1～6 Alkyl group; preferably hydroxyl group;

[0063] R 3 Hydroxyl group, C 1～4 Alkyl or C 1～6 Alkoxy group; preferably C 1～6 Alkyloxy group; more preferably C 1～4 Alkoxy groups (e.g., ethoxy groups).

[0064] In some preferred embodiments, X is a nitrogen atom. The fused-ring heterocyclic compound has a double bond and the structure shown in general formula (VI):

[0065]

[0066] In the formula, R 1 For unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-2 Halogen, cyano, nitro, C 1～6 Alkyl, C 1～6 Alkoxy; preferably, R 1 An unsubstituted phenyl group or at least one hydrogen atom is halogenated or C 1～4 Alkyl-substituted phenyl;

[0067] R 3 Hydroxyl group, C 1～4 Alkyl, C 1～6 Alkyl groups, heterocyclic groups containing at least one nitrogen atom, or Ra and Rb are independently selected from hydrogen or C, respectively. 1～4 Alkyl; preferably, R 3 Hydroxyl group, C 1～4Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl), C 1～4 Alkoxy (e.g., ethoxy), five- or six-membered ring imino (e.g., )or Ra and Rb are independently selected from hydrogen, methyl, or ethyl (e.g.: ).

[0068] In some preferred embodiments, X is a nitrogen atom. The fused-ring heterocyclic compound has a double bond and the structure shown in general formula (VI):

[0069]

[0070] In the formula, R 1 A phenyl group that is either unsubstituted or has at least one hydrogen atom substituted by a halogen.

[0071] R 3 Hydroxyl group, C 1～4 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl), C 1～4 Alkoxy groups (e.g., ethoxy groups).

[0072] In some preferred embodiments, the fused-ring heterocyclic compound has any of the following structures:

[0073]

[0074] The compounds represented by general formula (I) can be prepared using synthetic methods known in the art or in combination with methods known in the art. The solvents, temperatures, and other reaction conditions given in this invention are exemplary and can be varied according to methods well known in the art. The compounds of the embodiments described in this invention can be synthesized according to the methods described in the embodiments, using appropriate starting materials, or can be synthesized using methods similar to those described in the embodiments, depending on their specific structures. The starting materials used to synthesize the compounds of the embodiments of this invention can be prepared by known synthetic methods or similar methods described in the literature, or obtained from commercial sources. The compounds can be further resolved to obtain their stereoisomers by methods well known in the art, such as crystallization, chromatography, etc., with resolution conditions readily obtained by those skilled in the art through conventional means or limited experimentation.

[0075] A second aspect of the present invention provides a method for preparing the above-mentioned fused-ring heterocyclic compounds (II-1 to II-18), the method comprising step (1):

[0076] Under alkaline conditions, M1 and The fused-ring heterocyclic compounds (Ⅱ-1 to Ⅱ-18) are obtained by performing the following reaction;

[0077]

[0078] Among them, R 1 It is an unsubstituted five-membered heteroaryl, an unsubstituted six-membered heteroaryl, or an unsubstituted or at least one hydrogen atom surrounded by R. 1-2 Substituted phenyl, wherein R 1-2 Halogen, C 1～6 Alkyl, C 1～6 alkoxy group; the halogen is preferably fluorine, chlorine or bromine; the C 1～6 Alkyl groups are preferably C 1～4 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl); the C 1～6 Alkoxy C 1～4 Alkyl groups (e.g., methoxy groups);

[0079] R 3 C 1～4 Alkyl, C 1～6 Alkoxy; the C 1～4 The alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl (e.g., methyl); the C 1～6 Alkoxy groups are preferably C 1～4 Alkyl groups (e.g., methoxy, ethoxy, or propoxy).

[0080] In some preferred embodiments, the reaction described in step (1) is carried out in a polar solvent, preferably in N,N-dimethylformamide;

[0081] The reaction described in step (1) is carried out in a nitrogen atmosphere;

[0082] In step (1), the base is a weak base, preferably sodium carbonate or potassium carbonate, for example, potassium carbonate;

[0083] In step (1), the reaction temperature is 70°C to 90°C, for example, 80°C;

[0084] In step (1), the reaction time is 11 to 13 hours, for example 12 hours;

[0085] In step (1), the reaction further includes extraction, drying and vacuum distillation to remove the solvent.

[0086] In some preferred embodiments, in step (1), the extraction is performed by alternating extraction with ethyl acetate and water in a single process;

[0087] In step (1), the drying is performed using anhydrous sodium sulfate;

[0088] The step (1) is followed by step (2): purifying the product obtained in step (1).

[0089] In some preferred embodiments, the purification is column chromatography purification.

[0090] In some preferred embodiments, the reaction includes the step of: under nitrogen protection, reacting M1, Potassium carbonate was dissolved in anhydrous N,N-dimethylformamide and reacted at 80°C for 11–13 hours. After the reaction was complete as monitored by thin-layer chromatography, the mixture was cooled to room temperature. The reaction solution was extracted with ethyl acetate, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain the fused-ring heterocyclic compounds (II-1 to II-18).

[0091] In some preferred embodiments, the product obtained in step (1) is hydrolyzed to obtain the fused-ring heterocyclic compound (Ⅱ-19) of the present invention; preferably, the hydrolysis is carried out in an aqueous sodium hydroxide solution.

[0092] The fused-ring heterocyclic compound (Ⅱ-19) of the present invention can be obtained; preferably, the hydrolysis is carried out in an aqueous sodium hydroxide solution.

[0093] In some preferred embodiments, the product obtained in step (1) is hydrolyzed, and then added to... The reaction, wherein Ra, Rb, and Rc are independently selected from hydrogen, C, and C, respectively. 1～4 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl), C 1～4 Alkoxy groups (e.g., ethoxy groups); preferably, Selected from The fused ring compounds (Ⅱ-20~Ⅱ-36) described in this invention can be obtained.

[0094] Those skilled in the art, based on the technical solutions described in this invention and common knowledge, will know that reacting the product obtained in step (1) in the presence of sodium borohydride reducing agent will yield the fused ring compound (Ⅱ-41) described in this invention.

[0095] A second aspect of the present invention also provides a method for preparing the above-mentioned fused-ring heterocyclic compounds (Ⅲ-1 to Ⅲ-4), the method comprising step (a):

[0096] Under alkaline conditions, M2 and The fused-ring heterocyclic compounds (Ⅲ-1 to Ⅲ-4) are obtained by performing the following reaction;

[0097]

[0098] Among them, R 1 A phenyl group that is either unsubstituted or has at least one hydrogen atom substituted by a halogen.

[0099] R 3 Hydroxyl group, C 1～4 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl), C 1～4 Alkoxy groups (e.g., ethoxy groups).

[0100] In some preferred embodiments, the reaction described in step (1) is carried out in a polar solvent, preferably in N,N-dimethylformamide;

[0101] The reaction described in step (a) is carried out in a nitrogen atmosphere;

[0102] In step (a), the base is a weak base, preferably sodium carbonate or potassium carbonate, for example, potassium carbonate;

[0103] In step (a), the reaction temperature is 70°C to 90°C, for example, 80°C;

[0104] In step (a), the reaction time is 11 to 13 hours, for example, 12 hours;

[0105] In step (a), the reaction further includes extraction, drying, and vacuum distillation to remove the solvent.

[0106] In some preferred embodiments, in step (a), the extraction is performed by alternating extraction with ethyl acetate and water in a single operation;

[0107] In step (a), the drying is performed using anhydrous sodium sulfate;

[0108] The step (a) is followed by another step (a): purifying the product obtained in step (a).

[0109] In some preferred embodiments, the purification is column chromatography purification.

[0110] In some preferred embodiments, the reaction includes the step of: under nitrogen protection, reacting M2, Potassium carbonate was dissolved in anhydrous N,N-dimethylformamide and reacted at 80°C for 11–13 hours. After the reaction was complete as monitored by thin-layer chromatography, the mixture was cooled to room temperature. The reaction solution was extracted with ethyl acetate, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain the fused-ring heterocyclic compounds (Ⅲ-1–Ⅲ-4).

[0111] In some preferred embodiments, the product obtained in step (a) is hydrolyzed, and then added to... The reaction, wherein Ra, Rb, and Rc are independently selected from hydrogen, C, and C, respectively. 1～4 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl), C 1～4 Alkoxy groups (e.g., ethoxy groups); preferably, Selected from The fused ring compounds (Ⅲ-6 to Ⅲ-10) described in this invention can be obtained.

[0112] In some preferred embodiments, M1 or M2 can be prepared by the following reaction: under alkaline conditions, α-bromoketone reacts with pyrrole-2-carboxaldehyde to obtain M1 or M2.

[0113]

[0114] A third aspect of the present invention provides a pharmaceutical composition comprising a fused-ring heterocyclic compound, or a pharmaceutically acceptable salt, stereoisomer, solvent-fused-ring heterocyclic compound, or prodrug provided in the first aspect of the present invention.

[0115] The fourth aspect of the present invention provides the use of the above-mentioned fused-ring heterocyclic compound, or a pharmaceutically acceptable salt, stereoisomer, solvent compound or prodrug thereof, in the preparation of a TRPM2 inhibitor drug.

[0116] The fifth aspect of the present invention provides the use of the above-described or pharmaceutical composition in the preparation of a TRPM2 inhibitor drug.

[0117] The sixth aspect of the present invention provides the use of the above-mentioned fused-ring heterocyclic compound or pharmaceutical composition in the preparation of a medicament for treating TRPM2 dysfunction.

[0118] In some preferred embodiments, the TRPM2 dysfunction includes: spinal cord injury or pain, cardiovascular and cerebrovascular diseases, Alzheimer's disease, neuropathic pain, Parkinson's disease, bipolar disorder, or amyotrophic lateral sclerosis; preferably, cardiovascular and cerebrovascular diseases.

[0119] In some preferred embodiments, the cardiovascular disease is caused by oxidative stress induced by ischemia / reperfusion.

[0120] In some preferred embodiments, the cardiovascular and cerebrovascular diseases include stroke, cerebral thrombosis, or cerebrovascular accident.

[0121] A seventh aspect of the present invention provides a method for preventing and / or treating TRPM2 dysfunction, the method comprising the step of administering an effective dose of the above-mentioned fused-ring heterocyclic compound or pharmaceutical composition to a patient with TRPM2 dysfunction.

[0122] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0123] The reagents and raw materials used in this invention are all commercially available.

[0124] The embodiments of the present invention have at least the following advantages over the prior art:

[0125] (1) The fused-ring heterocyclic compound provided in the first aspect of the present invention can be used as a TRPM2 inhibitor, which helps to further elucidate the function of the TRPM2 channel, helps to confirm its role as a therapeutic target for a variety of diseases, and helps to develop drugs targeting this target.

[0126] (2) The fused-ring heterocyclic compound provided in the first aspect of the present invention can be used as a TRPM2 inhibitor to prepare a drug for treating TRPM2 dysfunction. Attached Figure Description

[0127] One or more embodiments are illustrated by way of example with reference to the accompanying drawings, and these illustrative descriptions do not constitute a limitation on the embodiments.

[0128] Figure 1 This is a schematic diagram of the electrophysiological representative currents of the fused-ring heterocyclic compounds II-1, II-19 and II-36 described in Example 66 of the present invention inhibiting the TRPM2 channel current;

[0129] Figure 2 This is a schematic diagram of the electrophysiological results of current inhibition of voltage-gated channels, NMDA receptors, ASIC channels, TRPM8 channels, TRPC6 channels, TRPV4 channels and TRPV1 channels by the fused-ring heterocyclic compound II-1 described in Example 67 of the present invention.

[0130] Figure 3 This is a schematic diagram showing the TTC staining results of compound II-1 and the positive control drug (edaravone) on the ischemic side of mouse brain tissue after the transient middle cerebral artery occlusion (tMACO) model was established in C57BL / 6 mice according to Example 68 of the present invention.

[0131] Figure 4 This is a schematic diagram of the infarct volume of mouse brain tissue in Embodiment 68 of the present invention;

[0132] Figure 5 This is a schematic diagram of the neuromotor dysfunction scoring results of each group of model mice 24 hours after ischemia-reperfusion in Example 68 of the present invention. Detailed Implementation

[0133] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the various embodiments of the present invention will be described in detail below with reference to the embodiments. However, those skilled in the art will understand that many technical details have been presented in the various embodiments of the present invention to enable the reader to better understand this application. However, the technical solutions claimed in this application can be implemented even without these technical details and various changes and modifications based on the following embodiments.

[0134]

[0135] Example 1: Preparation of ethyl 5-benzoimide-7-carboxylate (II-1).

[0136] Step a1: Under nitrogen protection, pyrrole-2-carboxaldehyde (0.95 g, 10.0 mmol) and potassium carbonate (1.66 g, 12.0 mmol) were dissolved in 50 mL of anhydrous acetonitrile. Then, 2-bromo-1-phenylethane-1-one (2.3 g, 12.0 mmol) was added in portions. After complete addition, the mixture was heated to 60°C and reacted overnight. Thin-layer chromatography was used to monitor the complete reaction of the starting material. After cooling to room temperature, the mixture was filtered to remove potassium carbonate. The filtrate was distilled under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 1-(2-oxo-2-phenylethyl)-1H-pyrrole-2-carboxaldehyde as a white solid.

[0137] Step b: Under nitrogen protection, the compound 1-(2-oxo-2-phenylethyl)-1H-pyrrole-2-carboxaldehyde (852 mg, 4.0 mmol), ethyl propynate (470 mg, 4.8 mmol), and potassium carbonate (662 mg, 4.8 mmol) obtained in the previous step were dissolved in 25 mL of anhydrous N,N-dimethylformamide and reacted overnight at 80°C. After the reaction was monitored by thin-layer chromatography to ensure complete reaction of the starting materials, the mixture was cooled to room temperature. The reaction solution was extracted with 100 mL and 50 mL of ethyl acetate, and the aqueous phase was extracted twice with ethyl acetate (50 mL × 2). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a yellow solid (II-1, 63%). 1¹H NMR (500MHz, CDCl₃): δ 8.93 (m, 1H), 8.47 (d, J = 1.5Hz, 1H), 7.84 (dd, J = 8.0, 1.5Hz, 2H), 7.78 (d, J = 1.5Hz, 1H), 7.66 (tt, J = 7.5, 1.5Hz, 1H), 7.55 (t, J = 7.5Hz, 2H), 7.10 (dd, J = 4.0, 3.0Hz, 1H), 7.03 (dd, J = 4.0, 1.0Hz, 1H), 4.38 (q, J = 7.0Hz, 2H), 1.40 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 19 H 17 NO3[M+H] + 294.1130, detected value 294.1132.

[0138] Example 2: Preparation of 5-benzoimide-7-carboxylic acid propyl ester (II-2).

[0139] According to the method of Example 1, propyl propargyl (538 mg, 4.8 mmol) was used instead of ethyl propargyl to obtain a yellow solid (II-2, 54%). 1 H NMR (500MHz, CDCl3): δ8.74(m,1H),8.42(d,J=1.0Hz,1H),7.76(dd,J=7.5,2.0Hz,2H),7.64(d,J=2.0Hz,1H),7.53(tt,J=7.5,1.5Hz,1H),7.47(t,J =7.5Hz,2H),7.08(dd,J=4.0,3.0Hz,1H),7.01(dd,J=4.0,1.0Hz,1H),4.33(q,J=7.0Hz,2H),1.85(m,2H),1.04(t,J=7.0Hz,3H); HRMS(ESI):m / z predicted value C 18 H 15 NO3[M+H] + 308.1287, detected value 308.1295.

[0140] Example 3: Preparation of 1-(5-benzoimide-7-yl)ethane-1-one (II-3).

[0141] According to the method of Example 1, ethyl propargyl ester was replaced with propargyl 3-yn-2-one (326 mg, 4.8 mmol) to obtain a yellow solid (II-3, 57%). 1¹H NMR (500MHz, CDCl₃): δ 8.87 (m, 1H), 8.31 (m, 1H), 7.81 (dt, J = 7.5, 2.0Hz, 2H), 7.76 (d, J = 2.0Hz, 1H), 7.64 (tt, J = 7.0, 1.0Hz, 1H), 7.53 (tt, J = 7.0, 2.0Hz, 2H), 7.08 (dd, J = 4.5, 3.0Hz, 1H), 7.05 (dd, J = 4.5, 1.0Hz, 1H), 2.58 (s, 3H); HRMS (ESI): m / z predicted value C 18 H 15 NO3[M+H] + 264.1025, detected value 264.1030.

[0142] Example 4: Preparation of methyl 5-(4-fluorobenzoyl)indoleazine-7-carboxylic acid (II-4).

[0143] Step a2: Under nitrogen protection, pyrrole-2-carboxaldehyde was dissolved in anhydrous N,N-dimethylformamide. The reaction solution was cooled to 0°C in an ice bath, and then sodium hydride (0.29 g, 12.0 mmol) was added in batches. After complete addition, the reaction was carried out at 0°C for 30 minutes. Then, 2-bromo-1-(4-fluorophenyl)ethane-1-one (2.6 g, 12.0 mmol) dissolved in N,N-dimethylformamide was added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out overnight. After the reaction was monitored by thin-layer chromatography, saturated ammonium chloride solution was added dropwise to the reaction solution in an ice bath. After the addition was complete, the reaction solution was extracted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a white solid, which was directly used in the next step of the reaction. This method is suitable for the synthesis of R. 1 M1 is an intermediate consisting of fluorinated benzene rings, furan rings, thiophene rings, and pyridine rings.

[0144] According to the method of Example 2, 2-bromo-1-(4-fluorophenyl)ethane-1-one (2.6 g, 12.0 mmol) was used instead of 2-bromo-1-phenylethane-1-one, and methyl propargylate (403 mg, 4.8 mmol) was used instead of ethyl propargylate to give a yellow solid (II-4, 45%). 1H NMR (500MHz, CDCl3): δ 8.86 (d, J = 2.5Hz, 1H), 8.47 (d, J = 1.5Hz, 1H), 7.89 (td, J = 5.5, 2.0Hz, 2H), 7.71 (d, J = 1.5Hz, 1H), 7.24 (t, J = 7.5Hz, 2H), 7.10 (q, J = 7.0Hz, 1H), 7.04 (dd, J = 4.0, 1.0Hz, 1H), 3.92 (s, 3H); HRMS (ESI): m / z predicted value C 17 H 12 FNO3[M+H] + 298.0897, detected value 298.0899.

[0145]

[0146] Example 5: Preparation of ethyl 5-(4-fluorobenzoyl)indoleazine-7-carboxylate (II-5).

[0147] According to the method of Example 4, methyl propargylate (346 mg, 4.8 mmol) was used instead of ethyl propargylate to obtain a yellow solid (II-5, 56%). 1 H NMR (500MHz, CDCl3): δ 8.86 (d, J = 2.5Hz, 1H), 8.47 (J = 1.5Hz, 1H), 7.88 (td, J = 5.5, 2.0Hz, 2H), 7.73 (J = 1.5Hz, 1H), 7.24 (t, J = 8.5Hz, 2H), 7.10 (dd, J = 4.5, 2.0Hz, 1H), 7.03 (dd, J = 4.5, 1.5Hz, 1H), 4.39 (q, J = 7.0Hz, 2H), 1.40 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 18 H 14 FNO3[M+H] + 312.1036, detected value 312.1038.

[0148]

[0149] Example 6: Preparation of methyl 5-(3-fluorobenzoyl)indoleazine-7-carboxylic acid (II-6).

[0150] According to the method of Example 4, 2-bromo-1-(3-fluorophenyl)ethane-1-one (2.6 g, 12.0 mmol) was used instead of 2-bromo-1-(4-fluorophenyl)ethane-1-one to give a yellow solid (II-6, 61%). 1H NMR (500MHz, CDCl3): δ 8.95 (d, J = 2.0Hz, 1H), 8.50 (d, J = 1.5Hz, 1H), 7.77 (d, J = 1.5Hz, 1H), 7.60 (d, J = 7.5Hz, 1H), 7.54 (m, 2H), 7.36 (tdd, J = 8.5, 2.5, 1.0Hz, 1H), 7.12 (t, J = 6.5Hz, 1H), 7.06 (dd, J = 5.5Hz, 1H), 3.93 (s, 3H); HRMS (ESI): m / z predicted value C 17 H 12 FNO3[M+H] + 298.0897, detected value 298.0901.

[0151]

[0152] Example 7: Preparation of ethyl 5-(3-fluorobenzoyl)indoleazine-7-carboxylate (II-7).

[0153] According to the method of Example 4, 2-bromo-1-(3-fluorophenyl)ethane-1-one (2.6 g, 12.0 mmol) was used instead of 2-bromo-1-(4-fluorophenyl)ethane-1-one, and ethyl propynate (403 mg, 4.8 mmol) was used instead of methyl propynate to obtain a yellow solid (II-7, 58%). 1 H NMR (500MHz, CDCl3): δ 8.95 (d, J = 2.5Hz, 1H), 8.49 (d, J = 1.5Hz, 1H), 7.79 (d, J = 1.5Hz, 1H), 7.60 (dt, J = 7.5, 1.0Hz, 1H), 7.54 (m, 1H), 7.36 (tdd, J = 8.0, 2.5Hz, 1H), 7.12 (t, J = 7.0Hz, 1H), 7.06 (dd, J = 4.5, 1.0Hz, 1H), 4.39 (q, J = 7.0Hz, 2H), 1.40 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 17 H 12 FNO3[M+H] + 312.1036, detected value 312.1039.

[0154]

[0155] Example 8: Preparation of methyl 5-(2-fluorobenzoyl)indoleazine-7-carboxylic acid (II-8).

[0156] According to the method of Example 4, 2-bromo-1-(2-fluorophenyl)ethane-1-one (2.6 g, 12.0 mmol) was used instead of 2-bromo-1-(4-fluorophenyl)ethane-1-one to give a yellow solid (II-8, 47%). 1 H NMR (500MHz, CDCl3): δ 9.24 (d, J = 2.0Hz, 1H), 8.51 (d, J = 1.0Hz, 1H), 7.79 (t, J = 1.5Hz, 1H), 7.59 (m, 2H), 7.33 (t, J = 1.5Hz, 1H), 7.24 (t, J = 9.0Hz, 1H), 7.15 (dd, J = 4.0, 2.5Hz, 1H), 7.08 (d, J = 4.0Hz, 1H), 3.90 (s, 3H); HRMS (ESI): m / z predicted value C 17 H 12 FNO3[M+H] + 298.0897, detected value 298.0898.

[0157]

[0158] Example 9: Preparation of ethyl 5-(3-chlorobenzoyl)indoleazine-7-carboxylate (II-9).

[0159] According to the method of Example 1, 2-bromo-1-(3-chlorophenyl)ethane-1-one (2.8 g, 12.0 mmol) was used instead of 2-bromo-1-phenylethane-1-one to give a yellow solid (II-9, 71%). 1 H NMR (500MHz, CDCl3): δ8.74(d,J=2.0Hz,1H),8.26(d,J=2.0Hz,1H),7.57(d,J=1.5Hz,1H),7.42(dd,J=7.5,1.5Hz,1H),7.36(m,2H),7.23( dd,J=4.0,3.0Hz,1H),7.12(t,J=7.0Hz,1H),7.03(dd,J=4.5,1.0Hz,1H),4.17(q,J=7.0Hz,2H),1.41(t,J=7.0Hz,3H); HRMS(ESI):m / z predicted value C 17 H 12 ClNO3[M+H] + 328.0740, detected value 328.0745.

[0160]

[0161] Example 10: Preparation of ethyl 5-(3-bromobenzoyl)indoleazine-7-carboxylic acid (II-10).

[0162] According to the method of Example 1, 2-bromo-1-(3-bromophenyl)ethane-1-one (3.3 g, 12.0 mmol) was used instead of 2-bromo-1-phenylethane-1-one to give a yellow solid (II-10, 65%). 1 H NMR (500MHz, CDCl3): δ8.72(d,J=1.5Hz,1H),8.24(d,J=2.0Hz,1H),7.56(m,1H),7.41(dd,J=7.0,2.0Hz,1H),7.34(m,2H),7.21(dd,J =4.0, 3.0Hz, 1H), 7.09 (t, J = 7.0Hz, 1H), 7.01 (dd, J = 4.5, 1.0Hz, 1H), 4.18 (q, J = 7.0Hz, 2H), 1.40 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 17 H 12 BrNO3[M+H] + 372.0235, detected value 372.0238.

[0163]

[0164] Example 11: Preparation of ethyl 5-(3-methylbenzoyl)indoleazine-7-carboxylate (II-11).

[0165] According to the method of Example 1, 2-bromo-1-(m-tolyl)ethane-1-one (2.5 g, 12.0 mmol) was used instead of 2-bromo-1-phenylethane-1-one to give a yellow solid (II-11, 74%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.61 (m, 1H), 8.18 (d, J = 2.0Hz, 1H), 7.49 (m, 1H), 7.35 (m, 3H), 7.17 (dd, J = 4.0, 3.0Hz, 1H), 7.08 (t, J = 7.0Hz, 1H), 7.02 (dd, J = 4.5, 1.5Hz, 1H), 4.21 (q, J = 7.0Hz, 2H), 1.41 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 18 H 15 NO3[M+H] + 308.1287, detected value 308.1285.

[0166]

[0167] Example 12: Preparation of ethyl 5-(3-methoxybenzoyl)indoleazine-7-carboxylate (II-12).

[0168] According to the method of Example 1, 2-bromo-1-phenylethane-1-one (2.7 g, 12.0 mmol) was used instead of 2-bromo-1-phenylethane-1-one to give a yellow solid (II-12, 78%). 1 H NMR (500MHz, CDCl3): δ 8.67 (d, J = 2.0Hz, 1H), 8.18 (d, J = 1.5Hz, 1H), 7.47 (m, 1H), 7.36 (m, 2H), 7.21 (dd, J = 4.0, 3.0Hz, 1H), 7.13 (t, J = 7.0Hz, 1H), 7.04 (dd, J = 4.5, 1.0Hz, 1H), 4.20 (q, J = 7.0Hz, 2H), 3.64 (s, 3H), 1.41 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 19 H 17 NO4[M+H] + 324.1236, detected value 324.1238.

[0169]

[0170] Example 13: Preparation of methyl 5-(furan-2-carbonyl)indoleazine-7-carboxylic acid (II-13).

[0171] According to the method of Example 1, 2-bromo-1-(furan-2-yl)ethane-1-one (2.3 g, 12.0 mmol) was used instead of 2-bromo-1-phenylethane-1-one, and methyl propargylate (403 mg, 4.8 mmol) was used instead of ethyl propargylate to give a yellow solid (II-13, 65%). 1 H NMR (500MHz, CDCl3): δ8.79(d,J=3.0Hz,1H),8.47(d,J=1.0Hz,1H),8.19(d,J=1.5Hz,1H),7.80(dd,J=1.5,0.5Hz,1H),7.35(dd,J= 3.5, 0.5Hz, 1H), 7.07 (dd, J=4.5, 3.0Hz, 1H), 7.01 (J=4.5, 1.0Hz, 1H), 6.68 (dd, J=4.0, 2.0Hz, 1H), 3.97 (s, 3H); HRMS (ESI): m / z predicted value C 15 H 11 NO4[M+H] + 270.0766, detected value 270.0768.

[0172]

[0173] Example 14: Preparation of ethyl 5-(furan-2-carbonyl)indoleazine-7-carboxylate (II-14).

[0174] According to the method of Example 1, 2-bromo-1-(furan-2-yl)ethane-1-one (2.3 g, 12.0 mmol) was used instead of 2-bromo-1-phenylethane-1-one to give a yellow solid (II-14, 57%). 1 H NMR (500MHz, CDCl3): δ8.72(d,J=3.0Hz,1H),8.45(d,J=1.0Hz,1H),8.14(d,J=1.5Hz,1H),7.79(dd,J=1.5,0.5Hz,1H),7.42(dd,J=3.5,0.5Hz,1H), 7.14 (dd, J=4.5, 3.0Hz, 1H), 6.94 (J=4.5, 1.0Hz, 1H), 6.65 (dd, J=4.0, 2.0Hz, 1H), 4.37 (q, J=7.0Hz, 2H), 1.49 (t, J=7.0Hz, 3H); HRMS (ESI): m / z predicted value C 16 H 13 NO4[M+H] + 284.0923, detected value 284.0927.

[0175]

[0176] Example 15: Preparation of methyl 5-(thiophene-2-carbonyl)indoleazine-7-carboxylic acid (II-15).

[0177] According to the method of Example 1, 2-bromo-1-(thiophen-2-yl)ethane-1-one (2.4 g, 12.0 mmol) was used instead of 2-bromo-1-phenylethane-1-one, and methyl propargylate (403 mg, 4.8 mmol) was used instead of ethyl propargylate to give a yellow solid (II-15, 78%). 1 H NMR (500MHz, CDCl3): δ8.65(m,1H),8.46(d,J=1.5Hz,1H),7.99(d,J=1.5Hz,1H),7.81(dd,J=5.0,1.0Hz,1H),7.78(dd,J=4.0,1. 0Hz, 1H), 7.24 (dd, J=5.0, 4.0Hz, 1H), 7.06 (dd, J=4.5, 3.0Hz, 1H), 7.00 (dd, J=4.5, 1.0Hz, 1H), 3.96 (s, 3H); HRMS (ESI): m / z predicted value C 15 H 11 NO3S[M+H]+ 286.0538, detected value 286.0540.

[0178]

[0179] Example 16: Preparation of ethyl 5-(thiophene-2-carbonyl)indoleazine-7-carboxylate (II-16).

[0180] According to the method of Example 1, 2-bromo-1-(thiophen-2-yl)ethane-1-one (2.4 g, 12.0 mmol) was used instead of 2-bromo-1-phenylethane-1-one to give a yellow solid (II-16, 76%). 1 H NMR (500MHz, CDCl3): δ8.59(m,1H),8.37(d,J=1.5Hz,1H),7.91(d,J=1.5Hz,1H),7.83(dd,J=4.5,1.5Hz,1H),7.75(dd,J=4.0,1.5Hz,1H),7.21( dd,J=4.5,4.0Hz,1H),7.03(dd,J=4.5,3.0Hz,1H),6.97(dd,J=4.5,1.5Hz,1H),4.35(q,J=7.0Hz,2H),1.47(t,J=7.0Hz,3H); HRMS(ESI):m / z predicted value C 16 H 13 NO3S[M+H] + 300.0694, detected value 300.0697.

[0181]

[0182] Example 17: Preparation of methyl 5-methylpyridinimide-7-carboxylic acid ester (II-17).

[0183] According to the method of Example 1, 2-bromo-1-(pyridin-2-yl)ethane-1-one (2.3 g, 12.0 mmol) was used instead of 2-bromo-1-phenylethane-1-one, and methyl propargylate (403 mg, 4.8 mmol) was used instead of ethyl propargylate to give a yellow solid (II-17, 78%). 1¹H NMR (500MHz, CDCl₃): 9.13 (m, 1H), 8.82 (m, 1H), 8.56 (d, J = 1.5Hz, 1H), 8.23 ​​(d, J = 1.5Hz, 1H), 8.04 (dt, J = 7.5, 1.5Hz, 1H), 7.97 (ddd, J = 9.0, 7.0, 1.0Hz, 1H), 7.54 (ddd, J = 8.5, 7.0, 1.0Hz, 1H), 7.10 (dd, J = 4.5, 2.5Hz, 1H), 7.03 (dd, J = 4.5, 1.0Hz, 1H), 4.05 (s, 3H); HRMS (ESI): m / z predicted value C 16 H 12 N₂O₃[M+H] + 281.0926, detected value 281.0929.

[0184]

[0185] Example 18: Preparation of ethyl 5-methylpyridineimide-7-carboxylate (II-18).

[0186] According to the method of Example 1, 2-bromo-1-(pyridin-2-yl)ethane-1-one (2.3 g, 12.0 mmol) was used instead of 2-bromo-1-phenylethane-1-one to give a yellow solid (II-18, 76%). 1 ¹H NMR (500MHz, CDCl₃): δ 9.07 (m, 1H), 8.74 (m, 1H), 8.46 (d, J = 1.5Hz, 1H), 8.21 (d, J = 1.5Hz, 1H), 8.00 (dt, J = 8.0, 1.0Hz, 1H), 7.93 (ddd, J = 9.0, 7.5, 1.5Hz, 1H), 7.51 (ddd, J = 8.0, 6.5, 1.5Hz, 1H), 7.08 (dd, J = 4.5, 2.5Hz, 1H), 7.01 (dd, J = 4.5, 1.0Hz, 1H), 4.36 (q, J = 7.0Hz, 2H), 1.36 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 17 H 14 N₂O₃[M+H] + 295.1083, detected value 295.1088.

[0187]

[0188] Example 19: Preparation of 5-benzoimide-7-carboxylic acid (II-19).

[0189] Step c: Dissolve compound II-1 (2.9 g, 10 mmol) in 30 mL of ethanol, add 10 mL of 2N sodium hydroxide solution, and react the reaction solution overnight at 80°C. After the reaction of the starting material is complete as monitored by thin-layer chromatography, remove the ethanol by vacuum distillation. Adjust the remaining solution to acidity with hydrochloric acid solution, and a yellow solid precipitates out. Filter the solution, wash the solid with water, and dry it to obtain a yellow solid (II-19, 95%). 1 H NMR (500MHz, CDCl3): δ 12.05 (s, 1H), 8.74 (d, J = 2.0Hz, 1H), 8.35 (J = 2.0Hz, 1H), 7.57 (m, 3H), 7.35 (dd, J = 7.5, 2.0Hz, 1H), 7.21 (t, J = 8.5Hz, 2H), 7.10 (dd, J = 4.5, 2.5Hz, 1H), 7.03 (dd, J = 4.5, 1.5Hz, 1H); HRMS (ESI): m / z predicted value C 16 H 11 NO3[M+H] + 266.0817, detected value 266.1818.

[0190]

[0191] Example 20: Preparation of 5-benzoimide-7-carboxamide (II-20).

[0192] Step d: Compound Ⅱ-19 (275 mg, 1 mmol), 1-hydroxybenzotriazole (64 mg, 0.3 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (229 mg, 1.2 mmol) were dissolved in 10 mL of anhydrous tetrahydrofuran. N,N-diisopropylethylamine (168 mg, 1.3 mmol) was added at room temperature, and the reaction was carried out for 8 hours at room temperature until the reaction was complete as monitored by thin-layer chromatography. Then, ammonium chloride (107 mg, 2 mmol) was added, and the reaction was carried out for 2 hours at room temperature. After the reaction of the starting materials was complete as monitored by thin-layer chromatography, the solvent was removed by vacuum distillation of the reaction solution. The crude product was purified by silica gel column chromatography to obtain a red solid (Ⅱ-20, 87%). 1 HNMR (500MHz, d6-DMSO): δ 8.75 (s, 1H), 8.50 (s, 1H), 8.10 (s, 1H), 7.82 (d, J = 7.0Hz, 2H), 7.72 (t, J = 7.5Hz, 1H), 7.62 (m, 3H), 7.44 (s, 1H), 7.11 (t, J = 3.5Hz, 1H), 7.02 (d, J = 4.0Hz, 1H); HRMS (ESI): m / z predicted value C 16 H 12 N₂O₂[M+H] +265.0977, detected value 265.0979.

[0193]

[0194] Example 21: Preparation of 5-benzoyl-N-ethylindoleazine-7-carboxamide (II-21).

[0195] According to the method of Example 20, ethylamine (90 mg, 2.0 mmol) was used instead of ammonium chloride to obtain a yellow solid (II-21, 86%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.82 (d, J = 2.0Hz, 1H), 8.01 (d, J = 1.5Hz, 1H), 7.81 (dd, J = 8.0, 1.0Hz, 2H), 7.62 (m, 2H), 7.52 (t, J = 7.5Hz, 2H), 7.05 (dd, J = 4.0, 2.5Hz, 1H), 6.91 (dd, J = 3.5, 1.0Hz, 1H), 6.01 (s, 1H), 3.47 (m, 2H), 1.24 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 18 H 16 N₂O₂[M+H] + 293.1290, detected value 293.1292.

[0196]

[0197] Example 22: Preparation of 5-benzoyl-N,N-dimethylindoleazine-7-carboxamide (II-22).

[0198] According to the method of Example 20, dimethylamine (90 mg, 2 mmol) was used instead of ammonium chloride to obtain a yellow solid (II-22, 85%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.82 (d, J = 2.0Hz, 1H), 7.82 (d, J = 1.5Hz, 1H), 7.79 (dd, J = 7.0, 1.5Hz, 2H), 7.60 (tt, J = 7.5, 1.0Hz, 1H), 7.50 (t, J = 8.0Hz, 2H), 7.29 (d, J = 1.5Hz, 1H), 7.00 (dd, J = 4.0, 2.5Hz, 1H), 6.86 (dd, J = 4.5, 1.0Hz, 1H), 3.08 (s, 6H). HRMS (ESI): m / z predicted value C 18 H 16 N₂O₂[M+H] + 293.1290, detected value 293.1292.

[0199]

[0200] Example 23: Preparation of 5-benzoyl-N,N-diethylindoleazine-7-carboxamide (II-23).

[0201] According to the method of Example 20, diethylamine (146 mg, 2 mmol) was used instead of ammonium chloride to obtain a yellow solid (II-23, 89%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.81 (d, J = 3.0Hz, 1H), 7.79 (m, 3H), 7.61 (tt, J = 7.5, 1.0Hz, 1H), 7.50 (t, J = 8.0Hz, 2H), 7.23 (d, J = 2.0Hz, 1H), 7.04 (dd, J = 4.5, 3.0Hz, 1H), 6.84 (dd, J = 4.5, 1.5Hz, 1H), 3.43 (m, 4H), 1.19 (m, 6H); HRMS (ESI): m / z predicted value C 20 H 20 N₂O₂[M+H] + 321.1603, detected value 321.1606.

[0202]

[0203] Example 24: Preparation of 5-benzoyl-N-ethyl-N-methylindoleazine-7-carboxamide (II-24).

[0204] According to the method of Example 20, methyl ethylamine (118 mg, 2 mmol) was used instead of ammonium chloride to obtain a yellow solid (II-24, 88%). 1 NMR (500MHz, CDCl3): δ 8.84 (d, J = 1.5Hz, 1H), 7.82 (m, 3H), 7.63 (t, J = 8.0Hz, 1H), 7.53 (t, J = 8.0Hz, 2H), 7.29 (m, 1H), 7.08 (dd, J = 4.0, 3.0Hz, 1H), 6.88 (dd, J = 3.5, 1.0Hz, 1H), 3.49 (m, 2H), 3.06 (m, 3H), 1.20 (m, 6H); HRMS (ESI): m / z predicted value C 19 H 18 N₂O₂[M+H] + 307.1447, detected value 307.1449.

[0205]

[0206] Example 25: Preparation of 5-benzoyl-N-methoxy-N-methylindoleazine-7-carboxamide (II-25).

[0207] According to the method of Example 20, N,O-dimethylhydroxylamine (122 mg, 2 mmol) was used instead of ammonium chloride to obtain a yellow solid (II-25, 85%). 1 NMR (500MHz, CDCl3): δ 8.82 (d, J = 1.5Hz, 1H), 7.79 (m, 3H), 7.58 (t, J = 8.0Hz, 1H), 7.49 (t, J = 8.0Hz, 2H), 7.27 (m, 1H), 7.05 (dd, J = 4.5, 3.0Hz, 1H), 6.85 (dd, J = 4.5, 1.5Hz, 1H), 3.59 (s, 2H), 3.36 (s, 3H); HRMS (ESI): m / z predicted value C 18 H 16 N₂O₃[M+H] + 309.1239, detected value 209.1243.

[0208]

[0209] Example 26: Preparation of aziridine-1-yl(5-benzoimide-7-yl) methyl ketone (II-26).

[0210] According to the method of Example 20, aziridine (122 mg, 2 mmol) was used instead of ammonium chloride to give a yellow solid (II-26, 77%). 1 H NMR (500MHz, CDCl3): δ8.91(d,J=2.0Hz,1H),7.93(d,J=2.0Hz,1H),7.87(dd,J=7.5,2.0Hz,2H),7.67(tt,J=7.5,1.0Hz,1H),7.54(t,J=7 .5Hz, 2H), 7.33 (d, J = 2.0Hz, 1H), 7.07 (dd, J = 4.0, 2.5Hz, 1H), 6.92 (dd, J = 4.5, 1.5Hz, 1H), 4.06 (m, 4H), 3.58 (m, 2H); HRMS (ESI): m / z predicted value C 19 H 16 N₂O₂[M+H] + 305.1290, detected value 305.1294.

[0211]

[0212] Example 27: Preparation of (5-benzoimide-7-yl)(pyrrolidine-1-yl) methyl ketone (II-27).

[0213] According to the method of Example 20, pyrrolidine (142 mg, 2 mmol) was used instead of ammonium chloride to give a yellow solid (II-27, 82%). 1 H NMR (500MHz, CDCl3): δ8.84(d,J=2.0Hz,1H),7.81(d,J=2.0Hz,1H),7.77(dd,J=8.0,1.5Hz,2H),7.59(t,J=7.5Hz,1H),7.43(t,J=8.0 Hz, 2H), 7.29 (d, J = 2.0Hz, 1H), 7.04 (dd, J = 4.0, 2.5Hz, 1H), 6.87 (dd, J = 4.5, 1.0Hz, 1H), 3.94 (m, 4H), 2.17 (m, 4H); HRMS (ESI): m / z predicted value C 20 H 18 N₂O₂[M+H] + 319.1447, detected value 319.1451.

[0214]

[0215] Example 28: Preparation of (5-benzoimide-7-yl)(piperidin-1-yl)methyl ketone (II-28).

[0216] According to the method of Example 20, piperidine (170 mg, 2 mmol) was used instead of ammonium chloride to give a yellow solid (II-28, 84%). δ 8.79 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 1.5 Hz, 1H), 7.62 (dd, J = 7.5, 2.0 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 7.25 (m, 1H), 7.01 (dd, J = 4.0, 2.5 Hz, 1H), 6.84 (dd, J = 4.5, 1.5 Hz, 1H), 3.87 (m, 4H), 1.93 (m, 4H), 1.52 (m, 2H); HRMS (ESI): m / z predicted value C 21 H 20 N₂O₂[M+H] + 333.1603, detected value 333.1608.

[0217]

[0218] Example 29: Preparation of (5-benzoylindoleazine-7-yl)(piperazine-1-yl)methyl ketone (II-29).

[0219] According to the method of Example 20, piperazine (172 mg, 2 mmol) was used instead of ammonium chloride to obtain a yellow solid (II-29, 85%). 1 NMR (500MHz, CDCl3): δ8.81(d,J=2.0Hz,1H),7.76(m,3H),7.54(t,J=7.5Hz,1H),7.43(t,J=7.5Hz,2H),7.24(d,J=1.5Hz, 1H), 7.03 (dd, J=4.5, 3.0Hz, 1H), 6.82 (dd, J=4.5, 1.0Hz, 1H), 4.01 (s, 1H), 3.62 (m, 4H), 3.47 (m, 4H); HRMS (ESI): m / z predicted value C 20 H 19 N3O2[M+H] + 334.1556, detected value 334.1558.

[0220]

[0221] Example 30: Preparation of (5-benzoimide-7-yl)(morpholino) methyl ketone (II-30).

[0222] According to the method of Example 20, morpholine (174 mg, 2 mmol) was used instead of ammonium chloride to give a yellow solid (II-30, 81%). δ 8.82 (d, J = 1.5 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.68 (dd, J = 7.5, 2.0 Hz, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.07 (dd, J = 4.0, 2.5 Hz, 1H), 6.91 (dd, J = 4.5, 1.0 Hz, 1H), 4.05 (m, 4H), 3.93 (m, 4H); HRMS (ESI): m / z predicted value C 20 H 18 N₂O₃[M+H] + 335.1396, detected value 335.1399.

[0223]

[0224] Example 31: Preparation of (5-benzoimide-7-yl)(4-methylpiperazin-1-yl) methyl ketone (II-31).

[0225] According to the method of Example 20, 4-methylpiperazine (200 mg, 2 mmol) was used instead of ammonium chloride to give a yellow solid (II-31, 85%). δ 8.91 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 1.5 Hz, 1H), 7.78 (dd, J = 8.0, 2.0 Hz, 2H), 7.69 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.31 (m, 1H), 7.11 (dd, J = 4.0, 2.5 Hz, 1H), 6.93 (dd, J = 4.5, 1.5 Hz, 1H), 3.72 (m, 4H), 2.93 (m, 4H), 2.78 (s, 3H); HRMS (ESI): m / z predicted value C 21 H 21 N3O2[M+H] + 348.1712, detected value 348.1712.

[0226]

[0227] Example 32: Preparation of N,N-diethyl-5-(2-fluorobenzoyl)indoleazine-7-carboxamide (II-32).

[0228] Step c: Dissolve compound II-8 (1.5 g, 5 mmol) in 15 mL of ethanol, add 5 mL of 2N sodium hydroxide solution, and react the reaction solution at 80°C overnight. After the reaction of the starting material is complete as monitored by thin-layer chromatography, remove the ethanol by vacuum distillation. Adjust the remaining solution to slightly acidic with hydrochloric acid solution, and a yellow solid precipitates out. Filter the solid, wash it with water, and dry it to obtain a yellow solid (1.3 g, 94%).

[0229] Step d: The yellow solid (283 mg, 1 mmol), 1-hydroxybenzotriazole (64 mg, 0.3 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (229 mg, 1.2 mmol) from the previous step were dissolved in 10 mL of anhydrous tetrahydrofuran. N,N-diisopropylethylamine (168 mg, 1.3 mmol) was added at room temperature, and the reaction was carried out for 8 hours at room temperature until the reactants were completely reacted as monitored by thin-layer chromatography. Then, diethylamine (146 mg, 2 mmol) was added, and the reaction was carried out for 2 hours at room temperature. After the reactants were completely reacted as monitored by thin-layer chromatography, the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a red solid (II-32, 87%). 1H NMR (500MHz, CDCl3): δ8.84(m,1H),7.81(d,J=1.5Hz,1H),7.55(dt,J=7.5,1.0Hz,1H),7.49(m,2H),7.30(dddd,J=11.0,7.5,3.0,1.5Hz,1H),7 .26 (d, J = 2.0Hz, 1H), 7.05 (dd, J = 4.5, 3.0Hz, 1H), 6.86 (dd, J = 4.5, 1.5Hz, 1H), 3.45 (q, J = 7.0Hz, 4H), 1.12 (t, J = 7.0Hz, 6H); HRMS (ESI): m / z predicted value C 20 H 19 FN2O2[M+H] + 339.1509, detected value 339.1510.

[0230]

[0231] Example 33: Preparation of (5-(2-fluorobenzoyl)indoleazine-7-yl)(pyrrolidine-1-yl)methyl ketone (II-33).

[0232] According to the method of Example 32, pyrrolidine (142 mg, 2 mmol) was used instead of diethylamine to obtain a yellow solid (II-33, 81%). 1 H NMR (500MHz, CDCl3): δ8.87(m,1H),7.83(d,J=2.0Hz,1H),7.57(dt,J=8.0,1.5Hz,1H),7.52(m,2H),7.33(1H,dddd,J=11.5,8.0,3.5, 2.0Hz), 7.29 (1H, d, J = 1.5Hz), 7.08 (1H, dd, J = 4.5, 2.5Hz), 6.89 (1H, dd, J = 4.5, 1.0Hz), 3.57 (m, 4H), 1.82 (m, 4H); HRMS (ESI): m / z predicted value C 20 H 17 FN2O2[M+H] + 337.1352, detected value 337.1356.

[0233]

[0234] Example 34: Preparation of N,N-diethyl-5-pyridinimide-7-carboxamide (II-34).

[0235] According to the method of Example 32, compound II-9 was replaced with compound II-17 (1.4 g, 5 mmol) to give a yellow solid (II-34, 89%). 1 H NMR (500MHz, CDCl3): 9.17 (m, 1H), 8.85 (m, 1H), 8.61 (d, J = 2.0Hz, 1H), 8.27 (d, J = 2.0Hz, 1H), 8.09 (dt, J = 8.0, 2.0Hz, 1H), 7.99 (ddd, J = 8.5, 7.5, 2. 0Hz, 1H), 7.56 (ddd, J = 8.5, 7.0, 1.5Hz, 1H), 7.13 (dd, J = 4.5, 2.5Hz, 1H), 7.05 (dd, J = 4.5, 1.5Hz, 1H), 3.34 (m, 4H), 1.24 (m, 6H); HRMS (ESI): m / z predicted value C 19 H 19 N3O2[M+H] + 322.1556, detected value 322.1557.

[0236]

[0237] Example 35: Preparation of (5-benzoimide-7-yl)(4-methylpiperazin-1-yl) methyl ketone (II-35).

[0238] According to the method of Example 32, compound II-9 was replaced with compound II-17 (1.4 g, 5 mmol) and diethylamine was replaced with pyrrolidine (142 mg, 2 mmol) to obtain a yellow solid (II-35, 85%). 1 H NMR (500MHz, CDCl3): 9.11 (m, 1H), 8.76 (m, 1H), 8.57 (m, 1H), 8.23 ​​(d, J = 2.0Hz, 1H), 8.04 (dt, J = 7.5, 2.0Hz, 1H), 7.94 (ddd, J = 8.0, 7.0, 1.5Hz, 1H), 7.52 (ddd, J=8.0, 7.0, 1.5Hz, 1H), 7.10 (dd, J=4.5, 2.5Hz, 1H), 7.01 (dd, J=4.5, 1.0Hz, 1H), 3.49 (m, 4H) 1.74 (m, 4H); HRMS (ESI): m / z predicted value C 19 H 17 N3O2[M+H] + 320.1399, detected value 320.1403.

[0239]

[0240] Example 36: Preparation of (5-pyridyllinpolyazine-7-yl)(piperazine-1-yl)methyl ketone (II-36).

[0241] According to the method of Example 32, compound II-9 was replaced with compound II-17, and diethylamine was replaced with piperazine (172 mg, 2 mmol), to obtain a yellow solid (II-36, 73%). 1 H NMR (500MHz, CDCl3): δ9.05 (m, 1H), 8.71 (m, 1H), 8.54 (d, J = 1.5Hz, 1H), 8.18 (d,J=2.0Hz,1H),7.99(dt,J=7.5,2.0Hz,1H),7.91(ddd,J=8.5,7.0,1.5Hz,1 H),7.48(ddd,J=8.5,7.5,1.5Hz,1H),7.07(dd,J=4.5,2.5Hz,1H),6.98(dd,J =4.5,1.5Hz,1H),4.13(s,1H),3.54(m,4H),3.14(m,4H); HRMS(ESI):m / z predicted value C 19 H 18 N4O2[M+H] + 335.1508, detected value 335.1510.

[0242]

[0243] Example 37: Preparation of (5-benzoimide-7-yl)(piperazin-1-yl)methyl ketone hydrochloride (II-37).

[0244] Step e: Dissolve compound II-29 (33 mg, 0.1 mmol) in diethyl ether, add hydrochloric acid methanol solution, react at room temperature for 2 hours until the reaction of the starting material is complete as monitored by thin-layer chromatography, and filter to obtain a yellow solid (II-37, 98%). 1 NMR (500MHz, CDCl3): δ 10.43 (s, 2H), 9.04 (d, J = 1.5Hz, 1H), 7.94 (m, 3H), 7.73 (t, J = 7.0Hz, 1H), 7.61 (t, J = 7.0Hz, 2H), 7.42 (d, J = 2.0Hz, 1H), 7.13 (dd, J = 4.5, 3.0Hz, 1H), 6.95 (dd, J = 4.5, 1.5Hz, 1H), 4.43 (m, 4H), 3.76 (m, 4H); HRMS (ESI): m / z predicted value C 20 H 20 ClN3O2[M] + 334.1556, detected value 334.1560.

[0245]

[0246] Example 38: Preparation of N,N-diethyl-5-pyridineimide-7-carboxamide hydrochloride (II-38).

[0247] According to the method of Example 37, compound II-29 was replaced with compound II-34 (36 mg, 0.1 mmol) to give a yellow solid (II-38, 87%). 1 H NMR (500MHz, CDCl3): 11.54(1H,s),9.31(d,J=2.0Hz,1H),8.95(m,2H),8.46(d,J=2.0Hz,1H),8.19(t,J=8.0Hz,1H),8.13(ddd,J=8.0,7.0,2.0H z,1H),7.72(ddd,J=8.0,7.5,1.5Hz,1H),7.23(dd,J=4.5,3.0Hz,1H),7.09(dd,J=4.5,1.0Hz,1H),3.54(m,4H),1.37(m,6H); HRMS(ESI):m / z predicted value C 19 H 20 ClN3O2[M] + 322.1556, detected value 322.1559.

[0248]

[0249] Example 39: Preparation of (5-methylpyridinimide-7-yl)(pyrrolidine-1-yl)methyl ketone hydrochloride (II-39).

[0250] According to the method of Example 37, compound II-29 was replaced with compound II-35 (32 mg, 0.1 mmol) to obtain a yellow solid (II-39, 92%). 1 ¹H NMR (500MHz, CDCl₃): 11.27 (1H, s), 9.27 (m, 1H), 8.85 (m, 1H), 8.67 (m, 1H), 8.17 (m, 2H), 8.04 (ddd, J = 8.5, 7.0, 1.5Hz, 1H), 7.59 (ddd, J = 8.0, 7.0, 1.5Hz, 1H), 7.19 (dd, J = 4.5, 3.0Hz, 1H), 7.05 (d, J = 4.0Hz, 1H), 3.65 (m, 4H), 1.86 (m, 4H); HRMS (ESI): m / z predicted value C 19 H 18 ClN3O2[M] +320.1399, detected value 320.1340.

[0251]

[0252] Example 40: Preparation of (5-pyridyllindoazine-7-yl)(piperazine-1-yl)methyl ketone hydrochloride (II-40).

[0253] According to the method of Example 37, compound II-29 was replaced with compound II-36 (36 mg, 0.1 mmol) to give a yellow solid (II-40, 91%). 1 H NMR (500MHz, CDCl3): 10.94 (1H, s), 9.16 (m, 1H), 8.87 (m, 1H), 8.62 (d, J = 2.0 Hz,1H),8.26(m,1H),8.05(t,J=8.0Hz,1H),7.98(ddd,J=8.0,7.5,1.5Hz,1H ),7.54(ddd,J=8.0,7.5,1.5Hz,1H),7.11(dd,J=4.5,2.5Hz,1H),7.02(dd,J =4.5,1.0Hz,1H),5.34(s,1H),3.78(m,4H),3.47(m,4H); HRMS(ESI):m / z predicted value C 19 H 19 ClN4O2[M] + 335.1508, detected value 335.1511.

[0254]

[0255] Example 41: Preparation of 1-(5-(hydroxy(phenyl)methyl)indoleazine-7-yl)prop-1-one (II-41).

[0256] Step f: Under nitrogen protection, compound II-1 (293 mg, 1 mmol) was dissolved in anhydrous methanol. The reaction solution was kept in an ice bath at 0°C. Sodium borohydride was added to the reaction solution in batches. The reaction was carried out at 0°C for 2 hours. After the reaction of the starting material was monitored by thin-layer chromatography, the reaction solution was quenched with saturated ammonium chloride solution in an ice bath. The solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a white solid (II-41, 97%). 1¹H NMR (500MHz, CDCl₃): δ 8.24 (d, J = 1.5Hz, 1H), 7.47 (dt, J = 8.0, 1.5Hz, 2H), 7.37 (m, 5H), 6.83 (dd, J = 4.0, 3.0Hz, 1H), 6.79 (dd, J = 4.5, 1.5Hz, 1H), 6.04 (d, J = 4.0Hz, 1H), 4.38 (q, J = 7.0Hz, 2H), 2.70 (d, J = 3.0Hz, 1H), 1.42 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 18 H 17 NO3[M+H] + 296.1287, detected value 296.1290.

[0257]

[0258] Example 42: Preparation of 5-(hydroxy(phenyl)methylindoleazine-7-carboxylic acid (II-42)).

[0259] According to the method of Example 41, compound II-1 was replaced with compound II-1 (265 mg, 1 mmol) to give a white solid (II-42, 94%). 1 H NMR (500MHz, CDCl3): δ12.72(s,1H),8.14(d,J=1.0Hz,1H),7.63(s,1H),7.42(d,J=7.0Hz,2H),7.36(t,J=7.0Hz,2H),7.30(tt,J=7.0,1.0Hz ,1H),6.86(dd,J=3.5,2.0Hz,1H),6.82(dd,J=4.0,1.0Hz,1H),6.38(d,J=4.0Hz,1H),6.01(d,J=5.0Hz,1H),3.34(s,1H); HRMS(ESI):m / z predicted value C 16 H 13 NO3[M+H] + 268.0974, detected value 268.0979.

[0260]

[0261] Example 43: Preparation of N-ethyl-5-(hydroxy(phenyl)methyl)indoleazine-7-carboxamide (II-43).

[0262] According to the method of Example 41, compound II-1 was replaced with compound II-21 (293 mg, 1 mmol) to give a white solid (II-43, 95%). 1H NMR (500MHz, CDCl3): δ8.01(d,J=1.5Hz,1H),7.48(dt,J=7.0Hz,2H),7.43(d ,J=2.0Hz,1H),7.36(t,J=7.0Hz,2H),7.30(t,J=7.0Hz,1H),7.21(d,J=1.5Hz ,1H),6.78(dd,J=4.0,3.0Hz,1H),6.71(dd,J=4.0,0.5Hz,1H),6.04(s,1H),4 .66 (s, 1H), 3.44 (q, J = 7.0Hz, 2H), 1.26 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 18 H 18 N₂O₂[M+H] + 295.1447, detected value 295.1448.

[0263]

[0264] Example 44: Preparation of 5-(hydroxy(phenyl)methyl)-N,N-dimethylindoleazine-7-carboxamide (II-44).

[0265] According to the method of Example 41, compound II-1 was replaced with compound II-22 (293 mg, 1 mmol) to give a white solid (II-44, 97%). 1 ¹H NMR (500MHz, CDCl₃): δ 7.50 (d, J = 1.5Hz, 1H), 7.41 (dd, J = 7.0, 2.0Hz, 2H), 7.34 (m, 3H), 7.29 (d, J = 2.0Hz, 1H), 6.77 (m, 2H), 6.59 (dd, J = 4.0, 1.0Hz, 1H), 5.97 (s, 1H), 3.36 (s, 1H), 3.06 (s, 6H); HRMS (ESI): m / z predicted value C 18 H 18 N₂O₂[M+H] + 295.1447, detected value 295.1451.

[0266]

[0267] Example 45: Preparation of N,N-diethyl-5-(hydroxy(phenyl)methyl)indoleazine-7-carboxamide (II-45).

[0268] According to the method of Example 41, compound II-1 was replaced with compound II-23 (321 mg, 1 mmol) to give a white solid (II-45, 96%). 1H NMR (500MHz, CDCl3): δ7.44(d,J=1.0Hz,1H),7.40(dd,J=7.5,1.5Hz,2H),7.32(m,3H),7.26(m,1H),6.75(dd,J=4.0,3.0 Hz,1H),6.71(s,1H),6.56(dd,J=4.0,1.0Hz,1H),5.95(s,1H),3.57(s,1H),3.42(m,4H)1.16(m,6H); HRMS(ESI):m / z predicted value C 20 H 22 N₂O₂[M+H] + 323.1760, detected value 323.1763.

[0269]

[0270] Example 46: Preparation of N-ethyl-5-(hydroxy(phenyl)methyl)-N-methylindoleazine-7-carboxamide (II-46).

[0271] According to the method of Example 41, compound II-1 was replaced with compound II-25 (307 mg, 1 mmol) to give a white solid (II-46, 97%). 1 ¹H NMR (500MHz, CDCl₃): δ 7.51 (s, 1H), 7.44 (d, J = 7.0Hz, 2H), 7.34 (m, 5H), 6.78 (m, 2H), 6.62 (d, J = 4.0Hz, 1H), 6.00 (s, 1H), 3.46 (m, 2H), 3.05 (s, 3H), 1.20 (m, 3H); HRMS (ESI): m / z predicted value C 19 H 20 N₂O₂[M+H] + 309.1603, detected value 309.1606.

[0272]

[0273] Example 47: Preparation of ethyl 5-(acetoxy(phenyl)methyl)indoleazine-7-carboxylate (II-47).

[0274] Step g1: Under nitrogen protection, compound II-41 (296 mg, 1 mmol) and triethylamine (122, 1.2 mmol) were dissolved in anhydrous dichloromethane. After the reaction solution was cooled to 0 degrees Celsius, acetyl chloride (94 mg, 1.2 mmol) was added dropwise. After the addition was completed, the reaction was carried out at room temperature for 8 hours. After the reaction of the starting materials was monitored by thin-layer chromatography, 2 mL of saturated ammonium chloride solution was added dropwise to the reaction solution under ice bath. After the addition was completed, the reaction solution was extracted with dichloromethane (15 mL) and water (15 mL). The aqueous phase was extracted twice with dichloromethane (15 mL). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a pale yellow solid (II-47, 82%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.28 (d, J = 1.0Hz, 1H), 7.44 (m, 2H), 7.39 (m, 3H), 7.34 (d, J = 2.5Hz, 1H), 7.27 (d, J = 1.0Hz, 1H), 7.19 (s, 1H), 6.86 (dd, J = 4.0, 3.0Hz, 1H), 6.83 (dd, J = 4.5, 1.0Hz, 1H), 4.40 (q, J = 7.0Hz, 2H), 2.24 (s, 3H), 1.43 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 20 H 19 NO4[M+H] + 338.1392, detected value 338.1395.

[0275]

[0276] Example 48: Preparation of ethyl 5-(butyryloxy)(phenyl)methyl)indoleazine-7-carboxylate (II-48).

[0277] According to the method of Example 47, butyryl chloride (127 mg, 1.2 mmol) was used instead of acetyl chloride to give a pale yellow solid (II-48, 77%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.28 (s, 1H), 7.39 (m, 6H), 7.27 (s, 1H), 7.21 (s, 1H), 6.86 (dd, J = 4.0, 2.5Hz, 1H), 6.83 (dd, J = 3.5, 0.5Hz, 1H), 4.40 (m, 2H), 2.40 (t, J = 7.5Hz, 2H), 1.70 (m, 2H), 1.40 (t, J = 7.0Hz, 3H), 0.97 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 22 H 23 NO4[M+H]+ 366.1705, detected value 366.1707.

[0278]

[0279] Example 49: Preparation of ethyl 5-((octyloxy)(phenyl)methyl)indoleazine-7-carboxylate (II-49).

[0280] According to the method of Example 47, octanoyl chloride (194 mg, 1.2 mmol) was used instead of acetyl chloride to give a pale yellow solid (II-49, 64%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.26 (d, J = 1.0Hz, 1H), 7.43 (m, 2H), 7.36 (m, 3H), 7.31 (d, J = 2.0Hz, 1H), 7.25 (s, 1H), 7.18 (s, 1H), 6.84 (dd, J = 4.0, 2.5Hz, 1H), 6.81 (dd, J = 4.0, 1.0Hz, 1H), 4.37 (t, J = 7.5Hz, 2H), 2.37 (t, J = 7.5Hz, 2H), 1.64 (m, 2H), 1.38 (m, 9H), 0.87 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 25 H 29 NO4[M+H] + 408.2175, detected value 408.2177.

[0281]

[0282] Example 50: Preparation of (7-(diethylcarbamoyl)indole-5-yl)(phenyl)acetic acid methyl ester (II-50).

[0283] According to the method of Example 47, compound II-41 was replaced with compound II-45 (322 mg, 1 mmol) to give a pale yellow solid (II-50, 79%). 1 H NMR (500MHz, CDCl3): δ7.46(d,J=1.5Hz,1H),7.42(dd,J=7.0,2.0Hz,2H),7.34(m,3H),7.21(d,J=2.0Hz,1H),6.77(dd,J=4.0, 3.0Hz,1H),6.73(s,1H),6.57(dd,J=4.0,1.0Hz,1H),5.96(s,1H),3.41(m,4H),3.07(s,3H),1.19(m,6H); HRMS(ESI):m / z predicted value C 22 H 24N₂O₃[M+H] + 365.1865, detected value 365.1866.

[0284]

[0285] Example 51: Preparation of methyl (7-(diethylcarbamoyl)indoleaza-5-yl)(phenyl)butyrate (II-51).

[0286] According to the method of Example 47, compound II-41 was replaced with compound II-45 (322 mg, 1 mmol) and acetyl chloride was replaced with butyryl chloride (127 mg, 1.2 mmol) to give a pale yellow solid (II-51, 72%). 1 ¹H NMR (500MHz, CDCl₃): δ 7.43 (m, 1H), 7.39 (d, J = 7.0Hz, 2H), 7.31 (m, 3H), 7.19 (d, J = 2.0Hz, 1H), 6.75 (dd, J = 4.0, 2.5Hz, 1H), 6.71 (s, 1H), 6.54 (dd, J = 4.0, 1.5Hz, 1H), 5.93 (s, 1H), 3.41 (m, 4H), 2.40 (t, J = 7.5Hz, 2H), 1.70 (m, 2H), 1.21 (m, 6H), 0.97 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 24 H 28 N₂O₃[M+H] + 393.2178, detected value 393.2183.

[0287]

[0288] Example 52: Preparation of (7-(diethylcarbamoyl)indole-5-yl)(phenyl)octanoate methyl ester (II-52).

[0289] According to the method of Example 47, compound II-41 was replaced with compound II-45 (322 mg, 1.0 mmol) and acetyl chloride (194 mg, 1.2 mmol) (127 mg, 1.2 mmol) was replaced with octanoyl chloride to give a pale yellow solid (II-52, 72%). 1HNMR (500MHz, CDCl3): δ 7.42 (d, J = 2.0Hz, 1H), 7.37 (dd, J = 7.0, 1.5Hz, 2H), 7.28 (m, 3H), 7.18 (d, J = 2.0Hz, 1H), 6.72 (dd, J = 4.0, 2.5Hz, 1H), 6.69 (s, 1H), 6.51 (dd, J = 4.0, 1.0Hz, 1H), 5.91 (s, 1H), 3.37 (m, 4H), 2.35 (t, J = 7.5Hz, 2H), 1.31 (m, 15H), 0.92 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 28 H 36 N₂O₃[M+H] + 449.2804, detected value 449.2805.

[0290]

[0291] Example 53: Preparation of (5-benzoimide-7-yl)(4-methylpiperazin-1-yl) methyl ketone (II-53).

[0292] Step g2: Under nitrogen protection, compound II-41 (30 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 mL). After the reaction solution was cooled to 0°C, sodium hydride (5 mg, 0.12 mmol) was added. After reacting at 0°C for 30 minutes, iodomethane (17 mg, 0.12 mmol) was added dropwise. After the addition was complete, the reaction was carried out at room temperature for 8 hours. After the reaction of the starting material was monitored by thin-layer chromatography, 2 mL of saturated ammonium chloride solution was added dropwise to the reaction solution under ice bath. After the addition was complete, the reaction solution was extracted with 5 mL of ethyl acetate and 5 mL of water. The aqueous phase was extracted twice with 5 mL of ethyl acetate. The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a pale yellow solid (II-53, 85%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.14 (m, 1H), 7.36 (t, J = 8.0Hz, 2H), 7.27 (m, 5H), 6.71 (dd, J = 4.0, 2.5Hz, 1H), 6.68 (dd, J = 4.5, 1.0Hz, 1H), 5.68 (s, 1H), 4.35 (q, J = 7.0Hz, 2H), 3.31 (s, 3H), 1.41 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 19 H 19 NO3[M+H] + 310.1443, detected value 310.1447.

[0293]

[0294] Example 54: Ethyl 5-(phenyl(propoxy)methylindoleazine-7-carboxylate).

[0295] According to the method of Example 53, iodopropane (20 mg, 0.12 mmol) was used instead of iodomethane (II-54, 65%). δ 8.26 (d, J = 2.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.25 (m, 3H), 6.74 (dd, J = 4.0, 2.5 Hz, 1H), 6.63 (dd, J = 4.5, 1.5 Hz, 1H), 5.72 (s, 1H), 4.37 (q, J = 7.0 Hz, 2H), 3.2 (t, J = 7.0 Hz, 2H), 1.52 (m, 2H), 1.41 (t, J = 7.0 Hz, 3H), 0.94 (t, J = 7.0 Hz, 3H); HRMS (ESI): m / z predicted value C 21 H 23 NO3[M+H] + 338.1756, detected value 338.1758.

[0296]

[0297] Example 55: Preparation of methyl 5-benzoylimidazo[1,2-a]pyridine-7-carboxylic acid (ⅠII-1).

[0298] Step h: Under nitrogen protection, imidazole (680 mg, 10 mmol) and potassium carbonate (1.7 mg, 12 mmol) were added in anhydrous acetonitrile (30 mL), followed by the addition of 2-bromo-1-phenylethane-1-one (2.4 g, 12 mmol) in portions. After complete addition, the mixture was heated to 60°C and reacted overnight. Thin-layer chromatography was used to monitor the complete reaction of the starting material. The mixture was then cooled to room temperature, and potassium carbonate was removed by filtration. The solvent in the filtrate was removed by vacuum distillation. The crude product was purified by silica gel column chromatography, and the resulting white solid was used directly in the next step of the reaction.

[0299] Step i: Under nitrogen protection, the product from the previous step, 2-(1H-imidazol-1-yl)-1-phenylethane-1-one (930 mg, 5 mmol), was dissolved in anhydrous dichloromethane (30 mL), and then phosphorus oxychloride (912 mg, 6 mmol) was added. The reaction solution was kept in an ice bath at 0°C. N,N-dimethylformamide (438 mg, 6 mmol) was slowly added to the reaction solution. The reaction was carried out at 0°C for 2 hours. After the reaction was complete as monitored by thin-layer chromatography, the reaction solution was extracted with 50 mL of ethyl acetate and 50 mL of water. The aqueous phase was extracted twice with 50 mL of ethyl acetate. The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a white solid.

[0300] Step j: Under nitrogen protection, the product obtained in the previous step, 1-(2-oxo-2-phenylethyl)-1H-imidazol-2-aminocarboxaldehyde (428 mg, 2 mmol), methyl propynate (202 mg, 2.4 mmol), and potassium carbonate (331 mg, 2.4 mmol) were dissolved in anhydrous N,N-dimethylformamide (6 mL). The reaction was carried out overnight at 80°C. After the reaction was monitored by thin-layer chromatography to ensure complete reaction of the starting materials, the mixture was cooled to room temperature. The reaction solution was extracted with 15 mL of ethyl acetate and 15 mL of water. The aqueous phase was extracted twice with 15 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a yellow solid (III-1, 74%). 1 H NMR (500MHz, CDCl3): δ 8.91 (s, 1H), 8.61 (d, J = 1.0Hz, 1H), 7.99 (d, J = 1.0Hz, 1H), 7.95 (d, J = 1.5Hz, 1H), 7.83 (dt, J = 7.0, 1.5Hz, 2H), 7.68 (tt, J = 7.5, 1.0Hz, 1H), 7.56 (t, J = 7.5Hz, 2H), 3.95 (s, 3H); HRMS (ESI): m / z predicted value C 16 H 12 N₂O₃[M+H] + 282.0926, detected value 282.0929.

[0301]

[0302] Example 56: Preparation of methyl 5-(4-chlorobenzoyl)imidazo[1,2-a]pyridine-7-carboxylic acid (ⅠII-2).

[0303] According to the method of Example 55, 2-bromo-1-phenylethane-1-one (2.8 g, 12 mmol) was substituted for 2-bromo-1-phenylethane-1-one to give a yellow solid (III-2, 67%). 1 H NMR (500MHz, CDCl3): δ 8.93 (d, J = 1.5Hz, 1H), 8.64 (d, J = 1.0Hz, 1H), 8.01 (d, J = 1.0Hz, 1H), 7.97 (d, J = 1.5Hz, 1H), 7.86 (d, J = 7.0Hz, 2H), 7.57 (d, J = 7.5Hz, 2H), 3.92 (3H, s); HRMS (ESI): m / z predicted value C 16 H 11 ClN2O3[M+H] + 315.0536, detected value 315.0538.

[0304]

[0305] Example 57: Preparation of methyl 5-(4-methylbenzoyl)imidazo[1,2-a]pyridine-7-carboxylic acid (ⅠII-3).

[0306] According to the method of Example 55, 2-bromo-1-phenylethane-1-one (2.5 g, 12 mmol) was substituted for 2-bromo-1-phenylethane-1-one to give a yellow solid (III-3, 82%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.87 (m, 1H), 8.54 (d, J = 1.5Hz, 1H), 7.94 (d, J = 1.5Hz, 1H), 7.91 (d, J = 1.5Hz, 1H), 7.79 (d, J = 7.0Hz, 2H), 7.51 (d, J = 7.0Hz, 2H), 3.96 (3H, s); HRMS (ESI): m / z predicted value C 17 H 14 N₂O₃[M+H] + 295.1083, detected value 295.1088.

[0307]

[0308] Example 58: Preparation of ethyl 5-benzoylimidazo[1,2-a]pyridine-7-carboxylate (ⅠII-4).

[0309] According to the method of Example 55, ethyl propargyl ester (235 mg, 2.4 mmol) was used instead of methyl propargyl ester to obtain a yellow solid (III-4, 58%). 1H NMR (500MHz, CDCl3): δ 8.89 (s, 1H), 8.57 (d, J = 1.0Hz, 1H), 7.96 (d, J = 1.0Hz, 1H), 7.94 (d, J = 1.5Hz, 1H), 7.80 (dt, J = 7.0, 1.5Hz, 2H), 7.66 (tt, J = 7.0, 1.5Hz, 1H), 7.54 (t, J = 7.0Hz, 2H), 4.17 (q, J = 7.0Hz, 2H), 1.41 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 17 H 14 N₂O₃[M+H] + 295.1083, detected value 295.1085.

[0310]

[0311] Example 59: Preparation of 5-benzoimide azo[1,2-a]pyridine-7-carboxylic acid (ⅠII-5).

[0312] Step k: Dissolve compound III-4 (588 mg, 2 mmol) in 6 mL of ethanol, add 2 N sodium hydroxide solution (2 mL), stir the reaction solution at 80 °C overnight, monitor the reaction of the starting material by thin-layer chromatography until the reaction is complete, remove the ethanol by vacuum distillation, adjust the remaining solution to acidity with hydrochloric acid solution, a yellow solid precipitates, filter, wash the solid with water and dry to obtain a yellow solid (III-5, 94%). 1 H NMR (500MHz, CDCl3): δ 12.27 (1H, s), 8.87 (s, 1H), 8.54 (s, 1H), 7.93 (d, J = 1.5Hz, 1H), 7.91 (d, J = 1.5Hz, 1H), 7.78 (dt, J = 7.0, 1.0Hz, 2H), 7.63 (tt, J = 7.0, 1.0Hz, 1H), 7.52 (t, J = 7.0Hz, 2H); HRMS (ESI): m / z predicted value C 15 H 10 N₂O₃[M+H] + 267.0770, detected value 267.0771.

[0313]

[0314] Example 60: Preparation of 5-benzoyl-N,N-dimethylimidazolium[1,2-a]pyridine-7-carboxamide (ⅠII-6).

[0315] Step 1: Compound III-5 (53 mg, 0.2 mmol), 1-hydroxybenzotriazole (13 mg, 0.06 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24 mmol) were dissolved in 2 mL of anhydrous tetrahydrofuran. N,N-diisopropylethylamine (34 mg, 0.26 mmol) was added at room temperature, and the reaction was carried out for 8 hours at room temperature until the reaction of III-5 was complete as monitored by thin-layer chromatography. Then, dimethylamine (11 mg, 0.24 mmol) was added, and the reaction was carried out for 2 hours at room temperature. After the reaction of the starting materials was complete as monitored by thin-layer chromatography, the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a yellow solid (III-6, 86%). 1 H NMR (500MHz, CDCl3): δ 8.87 (d, J = 2.0Hz, 1H), 8.55 (d, J = 1.5Hz, 1H), 7.92 (d, J = 1.5Hz, 1H), 7.87 (d, J = 1.5Hz, 1H), 7.73 (dt, J = 7.5, 1.5Hz, 2H), 7.67 (tt, J = 7.5, 1.5Hz, 1H), 7.50 (t, J = 7.0Hz, 2H), 3.27 (s, 6H); HRMS (ESI): m / z predicted value C 17 H 15 N3O2[M+H] + 294.1243, detected value 294.1245.

[0316]

[0317] Example 61: Preparation of 5-benzoyl-N-ethylimidazo[1,2-a]pyridine-7-carboxamide (ⅠII-7).

[0318] According to the method of Example 60, ethylamine (11 mg, 0.24 mmol) was used instead of dimethylamine to obtain a yellow solid (III-7, 88%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.85 (m, 1H), 8.56 (d, J = 1.5Hz, 1H), 7.94 (d, J = 1.0Hz, 1H), 7.86 (d, J = 1.0Hz, 1H), 7.74 (dt, J = 7.5, 1.5Hz, 2H), 7.65 (tt, J = 7.0, 1.5Hz, 1H), 7.50 (t, J = 7.5Hz, 2H), 5.85 (m, 1H), 3.47 (m, 2H), 1.24 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 17 H 15 N3O2[M+H] +294.1243, detected value 294.1247.

[0319]

[0320] Example 62: Preparation of 5-benzoyl-N,N-diethylimidazolium[1,2-a]pyridine-7-carboxamide (ⅠII-8).

[0321] According to the method of Example 60, diethylamine (18 mg, 0.24 mmol) was used instead of dimethylamine to obtain a yellow solid (III-8, 79%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.86 (m, 1H), 8.54 (d, J = 1.5Hz, 1H), 7.91 (d, J = 1.5Hz, 1H), 7.89 (d, J = 1.5Hz, 1H), 7.74 (dt, J = 7.0, 1.0Hz, 2H), 7.65 (tt, J = 7.0, 1.0Hz, 1H), 7.48 (t, J = 7.0Hz, 2H), 3.56 (m, 4H), 1.14 (m, 6H); HRMS (ESI): m / z predicted value C 19 H 19 N3O2[M+H] + 322.1556, detected value 322.1557.

[0322]

[0323] Example 63: Preparation of (5-benzoylimidazo[1,2-a]pyridin-7-yl)(pyrrolidine-1-yl)methyl ketone (ⅠII-9).

[0324] According to the method of Example 60, pyrrolidine (17 mg, 0.24 mmol) was used instead of dimethylamine to give a yellow solid (III-9, 73%). 1 H NMR (500MHz, CDCl3): δ 8.86 (d, J = 1.5Hz, 1H), 8.56 (d, J = 1.5Hz, 1H), 7.93 (d, J = 1.5Hz, 1H), 7.87 (d, J = 1.5Hz, 1H), 7.72 (dt, J = 7.0, 1.0Hz, 2H), 7.63 (tt, J = 7.0, 1.0Hz, 1H), 7.50 (t, J = 7.0Hz, 2H), 3.63 (m, 4H), 1.43 (m, 4H); HRMS (ESI): m / z predicted value C 19 H 17 N3O2[M+H] + 320.1399, detected value 320.1402.

[0325]

[0326] Example 64: Preparation of (5-benzoylimidazolium[1,2-a]pyridin-7-yl)(piperidin-1-yl)methyl ketone (ⅠⅡ-10).

[0327] According to the method of Example 60, replacing dimethylamine with piperidine (20 mg, 0.24 mmol) yielded a yellow solid (III-10, 77%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.89 (m, 1H), 8.55 (d, J = 1.0Hz, 1H), 7.93 (d, J = 1.5Hz, 1H), 7.90 (d, J = 1.5Hz, 1H), 7.72 (dt, J = 7.0, 1.0Hz, 2H), 7.67 (tt, J = 7.0, 1.0Hz, 1H), 7.50 (t, J = 7.0Hz, 2H), 3.74 (m, 4H), 1.95 (m, 4H), 1.47 (m, 2H); HRMS (ESI): m / z predicted value C 20 H 19 N3O2[M+H] + 334.1556, detected value 334.1558.

[0328]

[0329] Example 65: Preparation of ethyl 5-(hydroxy(phenyl)methylimidazo[1,2-a]pyridine-7-carboxylate (ⅠII-11).

[0330] Step m: Under nitrogen protection, compound III-4 (294 mg, 1 mmol) was dissolved in anhydrous methanol (4 mL). The reaction solution was kept in an ice bath at 0°C. Sodium borohydride (152 mg, 4 mmol) was added to the reaction solution in batches. The reaction was carried out at 0°C for 2 hours. After the reaction of the starting material was monitored by thin-layer chromatography, the reaction solution was quenched with 5 mL of saturated ammonium chloride solution in an ice bath. The solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to obtain a white solid (III-11, 93%). 1 ¹H NMR (500MHz, CDCl₃): δ 8.37 (m, 1H), 7.51 (d, J = 1.5Hz, 1H), 7.28 (m, 2H), 7.21 (dt, J = 7.0, 1.5Hz, 2H), 7.14 (tt, J = 7.0, 1.5Hz, 1H), 7.03 (t, J = 7.0Hz, 2H), 5.83 (s, 1H), 4.52 (s, 1H), 4.15 (q, J = 7.0Hz, 2H), 1.40 (t, J = 7.0Hz, 3H); HRMS (ESI): m / z predicted value C 17 H16 N₂O₃[M+H] + 297.1239, detected value 297.1243.

[0331] Example 66: Biological Evaluation

[0332] The substituted indoleazine and pyridine derivatives of the present invention have inhibitory effects on the TRPM2 channel. The pharmacological activity was determined using whole-cell patch-clamp technique, and the corresponding steps are as follows.

[0333] Step 1: Cell Preparation

[0334] HEK293 cells stably expressing the human TRPM2 channel were incubated in DMEM / F-12 medium containing 10% bovine serum, 50 units / mL penicillin, and 50 mg / mL streptomycin at 5% CO2 and 37°C.

[0335] Step 2: Electrophysiological testing

[0336] Cells were preserved in extracellular fluid (147mM NaCl, 2mM KCl, 1mM MgCl2, 2mM CaCl2, 10mM HEPES, 13mM glucose, pH 7.4) before testing. The electrode was filled with electrode internal fluid (147mM NaCl, 0.05mM EGTA, 1mM MgCl2, 10mM HEPES, 0.5mM ADPR, pH 7.3), and the resistance was maintained at 3–5 MΩ.

[0337] ADPR was administered intracellularly via electrodes, with a concentration of 500 μM used to activate TRPM2. Once a steady current was detected, the extracellular fluid was perfused with a corresponding concentration of fused-ring heterocyclic compound II-1 for at least 60 seconds. Changes in current magnitude were recorded using a voltage ramp mode, with the voltage changing from -100 mV to +100 mV over 500 ms. The normal clamping voltage was 0 mV, and each TRPM lasted 5 seconds. Finally, the extracellular fluid was replaced with a solution at pH 5.0 to block the TRPM2 current. The electrophysiological current test results are shown in Table 1, and the obtained electrophysiological current graphs are shown in [Table 1]. Figure 1 .

[0338] Similarly, other fused-ring heterocyclic compounds (II-2 to II-54, III-1 to III-11) were administered in extracellular fluid at appropriate concentrations, and electrophysiological tests were performed using the same method. The results are shown in Table 1. Representative electrophysiological current maps showing the inhibition of TRPM2 channel current by some fused-ring heterocyclic compounds (II-9, II-19, and II-36) are shown in Table 1. Figure 1 .

[0339] Table 1 shows the IC50 values ​​for TRPM2 inhibition by some fused-ring heterocyclic compounds. 50 data

[0340]

[0341]

[0342] Example 67: TRPM2 Channel Specificity Test Experiment

[0343] According to the method of Example 66, the inhibitory effect of the fused-ring heterocyclic compound II-1 of the present invention on different channels was detected to determine the specificity of the compound's effect on the TRPM2 channel.

[0344] HEK293T cells stably expressing voltage-gated channels, NMDA receptors, ASIC channels, TRPM8 channels, TRPC6 channels, TRPV4 channels, and TRPV1 channels were treated with voltage clamping, the agonist NMDA, acidic pH, menthol, M085, GSK, and capsaicin, respectively. The voltage across the cell membrane was then clamped to -100 mV using patch-clamp technology. When the potential across the cell membrane changed, a compensating current was input, allowing the measurement of the inward current, which reflects the degree of channel activation. After adding the compounds, changes in current magnitude were used to determine whether the compounds inhibited the activation of the aforementioned channels. The results are shown in [Figure showing results]. Figure 2 .

[0345] Test results show that the fused-ring heterocyclic compound of the present invention has specificity in inhibiting TRPM2 current, and has no inhibitory effect on voltage-gated channels, NMDA receptors, acid channels, TRPM8 channels, TRPC6 channels, TRPV1 channels, TRPV4 channels, etc.

[0346] Example 68: Study on the protective activity of the fused-ring heterocyclic compound II-I described in this invention against ischemia / reperfusion injury.

[0347] 1) Establishment of a mouse model of transient focal cerebral ischemia-middle cerebral artery occlusion (tMCAO)

[0348] Male C57BL / 6 mice (22-25g) were anesthetized with isoflurane inhalation gas. A laser Doppler flowmeter fiber optic probe was glued to the skull to monitor cerebral blood flow to the cortex supplied by the middle cerebral artery (MCA). Mice were fixed in a supine position, hair was removed from the midline of the neck, and the area was routinely disinfected with 75% alcohol. A 1.5cm incision was made in the midline of the neck, and the skin was opened. The muscle and fascia were dissected along the inner edge of the sternocleidomastoid muscle. The right carotid sheath was bluntly dissected to expose the right common carotid artery (CCA), external carotid artery (ECA), and internal carotid artery (ICA). After satisfactory exposure, the CCA and ICA were temporarily clamped with arterial clamps. A small incision was made proximal to the ECA using microsurgical scissors. A nylon monofilament suture was inserted through this incision along the ECA and gently pushed into the cranium approximately 11.5±0.5mm along the direction of the ICA, thus blocking the origin of the middle cerebral artery. Based on cerebral blood flow monitoring data, only animals whose blood flow value dropped to 20% of the baseline value were selected. After 90 minutes of ischemia, the monofilament suture was gently removed, the arterial stump was tightly tied, the surgical wound was inspected, and after thorough hemostasis, a small amount of penicillin powder was applied locally to prevent infection. The subcutaneous tissue and skin were sutured layer by layer to complete the ischemia-reperfusion injury model. A heating plate was used to maintain the animal's body temperature during the operation. After the operation, the sutured mice were placed in an incubator until they regained activity. Animals in the sham-operated group underwent the same surgical procedure, but without the middle cerebral artery occlusion.

[0349] 2) Animal grouping and dosing regimen

[0350] Clean-grade male C57BL / 6 mice were randomly divided into three groups: a sham-operated group, a positive control group (edaravone, 3 mg / kg), and a group receiving compound II-1 at a dose of 3 mg / kg. Three hours after ischemia-reperfusion, mice were injected via tail vein with either edaravone or I-1, while the sham-operated group received an equal volume of physiological saline. Both II-1 and edaravone were dissolved in 0.9% physiological saline solution. Neurological function scores and TTC staining were performed 24 hours after ischemia-reperfusion. Results are shown below. Figure 3 , 4 And 5.

[0351] 3) Measurement of cerebral infarction volume

[0352] Twenty-four hours after ischemia-reperfusion in mice, the brains were harvested by decapitation. The brain slices were uniformly sectioned in the coronal plane to a thickness of approximately 2 mm. The slices were placed in 0.25% triphenyltetrazolium chloride (TTC) solution and incubated at 37°C in the dark for 30 minutes. After staining, they were fixed overnight in 4% paraformaldehyde neutral buffer (pH 7.4). Macro photography was performed, and the infarct volume was calculated and statistically analyzed using ImageJ image analysis software. The results are shown below. Figure 4 The formula for calculating the percentage of infarct volume is: (sum of uninfarcted areas on the left side - sum of uninfarcted areas on the right side) / sum of uninfarcted areas on the left side × 100%.

[0353] 4) Neurological function testing

[0354] According to the five-level four-point scoring system, the mortality rate and neuromotor dysfunction scores of mice in each group were calculated. The results are shown below. Figure 5 The neurological function scoring criteria are as follows: 0 points: no neurological deficit symptoms; 1 point: the forelimb on the opposite side of cerebral ischemia cannot be fully extended when the tail is lifted; 2 points: the experimental animal circles towards the opposite side of cerebral ischemia; 3 points: the experimental animal falls towards the opposite side of cerebral ischemia when crawling; 4 points: the experimental animal cannot walk independently and loses consciousness.

[0355] 5) Evaluation of activity results

[0356] The fused-ring heterocyclic compound II-1 described in this invention can significantly reduce the volume of cerebral infarction induced by tMCAO in mice and significantly reduce the neuromotor dysfunction score induced by tMCAO, and has similar pharmacological activity to the positive control drug edaravone at the same concentration.

[0357] Those skilled in the art will understand that the above embodiments are specific examples of implementing the present invention, and in practical applications, various changes in form and detail may be made without departing from the spirit and scope of the present invention.

Claims

1. A fused-ring heterocyclic compound, or a pharmaceutically acceptable salt and stereoisomer thereof, said fused-ring heterocyclic compound having the structure shown in general formula (I): I In the formula, R 1 For unsubstituted or at least one hydrogen atom is R 1-1 Substituted furanyl, thiophene, or pyridyl; or R 1 For unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein, R 1-1 Halogen or C 1~6 Alkyl, R 1-2 Halogen, C 1~6 Alkyl or C 1~6 Alkoxy; Indicates a single bond or a double bond, when When it is a single bond, R 2 Hydroxyl group, C 2~12 Acyloxy or C 1~6 alkoxy; when When it is a double bond, R 2 It is an oxygen atom; R 3 Hydroxyl group, C 1~4 alkyl, Or azirmonobutan-1-yl, pyrrolidan-1-yl, piperidin-1-yl, piperazin-1-yl, morpholino-1-yl, wherein Ra and Rb are independently selected from hydrogen and C, respectively. 1~4 Alkyl or C 1~4 Alkoxy; X is a carbon atom or a nitrogen atom.

2. The fused-ring heterocyclic compound according to claim 1, characterized in that, The R 1 For unsubstituted or at least one hydrogen atom is R 1-1 Substituted furanyl, thiophene, or pyridyl, wherein the R 1-1 Halogen or C 1~4 alkyl; Or, the R 1 For unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, said R 1-2 Halogen, C 1~4 Alkyl or C 1~4 Alkoxy; And / or, Representing a single bond, the R 2 Hydroxyl group, C 2~8 Acyloxy or C 1~4 Alkoxy; or, It is a double bond, R 2 It is an oxygen atom; And / or, R 3 Hydroxyl group, C 1~4 Alkyl, aziridine-1-yl, pyrrolidine-1-yl, piperidin-1-yl, piperazine-1-yl, morpholin-1-yl or Ra and Rb are independently selected from hydrogen, methyl, ethyl, methoxy, or ethoxy, respectively.

3. The fused-ring heterocyclic compound according to claim 2, characterized in that, The R 1 For unsubstituted or at least one hydrogen atom is R 1-1 Substituted furanyl, thiophene, or pyridyl, wherein the R 1-1 It can be fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; Or, the R 1 For unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, said R 1-2 It can be fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, or ethoxy. And / or, Representing a single bond, the R 2 Hydroxyl, methoxy, ethoxy, propoxy or Where Re is C 1~7 alkyl; or, It is a double bond, R 2 It is an oxygen atom; And / or, R 3 The derivatives are hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, aziridine-1-yl, pyrrolidine-1-yl, piperidin-1-yl, piperazine-1-yl, morpholino-1-yl, etc. , , , , or .

4. The fused-ring heterocyclic compound according to claim 1, characterized in that, The fused-ring heterocyclic compound has the structure shown in general formula (II): II In the formula, R 1 For unsubstituted or at least one hydrogen atom is R 1-1 Substituted furanyl, thiophene, or pyridyl; or unsubstituted or with at least one hydrogen atom replaced by R 1-2 Substituted phenyl, wherein R 1-1 Halogen or C 1~6 Alkyl, R 1-2 Halogen, C 1~6 Alkyl or C 1~6 Alkoxy; Indicates a single bond or a double bond, when When it is a single bond, R 2 Hydroxyl group, C 2~12 Acyloxy or C 1~6 alkoxy; when When it is a double bond, R 2 It is an oxygen atom; R 3 Hydroxyl group, C 1~4 alkyl, Or azirmonobutan-1-yl, pyrrolidan-1-yl, piperidin-1-yl, piperazin-1-yl, morpholino-1-yl, wherein Ra and Rb are independently selected from hydrogen and C, respectively. 1~4 Alkyl or C 1~4 Alkyl group.

5. The fused-ring heterocyclic compound according to claim 4, characterized in that, The fused-ring heterocyclic compound has the structure shown in general formula (III): III In the formula, R 1 For unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-2 Halogen, C 1~6 Alkyl or C 1~6 Alkoxy; R 2 Hydroxyl group, C 2~12 Acyloxy or C 1~6 Alkoxy; R 3 Hydroxyl group, C 1~4 alkyl or Ra and Rb are independently selected from hydrogen and C, respectively. 1~4 Alkyl or C 1~4 Alkyl group.

6. The fused-ring heterocyclic compound according to claim 4, characterized in that, The fused-ring heterocyclic compound has the structure shown in general formula (Ⅳ): Ⅳ In the formula, R 1 For unsubstituted or at least one hydrogen atom is R 1-1 Substituted furanyl, thiophene, or pyridyl; or R 1 For not replaced or by R 1-2 Substituted phenyl, wherein R 1-1 Halogen or C 1~6 Alkyl, R 1-2 Halogen, C 1~6 Alkyl or C 1~6 Alkoxy; R 3 Hydroxyl group, C 1~4 Alkyl, aziridine-1-yl, pyrrolidine-1-yl, piperidin-1-yl, piperazine-1-yl, morpholin-1-yl or Ra and Rb are independently selected from hydrogen and C, respectively. 1~4 Alkyl or C 1~4 Alkyl group.

7. The fused-ring heterocyclic compound according to claim 4, characterized in that, The fused-ring heterocyclic compound has the structure shown in general formula (Ⅳ): Ⅳ In the formula, R 1 It is an unsubstituted furanyl, thiophene, or pyridyl group; or it is unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-2 Halogen, C 1~6 Alkyl or C 1~6 Alkoxy; R 3 C 1~4 alkyl.

8. The fused-ring heterocyclic compound according to any one of claims 1 to 4, characterized in that, The fused-ring heterocyclic compound is selected from any of the following structures: 。 9. The fused-ring heterocyclic compound according to claim 1, characterized in that, In the fused-ring heterocyclic compound, X is a nitrogen atom.

10. The fused-ring heterocyclic compound according to claim 9, characterized in that, The fused-ring heterocyclic compound has the structure shown in general formula (V): Ⅴ In the formula, R 1 For unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-2 Halogen, C 1~6 Alkyl or C 1~6 Alkoxy; R 2 Hydroxyl or C 1~6 Alkoxy; R 3 Hydroxyl or C 1~4 alkyl.

11. The fused-ring heterocyclic compound according to claim 9, characterized in that, The fused-ring heterocyclic compound has the structure shown in general formula (VI): Ⅵ In the formula, R 1 For unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-2 Halogen, C 1~6 Alkyl or C 1~6 Alkoxy; R 3 Hydroxyl group, C 1~4 Alkyl, aziridine-1-yl, pyrrolidine-1-yl, piperidinyl-1-yl, piperazinyl-1-yl, morpholino-1-yl or Ra and Rb are independently selected from hydrogen or C, respectively. 1~4 alkyl.

12. The fused-ring heterocyclic compound according to claim 9, characterized in that, The fused-ring heterocyclic compound has the structure shown in general formula (VI): Ⅵ In the formula, R 1 A phenyl group that is either unsubstituted or has at least one hydrogen atom substituted by a halogen. R 3 Hydroxyl or C 1~4 alkyl.

13. The fused-ring heterocyclic compound according to any one of claims 1-3 and 9-11, characterized in that, The fused-ring heterocyclic compound is selected from any of the following structures: 。 14. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises any one of the fused-ring heterocyclic compounds of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof.

15. The use of the fused-ring heterocyclic compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a TRPM2 inhibitor medicament.

16. The application according to claim 15, characterized in that, The TRPM2 dysfunction disorders include: spinal cord injury or pain, cardiovascular and cerebrovascular diseases, Alzheimer's disease, neuropathic pain, Parkinson's disease, bipolar disorder, or amyotrophic lateral sclerosis.

17. The application according to claim 16, characterized in that, The cardiovascular and cerebrovascular diseases mentioned above are caused by oxidative stress resulting from ischemia / reperfusion.

18. The application according to claim 16 or 17, characterized in that, The cardiovascular and cerebrovascular diseases mentioned include stroke, cerebral thrombosis, or cerebrovascular accident.

19. Use of the pharmaceutical composition of claim 14 in the preparation of a TRPM2 inhibitor medicament.

20. A method for preparing the fused-ring heterocyclic compound as described in claim 7, characterized in that, The method includes step (1): Under alkaline conditions, M1 and The fused-ring heterocyclic compound is obtained by performing the following reaction; ， Among them, R 1 For unsubstituted furanyl, thiophene, or pyridyl groups, unsubstituted or at least one hydrogen atom is R 1-2 Substituted phenyl, wherein R 1-2 Halogen, C 1~6 Alkyl or C 1~6 Alkoxy; R 3 C 1~4 alkyl.

21. A method for preparing the fused-ring heterocyclic compound as described in claim 12, characterized in that, The method includes step (a): Under alkaline conditions, M2 and The fused-ring heterocyclic compound is obtained by performing the following reaction; ； Among them, R 1 A phenyl group that is either unsubstituted or has at least one hydrogen atom substituted by a halogen. R 3 Hydroxyl or C 1~4 alkyl.

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