Benzene ring compounds and their uses

Abstract

The present invention relates to a benzene ring compound and its use, and specifically provides a compound of Formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof. The compound described in the present invention has excellent therapeutic effects against tumors. [Formula 1] JPEG2023553687000477.jpg36147

Description

[Technical Field]

[0001] The present invention relates to the technical field of medicine, and relates to benzene ring compounds and their uses. [Background technology]

[0002] Tumors, as a common disease that seriously endangers human health, have been steadily increasing the mortality rate from malignant tumors. Due to the heterogeneity of tumors and individual patient differences, simply using the same treatment or drug for each tumor based on its origin and pathological characteristics can easily lead to problems caused by inappropriate treatment, delaying important treatment time and opportunities for patients. Therefore, there is a great need to adopt personalized treatment for various patient conditions. With the development of biological technology, tumor treatment has entered the era of precision medicine, and changes in tumor-related gene expression have been discovered one after another, indicating that related gene transformation plays an important role in the development of malignant tumors. The discovery and application of biomarkers can provide precise guidance for the application of relevant drugs, enabling personalized tumor treatment, achieving targeted dosing, and significantly improving therapeutic efficacy.

[0003] Therefore, there is an urgent need in the art to develop drugs that can precisely treat tumors. Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide a compound capable of safely and effectively suppressing tumors and use thereof.

[0005] Furthermore, the present invention aims to provide a marker for determining whether the compounds of the present invention are suitable for the prevention and / or treatment of tumor patients based on the mitochondrial oxidative phosphorylation pathway, the mitochondrial permeability transition pore, the NNMT gene, and / or the methylation level of DNA CpG sites in the NNMT gene region. The compounds of the present invention have significantly superior therapeutic effects against tumors with upregulated mitochondrial oxidative phosphorylation pathway, low activity of the mitochondrial permeability transition pore, low or no expression of the NNMT gene, and / or hypermethylation of DNA CpG sites in the NNMT gene region. [Means for solving the problem]

[0006] A first aspect of the present invention provides a compound of formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof: [ka] where: Ring A represents a substituted or unsubstituted C6-C16 aryl ring, a substituted or unsubstituted C3-C16 cycloalkyl ring, a substituted or unsubstituted 3- to 16-membered heterocycloalkyl ring, or a substituted or unsubstituted 3- to 16-membered heteroaryl ring; Ring B represents an unsubstituted or substituted C6-C16 aryl ring, a substituted or unsubstituted C3-C16 cycloalkyl ring, a substituted or unsubstituted 3- to 16-membered heterocycloalkyl ring, or a substituted or unsubstituted 3- to 16-membered heteroaryl ring; R1 is [ka] represents; R2 is a hydrogen atom, [ka] represents; R3 represents nothing, a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, F3C-, F3C-O-, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C1-C8 alkoxyl group, a substituted or unsubstituted C1-C8 alkylthiol group, a substituted or unsubstituted C6-C16 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, a substituted or unsubstituted C6-C16 aryl group-substituted or unsubstituted C1-C10 alkyl group-, or a substituted or unsubstituted 5-12 membered heteroaryl group-substituted or unsubstituted C1-C10 alkyl group; R4 and R5 each independently represent a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C1-C8 alkoxyl group, a substituted or unsubstituted C1-C8 alkylthiol group, a substituted or unsubstituted C6-C16 aryl group, or a substituted or unsubstituted 5-12 membered heteroaryl group; R6 represents a substituted or unsubstituted C6-C16 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, a substituted or unsubstituted 3-16 membered cycloalkyl group, or a substituted or unsubstituted 3-16 membered heterocycloalkyl group; n represents 0, 1, 2, 3, 4, 5 or 6; Ring C represents an unsubstituted or substituted C6-C16 aryl ring, a substituted or unsubstituted C3-C16 cycloalkyl ring, a substituted or unsubstituted 3- to 16-membered heterocycloalkyl ring, or a substituted or unsubstituted 3- to 16-membered heteroaryl ring; R7 represents a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C1-C8 alkoxyl group, a substituted or unsubstituted C1-C8 alkylthiol group, a substituted or unsubstituted C6-C16 aryl group, or a substituted or unsubstituted 5-12 membered heteroaryl group; R8 and R9, joined together, form a substituted or unsubstituted 3- to 16-membered cycloalkyl ring or a substituted or unsubstituted 3- to 16-membered heterocycloalkyl ring; R 10 and R 11 each independently represent a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, F3C-O-, F3C-, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C1-C8 alkoxyl group, a substituted or unsubstituted C1-C8 alkylthiol group, a substituted or unsubstituted C6-C16 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, a substituted or unsubstituted C6-C16 aryl group-substituted or unsubstituted C1-C10 alkyl group-, a substituted or unsubstituted 5-12 membered heteroaryl group-substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C6 alkyl group-C(O)-; or R 10 and R 11 are joined to form a substituted or unsubstituted 3- to 16-membered heterocycloalkyl ring or a substituted or unsubstituted 3- to 16-membered heteroaryl ring; R 12 and R 13 each independently represent a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, F3C-, F3C-O-, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted C1-C8 alkoxyl group, a substituted or unsubstituted C1-C8 alkylthiol group, a substituted or unsubstituted C6-C16 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, a substituted or unsubstituted C6-C16 aryl group-substituted or unsubstituted C1-C10 alkyl group-, or a substituted or unsubstituted 5-12 membered heteroaryl group-substituted or unsubstituted C1-C10 alkyl group-; The optional "substitution" refers to the replacement of one or more (preferably 1, 2, 3, 4, 5, 6, 7, or 8) hydrogen atoms on the ring or atomic group with a substituent selected from a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C1-C8 halogenated alkyl group, a C3-C8 halogenated cycloalkyl group, a halogen atom, a nitro group, -CN, a hydroxyl group, a mercapto group, an amino group, F3C-, F3C-O-, a C1-C4 carboxyl group, a C2-4 ester group, a C2-C4 acylamino group, a C1-C8 alkoxyl group, a C1-C8 alkylthiol group, a C1-C8 halogenated alkoxyl group, a C1-C8 halogenated alkylthiol group, a C6-C12 aryl group, a 5-10-membered heteroaryl group, and a 5-10-membered heterocycloalkyl group; The heterocyclic rings of the heterocycloalkyl group, heteroaryl group, heterocycloalkyl ring, and heteroaryl ring each independently contain 1 to 4 (preferably 1, 2, 3, or 4) heteroatoms selected from N, O, and S.

[0007] In another preferred example, the optional "substitution" refers to the replacement of one or more (preferably 1, 2, 3, 4, 5, 6, 7, or 8) hydrogen atoms on the ring or atomic group with a substituent selected from a C-C alkyl group, a C-C cycloalkyl group, a C-C halogenated alkyl group, a C-C halogenated cycloalkyl group, a halogen atom, a nitro group, -CN, a hydroxyl group, a mercapto group, an amino group, F3C-O-, F3C-, a C-C carboxyl group, a C2-4 ester group, a C2-C4 acylamino group, a C-C alkoxyl group, a C-C alkylthiol group, a C-C halogenated alkoxyl group, a C-C halogenated alkylthiol group, a C-C aryl group, a 5-10 membered heteroaryl group, and a 5-10 membered heterocycloalkyl group.

[0008] In another preferred example, the optional "substitution" refers to the replacement of one or more (preferably 1, 2, 3, 4, 5, 6, 7, or 8) hydrogen atoms on the ring or atomic group with a substituent selected from a C-C alkyl group, a C-C cycloalkyl group, a C-C halogenated alkyl group, a C-C halogenated cycloalkyl group, a halogen atom, a nitro group, -CN, a hydroxyl group, a mercapto group, an amino group, F3C-O-, F3C-, a C-C carboxyl group, a C2-4 ester group, a C2-C4 acylamino group, a C-C alkoxyl group, a C-C alkylthiol group, a C-C halogenated alkoxyl group, a C-C halogenated alkylthiol group, a C6-C12 aryl group, a 5-10-membered heteroaryl group, and a 5-10-membered heterocycloalkyl group.

[0009] In another preferred example, the heterocyclic rings of the heterocycloalkyl group, heteroaryl group, heterocycloalkyl ring, and heteroaryl ring each independently contain 1 to 4 (preferably 1, 2, 3, or 4) heteroatoms selected from N, O, and S.

[0010] In another preferred embodiment, the halogen atom is F, Cl, Br, or I.

[0011] In another preferred embodiment, the cycloalkyl ring has one, two or three C=C cyclic double bonds.

[0012] In another preferred embodiment, the heterocycloalkyl ring has one, two, or three C=C cyclic double bonds. In another preferred embodiment, the heterocyclic ring of the heterocycloalkyl group, heteroaryl group, heterocycloalkyl ring, and heteroaryl ring each independently has one to four (preferably one, two, three, or four) heteroatoms selected from N, O, and S.

[0013] In another preferred embodiment, ring A represents a substituted or unsubstituted C6-C12 aryl ring, a substituted or unsubstituted C3-C12 cycloalkyl ring, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl ring, or a substituted or unsubstituted 3- to 12-membered heteroaryl ring.

[0014] In another preferred example, ring A represents a substituted or unsubstituted C6-C10 aryl ring, a substituted or unsubstituted C3-C10 cycloalkyl ring, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl ring, or a substituted or unsubstituted 3- to 10-membered heteroaryl ring.

[0015] In another preferred example, ring A represents a substituted or unsubstituted C6-C8 aryl ring, a substituted or unsubstituted C3-C8 cycloalkyl ring, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl ring, or a substituted or unsubstituted 5- to 8-membered heteroaryl ring.

[0016] In another preferred example, ring A represents an unsubstituted or substituted 5-membered heterocycloalkyl ring, a substituted or unsubstituted 6-membered heterocycloalkyl ring, a substituted or unsubstituted 7-membered heterocycloalkyl ring, a substituted or unsubstituted 8-membered heterocycloalkyl ring, a substituted or unsubstituted 5-membered heteroaryl ring, a substituted or unsubstituted 6-membered heteroaryl ring, a substituted or unsubstituted 7-membered heteroaryl ring, or a substituted or unsubstituted 8-membered heteroaryl ring.

[0017] In another preferred example, ring A represents a substituted or unsubstituted 5-membered heteroaryl ring, a substituted or unsubstituted 6-membered heteroaryl ring, a substituted or unsubstituted 7-membered heteroaryl ring, or a substituted or unsubstituted 8-membered heteroaryl ring.

[0018] In another preferred example, ring A represents a substituted or unsubstituted pyridine ring, a substituted or unsubstituted pyrimidine ring, a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthoyl ring, a substituted or unsubstituted thiazole ring, a substituted or unsubstituted imidazole ring, or a substituted or unsubstituted pyrrolyl ring.

[0019] In another preferred example, ring A represents a pyridine ring, a pyrimidine ring, a benzene ring, a naphthoyl ring, a thiazole ring, or an imidazole ring.

[0020] In another preferred embodiment, R1 is bonded to a heteroatom on ring A.

[0021] In another preferred embodiment, R 1 is bonded to an N, O, or S atom on ring A.

[0022] In another preferred example, R1 is bonded to the N atom on ring A.

[0023] In another preferred embodiment, R2 is bonded to a carbon atom on ring A.

[0024] In another preferred embodiment, ring B is an unsubstituted or substituted C6-C12 aryl ring, a substituted or unsubstituted C3-C12 cycloalkyl ring, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl ring, or a substituted or unsubstituted 3- to 12-membered heteroaryl ring.

[0025] In another preferred embodiment, ring B is an unsubstituted or substituted C6-C10 aryl ring, a substituted or unsubstituted C3-C10 cycloalkyl ring, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl ring, or a substituted or unsubstituted 3- to 10-membered heteroaryl ring.

[0026] In another preferred embodiment, ring B represents an unsubstituted or substituted C6-C8 aryl ring, a substituted or unsubstituted C5-C8 cycloalkyl ring, a substituted or unsubstituted 5-8 membered heterocycloalkyl ring, or a substituted or unsubstituted 5-8 membered heteroaryl ring.

[0027] In another preferred example, ring B represents an unsubstituted or substituted 5-membered heterocycloalkyl ring, a substituted or unsubstituted 6-membered heterocycloalkyl ring, a substituted or unsubstituted 7-membered heterocycloalkyl ring, a substituted or unsubstituted 8-membered heterocycloalkyl ring, a substituted or unsubstituted 5-membered heteroaryl ring, a substituted or unsubstituted 6-membered heteroaryl ring, a substituted or unsubstituted 7-membered heteroaryl ring, or a substituted or unsubstituted 8-membered heteroaryl ring.

[0028] In another preferred embodiment, the cycloalkyl ring has one, two or three C=C cyclic double bonds.

[0029] In another preferred example, ring B represents an unsubstituted or substituted tetrahydropyridine ring, a substituted or unsubstituted pyrrolyl ring, a substituted or unsubstituted dihydropyrrole ring, a substituted or unsubstituted imidazole ring, or a substituted or unsubstituted pyrazole ring.

[0030] In another preferred embodiment, ring B is selected from the group consisting of: no ring, a tetrahydropyridine ring, a piperidine ring, a pyrrolyl ring, a dihydropyrrole ring, a tetrahydropyrrole ring, an imidazole ring, a pyrazole ring, a pyridine ring, [ka] Represents.

[0031] In another preferred embodiment, R3 is bonded to a carbon atom on ring B.

[0032] In another preferred embodiment, R3 is bonded to a heteroatom on ring B.

[0033] In another preferred embodiment, R3 is bonded to an N, O, or S atom on ring B.

[0034] In another preferred example, R3 is bonded to the N atom on ring B.

[0035] In another preferred example, [ka] The bonding state between and ring A is [ka] is.

[0036] In another preferred example, [ka] The bonding state between and ring A is [ka] is.

[0037] In another preferred embodiment, the tetrahydropyridine ring is a 1,2,3,4-tetrahydropyridine ring.

[0038] In another preferred example, the pyrrolyl ring is a 1-hydropyrrole ring.

[0039] In another preferred embodiment, the dihydropyrrole ring is a 2,3-dihydropyrrole ring.

[0040] In another preferred embodiment, ring B is absent. It should be understood that the present invention is such that when ring B is absent, the structure of the compound of formula I is as shown in structure I-1. [ka]

[0041] In another preferred embodiment, the compound of formula I is as follows: I-1. [ka]

[0042] In another preferred embodiment, ring B is absent and R2 is [ka] Represents.

[0043] In another preferred embodiment, ring B is a substituted or unsubstituted C6-C16 aryl ring, a substituted or unsubstituted C3-C16 cycloalkyl ring, a substituted or unsubstituted 3- to 16-membered heterocycloalkyl ring, or a substituted or unsubstituted 3- to 16-membered heteroaryl ring; and R2 represents a hydrogen atom.

[0044] In another preferred example, R1 is [ka] Represents.

[0045] In another preferred example, R1 is [ka] Represents.

[0046] In another preferred embodiment, R2 is a hydrogen atom, or [ka] Represents.

[0047] In another preferred embodiment, R2 is a hydrogen atom, or [ka] Represents.

[0048] In another preferred example, R3 represents a hydrogen atom, a halogen atom, —CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, F3C—, F3C—O—, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C1-C8 alkoxyl group, a substituted or unsubstituted C1-C8 alkylthiol group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted C6-C12 aryl group-substituted or unsubstituted C1-C8 alkyl group-, or a substituted or unsubstituted 5-10 membered heteroaryl group-substituted or unsubstituted C1-C8 alkyl group-.

[0049] In another preferred example, R3 represents a hydrogen atom, a halogen atom, —CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, F3C—, F3C—O—, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C1-C6 alkoxyl group, a substituted or unsubstituted C1-C6 alkylthiol group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted C6-C10 aryl group-substituted or unsubstituted C1-C4 alkyl group-, or a substituted or unsubstituted 5-10 membered heteroaryl group-substituted or unsubstituted C1-C4 alkyl group-.

[0050] In another preferred example, R3 represents a hydrogen atom, a halogen atom, —CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, F3C—, F3C—O—, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C1-C4 alkoxyl group, a substituted or unsubstituted C1-C4 alkylthiol group, a substituted or unsubstituted C6-C8 aryl group, a substituted or unsubstituted 5-8 membered heteroaryl group, a substituted or unsubstituted C6-C8 aryl group-substituted or unsubstituted C1-C2 alkyl group-, or a substituted or unsubstituted 5-8 membered heteroaryl group-substituted or unsubstituted C1-C2 alkyl group-.

[0051] In another preferred example, R3 represents a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl group-methyl group, a substituted or unsubstituted pyridine group, a substituted or unsubstituted pyridine group-methyl group, a substituted or unsubstituted phenyl group-ethyl group, or a substituted or unsubstituted pyridine group-ethyl group.

[0052] In another preferred example, R3 represents a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl group-methyl group, a substituted or unsubstituted pyridine group, a substituted or unsubstituted pyridine group-methyl group, a substituted or unsubstituted phenyl group-ethyl group, or a substituted or unsubstituted pyridine group-ethyl group.

[0053] In another preferred example, R3 represents a hydrogen atom, a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted propyl group, a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl group-methyl group, a substituted or unsubstituted pyridine group, a substituted or unsubstituted pyridine group-methyl group, a substituted or unsubstituted phenyl group-ethyl group, or a substituted or unsubstituted pyridine group-ethyl group.

[0054] In another preferred example, the substituted or unsubstituted phenyl group refers to a monosubstituted or unsubstituted phenyl group.

[0055] In another preferred example, in the substituted or unsubstituted phenyl group, the substituted or unsubstituted phenyl group refers to a mono-substituted or unsubstituted phenyl group, and substitution refers to ortho-, para- or meta-substitution of the phenyl group.

[0056] In another preferred example, the substituted or unsubstituted phenyl group refers to a mono-substituted or unsubstituted phenyl group, and the substitution refers to ortho-, para-, or meta-substitution of the phenyl group. The substituent refers to a halogen atom (e.g., a chlorine atom), a nitro group, an amino group, a C1-C4 alkyl group (methyl group), a C1-C4 alkoxyl group, a C1-C4 alkylthiol group, F3C-, or F3C-O-.

[0057] In another preferred example, the substituted or unsubstituted phenyl group in the substituted or unsubstituted phenyl group-methyl group refers to a monosubstituted or unsubstituted phenyl group.

[0058] In another preferred example, in the substituted or unsubstituted phenyl group-methyl group, the substituted or unsubstituted phenyl group refers to a mono-substituted or unsubstituted phenyl group, and substitution refers to ortho-, para- or meta-substitution of the phenyl group.

[0059] In another preferred example, the substituted or unsubstituted phenyl group-methyl group refers to a mono-substituted or unsubstituted phenyl group, and the substitution refers to ortho-, para-, or meta-substitution of the phenyl group. The substituent refers to a halogen atom (e.g., a chlorine atom), a nitro group, an amino group, a C1-C4 alkyl group (methyl group), a C1-C4 alkoxyl group, a C1-C4 alkylthiol group, F3C-, or F3C-O-.

[0060] In another preferred example, the substituted phenyl group refers to a monosubstituted phenyl group.

[0061] In another preferred example, R4 and R5 each independently represent a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C1-C8 alkoxyl group, a substituted or unsubstituted C1-C8 alkylthiol group, a substituted or unsubstituted C6-C12 aryl group, or a substituted or unsubstituted 5-10 membered heteroaryl group.

[0062] In another preferred example, R4 and R5 each independently represent a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C1-C8 alkoxyl group, a substituted or unsubstituted C1-C8 alkylthiol group, a substituted or unsubstituted C6-C12 aryl group, or a substituted or unsubstituted 5-10 membered heteroaryl group.

[0063] In another preferred example, R4 and R5 each independently represent a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C1-C4 alkoxyl group, a substituted or unsubstituted C1-C4 alkylthiol group, a substituted or unsubstituted C6-C8 aryl group, or a substituted or unsubstituted 5-8 membered heteroaryl group.

[0064] In another preferred example, R4 and R5 each independently represent a hydrogen atom, a methyl group, an ethyl group, a propyl group, or a butyl group.

[0065] In another preferred embodiment, n represents 0, 1, 2, 3, 4, 5, or 6. In the present invention, when n is 0, [ka] but [ka] It should be understood that this refers to:

[0066] In another preferred example, R6 represents a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, a substituted or unsubstituted 3-12 membered cycloalkyl group, or a substituted or unsubstituted 3-12 membered heterocycloalkyl group.

[0067] In another preferred example, R6 represents a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, or a substituted or unsubstituted 3-8 membered heterocycloalkyl group.

[0068] In another preferred example, R6 represents a substituted or unsubstituted C6-C8 aryl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, or a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group.

[0069] In another preferred example, R6 represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridine group, or a substituted or unsubstituted pyrazine group.

[0070] In another preferred example, the substituted or unsubstituted phenyl group refers to a monosubstituted or unsubstituted phenyl group.

[0071] In another preferred embodiment, the substituted or unsubstituted phenyl group refers to a mono-substituted or unsubstituted phenyl group, and substitution refers to ortho-, para- or meta-substitution of the phenyl group.

[0072] In another preferred embodiment, the substituted or unsubstituted phenyl group refers to a mono-substituted or unsubstituted phenyl group, and the substitution refers to ortho-, para-, or meta-substitution of the phenyl group. The substituent refers to a halogen atom, a nitro group, an amino group, a C1-C4 alkyl group, a C1-C4 alkoxyl group, a C1-C4 alkylthiol group, F3C-, F3C-O-, a C6-C12 aryl group, or a 5- to 10-membered heteroaryl group.

[0073] In another preferred embodiment, the substituted or unsubstituted phenyl group refers to a mono-substituted or unsubstituted phenyl group, and the substitution refers to ortho-, para-, or meta-substitution of the phenyl group. The substituent refers to a halogen atom, a nitro group, an amino group, a C1-C4 alkyl group, a C1-C4 alkoxyl group, a C1-C4 alkylthiol group, F3C-, F3C-O-, or a phenyl group.

[0074] In another preferred example, the substituted phenyl group refers to a monosubstituted phenyl group.

[0075] In another preferred example, R6 is a meta-nitrophenyl group, an ortho-nitrophenyl group, a para-nitrophenyl group, a phenyl group, a para-methylphenyl group, an ortho-methylphenyl group, a meta-methylphenyl group, a para-aminophenyl group, an ortho-aminophenyl group, a meta-aminophenyl group, a para-methoxyphenyl group, an ortho-methoxyphenyl group, a meta-methoxyphenyl group, a para-trifluoromethoxyphenyl group, an ortho-trifluoromethoxyphenyl group, a meta-trifluoromethoxyphenyl group, a para-halogenated phenyl group, an ortho-halogenated phenyl group, a meta-halogenated phenyl group, a para-trifluoromethylphenyl group, an ortho-trifluoromethylphenyl group, a meta-trifluoromethylphenyl group, a para-phenylphenyl group, an ortho-phenylphenyl group, a meta-phenylphenyl group, a pyridine group, [ka] , a pyrazine group, or a monomethyl-substituted pyrazine group.

[0076] In another preferred example, R7 represents a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C1-C8 alkoxyl group, a substituted or unsubstituted C1-C8 alkylthiol group, a substituted or unsubstituted C6-C12 aryl group, or a substituted or unsubstituted 5-10 membered heteroaryl group.

[0077] In another preferred example, R7 represents a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 alkoxyl group, a substituted or unsubstituted C1-C4 alkylthiol group, a substituted or unsubstituted C6-C8 aryl group, or a substituted or unsubstituted 5-8 membered heteroaryl group.

[0078] In another preferred example, R7 represents a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C6 alkoxyl group, a substituted or unsubstituted C1-C4 alkylthiol group, a substituted or unsubstituted C6-C8 aryl group, or a substituted or unsubstituted 5-8 membered heteroaryl group.

[0079] In another preferred example, R7 represents a hydrogen atom.

[0080] In another preferred example, R8 and R9 are joined to form a substituted or unsubstituted 3- to 12-membered cycloalkyl ring or a substituted or unsubstituted 3- to 12-membered heterocycloalkyl ring.

[0081] In another preferred example, R8 and R9 are joined to form a substituted or unsubstituted 3- to 10-membered cycloalkyl ring or a substituted or unsubstituted 3- to 10-membered heterocycloalkyl ring.

[0082] In another preferred example, R8 and R9 are joined to form a substituted or unsubstituted 3- to 8-membered cycloalkyl ring or a substituted or unsubstituted 3- to 8-membered heterocycloalkyl ring.

[0083] In another preferred example, R8 and R9 are joined to form a substituted or unsubstituted 5- to 8-membered cycloalkyl ring or a substituted or unsubstituted 5- to 8-membered heterocycloalkyl ring.

[0084] In another preferred example, R8 and R9 are joined to form a substituted or unsubstituted 5- or 6-membered cycloalkyl ring or a substituted or unsubstituted 5- or 6-membered heterocycloalkyl ring.

[0085] In another preferred example, R8 and R9 are joined to form a substituted or unsubstituted 5-membered cycloalkyl ring or a substituted or unsubstituted 6-membered heterocycloalkyl ring.

[0086] In another preferred embodiment, the cycloalkyl ring has one, two or three C=C cyclic double bonds.

[0087] In another preferred example, R8 and R9 combine to form a substituted or unsubstituted cyclopentene or cyclohexene ring.

[0088] In another preferred embodiment, ring C represents an unsubstituted or substituted C6-C12 aryl ring, a substituted or unsubstituted C3-C12 cycloalkyl ring, a substituted or unsubstituted 3- to 12-membered heterocycloalkyl ring, or a substituted or unsubstituted 3- to 12-membered heteroaryl ring.

[0089] In another preferred embodiment, ring C represents an unsubstituted or substituted C6-C10 aryl ring, a substituted or unsubstituted C3-C10 cycloalkyl ring, a substituted or unsubstituted 3- to 10-membered heterocycloalkyl ring, or a substituted or unsubstituted 3- to 10-membered heteroaryl ring.

[0090] In another preferred embodiment, ring C represents an unsubstituted or substituted C6-C8 aryl ring, a substituted or unsubstituted C5-C10 cycloalkyl ring, a substituted or unsubstituted 5-10 membered heterocycloalkyl ring, or a substituted or unsubstituted 5-8 membered heteroaryl ring.

[0091] In another preferred example, ring C represents a substituted or unsubstituted benzene ring or a substituted or unsubstituted pyridine ring.

[0092] In another preferred example, ring C represents a substituted or unsubstituted benzene ring or a substituted or unsubstituted pyridine ring; the optional "substitution" refers to the replacement of one, two, or three hydrogen atoms on the atomic group with a substituent selected from a methyl group, a halogen atom, a nitro group, -CN, a hydroxyl group, a mercapto group, an amino group, F3C-O-, F3C-, and a methoxy group.

[0093] Another good example is R 10 and R 11each independently represent a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, F3C-O-, F3C-, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted C1-C8 alkoxyl group, a substituted or unsubstituted C1-C8 alkylthiol group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, a substituted or unsubstituted C6-C12 aryl group-substituted or unsubstituted C1-C8 alkyl group-, a substituted or unsubstituted 5-12 membered heteroaryl group-substituted or unsubstituted C1-C8 alkyl group, or a substituted or unsubstituted C1-C4 alkyl group -C(O)-; or R 10 and R 11 are joined to form a substituted or unsubstituted 3- to 12-membered heterocycloalkyl ring, or a substituted or unsubstituted 3- to 12-membered heteroaryl ring.

[0094] Another good example is R 10 and R 11 each independently represent a hydrogen atom, a halogen atom, -CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, F3C-, F3C-O-, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C1-C6 alkoxyl group, a substituted or unsubstituted C1-C6 alkylthiol group, a substituted or unsubstituted C6-C8 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted C6-C10 aryl group-substituted or unsubstituted C1-C4 alkyl group-, a substituted or unsubstituted 5-10 membered heteroaryl group-substituted or unsubstituted C1-C4 alkyl group, or a substituted or unsubstituted C1-C4 alkyl group -C(O)-; or R 10 and R 11 are joined to form a substituted or unsubstituted 5-12 membered heterocycloalkyl ring, or a substituted or unsubstituted 5-12 membered heteroaryl ring.

[0095] Another good example is R 10 and R 11each independently represent a hydrogen atom, a halogen atom, —CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, F3C—O—, F3C—, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C1-C4 alkoxyl group, a substituted or unsubstituted C1-C4 alkylthiol group, a substituted or unsubstituted C6-C8 aryl group, a substituted or unsubstituted 5-8 membered heteroaryl group, a substituted or unsubstituted C6-C8 aryl group-substituted or unsubstituted C1-C2 alkyl group-, a substituted or unsubstituted 5-8 membered heteroaryl group-substituted or unsubstituted C1-C2 alkyl group-, or a substituted or unsubstituted C1-C4 alkyl group-C(O)—; or R 10 and R 11 are joined to form a substituted or unsubstituted 5-12 membered heterocycloalkyl ring, or a substituted or unsubstituted 5-12 membered heteroaryl ring.

[0096] In another preferred example, the substituted or unsubstituted 3- to 12-membered heterocycloalkyl ring is a fused heterocycloalkyl ring of a substituted or unsubstituted C6-C8 aryl ring and a substituted or unsubstituted C5-C8 monocyclic ring.

[0097] In another preferred example, the substituted or unsubstituted 5-12 membered heterocycloalkyl ring is a fused heterocycloalkyl ring of a substituted or unsubstituted C6-C8 aryl ring and a substituted or unsubstituted C5-C8 monocyclic ring.

[0098] Another good example is R 10 and R 11 each independently represent a methyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl group-C1-C2 alkyl group-, a substituted or unsubstituted pyridine group, a substituted or unsubstituted pyridine group-C1-C2 alkyl group-, or a substituted or unsubstituted C1-C3 alkyl group-C(O)-; or R 10 and R 11 are linked to form a substituted or unsubstituted isoquinoline ring, a substituted or unsubstituted quinoline ring, a substituted or unsubstituted tetrahydroisoquinoline ring, a substituted or unsubstituted tetrahydroquinoline ring, or a substituted or unsubstituted dihydroisoquinoline-1 ketone ring.

[0099] In another preferred embodiment, the tetrahydroquinoline ring refers to a 1,2,3,4-tetrahydroquinoline ring.

[0100] In another preferred example, the dihydroisoquinoline-1 ketone ring refers to a 3,4-dihydroisoquinoline-1 ketone ring.

[0101] In another preferred example, the substituted or unsubstituted phenyl group-C1-C2 alkyl group- refers to a substituted or unsubstituted phenyl group-methyl group- or a substituted or unsubstituted phenyl group-ethyl group-.

[0102] In another preferred example, in the substituted or unsubstituted phenyl group-C1-C2 alkyl group-, the substituted or unsubstituted phenyl group refers to a monosubstituted or unsubstituted phenyl group.

[0103] In another preferred example, in the substituted or unsubstituted phenyl group-C1-C2 alkyl group-, the substituted or unsubstituted phenyl group refers to a mono-substituted or unsubstituted phenyl group, and substitution refers to ortho-substitution, para-substitution or meta-substitution of the phenyl group.

[0104] In another preferred example, in the substituted or unsubstituted phenyl group-C1-C2 alkyl group-, the substituted or unsubstituted phenyl group refers to a mono-substituted or unsubstituted phenyl group, and the substitution refers to ortho-, para-, or meta-substitution of the phenyl group. The substituent refers to a halogen atom, a nitro group, an amino group, a C1-C4 alkyl group, a C1-C4 alkoxyl group, a C1-C4 alkylthiol group, F3C-, or F3C-O-.

[0105] In another preferred example, the substituted phenyl group refers to a monosubstituted phenyl group.

[0106] In another preferred example, the substituted or unsubstituted phenyl group-C1-C2 alkyl group- refers to a substituted or unsubstituted phenyl group-methyl group- or a substituted or unsubstituted phenyl group-ethyl group-.

[0107] Another good example is R 12 and R 13 each independently represent a hydrogen atom, a halogen atom, —CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, F3C—, F3C—O—, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C1-C6 alkoxyl group, a substituted or unsubstituted C1-C6 alkylthiol group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 5- to 12-membered heteroaryl group, a substituted or unsubstituted C6-C12 aryl group-substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted 5- to 12-membered heteroaryl group-substituted or unsubstituted C1-C6 alkyl group.

[0108] Another good example is R 12 and R 13 each independently represent a hydrogen atom, a halogen atom, —CN, a hydroxyl group, a mercapto group, a nitro group, an amino group, F3C—, F3C—O—, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkoxyl group, a substituted or unsubstituted C1-C4 alkylthiol group, a substituted or unsubstituted C6-C8 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted C6-C8 aryl group-substituted or unsubstituted C1-C2 alkyl group, or a substituted or unsubstituted 5-8 membered heteroaryl group-substituted or unsubstituted C1-C2 alkyl group.

[0109] Another good example is R 12 and R 13 each independently represents a hydrogen atom, a halogen atom, or a phenyl group.

[0110] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-2. [ka] where R4, R5, R6 and n are as defined above.

[0111] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-3. [ka] where R4, R5, R6 and n are as defined above.

[0112] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-4. [ka] where R4, R5, R6, R 10 , R 11 and n is as defined above.

[0113] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-5. [ka] where R4, R5, R6, R 10 , R 11 and n is as defined above.

[0114] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-6. [ka] where R3, R4, R5, R6 and n are as defined above.

[0115] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-7. [ka] where R3 is as defined above; R 15 , R 16 and R 17each independently represents a hydrogen atom, a halogen atom (for example, Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3.

[0116] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-8. [ka] where R3 is as defined above; R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (for example, Cl), a methyl group, a nitro group, or a phenyl group.

[0117] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-9. [ka] wherein R3, R4, R5, R6 and n are as defined above; a represents 0, 1 or 2; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0118] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-10. [ka] wherein R3, R4, R5, R6 and n are as defined above; a represents 0, 1 or 2; Each R 18independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0119] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-11. [ka] wherein R3, R4, R5, R6 and n are as defined above; a represents 0, 1 or 2; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0120] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-12. [ka] wherein R3, R4, R5, R6 and n are as defined above; a represents 0, 1, 2 or 3; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0121] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-13. [ka] wherein R3, R4, R5, R6 and n are as defined above; a represents 0, 1, 2, 3 or 4; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0122] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-14. [ka] wherein R3, R4, R5, R6 and n are as defined above; a represents 0, 1, 2 or 3; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0123] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-15. [ka] wherein R3, R4, R5, R6 and n are as defined above; a represents 0, 1 or 2; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0124] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-16. [ka] wherein R3, R4, R5, R6 and n are as defined above; a represents 0, 1 or 2;

[0125] Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0126] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-17. [ka] wherein R3, R4, R5, R6 and n are as defined above; a represents 0, 1 or 2; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0127] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-18. [ka] where R3, R4, R5, R6 and n are as defined above.

[0128] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-19. [ka] where R3 is as defined above.

[0129] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-20. [ka] wherein R3, R4, R5, R6 and n are as defined above; a represents 0, 1, 2, 3, 4 or 5; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0130] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-21. [ka] where R3 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (e.g., Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3; a represents 0, 1, 2, 3, 4 or 5; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0131] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-22. [ka] where R3 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (e.g., Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3; a represents 1, 2, 3, 4 or 5; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0132] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-23. [ka] wherein R3, R4, R5, R6 and n are as defined above; a represents 1, 2, 3, 4 or 5;

[0133] Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0134] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-24. [ka] where R3 is as defined above; a represents 0, 1, 2, 3, 4 or 5; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (e.g., Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0135] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-25. [ka] where R3 is as defined above; a represents 0, 1, 2, 3, 4 or 5; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (e.g., Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0136] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-26. [ka] where R 10 , R 11and ring C is as defined above.

[0137] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-27. [ka] where R 10 , R 11 and ring C is as defined above.

[0138] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-28. [ka] where R 10 and R 11 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (for example, Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3.

[0139] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-29. [ka] where R 10 and R 11 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (for example, Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3.

[0140] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-30. [ka] where R 10 and R 11 is as defined above; R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (for example, Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3.

[0141] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-31. [ka] where R 10 and R 11 is as defined above; R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (for example, Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3.

[0142] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-32. [ka] where R3 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (e.g., Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3; a represents 0, 1, 2 or 3; Each R 18independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0143] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-33. [ka] where R3 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (e.g., Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3; a represents 0, 1, 2 or 3; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0144] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-34. [ka] where R3 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (e.g., Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3; a represents 0, 1, 2 or 3; Each R 18independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0145] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-35. [ka] where R3 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (e.g., Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3; a represents 0, 1, 2 or 3; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0146] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-36. [ka] where R3 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (e.g., Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3; a represents 0, 1, 2 or 3; Each R 18independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0147] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-37. [ka] where R3 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (e.g., Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3; a represents 0, 1, 2 or 3; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0148] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-38. [ka] wherein R3, R4, R5, R6 and n are as defined above; a represents 0, 1, 2 or 3; Each R 18 independently represent a hydrogen atom, a halogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, or a substituted or unsubstituted 5- to 8-membered heteroaryl group.

[0149] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-39. [ka] where R 10 and R 11 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (for example, Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3.

[0150] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-40. [ka] where R4, R5, R6, R 10 , R 11 and n is as defined above; R 19 represents a hydrogen atom or a substituted or unsubstituted C1-C6 alkyl group.

[0151] Another good example is R 19 represents a hydrogen atom or a substituted or unsubstituted C1-C4 alkyl group (for example, a methyl group).

[0152] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-41. [ka] where R4, R5, R6, R 10 , R 11 and n is as defined above; R 20 represents a hydrogen atom or a halogen atom.

[0153] Another good example is R 19represents a hydrogen atom or a substituted or unsubstituted C1-C4 alkyl group (for example, a methyl group).

[0154] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-42. [ka] where R4, R5, R6 and n are as defined above.

[0155] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-43. [ka] where R3 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, a halogen atom (e.g., Cl, F), a methyl group, a nitro group, a phenyl group, -OCF3, or -CF3; R 19 represents a hydrogen atom or a substituted or unsubstituted C1-C6 alkyl group.

[0156] Another good example is R 19 represents a hydrogen atom or a substituted or unsubstituted C1-C4 alkyl group (for example, a methyl group).

[0157] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-44. [ka] where R3 is as defined above; R 14 , R 15 , R 16 and R 17 each independently represents a hydrogen atom, —CF3, a halogen atom (e.g., Cl, F), a methyl group, a nitro group, a phenyl group, or —OCF3; R19 represents a hydrogen atom or a substituted or unsubstituted C1-C6 alkyl group.

[0158] Another good example is R 19 represents a hydrogen atom or a substituted or unsubstituted C1-C4 alkyl group (for example, a methyl group).

[0159] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-45. [ka] where R4, R5, R6, R 10 , R 11 and n is as defined above.

[0160] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-46. [ka] where R4, R5, R6, R 10 , R 11 and n is as defined above.

[0161] In another preferred example, the pharmaceutically acceptable salt of the compound of formula I is a salt formed by the compound of formula I with an acid selected from any one of hydrochloric acid, galactaric acid, D-glucuronic acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, aspartic acid, and glutamic acid, or a combination thereof.

[0162] In another preferred embodiment, the compound of formula I has the following structure: [ka] JPEG0007747351000065.jpg189147JPEG0007747351000066.jpg217147JPEG0007747351000067.jpg242147JPEG000 7747351000068.jpg228147JPEG0007747351000069.jpg226147JPEG0007747351000070.jpg217147JPEG00077473510 00071.jpg222147JPEG0007747351000072.jpg238147JPEG0007747351000073.jpg206147JPEG0007747351000074.j pg205147JPEG0007747351000075.jpg209147JPEG0007747351000076.jpg218147JPEG0007747351000077.jpg233147 JPEG0007747351000078.jpg237147JPEG0007747351000079.jpg238147JPEG0007747351000080.jpg232147JPEG000 7747351000081.jpg227147JPEG0007747351000082.jpg228147JPEG0007747351000083.jpg225147JPEG00077473510 00084.jpg240147JPEG0007747351000085.jpg226147JPEG0007747351000086.jpg220147JPEG0007747351000087.j pg239147JPEG0007747351000088.jpg227147JPEG0007747351000089.jpg233147JPEG0007747351000090.jpg115147

[0163] A second aspect of the present invention provides a pharmaceutical composition comprising (a) a compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier thereof.

[0164] A third aspect of the present invention provides the use of a compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a composition or formulation for use in the prevention and / or treatment of tumors.

[0165] In another preferred embodiment, the tumor is selected from lung cancer, pancreatic cancer, breast cancer, lymphoma, prostate cancer, brain cancer, leukemia, liver cancer, melanoma, intestinal cancer, kidney cancer, colon cancer, or a combination thereof.

[0166] In another preferred embodiment, the tumor is of human origin.

[0167] In another preferred embodiment, the tumor is a human tumor.

[0168] In another preferred embodiment, the colon cancer comprises colon adenocarcinoma.

[0169] In another preferred embodiment, the permeability transition pore of mitochondria in the cancer cells is made less active.

[0170] In another preferred embodiment, the cancer comprises a cancer in which the mitochondrial permeability transition pore is hypoactive.

[0171] In another preferred embodiment, the low activity of the mitochondrial permeability transition pore refers to the ratio (A1 / A0) between the activity or expression level A1 of the mitochondrial permeability transition pore in a certain cell (e.g., a tumor cell) and the activity or expression level A0 of the mitochondrial permeability transition pore in a normal cell (similar cell) being <1.0, preferably ≦0.8, and more preferably ≦0.7, ≦0.6, ≦0.5, ≦0.4, ≦0.3, ≦0.2, ≦0.1, or ≦0.05.

[0172] In another preferred embodiment, the identical cells refer to cells in which the activity of the mitochondrial permeability transition pore is normally expressed (similar tumor cells).

[0173] In another preferred embodiment, the identical cells refer to similar cells, which still normally express the activity of the mitochondrial permeability transition pore.

[0174] In another preferred embodiment, the normal cells refer to normal tissue cells in which the activity of the mitochondrial permeability transition pore is normally expressed (for example, cells derived from tumor cells, tumor-adjacent cells, or cancerous bladder tissue cells).

[0175] In another preferred embodiment, the breast cancer comprises triple-negative breast cancer.

[0176] In another preferred embodiment, the liver cancer is undifferentiated or poorly differentiated liver cancer.

[0177] In another preferred embodiment, the leukemia comprises acute myeloid leukemia.

[0178] In another preferred embodiment, the leukemia comprises M4 acute myeloid leukemia.

[0179] In another preferred embodiment, the lung cancer is selected from non-small cell lung cancer, small cell lung cancer, or a combination thereof.

[0180] In another preferred embodiment, the lymphoma comprises a B-cell lymphoma.

[0181] In another preferred embodiment, the intestinal cancer comprises rectal adenocarcinoma.

[0182] In another preferred embodiment, the rectal adenocarcinoma comprises Dukes' type C, grade IV rectal adenocarcinoma.

[0183] In another preferred embodiment, the brain tumor is selected from glioblastoma, medulloblastoma, or a combination thereof.

[0184] In another preferred embodiment, the kidney cancer comprises renal clear cell adenocarcinoma.

[0185] In another preferred embodiment, the mitochondrial oxidative phosphorylation pathway is upregulated and / or the mitochondrial permeability transition pore is hypoactive in cancer cells of said cancer.

[0186] In another preferred embodiment, the mitochondrial oxidative phosphorylation pathway is upregulated in cancer cells of said cancer.

[0187] In another preferred embodiment, the cancer comprises a cancer in which the mitochondrial oxidative phosphorylation pathway is upregulated.

[0188] In another preferred embodiment, the mitochondrial permeability transition pore is made less active in cancer cells of the cancer.

[0189] In another preferred embodiment, the upregulation of the mitochondrial oxidative phosphorylation pathway refers to the ratio (E1 / E0) between the level or expression level E1 of the mitochondrial oxidative phosphorylation pathway in a certain cell (e.g., a tumor cell) and the level or expression level E0 of the mitochondrial oxidative phosphorylation pathway in a normal cell (similar cell) being >1.0, preferably ≥1.2, and more preferably ≥1.5, ≥2, ≥3, or ≥5.

[0190] In another preferred embodiment, the identical cells refer to cells in which the mitochondrial oxidative phosphorylation pathway is normally expressed (similar tumor cells).

[0191] In another preferred embodiment, the same cells refer to similar cells, but in which the mitochondrial oxidative phosphorylation pathway is normally expressed at a level.

[0192] In another preferred embodiment, the normal cells refer to normal tissue cells (e.g., tumor cell-derived cells, tumor-adjacent cells, or cancerous bladder tissue cells) in which the level of the mitochondrial oxidative phosphorylation pathway is normally expressed.

[0193] In another preferred embodiment, the normal cells (analogous tumor cells) include cells that are insensitive to the compound of formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0194] In another preferred embodiment, the low activity of the mitochondrial permeability transition pore refers to the ratio (A1 / A0) between the activity or expression level A1 of the mitochondrial permeability transition pore in a certain cell (e.g., a tumor cell) and the activity or expression level A0 of the mitochondrial permeability transition pore in a normal cell (similar cell) being <1.0, preferably ≦0.8, and more preferably ≦0.7, ≦0.6, ≦0.5, ≦0.4, ≦0.3, ≦0.2, ≦0.1, or ≦0.05.

[0195] In another preferred embodiment, a patient suffering from the cancer is administered a mitochondrial permeability transition pore inhibitor to reduce the activity of the mitochondrial permeability transition pore in the cancer cells.

[0196] In another preferred embodiment, the activity of the mitochondrial permeability transition pore is reduced by an inhibitor of the mitochondrial permeability transition pore.

[0197] In another preferred embodiment, the level refers to the protein level and / or the mRNA level.

[0198] In another preferred embodiment, the expression refers to protein expression and / or mRNA expression.

[0199] In another preferred embodiment, the inhibitor of the mitochondrial permeability transition pore is selected from Cyclosporin A, a CyP-D protein inhibitor, a peroxide scavenger, or a combination thereof.

[0200] In another preferred embodiment, the tumor (cancer) includes a tumor in which the NNMT gene is underexpressed or not expressed.

[0201] In another preferred embodiment, the tumor (cancer) comprises a tumor with hypermethylation of nucleotide sites in the NNMT gene and / or hypermethylation of DNA CpG sites in the NNMT gene region.

[0202] In another preferred embodiment, the tumor comprises a tumor in which the nucleotide site in the NNMT gene is hypermethylated.

[0203] In another preferred embodiment, the tumor (cancer) comprises a tumor in which DNA CpG sites in the NNMT gene region are hypermethylated.

[0204] In another preferred embodiment, the NNMT gene is a human-derived NNMT gene.

[0205] In another preferred embodiment, the NNMT gene is a human NNMT gene.

[0206] In another preferred embodiment, a tumor in which the NNMT gene is under-expressed or not expressed refers to a tumor in which the NNMT protein cannot be detected with an NNMT antibody in 1 μg of protein extracted from the tumor, and more preferably in 5 μg, 10 μg, 100 μg or 1000 μg of protein.

[0207] In another preferred example, a tumor in which the NNMT gene is underexpressed or not expressed refers to a tumor in which the expression level of the NNMT gene in tumor cells is lower than the expression level of the NNMT gene in the same cells or normal cells (e.g., cancerous bladder tissue cells).

[0208] In another preferred example, a tumor in which the NNMT gene is underexpressed or not expressed refers to a tumor in which the ratio (E1 / E0) between the expression level E1 of the NNMT gene in tumor cells and the expression level E0 of the NNMT gene in the same cells or normal cells (e.g., cancerous bladder tissue cells) is <1.0.

[0209] In another preferred embodiment, a tumor in which the NNMT gene is underexpressed or not expressed refers to a tumor in which the ratio (E1 / E0) between the expression level E1 of the NNMT gene in a certain cell (e.g., a tumor cell) and the expression level E0 of the NNMT gene in the same cell or a normal cell (e.g., a cancerous bladder tissue cell) is <1.0, preferably ≦0.7, and more preferably ≦0.6, ≦0.5, ≦0.4, ≦0.3, ≦0.2, ≦0.1, ≦0.05, ≦0.01, ≦0.005, ≦0.001, ≦0.0001, ≦0.00001, ≦0.000001 or ≦0.0000001.

[0210] In another preferred embodiment, the identical cells refer to cells in which the NNMT gene is normally expressed (similar tumor cells).

[0211] In another preferred embodiment, the same cells refer to similar cells, which nevertheless normally express the NNMT gene.

[0212] In another preferred embodiment, the normal cells refer to normal tissue cells in which the NNMT gene is normally expressed (for example, cells derived from tumor cells, tumor-adjacent cells, or cancerous bladder tissue cells).

[0213] In another preferred embodiment, E0 is the expression level of the NNMT gene in cells in which the NNMT gene is normally expressed.

[0214] In another preferred embodiment, the cells in which the NNMT gene is normally expressed include cells that are insensitive to the compound of formula I, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0215] In another preferred example, a tumor in which the nucleotide site of the NNMT gene is hypermethylated refers to a tumor in which the methylation level of the nucleotide site of the NNMT gene in a certain cell (e.g., a tumor cell) is greater than the methylation level of the nucleotide site of the NNMT gene in the same cell or a normal cell (e.g., a cancerous bladder tissue cell).

[0216] In another preferred embodiment, a tumor in which the nucleotide site of the NNMT gene is hypermethylated refers to a tumor in which the ratio (L1 / L0) between the methylation level L1 of the nucleotide site of the NNMT gene in a certain cell (e.g., a tumor cell) and the methylation level L0 of the nucleotide site of the NNMT gene in the same cell or a normal cell (e.g., a cancerous bladder tissue cell) is >1.0, preferably ≧1.2 or ≧1.5, and more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50.

[0217] In another preferred embodiment, a tumor in which the nucleotide site of the NNMT gene is hypermethylated refers to a tumor in which the methylation level of the nucleotide site of the NNMT gene in a certain cell (e.g., tumor cell) is ≧1%, preferably ≧3%, ≧5%, ≧10%, ≧15% or ≧20%, and more preferably ≧25%, ≧30%, ≧40% or ≧50%.

[0218] In another preferred embodiment, the identical cells refer to cells in which the nucleotide site of the NNMT gene is normally methylated (similar tumor cells).

[0219] In another preferred embodiment, the same cell refers to a similar cell, but in which the nucleotide site of the NNMT gene is normally methylated.

[0220] In another preferred embodiment, the normal cells refer to normal tissue cells (for example, cells derived from tumor cells, tumor-adjacent cells, or cancerous bladder tissue cells) in which the nucleotide site of the NNMT gene is normally methylated.

[0221] In another preferred embodiment, cells in which the nucleotide site of the NNMT gene is normally methylated include cells that are insensitive to a compound of formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0222] In another preferred example, a tumor in which the nucleotide site of the NNMT gene is hypermethylated refers to a tumor in which the methylation level (M%) of the nucleotide site of the NNMT gene in a certain cell (e.g., a tumor cell) is ≧3% and less than M1%, where M1 is any positive integer between 3 and 100.

[0223] In another preferred example, M1 is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95 or 100.

[0224] In another preferred embodiment, the methylation level of the nucleotide site of the NNMT gene refers to the ratio between the number of methylated nucleotides in the NNMT gene region and the number of all nucleotides in the NNMT gene region.

[0225] In another preferred embodiment, the methylation level of the nucleotide site in the NNMT gene comprises the methylation level of the nucleotide site in the promoter region of the NNMT gene.

[0226] In another preferred embodiment, the nucleotide sequence of the NNMT gene promoter region is shown in SEQ ID NO:1.

[0227] In another preferred embodiment, the methylation level of the nucleotide site of the NNMT gene includes the methylation level of the nucleotide site within the region from 1050 bp before the transcription start site of the NNMT gene to 499 bp after the transcription start site.

[0228] In another preferred embodiment, the region from 1050 bp before the transcription initiation site of the NNMT gene to 499 bp after the transcription initiation site corresponds to positions 951 to 2500 of the nucleotide sequence shown in SEQ ID NO:1.

[0229] In another preferred embodiment, the methylation level of the nucleotide site of the NNMT gene includes the methylation level of the nucleotide site within the region from 1050 bp before the transcription start site of the NNMT gene to 193 bp before the transcription start site.

[0230] In another preferred example, the region from 1050 bp before the transcription initiation site to 193 bp before the transcription initiation site of the NNMT gene is positions 951 to 1808 of the nucleotide sequence shown in SEQ ID NO:1.

[0231] In another preferred embodiment, a tumor in which the DNA CpG sites in the NNMT gene region are hypermethylated refers to a tumor in which the methylation level of the DNA CpG sites in the NNMT gene region in a certain cell (e.g., a tumor cell) is higher than the methylation level of the DNA CpG sites in the NNMT gene region in the same cell or a normal cell (e.g., a cancerous bladder tissue cell).

[0232] In another preferred embodiment, a tumor in which the DNA CpG site of the NNMT gene region is hypermethylated refers to a tumor in which the ratio (W1 / W0) between the methylation level W1 of the DNA CpG site of the NNMT gene region of a certain cell (e.g., a tumor cell) and the methylation level W0 of the DNA CpG site of the NNMT gene region of the same cell or a normal cell (e.g., a cancerous bladder tissue cell) is >1.0, preferably ≧1.2 or ≧1.5, and more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50.

[0233] In another preferred embodiment, a tumor in which the DNA CpG sites in the NNMT gene region are hypermethylated refers to a tumor in which the methylation level of the DNA CpG sites in the NNMT gene region of a certain cell (e.g., tumor cell) is ≧1%, preferably ≧3%, ≧5%, ≧10%, ≧15% or ≧20%, and more preferably ≧25%, ≧30%, ≧40% or ≧50%.

[0234] In another preferred embodiment, the identical cells refer to cells in which DNA CpG sites in the NNMT gene region are normally methylated (similar tumor cells).

[0235] In another preferred embodiment, the same cells refer to similar cells, which nevertheless have normal methylation of DNA CpG sites in the NNMT gene region.

[0236] In another preferred embodiment, the normal cells refer to normal tissue cells (for example, tumor cell-derived cells, tumor-adjacent cells, or cancerous bladder tissue cells) in which DNA CpG sites in the NNMT gene region are normally methylated.

[0237] In another preferred embodiment, cells in which DNA CpG sites in the NNMT gene region are normally methylated include cells that are insensitive to a compound of formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0238] In another preferred example, a tumor in which the DNA CpG sites in the NNMT gene region are hypermethylated refers to a tumor in which the methylation level (M%) of the DNA CpG sites in the NNMT gene region of a certain cell (e.g., tumor cell) is ≧3% and M2% or less, where M2 is any positive integer between 3 and 100.

[0239] In another preferred embodiment, M2 is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95, or 100.

[0240] In another preferred embodiment, the methylation level of the CpG site refers to the ratio between the number of methylated CpG nucleotides in a certain gene region and the number of all nucleotides in the gene region.

[0241] In another preferred embodiment, the methylation level of the DNA CpG site in the NNMT gene region refers to the ratio between the number of methylated CpG nucleotides in a certain NNMT gene region and the number of all nucleotides in the NNMT gene region.

[0242] In another preferred embodiment, the methylation level of the CpG site refers to the ratio between the number of methylated CpG nucleotides in a certain gene region and the number of all CpG nucleotides in the gene region.

[0243] In another preferred embodiment, the methylation level of the DNA CpG site in the NNMT gene region refers to the ratio between the number of methylated CpG nucleotides in a certain NNMT gene region and the number of all CpG nucleotides in the NNMT gene region.

[0244] In another preferred embodiment, the methylation level of the DNA CpG site refers to the ratio between the number of methylated CpG sites in a certain region of DNA and the number of all CpG sites in the DNA in that region.

[0245] In another preferred embodiment, the methylation level of the DNA CpG site refers to the ratio between the number of methylated CpG nucleotides in a region of DNA and the number of all nucleotides in the region of DNA.

[0246] In another preferred embodiment, the methylation level of the DNA CpG site refers to the ratio between the number of methylated CpG nucleotides in a certain region of DNA and the number of all CpG nucleotides in the region of DNA.

[0247] In another preferred embodiment, the methylation level of the DNA CpG sites in the NNMT gene region refers to the ratio between the number of methylated CpG sites in the DNA of the NNMT gene region and the number of all CpG sites in the DNA of the NNMT gene region.

[0248] In another preferred embodiment, the methylation level of the DNA CpG site in the NNMT gene region refers to the ratio between the number of methylated CpG nucleotides in the DNA of the NNMT gene region and the number of all CpG nucleotides in the DNA of the NNMT gene region.

[0249] In another preferred embodiment, the methylation level of DNA CpG sites in the NNMT gene region includes the methylation level of DNA CpG sites in the NNMT gene promoter region.

[0250] In another preferred embodiment, the nucleotide sequence of the NNMT gene promoter region is shown in SEQ ID NO:1.

[0251] In another preferred embodiment, the methylation level of DNA CpG sites in the NNMT gene region includes the methylation level of DNA CpG sites in the region from 1050 bp before the transcription start site of the NNMT gene to 499 bp after the transcription start site.

[0252] In another preferred embodiment, the region from 1050 bp before the transcription initiation site of the NNMT gene to 499 bp after the transcription initiation site corresponds to positions 951 to 2500 of the nucleotide sequence shown in SEQ ID NO:1.

[0253] In another preferred embodiment, the methylation level of DNA CpG sites in the NNMT gene region includes the methylation level of DNA CpG sites in the region from 1050 bp before the transcription start site of the NNMT gene to 193 bp before the transcription start site.

[0254] In another preferred example, the region from 1050 bp before the transcription initiation site to 193 bp before the transcription initiation site of the NNMT gene is positions 951 to 1808 of the nucleotide sequence shown in SEQ ID NO:1.

[0255] In another preferred embodiment, the tumor is selected from lung cancer, kidney cancer, breast cancer, colon cancer, lymphoma, leukemia, pancreatic cancer, liver cancer, prostate cancer, or a combination thereof.

[0256] In another preferred embodiment, the expression comprises protein expression and / or mRNA expression.

[0257] In another preferred embodiment, the composition is a pharmaceutical composition.

[0258] In another preferred embodiment, the composition or formulation further comprises a pharmaceutically acceptable carrier.

[0259] In another preferred embodiment, the expression is mRNA expression or protein expression.

[0260] In another preferred embodiment, the composition or preparation is in the form of a solid, liquid or semi-solid.

[0261] In another preferred embodiment, the type of the composition or preparation is an oral preparation, an external preparation, or an injectable preparation.

[0262] In another preferred embodiment, the composition or preparation is in the form of a tablet, an injection, an infusion, an ointment, a gel, a solution, a pill, or a film.

[0263] In another preferred embodiment, the composition is a pharmaceutical composition.

[0264] In another preferred embodiment, the composition or formulation further comprises a pharmaceutically acceptable carrier.

[0265] A fourth aspect of the present invention provides the use of an inhibitor of the mitochondrial permeability transition pore in the preparation of a composition or formulation for enhancing the anticancer effect of an anticancer agent.

[0266] In another preferred embodiment, the anti-cancer agent is as defined in the first aspect of the present invention, a compound of formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0267] In another preferred embodiment, the cancer is as described in the first aspect of the invention.

[0268] In another preferred embodiment, the inhibitor of the mitochondrial permeability transition pore is selected from Cyclosporin A, a CyP-D protein inhibitor, a peroxide scavenger, or a combination thereof.

[0269] In another preferred embodiment, the CyP-D protein inhibitor is SfA, BKA, and ADP (a small molecule that regulates the activity of ANT protein).

[0270] In another preferred embodiment, the peroxide scavenger is selected from propofol, pyruvate, MCI-186, or a combination thereof.

[0271] A fifth aspect of the present invention provides an active ingredient combination comprising: (1) a first active ingredient as an anticancer agent; and (2) A second active ingredient that acts as an inhibitor of the mitochondrial membrane permeability transition pore.

[0272] In another preferred embodiment, the molar ratio between the first active ingredient and the second active ingredient is 0.01-600:1, preferably 0.05-500:1, and more preferably 0.1-400:1, 0.2-200:1, 0.5-100:1, 0.5-80:1 or 1-50:1.

[0273] In another preferred embodiment, the active ingredient combination has at least one independent active ingredient.

[0274] In another preferred embodiment, the active ingredient combination has a first active ingredient and a second active ingredient that are independent of each other.

[0275] A sixth aspect of the present invention provides a composition comprising the following components: (1) a first active ingredient as an anticancer agent; and (2) A second active ingredient that acts as an inhibitor of the mitochondrial membrane permeability transition pore.

[0276] In another preferred embodiment, the composition is a pharmaceutical composition.

[0277] In another preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0278] In another preferred embodiment, the content of the first active ingredient relative to the total weight of active ingredients in the composition is 0.01-99.99 wt%, preferably 0.1-99.9 wt%, and more preferably 1-99 wt%, 10-99 wt% or 20-99 wt%.

[0279] In another preferred embodiment, the content of the second active ingredient relative to the total weight of the active ingredients of the composition is 0.01-99.99 wt%, preferably 0.1-99.9 wt%, and more preferably 1-99 wt%, 10-99 wt% or 20-99 wt%.

[0280] A seventh aspect of the present invention provides a medical kit comprising the following formulation: (A) a first formulation containing a first active ingredient as an anticancer agent; and (B) A second formulation comprising a second active ingredient that is an inhibitor of the mitochondrial permeability transition pore.

[0281] In another preferred embodiment, the medical kit further comprises an instruction manual.

[0282] In another preferred embodiment, the first formulation and the second formulation are independent of each other.

[0283] In another preferred embodiment, the first and second formulations are combined with each other.

[0284] In another preferred embodiment, the instructions indicate that the first formulation and the second formulation are used in combination to enhance the antitumor activity of an anticancer drug.

[0285] In another preferred embodiment, the combination method comprises first administering a second preparation containing an inhibitor of the mitochondrial permeability transition pore, and then administering an anticancer drug.

[0286] An eighth aspect of the present invention provides an ex vivo non-therapeutic and non-diagnostic method for inhibiting cancer cells, said method comprising the step of contacting cancer cells with a compound of formula I according to the first aspect of the invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, to inhibit the cancer cells.

[0287] In another preferred embodiment, the contacting is an in vitro culture contacting.

[0288] A ninth aspect of the present invention provides a method for preventing and / or treating cancer, said method comprising the step of administering to a subject in need thereof a compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a combination of active ingredients according to the fifth aspect of the present invention, or a composition according to the sixth aspect of the present invention, or a medical kit according to the seventh aspect of the present invention, to prevent and / or treat cancer.

[0289] In another preferred embodiment, the subject is a human or non-human mammal (eg, rodents, rabbits, monkeys, livestock, dogs, cats).

[0290] A tenth aspect of the present invention provides a marker for determining whether a compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, is suitable for the prevention and / or treatment of a tumor patient; the marker comprises the mitochondrial oxidative phosphorylation pathway, the mitochondrial permeability transition pore, the NNMT gene, the methylation level of a nucleotide site in the NNMT gene, and / or the methylation level of a DNA CpG site in the NNMT gene region.

[0291] In another preferred embodiment, the marker comprises the expression level of the mitochondrial oxidative phosphorylation pathway, the activity of the mitochondrial permeability transition pore, the expression level of the NNMT gene, the methylation level of nucleotide sites in the NNMT gene and / or the methylation level of DNA CpG sites in the NNMT gene region.

[0292] In another preferred embodiment, the methylation level of the DNA CpG site in the NNMT gene region refers to the methylation level of the DNA CpG site in the NNMT gene promoter region.

[0293] In another preferred embodiment, the methylation level of DNA CpG sites in the NNMT gene region refers to the methylation level of DNA CpG sites in the region from 1050 bp before the transcription start site of the NNMT gene to 499 bp after the transcription start site.

[0294] In another preferred example, the methylation level of DNA CpG sites in the NNMT gene region refers to the methylation level of DNA CpG sites in the region from 1050 bp before the transcription start site of the NNMT gene to 193 bp before the transcription start site. In another preferred example, when the mitochondrial oxidative phosphorylation pathway is upregulated in tumor cells of a tumor patient, the compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof becomes suitable for the prevention and / or treatment of the tumor patient.

[0295] In another preferred example, when the activity of the mitochondrial permeability transition pore is reduced in tumor cells of a tumor patient, the compound of formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof becomes suitable for the prevention and / or treatment of the tumor patient.

[0296] In another preferred example, when the NNMT gene is underexpressed or not expressed in tumor cells of a tumor patient, and the nucleotide site of the NNMT gene is hypermethylated, and / or the DNA CpG site in the NNMT gene region is hypermethylated, the compound of formula I described in the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt becomes suitable for the prevention and / or treatment of the tumor patient.

[0297] In another preferred example, when the NNMT gene is highly expressed in tumor cells of a tumor patient, and the nucleotide site of the NNMT gene is hypomethylated, and / or the DNA CpG site in the NNMT gene region is hypomethylated, the compound of formula I according to the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt becomes unsuitable for the prevention and / or treatment of the tumor patient.

[0298] An eleventh aspect of the present invention provides a detection kit, comprising: (i) A detection reagent is provided for detecting the level of the mitochondrial oxidative phosphorylation pathway, the level of the mitochondrial membrane permeability transition pore, the expression level of the NNMT gene, and / or the methylation level of DNA CpG sites in the NNMT gene region.

[0299] In another preferred embodiment, the level refers to the protein level and / or mRNA level.

[0300] In another preferred embodiment, the detection sample of the detection kit contains tumor cells.

[0301] In another preferred embodiment, NNMT gene expression refers to mRNA expression or protein expression of the gene.

[0302] In another preferred embodiment, the methylation level of DNA CpG sites in the NNMT gene region includes the methylation level of DNA CpG sites in the NNMT gene promoter region.

[0303] In another preferred embodiment, the methylation level of DNA CpG sites in the NNMT gene region refers to the methylation level of DNA CpG sites in the region from 1050 bp before the transcription start site of the NNMT gene to 499 bp after the transcription start site.

[0304] In another preferred embodiment, the methylation level of the DNA CpG site in the NNMT gene region refers to the methylation level of the DNA CpG site in the region from 1050 bp before the transcription start site of the NNMT gene to 193 bp before the transcription start site.

[0305] A twelfth aspect of the present invention provides use of the detection kit according to the eleventh aspect of the present invention for the manufacture of a companion detection kit for determining whether a compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, is suitable for the prevention and / or treatment of a tumor patient.

[0306] In another preferred embodiment, the companion detection kit further comprises an instruction manual or label.

[0307] In another preferred embodiment, the instructions or label include: It is disclosed that the upregulation of the mitochondrial oxidative phosphorylation pathway in tumor cells of tumor patients makes the compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, suitable for the prevention and / or treatment of the tumor patient.

[0308] In another preferred embodiment, the instructions or label include: The present invention provides that when the mitochondrial permeability transition pore is made less active in tumor cells of a tumor patient, the compound of formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof becomes suitable for the prevention and / or treatment of the tumor patient.

[0309] In another preferred embodiment, the instructions or label include: The present invention provides that, when the NNMT gene is underexpressed or not expressed in tumor cells of a tumor patient, the nucleotide site of the NNMT gene is hypermethylated, and / or the DNA CpG site in the NNMT gene region is hypermethylated, the compound of formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof becomes suitable for the prevention and / or treatment of the tumor patient.

[0310] In another preferred embodiment, the instructions or label include: The present invention describes that when the NNMT gene is highly expressed in tumor cells of a tumor patient, and nucleotide sites in the NNMT gene are hypomethylated, and / or DNA CpG sites in the NNMT gene region are hypomethylated, the compound of formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof becomes unsuitable for the prevention and / or treatment of the tumor patient.

[0311] A thirteenth aspect of the present invention provides a medical kit, comprising: (i) a detection reagent used to detect the level of the mitochondrial oxidative phosphorylation pathway, the level of the mitochondrial membrane permeability transition pore, the expression level of the NNMT gene, the methylation level of the nucleotide site of the NNMT gene, and / or the methylation level of the DNA CpG site in the NNMT gene region; (ii) a compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0312] In another preferred embodiment, the medical kit further comprises an instruction manual or label.

[0313] In another preferred embodiment, the instructions or label include: It is disclosed that the upregulation of the mitochondrial oxidative phosphorylation pathway in tumor cells of tumor patients makes the compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, suitable for the prevention and / or treatment of the tumor patient.

[0314] In another preferred embodiment, the instructions or label include: The present invention provides that when the mitochondrial permeability transition pore is made less active in tumor cells of a tumor patient, the compound of formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof becomes suitable for the prevention and / or treatment of the tumor patient.

[0315] In another preferred embodiment, the instructions or label include: The present invention provides that, when the NNMT gene is underexpressed or not expressed in tumor cells of a tumor patient, the nucleotide site of the NNMT gene is hypermethylated, and / or the DNA CpG site in the NNMT gene region is hypermethylated, the compound of formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof becomes suitable for the prevention and / or treatment of the tumor patient.

[0316] In another preferred embodiment, the instructions or label include: The present invention describes that when the NNMT gene is highly expressed in tumor cells of a tumor patient, and nucleotide sites in the NNMT gene are hypomethylated, and / or DNA CpG sites in the NNMT gene region are hypomethylated, the compound of formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof becomes unsuitable for the prevention and / or treatment of the tumor patient.

[0317] A fourteenth aspect of the present invention provides a method for preventing and / or treating tumors, comprising administering to a subject in need thereof a compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0318] In another preferred embodiment, the tumor is as described in the first aspect of the invention.

[0319] In another preferred embodiment, the mitochondrial oxidative phosphorylation pathway is upregulated and / or the mitochondrial permeability transition pore is hypoactive in cancer cells of said cancer.

[0320] In another preferred embodiment, the subject's tumor comprises a tumor in which the NNMT gene is underexpressed or not expressed.

[0321] In another preferred embodiment, the subject's tumor comprises a tumor in which the nucleotide site in the NNMT gene is hypermethylated.

[0322] In another preferred embodiment, the subject's tumor comprises a tumor in which DNA CpG sites in the NNMT gene region are hypermethylated.

[0323] In another preferred embodiment, the subject is a human or non-human mammal (eg, rodents, rabbits, monkeys, livestock, dogs, cats).

[0324] A fifteenth aspect of the present invention provides an apparatus or system, the apparatus or system comprising: (i) a detection module used to detect the level of the mitochondrial oxidative phosphorylation pathway, the level of the mitochondrial membrane permeability transition pore, the expression level of the NNMT gene and / or the methylation level of DNA CpG sites in the NNMT gene region; (ii) an output module. The output module includes: the information that the mitochondrial oxidative phosphorylation pathway is upregulated in tumor cells of a tumor patient, making the compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, suitable for the prevention and / or treatment of said tumor patient; In another preferred example, information that when the activity of the mitochondrial permeability transition pore is reduced in tumor cells of a tumor patient, the compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof becomes suitable for the prevention and / or treatment of the tumor patient; Information that when the NNMT gene is underexpressed or not expressed in tumor cells of a tumor patient, and when nucleotide sites in the NNMT gene are hypermethylated, and / or when DNA CpG sites in the NNMT gene region are hypermethylated, the compound of formula I according to the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof becomes suitable for the prevention and / or treatment of the tumor patient; and / or When the NNMT gene is highly expressed in tumor cells of a tumor patient, and the nucleotide site of the NNMT gene is hypomethylated, and / or the DNA CpG site in the NNMT gene region is hypomethylated, the compound of formula I described in the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt is output as information that the compound is unsuitable for the prevention and / or treatment of the tumor patient.

[0325] In another preferred embodiment, the device comprises a gene detector or a protein detector.

[0326] In another preferred embodiment, the device or system further comprises a sample supply module.

[0327] In another preferred embodiment, the sample supply module is used to supply a tumor cell extract.

[0328] In another preferred embodiment, the device or system further comprises a data processing module.

[0329] In another preferred embodiment, the data processing module processes the expression level of the NNMT gene and / or the methylation level of the DNA CpG site in the NNMT gene region to obtain their numerical ranges.

[0330] In another preferred embodiment, the data processing module processes the expression level of the NNMT gene and / or the methylation level of the DNA CpG site in the NNMT gene promoter region to obtain their numerical ranges.

[0331] In another preferred embodiment, the data processing module processes the expression level of the NNMT gene and / or the methylation level of DNA CpG sites within the region from 1050 bp before the transcription start site of the NNMT gene to 499 bp after the transcription start site to obtain their numerical ranges.

[0332] In another preferred embodiment, the data processing module processes the expression level of the NNMT gene and / or the methylation level of DNA CpG sites within the region from 1050 bp before the transcription start site of the NNMT gene to 193 bp before the transcription start site to obtain their numerical ranges.

[0333] It should be understood that within the scope of the present invention, the above technical features of the present invention, when combined with the following specific technical features (e.g., examples), constitute new or preferred technical solutions, which will not be repeated here due to the limited size of the full text. [Brief explanation of the drawings]

[0334] [Figure 1] FIG. 1 shows the expression of the NNMT gene in sensitive and insensitive tumor cells. [Figure 2] FIG. 2 shows the methylation levels of DNA CpG sites in the NNMT gene promoter region in sensitive and insensitive tumor cells. [Figure 3]FIG. 3 shows the methylation levels of DNA CpG sites in the region from 1050 bp before the transcription start site to 499 bp after the transcription start site of the NNMT gene in sensitive and insensitive tumor cells. [Figure 4] FIG. 4 shows the methylation levels of DNA CpG sites in the region from 1050 bp before to 193 bp before the transcription start site in sensitive and insensitive tumor cells. DETAILED DESCRIPTION OF THE INVENTION

[0335] As a result of long-term and in-depth research and extensive screening, the present inventors unexpectedly discovered that a specific compound (the compound of Formula I, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt) effectively inhibits tumors. Furthermore, they unexpectedly discovered that the compound of the present invention can significantly inhibit the activity of tumor cells with inactive mPTP (mitochondrial oxidative phosphorylation pathway) at a low concentration (IC50). This indicates that the compound of the present invention has a strong inhibitory effect on tumor cells with low or inactive mPTP activity, but a weak inhibitory effect on tumor cells with high mPTP activity. Generally, the compound of the present invention has a weak effect on normal somatic cells with high mPTP activity, thereby maintaining the safety of the drug.

[0336] The present inventors have unexpectedly found for the first time that the compounds of the present invention have a clear inhibitory effect on tumor cells with low (or no) expression of the NNMT gene, hypermethylation of nucleotide sites in the NNMT gene, and / or hypermethylation of DNA CpG sites in the NNMT gene region. The expression level of the NNMT gene, the methylation level of nucleotide sites in the NNMT gene, and / or the methylation level of DNA CpG sites in the NNMT gene promoter region serve as markers for determining whether the compounds of the present invention are suitable for the prevention and / or treatment of tumor patients. The present inventors have achieved this invention based on this finding.

[0337] (term) As used herein, the terms "including," "comprising," and "having" may be used interchangeably and have closed, semi-closed, and open definitions. In other words, the terms include the meanings "consisting of" and "consisting essentially of."

[0338] The terms "anti-cancer agent" and "anti-tumor agent" may be used interchangeably.

[0339] The terms "cancer," "carcinosis," and "tumor" may be used interchangeably.

[0340] As used herein, the term "a cell" refers to a single cell (e.g., a single cancer cell) or a group of cells comprising multiple similar cells (e.g., tumor tissue).

[0341] "I C 50 The term "50% inhibiting concentration" refers to the concentration of an inhibitor at which 50% of the inhibitory effect is achieved.

[0342] As used herein, "IC50" and "IC 50 The terms "50% inhibiting concentration" may be used interchangeably and refer to the concentration of an inhibitor at which 50% of the inhibitory effect is achieved.

[0343] The term "mitochondria permeability transition pore" is abbreviated as mPTP (mitochondria permeability transition pore).

[0344] The term "mitochondrial oxidative phosphorylation pathway" is abbreviated as OXPHOS (Oxidative Phosphorylation), and is also called oxidative phosphorylation.

[0345] As used herein, "highly methylated DNA CpG sites," "hypermethylation of DNA CpG sites," and "high levels of methylation of DNA CpG sites" may be used interchangeably.

[0346] As used herein, "DNA CpG sites are hypomethylated," "hypomethylation of DNA CpG sites," and "low methylation levels of DNA CpG sites" may be used interchangeably.

[0347] As used herein, the term "methylation level of DNA CpG sites" refers to the ratio between the number of methylated CpG sites in a DNA region and the number of all CpG sites in that region.

[0348] As used herein, "methylation of DNA CpG sites," "methylation of CpG nucleotides," and "CpG methylation" may be used interchangeably.

[0349] As used herein, "the compounds of the present invention are suitable for tumor patients" means that the tumors of the tumor patients are sensitive to the compounds of the present invention.

[0350] As used herein, "the compounds of the present invention are not suitable for tumor patients" means that the tumors of the tumor patients are insensitive to the compounds of the present invention.

[0351] As used herein, the English name of the term "NNMT" is Nicotinamide N-Methyltransferase.

[0352] As used herein, the term "bp" refers to a base pair.

[0353] As used herein, the term "SST" refers to the transcription start site.

[0354] It should be understood that one skilled in the art can select the substituents and substitution patterns on the compounds of the present invention to produce chemically stable compounds, and can synthesize such compounds using techniques known in the art and the methods described below. When substituted with one or more substituents, it should be understood that these substituents can be located on the same carbon or on different carbons, as long as a stable structure is produced.

[0355] As used herein, the terms "substituted" or "substituted" refer to the replacement of hydrogen atoms on a group of atoms with non-hydrogen atom groups, as needed to satisfy their valences, and which produce chemically stable compounds, i.e., compounds that do not spontaneously undergo transformations such as cyclization or elimination.

[0356] As used herein, "R1", "R1" and "R 1 " have the same meaning and may be used interchangeably, and other similar definitions have the same meaning.

[0357] As used herein, [ka] represents the bonding site of the atomic group.

[0358] As used herein, the term "alkyl group" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched groups. A carbon number specification preceding the alkyl group (e.g., a C1-C6 alkyl group) indicates that the alkyl group contains 1 to 6 carbon atoms; for example, a C1-C4 alkyl group indicates an alkyl group containing 1 to 4 carbon atoms. Representative examples of these alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, or similar groups.

[0359] As used herein, the term "C2-C4 alkenyl group" refers to a hydrocarbyl group formed from a straight-chain or branched alkene molecule of two to four carbon atoms having one or more double bonds by the loss of one hydrogen atom attached to the double bond. Representative examples thereof include vinyl groups (CH2=CH-), (C(CH3)2=CH-), or similar groups.

[0360] As used herein, the term "C2-C4 alkynyl group" refers to a hydrocarbyl group formed from a straight or branched alkene molecule of two to four carbon atoms having one or more triple bonds by removing one hydrogen atom attached to the triple bond. Representative examples thereof include ethynyl groups (CH≡CH-), (HC-C≡CH-), or similar groups.

[0361] In the present invention, the term "halogen atom" refers to F, Cl, Br or I.

[0362] In the present invention, "halogenated" refers to being replaced with a halogen atom.

[0363] As used herein, the term "halogenated alkyl group" refers to an alkyl group in which one or more (preferably one, two, three, or four) hydrogen atoms are replaced with halogen atoms. The alkyl group and halogen atoms are as defined above. When the halogenated alkyl group is specified by the number of carbon atoms (e.g., a C1-C8 halogenated alkyl group), the halogenated alkyl group has 1 to 8 carbon atoms. For example, a C1-C6 halogenated alkyl group refers to a halogenated alkyl group containing 1 to 6 carbon atoms. Representative examples of these halogenated alkyl groups include, but are not limited to, -CF3, -CHF2, monofluoroisopropyl, difluorobutyl, or similar atomic groups.

[0364] As used herein, the term "cycloalkyl ring" refers to a fully or partially saturated monocyclic, bicyclic, or polycyclic (fused, bridged, or spiro) ring system. A carbon number specification (e.g., C3-C12) before a cycloalkyl ring indicates that the cycloalkyl ring has from 3 to 12 ring carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkyl ring" refers to a fully or partially saturated monocycloalkyl or dicycloalkyl ring having from 3 to 8 ring carbon atoms, including cyclopropyl, cyclobutyl, cycloamyl, cycloheptyl, or similar rings. A "spirocycloalkyl ring" refers to a bicyclic or polycyclic ring that shares a carbon atom (called a spiro atom) between monocyclic rings; these rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. A "fused cycloalkyl ring" refers to an all-carbon bicyclic or polycyclic ring in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, where one or more rings may contain one or more double bonds, but the shared adjacent pair of carbon atoms connecting the main chain is an adjacent pair of carbon atoms on the all-carbon bicyclic or polycyclic ring having a non-conjugated π-electron system. A "bridged cycloalkyl ring" refers to an all-carbon polycyclic ring in which any two rings share two carbon atoms that are not directly connected, where such rings may contain one or more double bonds, but neither ring has a completely conjugated π-electron system. Representative examples of these cycloalkyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cycloamyl, cycloheptyl, or similar rings.

[0365] As used herein, the term "cycloalkyl group" refers to a fully saturated or partially saturated monocyclic, bicyclic, or polycyclic (fused, bridged, or spiro) ring group. A carbon number specification (e.g., C3-C12) before a cycloalkyl group indicates that the cycloalkyl group has 3 to 12 ring carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkyl group" refers to a fully saturated or partially saturated monocycloalkyl or dicycloalkyl group having 3 to 8 ring carbon atoms, including cyclopropyl, cyclobutyl, cycloamyl, cycloheptyl, or similar groups. A "spirocycloalkyl group" refers to a bicyclic or polycyclic group that shares a carbon atom (called a spiro atom) between the rings; these groups may contain one or more double bonds, but neither group has a completely conjugated π-electron system. A "fused cycloalkyl group" refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, where one or more rings may contain one or more double bonds, but the attachment points to the main chain must be located at carbon atoms on the ring that has a non-conjugated pi-electron system. A "bridged cycloalkyl group" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, where such a group may contain one or more double bonds, but neither ring has a completely conjugated pi-electron system. Representative examples of these cycloalkyl groups are: [ka] Including, but not limited to:

[0366] As used herein, the term "halogenated cycloalkyl group" refers to a cycloalkyl group in which one or more (preferably one, two, three, or four) hydrogen atoms are replaced with halogen atoms. The cycloalkyl group and halogen atoms are as defined above. When the cycloalkyl group is specified by the number of carbon atoms (e.g., a C3-C8 halogenated cycloalkyl group), the cycloalkyl group has 3 to 8 ring carbon atoms. For example, a C3-C8 halogenated cycloalkyl group refers to a halogenated cycloalkyl group containing 3 to 8 ring carbon atoms. Representative examples of these halogenated cycloalkyl groups include, but are not limited to, a monofluorinated cyclopropyl group, a monochlorinated cyclobutyl group, a monofluorinated cycloamyl group, a difluorinated cycloheptyl group, or similar atomic groups.

[0367] The term "alkoxyl group" refers to the R-O- group, where R is an alkyl group. Alkyl groups are as defined above. When the carbon number specified before the alkoxyl group (e.g., a C1-C8 alkoxyl group) is specified, the alkyl group in the alkoxyl group has 1 to 8 carbon atoms. Representative examples of these alkoxyl groups include, but are not limited to, methoxy, ethoxy, N-propoxy, isopropoxy, t-butoxy, or similar groups.

[0368] As used herein, the term "alkylthiol group" refers to the R-O- group, where R is an alkyl group. The alkyl group is as defined above. When the alkylthiol group is specified by the number of carbon atoms (e.g., a C1-C8 alkoxyl group), it means that the alkyl group in the alkylthiol group has 1 to 8 carbon atoms. Representative examples of these alkylthiol groups include, but are not limited to, methylthio, ethylthio, N-propylthio, isopropylthio, t-butylthio, or similar groups.

[0369] As used herein, the term "halogenated alkoxyl group" refers to a halogenated alkyl group -O-, where the halogenated alkyl group is as defined above. For example, a C1-C6 halogenated alkoxyl group refers to a halogenated alkoxyl group having 1 to 6 carbon atoms. Representative examples of these halogenated alkoxyl groups include, but are not limited to, a monofluorinated methoxy group, a monofluorinated ethoxy group, a difluorinated butoxy group, or similar atomic groups.

[0370] As used herein, the term "halogenated alkylthiol group" refers to a halogenated alkyl group -S-. The halogenated alkyl group is as defined above. For example, a C1-C6 halogenated alkylthiol group refers to a halogenated alkylthiol group having 1 to 6 carbon atoms. Representative examples of these halogenated alkylthiol groups include, but are not limited to, a monofluoromethylthio group, a monofluoroethylthio group, a difluorobutylthiol group, or similar atomic groups.

[0371] The term "heterocycloalkyl ring," also referred to as "heterocycle," refers to a fully saturated or partially unsaturated ring (including, but not limited to, a 3- to 7-membered monocyclic ring, a 7- to 11-membered bicyclic ring, or an 8- to 16-membered tricyclic ring) in which at least one heteroatom is present in a ring having at least one carbon atom. The number of members in the heterocycle refers to the number of ring atoms in the heterocycloalkyl ring. For example, a 3- to 16-membered heterocycle refers to a heterocycle having 3 to 16 ring atoms. Each heterocycle having a heteroatom may have one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from nitrogen, oxygen, or sulfur atoms, where the nitrogen or sulfur atoms may be oxidized and the nitrogen atom may also be quaternized. The heterocycle may be bonded to any heteroatom or carbon atom residue in the ring or ring system molecule. Representative examples of these monocyclic heterocycloalkyl rings include, but are not limited to, an azetidinyl ring, an oxetane ring, an imidazoline ring, an imidazolidone ring, a tetrahydrofuranyl ring, a piperidinyl ring, a piperazinyl ring, a 2-oxypiperazinyl ring, a 2-oxypiperidinyl ring, a 4-piperidinone ring, a tetrahydropyranyl ring, a morpholine ring, a thiomorpholine ring, a thiomorpholine sulfoxide ring, a thiomorpholine sulfone ring, a 1,3-dioxane ring, a tetrahydro-1,1-dioxythiophene ring, etc. Polycyclic heterocycloalkyl rings include spiro, fused, and bridged heterocycles. The related spiro, fused, and bridged heterocycles are optionally connected to other rings by a single bond or further fused to other cycloalkyl, heterocycles, aryl, and heteroaryl rings through any two or more atoms on the ring, provided that the point of attachment to the main chain is on a carbon atom or heteroatom on the ring having a non-conjugated π-electron system.

[0372] The term "heterocycloalkyl group" refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, a 3- to 7-membered monocyclic ring, a 7- to 11-membered bicyclic ring, or an 8- to 16-membered tricyclic ring) in which at least one heteroatom is present in a ring having at least one carbon atom. The number of members preceding a heterocycloalkyl group refers to the number of ring atoms in the heterocycloalkyl group. For example, a 3- to 16-membered heterocycloalkyl group refers to a heterocycloalkyl group having 3 to 16 ring atoms. Each heterocycle having a heteroatom may have one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from nitrogen, oxygen, or sulfur atoms, where the nitrogen or sulfur atoms may be oxidized and the nitrogen atom may also be quaternized. The heterocycloalkyl group may be attached to any heteroatom or carbon atom in the ring or ring system. Representative examples of these single-ring heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetane, imidazoline, imidazolidone, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxypiperazinyl, 2-oxypiperidinyl, 4-piperidinone, tetrahydropyranyl, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, 1,3-dioxane, and tetrahydro-1,1-dioxythiophene. Polycyclic heterocycloalkyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. Related spirocyclic, fused-ring, and bridged-ring heterocycloalkyl groups are optionally connected to other atomic groups by a single bond or further fused to other cycloalkyl rings and heterocycles via any two or more atoms on the ring. Polycyclic heterocycloalkyl groups may have fused aromatic rings, but the points of attachment to the main chain must be on carbon atoms or heteroatoms on the rings that have non-conjugated pi-electron systems.

[0373] The term "aryl ring" refers to an all-carbon monocyclic or fused polycyclic ring (rings sharing adjacent pairs of carbon atoms) having a conjugated π electron system, and is an aromatic cyclic hydrocarbon compound. The carbon number specified before the aryl ring (e.g., a C6-C12 aryl group) indicates that the aryl ring has 6 to 12 ring carbon atoms. Representative examples of these aryl rings include phenyl rings and naphthoyl rings. Aryl rings can be fused to other carbocyclic rings (including saturated or unsaturated rings), but they must not contain heteroatoms such as nitrogen, oxygen, or sulfur atoms, and the connection point to the main chain must be on a carbon atom in the ring having a conjugated π electron system. Representative examples of these aryl rings include phenyl rings, naphthoyl rings, and similar rings.

[0374] The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic (rings sharing adjacent pairs of carbon atoms) atomic group having a conjugated π electron system, and is an atomic group of an aromatic cyclic hydrocarbon compound. The carbon number specified before the aryl group (e.g., a C6-C12 aryl group) indicates that the aryl group has 6 to 12 ring carbon atoms. Representative examples of these aryl groups include phenyl and naphthoyl groups. An aryl group can be fused to another cyclic atomic group (including a saturated or unsaturated ring), but it must not contain heteroatoms such as nitrogen, oxygen, or sulfur atoms, and the point of attachment to the main chain must be a carbon atom on the ring with a conjugated π electron system. Representative examples of these aryl groups are: [ka] Including, but not limited to:

[0375] The term "heteroaryl ring" refers to an aromatic heterocyclic ring having one or more (preferably one, two, three, or four) heteroatoms. The ring can be a single ring (monocyclic) or multiple fused or covalently linked rings (bicyclic, tricyclic, or polycyclic), and each heteroatom-containing heterocyclic ring can have one or more (e.g., one, two, three, or four) heteroatoms independently selected from oxygen, sulfur, and nitrogen atoms. The number of members used to qualify a heteroaryl ring refers to the number of ring atoms in the heteroaryl ring. For example, a 5-12-membered heteroaryl ring refers to a heteroaryl ring having 5 to 12 ring atoms. Representative examples of these heteroaryl rings include, but are not limited to, a pyrrolyl ring, a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, a thiadiazole ring, an isothiazole ring, a furan ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, a triazole ring, and a tetrazolyl ring.

[0376] The term "heteroaryl group" refers to an aromatic heterocyclic group having one or more (preferably one, two, three, or four) heteroatoms. The group can be a single ring (monocyclic) or multiple fused or covalently linked rings (bicyclic, tricyclic, or polycyclic), and each heteroatom-containing heterocycle can have one or more (e.g., one, two, three, or four) heteroatoms independently selected from oxygen, sulfur, and nitrogen atoms. The number of members in a heteroaryl group refers to the number of ring atoms in the heteroaryl group. For example, a 5-12-membered heteroaryl group refers to a heteroaryl group having from 5 to 12 ring atoms. Representative examples of these heteroaryl groups include, but are not limited to, pyrrolyl groups, pyrazole groups, imidazole groups, oxazole groups, isoxazole groups, thiazole groups, thiadiazole groups, isothiazole groups, furan groups, pyridine groups, pyrazine groups, pyrimidine groups, pyrazine groups, triazine groups, triazole groups, tetrazolyl groups, and the like.

[0377] As used herein, the term "carboxyl group" refers to a group of atoms of the formula -COOH or -alkyl-COOH, where alkyl is as defined above. For example, a "C2-C4 carboxyl group" refers to a group of atoms of the formula -C1-C3 alkyl-COOH. Representative examples of these carboxyl groups include, but are not limited to, -COOH, -CH2COOH, -C2H4COOH, or similar groups.

[0378] As used herein, the term "ester group" refers to a group of atoms of the formula -RC(O)-O- or -C(O)-OR, where alkyl (R) is as defined above. For example, a "C2-C4 ester group" refers to a group of atoms of the formula -C1-C3 alkyl group -C(O)-O- or a group of atoms of the formula -C(O)-O-C1-C3 alkyl group. Representative examples of these ester groups include, but are not limited to, CH3COO-, C2H5COO-, C3H8COO-, (CH3)2CHCOO-, -COOCH3, -COOC2H5, -COOC3H8, -COOC(CH3)3, or similar groups.

[0379] As used herein, the term "acylamino group" refers to the group RC(O)-N- or the group -C(O)-NR, where the alkyl group (R) is as defined above. For example, a "C2-C4 acylamino group" refers to the group -C1-C3 alkyl group -C(O)-N- or the group -C(O)-N-C1-C3 alkyl group. Representative examples of these acylamino groups include, but are not limited to, CH3CO-N-, CH5CO-N-, CH3CO-N-, (CH3)2CHCO-N-, -CO-N-CH3, -CO-N-C2H5, -CO-N-C3H8, or similar groups.

[0380] As used herein, an "amino group" alone or as part of another substituent refers to -NH2.

[0381] As used herein, a "nitro group" alone or as part of another substituent refers to -NO2.

[0382] As used herein, a "cyano group" alone or as part of another substituent refers to -CN.

[0383] As used herein, a "hydroxyl group" refers to -OH, either alone or as part of another substituent.

[0384] As used herein, a "mercapto group" alone or as part of another substituent refers to -SH.

[0385] As used herein, all substituents are intended to be unsubstituted unless expressly stated as "substituted." The term "substituted" refers to a particular substituent replacing one or more hydrogen atoms on a particular group of atoms. Specific substituents are those described above or appearing in each example. Preferably, the term "substituted" refers to the replacement of one or more (preferably 1, 2, 3, 4, 5, 6, 7, or 8) hydrogen atoms on a ring or atomic group with a substituent selected from a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C1-C8 halogenated alkyl group, a C3-C8 halogenated cycloalkyl group, a halogen atom, a nitro group, -CN, a hydroxyl group, a mercapto group, an amino group, a C1-C4 carboxyl group, a C2-C4 ester group, a C2-C4 acylamino group, a C1-C8 alkoxyl group, a C1-C8 alkylthiol group, a C1-C8 halogenated alkoxyl group, a C1-C8 halogenated alkylthiol group, a C6-C12 aryl group, a 5- to 10-membered heteroaryl group, and a 5- to 10-membered heterocycloalkyl group. Unless otherwise specified, an optionally substituted radical may have a substituent selected from a specified group at any substitutable position of the radical, and the substituent may be the same or different at each position.

[0386] In the present invention, "prevention" refers to a method of preventing the onset of a disease and / or its associated symptoms or protecting a subject from contracting the disease. As used herein, "prevention" also refers to delaying the onset of a disease and / or its associated symptoms, as well as reducing the subject's risk of contracting the disease.

[0387] "Treatment" according to the present invention means slowing or terminating the progression of the disease or eliminating the disease, but does not require 100% inhibition, elimination, or reversal. In some embodiments, tumor growth is reduced, inhibited, and / or reversed by at least about 10%, 30%, 50%, or 80%, etc., under the action of a compound or composition of the present invention, compared to levels observed in the absence of a composition, medical kit, food kit, health product kit, or active ingredient combination according to the present invention.

[0388] In the present invention, "prevention" refers to a method of preventing the onset of a disease and / or its associated symptoms or protecting a subject from contracting the disease.

[0389] "Treatment" according to the present invention means slowing or terminating the progression of a disease or eliminating the disease, but does not require 100% inhibition, elimination, or reversal. In some embodiments, the compound of the present invention reduces, inhibits, and / or reverses the associated disease (tumor) and its complications by at least about 10%, 30%, 50%, 80%, or 100%, etc., compared to levels observed in the absence of the compound.

[0390] (Mitochondrial oxidative phosphorylation pathway and mitochondrial permeability transition pore) The mitochondrial oxidative phosphorylation (OXPHOS) pathway, one of the most important pathways in the mitochondrion, synthesizes ATP using NADH and FADH derived from pathways such as the tricarboxylic acid cycle and fat oxidation. The mitochondrial oxidative phosphorylation pathway contains over 90 proteins, which are organized into five protein complexes: complex I, II, III, IV, and V.

[0391] The mitochondrial oxidative phosphorylation pathway is regulated by the mitochondria permeability transition pore (mPTP), and the compounds of the present invention are better able to inhibit cells with inactive mPTP.

[0392] As used herein, the terms "upregulated mitochondrial oxidative phosphorylation pathway" and "positive mitochondrial oxidative phosphorylation pathway" may be used interchangeably and refer to a state in which the level or expression level of the mitochondrial oxidative phosphorylation pathway in a cell (e.g., a tumor cell) is greater than the level or expression level of the mitochondrial oxidative phosphorylation pathway in a normal cell (similar cell). Preferably, the terms "upregulated mitochondrial oxidative phosphorylation pathway" and "positive mitochondrial oxidative phosphorylation pathway" refer to a state in which the ratio (E1 / E0) between the level or expression level of the mitochondrial oxidative phosphorylation pathway in a cell (e.g., a tumor cell) and the level or expression level of the mitochondrial oxidative phosphorylation pathway in a normal cell (similar cell) is greater than 1.0, preferably greater than 1.2, and more preferably greater than 1.5, greater than 2, greater than 3, or greater than 5.

[0393] In the present invention, "upregulation of the mitochondrial oxidative phosphorylation pathway" and "positive mitochondrial oxidative phosphorylation pathway" are characterized by mPTP activity. Inactivation of mPTP indicates "upregulation of the mitochondrial oxidative phosphorylation pathway" and "positive mitochondrial oxidative phosphorylation pathway." For example, when the ratio (A1 / A0) between the mPTP activity level or expression level A1 of a certain cell (e.g., a tumor cell) and the mPTP activity level or expression level A0 of a normal cell (similar cell) is <1.0, preferably ≦0.8, and more preferably ≦0.7, ≦0.6, ≦0.5, ≦0.4, ≦0.3, ≦0.2, ≦0.1, or ≦0.05, the cell is considered to be a cell in which the mitochondrial oxidative phosphorylation pathway is upregulated or positive.

[0394] In a preferred embodiment of the present invention, said level refers to the protein level and / or the mRNA level.

[0395] In a preferred embodiment of the present invention, said expression refers to protein expression and / or mRNA expression.

[0396] In the present invention, the level or expression level of the mitochondrial oxidative phosphorylation pathway and the activity level or expression level of mPTP are measured using standard methods, such as measuring the activity of mPTP or measuring the expression level of mPTP at the protein level or mRNA level.

[0397] (NNMT gene) In the present invention, the English name of NNMT is Nicotinamide N-Methyltransferase. Different databases have different identification numbers for the NNMT gene, such as HGNC: 7861; Entrez Gene: 4837; Ensembl: ENSG00000166741; OMIM: 600008; UniProtKB: P40261.

[0398] According to the human genome version GCF_000001405.25 (GRCh37.p13), the NNMT gene region is located from bp 114,128,528 to bp 114,184,258 on human chromosome 11, and is a DNA sequence with a total length of 55,731 bp. This region includes the NNMT gene promoter region, NNMT gene exon region, and NNMT gene intron region, and the transcription start site of the NNMT gene is at bp 114,166,535.

[0399] The NNMT gene promoter region is the nucleotide sequence from bp 114,164,535 to bp 114,167,034 on human chromosome 11, i.e., the sequence from 2,000 bp (inside [ ]) before the transcription start site of the NNMT gene to the transcription start site itself and 499 bp (lowercase) after it. The NNMT gene promoter region has a total length of 2,500 bp, and its nucleotide sequence is shown in the following SEQ ID NO:1.

[0400]

[0401] In the present invention, the region from 1050 bp before the transcription start site of the NNMT gene to 499 bp after the transcription start site corresponds to positions 951-2500 of the nucleotide sequence shown in SEQ ID NO:1.

[0402] In the present invention, the region from 1050 bp before the transcription initiation site of the NNMT gene to 193 bp before the transcription initiation site corresponds to positions 951-1808 of the nucleotide sequence shown in SEQ ID NO:1.

[0403] (DNA methylation) DNA methylation is a form of chemical modification of DNA that alters gene expression without changing the DNA sequence. DNA methylation refers to the covalent attachment of a methyl group to the carbon-5 position of cytosine in genomic CpG dinucleotides under the action of DNA methyltransferase. Many studies have shown that DNA methylation can alter chromatin structure, DNA morphology, DNA stability, and DNA-protein interaction patterns, potentially regulating gene expression.

[0404] DNA methylation is one of the first and most extensively studied epigenetic regulators. Broadly defined, DNA methylation refers to the chemical modification process in which specific bases in DNA sequences acquire a single methyl group via covalent bonding using S-adenosylmethionine as the methyl donor under the catalysis of DNA methyltransferase 1. This DNA methylation modification can occur at positions such as the C-5 position of cytosine, the N-6 position of adenine, and the N-7 position of guanine. In general, DNA methylation refers to the process in which the fifth carbon atom of cytosine in CpG dinucleotides is methylated. The resulting product, called 5-methylcytosine (5-mC), is the predominant form of DNA methylation in eukaryotes, including plants and animals. DNA methylation is a relatively stable modification that can be inherited to new generations of DNA during the DNA replication process under the action of DNA methyltransferases, making it an important regulator of epigenetic inheritance.

[0405] DNA methylation reactions can be divided into two types: the first type, in which DNA with two unmethylated strands is methylated, is called de novo methylation, and the second type, in which double-stranded DNA with one methylated strand is methylated on the other unmethylated strand, is called maintenance methylation.

[0406] Typically, DNA methylation is the methylation of DNA CpG sites. CpG dinucleotides are distributed unevenly throughout the human genome, with some segments of the genome retaining CpGs at higher than normal rates. CpG-enriched regions (also called CpG islands), primarily located in gene promoter and exon regions, are regions enriched in CpG dinucleotides, with over 60% of gene promoters containing CpG islands. Here, CpG stands for cytosine (C)-phosphate (p)-guanine (G).

[0407] Intracellular gene expression is regulated by various mechanisms, including signal transduction pathways, transcription factors, and epigenetic modifications. DNA methylation is an important method by which epigenetic modifications regulate gene expression. The DNA methylation level in a specific gene region always affects the expression level of that gene. DNA methylation, an epigenetic modification, has a more stable effect on gene expression and is less susceptible to the extracellular environment than regulation of gene expression by signal transduction pathways and transcription factors. DNA methylation is an ideal biomarker because it can be easily detected using existing technologies.

[0408] (Compound of Formula I) As used herein, "a compound of the invention," "a compound of Formula I of the invention," and "a compound of Formula I" may be used interchangeably and refer to a compound having the structure of Formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof. It should be understood that the term also includes mixtures of the above components. [ka]

[0409] Specifically, the compound of formula I is as described in the first aspect of the present invention.

[0410] Typically, the compounds of formula I of the present invention are the specific compounds (including their salts or free forms free of base ions) prepared by Examples 1 to 105 of the present invention.

[0411] In the present invention, it should be understood that when ring B is null, R3 is also null, i.e., when ring B is null, the compound of formula I has the following structure: [ka]

[0412] The compounds of formula I described in this embodiment can be prepared by organic synthesis methods known in the art.

[0413] The compounds of the present invention have excellent inhibitory effects on tumor cells, and are more effective in suppressing tumor cells in which the mitochondrial oxidative phosphorylation pathway is upregulated or mPTP is underactive, especially tumor cells in which mPTP is always off. Moreover, for normal somatic cells that usually have high mPTP activity, the compounds of the present invention have a weak inhibitory effect on normal somatic cells and have almost no toxic side effects, so that the compounds of the present invention can be used to develop safe and effective anticancer drugs.

[0414] The term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention with an acid or base and suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. One type of preferred salt is a salt formed by a compound of the present invention with an acid. Acids suitable for forming such salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid. Another type of preferred salt is a metal salt formed by a compound of the present invention and a base; bases suitable for forming such salts include, but are not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate, and organic bases such as ammonia, triethylamine, and diethylamine.

[0415] The present invention may be practiced by converting compounds such as those represented by formula I into their pharmaceutically acceptable salts in a conventional manner. For example, adding a solution of the corresponding acid to a solution of the compound, and removing the solvent after all the salts, allows the corresponding salts of the compounds of the present invention to be obtained.

[0416] Preferably, the compounds according to the present invention are prepared as per the examples of the present invention.

[0417] (cancer disease) The present invention provides that the compounds of the present invention have excellent inhibitory effects on tumor cells, and better suppress tumor cells with upregulation of the mitochondrial oxidative phosphorylation pathway, low activity of mPTP, low or no expression of the NNMT gene, hypermethylation of nucleotide sites in the NNMT gene, and / or hypermethylation of DNA CpG sites in the NNMT gene region.

[0418] In particular, the tumor of the present invention is as described in the first aspect of the present invention.

[0419] (Anticancer drug) In the present invention, the anti-cancer agent may be a compound of formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0420] (Inhibitors of the mitochondrial permeability transition pore and their use) In the present invention, the inhibitor of the mitochondrial permeability transition pore includes, but is not limited to, Cyclosporin A, a CyP-D protein inhibitor, a peroxide scavenger, or a combination thereof.

[0421] Typically, the CyP-D protein inhibitors include SfA, BKA and ADP (small molecules that regulate the activity of ANT proteins).

[0422] Typically, the peroxide scavenger includes, but is not limited to, propofol, pyruvate, MCI-186, or combinations thereof.

[0423] (marker) The present invention further provides markers for determining whether the compounds of the present invention are suitable for the prevention and / or treatment of tumor patients, including the mitochondrial oxidative phosphorylation pathway, the mitochondrial permeability transition pore, the NNMT gene, the methylation level of nucleotide sites in the NNMT gene, and / or the methylation level of DNA CpG sites in the NNMT gene region.

[0424] Compositions or Formulations, Active Ingredient Combinations and Dosage Methods The present invention further provides compositions or formulations, combinations of active ingredients and medical kits, said compositions or formulations, combinations of active ingredients and medical kits being used for the prevention and / or treatment of cancer.

[0425] Preferably, the composition of the present invention is a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier.

[0426] As used herein, "pharmaceutically acceptable carrier" refers to one or more compatible solid, semi-solid, liquid, and gel fillers that are suitable for human or animal use and must be of sufficient purity and sufficiently low toxicity. "Compatibility" refers to the ability of each component of a drug composition to be mixed with the active ingredient of the drug, and to be mixed with each other, without significantly reducing the efficacy of the drug.

[0427] In the present invention, the pharmaceutically acceptable carrier is not particularly limited and may be selected from materials commonly used in the art, prepared by conventional methods, or purchased from the market. Some pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (e.g., stearic acid and magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween), wetting agents (e.g., sodium lauryl sulfate), buffers, chelating agents, thickeners, pH adjusters, penetration enhancers, colorants, flavorings, stabilizers, antioxidants, preservatives, bacteriostats, heat-free raw water, etc.

[0428] In vitro studies and in vivo administration (e.g., intratumor administration) have shown that mitochondrial permeability transition pore inhibitors reduce mPTP activity in tumor cells and upregulate the mitochondrial oxidative phosphorylation pathway, thereby enhancing the therapeutic efficacy of antitumor drugs, thereby exerting a synergistic antitumor effect between the antitumor drug and the mPTP inhibitor.

[0429] The present invention provides active ingredient combinations, compositions and medical kits comprising an anti-tumor drug and an mPTP inhibitor for synergistic anti-tumor effects.

[0430] The present invention provides a combination of active ingredients comprising: (1) a first active ingredient as an anticancer agent; and (2) A second active ingredient that acts as an inhibitor of the mitochondrial membrane permeability transition pore.

[0431] In another preferred embodiment, the active ingredient combination has at least one independent active ingredient.

[0432] In another preferred embodiment, the active ingredient combination has a first active ingredient and a second active ingredient that are independent of each other.

[0433] The present invention further provides a composition comprising the following components: (1) a first active ingredient as an anticancer agent; and (2) A second active ingredient that acts as an inhibitor of the mitochondrial membrane permeability transition pore.

[0434] In another preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0435] In another preferred embodiment, the content of the first active ingredient relative to the total weight of active ingredients in the composition is 0.01-99.99 wt%, preferably 0.1-99.9 wt%, and more preferably 1-99 wt%, 10-99 wt% or 20-99 wt%.

[0436] In another preferred embodiment, the content of the second active ingredient relative to the total weight of the active ingredients of the composition is 0.01-99.99 wt%, preferably 0.1-99.9 wt%, and more preferably 1-99 wt%, 10-99 wt% or 20-99 wt%.

[0437] The present invention further provides a medical kit comprising the following formulation: (A) a first formulation containing a first active ingredient as an anticancer agent; and (B) A second formulation comprising a second active ingredient that is an inhibitor of the mitochondrial permeability transition pore.

[0438] In another preferred embodiment, the medical kit further comprises an instruction manual.

[0439] In another preferred embodiment, the first formulation and the second formulation are independent of each other.

[0440] In another preferred embodiment, the first and second formulations are combined with each other.

[0441] In another preferred embodiment, the instructions indicate that the first formulation and the second formulation are used in combination to enhance the antitumor activity of an anticancer drug.

[0442] In another preferred embodiment, the combination method comprises first administering a second preparation containing an inhibitor of the mitochondrial permeability transition pore, and then administering an anticancer drug.

[0443] Preferably, in the active ingredient combinations, compositions and / or medical kits of the present invention, the molar ratio between the first active ingredient and the second active ingredient is 0.01-600:1, preferably 0.05-500:1, and more preferably 0.1-400:1, 0.2-200:1, 0.5-100:1, 0.5-80:1 or 1-50:1.

[0444] In the present invention, the types of the composition or preparation include, but are not limited to, oral preparations, topical preparations, and injectable preparations.

[0445] Representative examples of the types of compositions or formulations include, but are not limited to, tablets, injections, infusions, ointments, gels, solutions, pills, or coatings.

[0446] Typically, the injection is an intratumoral injection.

[0447] The drug formulation should be consistent with the administration method. Preferred administration methods are oral administration and injection administration (such as intratumoral injection). When using a drug composition or formulation, an effective therapeutic amount of the drug is administered to the subject (e.g., a human or non-human mammal). As used herein, the term "effective therapeutic amount" refers to an amount that provides function or activity to humans and / or animals and is acceptable to humans and / or animals. It should be understood by those skilled in the art that the "effective therapeutic amount" varies depending on the form of the drug composition, the administration route, the auxiliary materials of the drug used, the severity of the disease, and the combination with other drugs.

[0448] In one dosage regimen, the safe and effective daily dosage of the first active ingredient is usually at least about 0.1 mg and in most cases not more than about 2500 mg. Preferably, this dosage is 1 mg to 500 mg; the safe and effective daily dosage of the second active ingredient is usually at least about 0.01 mg and in most cases not more than 2500 mg. Preferably, the dosage range is 0.1 mg to 2500 mg. Of course, the specific dosage must be determined taking into account factors such as the route of administration and the patient's health condition, and these factors are taken into account by a skilled physician.

[0449] The present invention has the following main beneficial effects: The present invention is the first to develop novel compounds that can suppress tumor cells efficiently and safely, particularly those with upregulation of the mitochondrial oxidative phosphorylation pathway or low activity of mPTP, and can significantly inhibit tumor cells with low or no expression of the NNMT gene and / or hypermethylation of DNA CpG sites in the NNMT gene region.

[0450] The present invention will now be further described in conjunction with specific examples. It should be understood that these embodiments are intended only to illustrate the present invention, without limiting the scope of the present invention. In the following examples, experimental methods that do not specify specific conditions generally follow general conditions or comply with manufacturer recommendations. Unless otherwise specified, percentages and ratios are calculated by weight.

[0451] Example 1 Preparation of compound AB24831A Step 1): [ka] Compound 1 (440 mg, 2 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (20 mL). Compound 2 (428.4 mg, 4.2 mmol), bistriphenylphosphine palladium dichloride (42 mg, 0.06 mmol), N,N-diisopropylethylamine (825 mg, 6.4 mmol), and cuprous iodide (19 mg, 0.1 mmol) were then added. The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. After detecting a new compound by thin-layer chromatography, the product was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 0-50%) to give compound 3 (130 mg, 33% yield).

[0452] Step 2): [ka] Compound 3 (130 mg, 0.47 mmol) was dissolved in dioxane (6 mL), followed by the addition of potassium t-butoxide (336.6 mg, 3 mmol). The mixture was then flushed with nitrogen three times, and the temperature was raised to 110 °C and stirred for 16 h. After detecting a new compound by thin-layer chromatography, the product was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound 4 (50 mg, 50% yield).

[0453] Step 3): [ka] Compound 4 (100 mg, 0.67 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 5 (312 mg, 1.34 mmol). The mixture was then flushed with nitrogen three times, and the temperature was raised to 80 °C and stirred overnight. After detecting a new compound by thin-layer chromatography, the product was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). After the organic phases were combined, the product was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified to obtain compound AB24831A (weight: 25.2 mg, yield: 8.1%).

[0454] Compound AB24831A: 1H NMR(400MHz,DMSO-d6)δ 13.53(s,1H),9.06(s,1H),8.24(d,J=7.1Hz,1H),8.14(d,J=6.5Hz,1H),8.08(d, J=7.4Hz,4H),7.74(d,J=7.6Hz,2H),7.64-7.55(m,3H),7.48(s,1H),6.36(s,2H). ESI-MS: Theoretical value [M-CF3COO] + 347.82, Observed: 347.25.

[0455] Example 2 Preparation of compound AB24828A Step 1): [ka] Compound 1 (140 mg, 0.66 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (10 mL). Compound 2 (161.4 mg, 1.39 mmol), bistriphenylphosphine palladium dichloride (14 mg, 0.02 mmol), N,N-diisopropylethylamine (272 mg, 2.11 mmol), and cuprous iodide (5.7 mg, 0.03 mmol) were added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. Upon detecting a new compound by thin-layer chromatography, the product was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound 3 (weight 100 mg, yield 75.7%).

[0456] Step 2): [ka] Compound 3 (100 mg, 0.47 mmol) was dissolved in dioxane (30 mL), followed by the addition of potassium t-butoxide (160 mg, 1.43 mmol). The mixture was then flushed with nitrogen three times, and the temperature was raised to 110 °C and stirred for 1 h. After detecting a new compound by thin-layer chromatography, the product was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound 4 (50 mg, 50% yield).

[0457] Step 3): [ka] Compound 4 (50 mg, 0.67 mmol) was dissolved in acetonitrile (10 mL), and then compound 5 (312 mg, 1.34 mmol) was added. After purging with nitrogen three times, the temperature was raised to 80 °C and the mixture was stirred overnight. When a new compound was detected by thin-layer chromatography, the solution was immediately concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified to obtain compound AB24828A (weight: 34.7 mg, yield: 10.9%).

[0458] Compound AB24828A 1 H NMR(400MHz,DMSO-d6)δ 13.15(s,1H),9.02(s,1H),8.21(d,J=6.1Hz,1H),8.07(d,J=8.4Hz,3H),7.74( d,J=7.0Hz,2H),7.31(d,J=29.2Hz,5H),6.74(s,1H),6.33(s,2H),4.33(s,2H). ESI-MS: Theoretical value [M-CF3COO] + 361.84, Observed: 361.25.

[0459] Example 3 Preparation of compound AB24861 Steps): [ka] Compound 1 (100 mg, 0.48 mmol) and compound 2 (123 g, 0.577 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 4 hours. Upon detecting a new compound by thin layer chromatography, the reaction solution was immediately filtered, and compound AB24861 (weight 110.0 mg, yield 67.2%) was obtained via the acetonitrile filter cake.

[0460] Compound AB24861 1H NMR(400MHz, DMSO-d6)δ 12.96(s,1H),9.15(s,1H),8.27(s,1H),8.22(s,1H),8.11(s,1H),8.04(d,J=7.4Hz,1H),7.56(d,J=7.1Hz,1H),7.47 (d,J=7.8Hz,1H),7.39(d,J=6.5Hz,1H),7.29(d,J=12.7Hz,4H),7.17(s,1H),6.27(s,2H),4.18(s,2H),2.43(s,3H). ESI-MS: Theoretical value [M-Br] + 341.43, Observed: 341.30.

[0461] Example 4 Preparation of compound AB24859 Step 1): [ka] Compound 1 (2.0 g, 15.5 mmol), compound 2 (5.6 g, 46.6 mmol), bis(dibenzylideneacetone)palladium (771.0 mg, 0.5 mmol), tri-tert-butylphosphine tetrafluoroborate (451.0 mg, 1 mmol), and triethylenediamine (5.24 g, 30 mmol) were dissolved in N,N-dimethylformamide (DMF) (50 mL), and the mixture was purged with nitrogen three times. After stirring at 120 °C for 16 hours, a new compound was detected by thin-layer chromatography. The mixture was cooled to room temperature, and water and ethyl acetate (100 mL x 3) were added to extract the product. After the organic phases were combined, the product was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether=66.6%) to give compound 3 (weight 70 mg, yield 2.16%).

[0462] Step 2): [ka] Compound 3 (97 mg, 0.5 mmol) and compound 4 (244 g, 1 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 16 hours. Upon detecting a new compound by thin layer chromatography, the reaction solution was immediately filtered and the filter cake was washed with acetonitrile to obtain compound AB24859 (weight 89 mg, yield 52.1%).

[0463] Compound AB24859: 1 H NMR(400MHz,DMSO-d6)δ 12.98(s,1H),9.17(s,1H),8.28-8.21(m,2H),8.09(d,J=6.6Hz,1H),7.94(d,J=7.7Hz,2H) ,7.43(d,J=7.8Hz,2H),7.34-7.24(m,4H),7.18(d,J=7.2Hz,1H),6.36(s,2H),2.41(s,3H). ESI-MS: Theoretical value [M-Br] + 341.43, Observed: 341.30.

[0464] Example 5 Preparation of compound AB24835A Step 1): [ka] Compound 1 (1.28 g, 10 mmol), compound 2 (4.02 g, 30 mmol), bis(dibenzylideneacetone)palladium (457.5 mg, 0.5 mmol), tri-tert-butylphosphine tetrafluoroborate (290.13 mg, 1 mmol), and triethylenediamine (3.36 g, 30 mmol) were dissolved in N,N-dimethylformamide (DMF) (50 mL), and the mixture was purged with nitrogen three times. After stirring at 120 °C for 16 hours, a new compound was detected by thin-layer chromatography. The mixture was cooled to room temperature, and water and ethyl acetate (100 mL x 3) were added to extract the product. After the organic phases were combined, the product was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether=66.6%) to give compound 3 (weight 1.1 g, yield 2.16%). ESI-MS: Theoretical value [M+1]+208.26, Observed value: 209.30.

[0465] Step 2): [ka] Compound 3 (208 mg, 1 mmol) and compound 4 (233.5 mg, 1 mmol) were dissolved in acetonitrile (10 mL) and stirred at 80° C. for 16 hours. Upon detecting a new compound by thin layer chromatography, the reaction solution was immediately filtered and the filter cake was washed with ethyl acetate to obtain compound AB24835A (weight 150 mg, yield 41.55%).

[0466] Compound AB24835A: 1 H NMR(400MHz,DMSO-d6)δ 12.98(s,1H),9.14(s,1H),8.30-8.19(m,2H),8.08(dd,J=22.2,7.3Hz,3H),7.72(d,J=7 .9Hz,2H),7.29(dt,J=14.9,7.5Hz,4H),7.18(d,J=7.0Hz,1H),6.35(s,2H),4.18(s,2H). ESI-MS: Theoretical value [M+1]+361.84, Observed value: 361.30.

[0467] Example 6 Preparation of compound AB24863 Step 1): [ka] Compound 1 (3.86 g, 30 mmol) was dissolved in N,N-dimethylformamide (DMF) (250 mL), followed by the sequential addition of compound 2 (12.1 g, 90 mmol), triethylenediamine (10.1 g, 90 mmol), tri-tert-butylphosphine tetrafluoroborate (870 mg, 3 mmol), and bis(dibenzylideneacetone)palladium (1.37 g, 1.5 mmol). The mixture was then purged with nitrogen three times, heated to 120 °C, and stirred for 2 hours and overnight. Upon detecting a new compound by thin-layer chromatography, the product was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane=10:1) to give compound 3 (weight 2.0 g, yield 32%).

[0468] Step 2): [ka] Compound 3 (100 mg, 0.5 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 4 (244 mg, 1 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 80 °C and stirred overnight. Upon detecting a new compound by thin-layer chromatography, the solution was immediately concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 10:1) to obtain compound AB24863 (weight 140 mg, yield 59.8%).

[0469] Compound AB24863 1 H NMR(400MHz,DMSO-d6)δ 13.01(s,1H),9.16(s,1H),8.46(d,J=7.9Hz,2H),8.26(dd,J=16.4,8.2Hz,4H),8.14(d,J= 6.9Hz,1H),7.31(dd,J=20.1,7.4Hz,4H),7.20(d,J=7.3Hz,1H),6.43(s,2H),4.20(s,2H). ESI-MS: Theoretical value [M-Br]+ 388.40, Observed value: 388.25.

[0470] Example 7 Preparation of compound AB24878 Step 1): [ka] Compound 1 (2.7 g, 23 mmol) and compound 2 (2.5 g, 19 mmol) were dissolved in N,N-dimethylformamide (DMF) (30 mL). Triethylenediamine (6.5 g, 58 mmol), bis(dibenzylideneacetone)palladium (890 mg, 0.97 mmol), and tri-tert-butylphosphine tetrafluoroborate (561 mg, 1.94 mmol) were added sequentially and the mixture was stirred in a sealed tube at 120 °C for 16 h. Thin-layer chromatography revealed a new compound. The product was extracted with water and ethyl acetate (60 mL), and the organic phase was concentrated under reduced pressure to give the residue. Finally, the residue was purified by column chromatography (methanol:dichloromethane = 5%) to give compound 3 (800 mg, 17.9% yield).

[0471] Step 2): [ka] Compound 3 (92 mg, 0.5 mmol) and compound 4 (244 g, 1 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 16 hours. Upon detecting a new compound by thin layer chromatography, the reaction solution was immediately filtered and the filter cake was washed with acetonitrile to obtain compound AB24878 (weight 116.2 mg, yield 53.02%).

[0472] Compound AB24878 1 H NMR(400MHz,DMSO-d6)δ 9.28(s,1H),8.77(d,J=11.6Hz,2H),8.59(d,J=8.2Hz,1H),8.48(s,2H),8.37(d,J=6.3Hz,1H),7.9 6(t,J=7.8Hz,1H),7.80(d,J=7.2Hz,2H),7.52(t,J=7.2Hz,2H),7.38(d,J=7.1Hz,1H),6.53(s,2H). ESI-MS: Theoretical value [M-Br] + 358.37, Observed: 358.30.

[0473] Example 8 Preparation of compound AB24872 Step 1): [ka] Compound 1 (500 mg, 3.6 mmol) was dissolved in dichloromethane (20 mL), and then Dess-Martin oxidant (2.02 g, 4.7 mmol) was added in an ice bath. The mixture was then stirred at room temperature for 2 h. Thin-layer chromatography revealed a new compound. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the resulting mixture was purified by column chromatography (ethyl acetate:petroleum ether = 0-10%) to give compound 2 (340 mg, 69.1% yield).

[0474] Step 2): [ka] Compound 2 (340 mg, 2.67 mmol), compound 3 (286 mg, 2.22 mmol), bis(dibenzylideneacetone)palladium (102 mg, 0.11 mmol), tri-tert-butylphosphine tetrafluoroborate (64 mg, 0.22 mmol), and triethylenediamine (750 mg, 6.68 mmol) were dissolved in N,N-dimethylformamide (DMF) (50 mL), and the mixture was purged with nitrogen three times. After stirring at 120 °C for 16 hours, a new compound was detected by thin-layer chromatography. The mixture was cooled to room temperature, and water and ethyl acetate (100 mL x 3) were added to extract the product. After the organic phases were combined, the product was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate: petroleum ether=66.6%) to give compound 4 (weight 200 mg, yield 37.9%).

[0475] Step 3): [ka] Compound 4 (200 mg, 0.96 mmol) and compound 5 (245 mg, 1.15 mmol) were dissolved in acetonitrile (10 mL), then flushed with nitrogen three times and stirred at room temperature for 5 hours. When a new compound was detected by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24872 (weight 92.6 mg, yield 28.3%).

[0476] Compound AB24872: 1 H NMR(400MHz,CD3OD)δ 10.11(s,1H),9.54(s,1H),9.20(dd,J=39.1,6.4Hz,2H),8.78(d,J=7.5Hz,2H),8.46-8.36(m, 2H), 8.22(dd,J=29.1,7.7Hz,3H),7.98(d,J=6.7Hz,1H),7.24(s,2H),3.22(d,J=11.7Hz,6H). ESI-MS: Theoretical value [M-Br]+ 341.43, Observed value: 341.25.

[0477] Example 9 Preparation of compound AB24854 Step 1): [ka] Compound 1 (8 g, 47.1 mmol) was dissolved in tetrahydrofuran (80 mL) and then 2.5 N lithium aluminum hydride in tetrahydrofuran (56 mL, 141.2 mmol) was added dropwise in an ice bath. The mixture was stirred at room temperature for 30 minutes, then heated to 75 °C and refluxed overnight. When a new compound was detected by thin-layer chromatography, the mixture was cooled to room temperature and water (56 mL) was added dropwise in an ice bath. Then, 15% aqueous sodium hydroxide (56 mL) and water (158 mL) were added sequentially. The aluminum salt was filtered off with diatomaceous earth. The product was extracted with ethyl acetate (100 mL x 3). After the organic phases were combined, the product was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding compound 2 (5.6 g, 75.76% yield).

[0478] Step 2): [ka] Compound 2 (3 g, 17.64 mmol) was dissolved in dichloromethane (50 mL), followed by the addition of Dess-Martin oxidant (8.97 g, 21.18 mmol) in an ice bath, followed by stirring at room temperature for 1 hour. A new compound was detected by thin-layer chromatography. Dichloromethane (50 mL) was added, and the aluminum salt was filtered off with diatomaceous earth. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the product was purified by column chromatography (ethyl acetate:petroleum ether = 0-10%) to give compound 3 (2.4 g, 80.9% yield).

[0479] Step 3): [ka] Compound 3-1 (1.67 g, 12.99 mmol) and compound 3 (2.4 g, 14.29 mmol) were dissolved in N,N-dimethylformamide (DMF) (30 mL). Bis(dibenzylideneacetone)palladium (595 mg, 0.65 mmol), tri-tert-butylphosphine tetrafluoroborate (377 mg, 1.31 mmol), and triethylenediamine (4.37 g, 38.97 mmol) were added and the mixture was stirred at 120 °C for 16 h. Thin-layer chromatography revealed a new compound. The product was extracted with water and ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to give the residue. Finally, the residue was purified by column chromatography (methanol:dichloromethane = 10%) to give compound 4 (1.2 g, 50% yield, crude product).

[0480] Step 4): [ka] Dissolve compound 4 (500 mg, 2.06 mmol) in acetonitrile (5 mL), then add compound 5 (660 mg, 3.09 mmol), then flush with nitrogen three times and stir overnight at room temperature. When a new compound is detected by thin-layer chromatography, the reaction mixture is centrifuged and the crude product is prepared to give compound AB24854 (20 mg, 2.59% yield).

[0481] Compound AB24854: 1 H NMR(400MHz,CD3OD)δ 9.02(s,1H),8.09(s,2H),7.97(dd,J=13.7,7.1Hz,3H),7.42(d,J=8.0Hz,2H),7.32-7.19(m,4H),6.27(s,2H),4.25(s,2H),2.45(s,3H). ESI-MS: Theoretical value [M-CF3COO] + 375.12, Observed: 375.20.

[0482] Example 10 Preparation of compound AB24945 Step 1): [ka] Compound 1 (200 mg, 1.69 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (20 mL), NaH (203 mg, 5.07 mmol) was added, and the mixture was stirred in an ice bath for 30 minutes. Compound 2 (289 mg, 1.86 mmol) was then added and the mixture was stirred at room temperature for 3 hours. After detecting a new compound by thin-layer chromatography, water (10 mL) and ethyl acetate (10 mL) were added to extract the product. Extraction with ethyl acetate was repeated three times, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 0-10%) to give compound 3 (260 mg, 73.8% yield).

[0483] Step 2): [ka] Compound 3 (130 mg, 0.625 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 4 (200 mg, 0.94 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Thin layer chromatography revealed a new compound, and the precipitated solid was filtered to give compound AB24945 (weight 70 mg, 32.8% yield).

[0484] Compound AB24945: 1 H NMR(400MHz,CDCl3)δ 10.96(s,1H),8.05(d,J=7.4Hz,2H),7.87(s,2H),7.78(s,1H),7.42(s,2 H),7.36-7.28(m,5H),6.81(d,J=11.9Hz,3H),5.70(s,2H),2.41(s,3H). ESI-MS: Theoretical value [M-Br] + 341.43, Observed: 341.10.

[0485] Example 11 Preparation of compound AB24837 Step 1): [ka] Compound 1 (440 mg, 2 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (20 mL). Compound 2 (428.4 mg, 4.2 mmol), bistriphenylphosphine palladium dichloride (42 mg, 0.06 mmol), N,N-diisopropylethylamine (825 mg, 6.4 mmol), and cuprous iodide (19 mg, 0.1 mmol) were then added. The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. After detecting a new compound by thin-layer chromatography, the product was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 0-50%) to give compound 3 (130 mg, 33% yield).

[0486] Step 2): [ka] Compound 3 (130 mg, 0.47 mmol) was dissolved in dioxane (6 mL), followed by the addition of potassium t-butoxide (336.6 mg, 3 mmol). The mixture was then flushed with nitrogen three times, and the temperature was raised to 110 °C and stirred for 16 h. After detecting a new compound by thin-layer chromatography, the product was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound 4 (50 mg, 50% yield).

[0487] Step 3): [ka] Compound 4 (340 mg, 1.75 mmol) was dissolved in acetic acid (5 mL), followed by the addition of palladium-carbon (100 mg, 3 mmol). The mixture was then purged with hydrogen three times and stirred at room temperature for 12 hours. A new compound was detected by thin-layer chromatography, which was then filtered and centrifuged to give compound 5 (weight 50 mg, yield 50%).

[0488] Step 4): [ka] Compound 6 (50 mg, 0.26 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 7 (182 mg, 0.78 mmol). The mixture was then flushed with nitrogen three times, and the temperature was raised to 80 °C and stirred overnight. When a new compound was detected by thin-layer chromatography, the product was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). After the organic phases were combined, the product was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified to obtain compound AB24837 (weight: 30 mg, yield: 33.71%).

[0489] Compound AB24837 1 H NMR(400MHz,DMSO-d6)δ 9.40(s,1H),8.05(d,J=6.6Hz,1H),8.00(d,J=8.0Hz,2H),7.93(s,1H),7.69(d,J=7.9Hz,2H),7.38(d,J=6.5Hz,2H ),7.32(d,J=6.5Hz,3H),6.82(d,J=6.5Hz,1H),5.87(s,2H),5.36(d,J=8.9Hz,1H),3.74-3.65(m,1H),2.99(s,1H). ESI-MS: Theoretical value [M-CF3COO] + 349.84, Observed: 349.00.

[0490] Example 12 Preparation of compound AB24827A Step 1): [ka] Compound 1 (440 mg, 2 mmol) was dissolved in N,N-dimethylformamide (DMF) (20 mL). Compound 2 (486 mg, 4.2 mmol), cuprous iodide (19 mg, 0.1 mmol), N,N-diisopropylethylamine (824 mg, 6.4 mmol), and bistriphenylphosphine palladium dichloride (42 mg, 0.06 mmol) were added sequentially. The mixture was then purged with nitrogen three times and stirred at room temperature for 16 h. Upon detecting a new compound by thin-layer chromatography, the product was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin layer chromatography (methanol:dichloromethane=10:1) to give compound 3 (weight 332 mg, yield 79.8%).

[0491] Step 2): [ka] Compound 3 (332 mg, 1.6 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the addition of potassium t-butoxide (538 mg, 4.8 mmol). The mixture was then flushed with nitrogen three times, and the temperature was raised to 100 °C and stirred overnight. Upon detecting a new compound by thin-layer chromatography, the solution was immediately concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 10:1) to give compound 4 (weight 189 mg, yield 56.7%).

[0492] Step 3): [ka] Compound 4 (189 mg, 0.9 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 5 (233 mg, 1.1 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 80 °C and stirred overnight. Upon detecting a new compound by thin-layer chromatography, the solution was immediately concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 10:1) to obtain compound AB24827A (9.3% yield).

[0493] Compound AB24827A: 1 H NMR(400MHz,DMSO-d6)δ 13.00(s,1H),9.08(s,1H),8.33(d,J=6.5Hz,1H),8.05(d,J=8.5Hz,2H),7.93(d,J=6.8Hz, 1H),7.72(d,J=8.3Hz,2H),7.28(d,J=28.2Hz,5H),6.80(s,1H),6.32(s,2H),4.23(s,2H). ESI-MS: Theoretical value [M-CF3COO] + 361.84, Observed: 361.25.

[0494] Example 13 Preparation of compound AB24887 Step 1): [ka] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (DMF) (20 mL), NaH (203 mg, 5.07 mmol) was added in an ice bath, and the mixture was stirred at 0 °C for 30 min. Compound 2 (318 mg, 1.86 mmol) was then added and the mixture was stirred at room temperature for 3 h. After detecting a new compound by thin-layer chromatography, water (30 mL) and ethyl acetate (30 mL x 3) were added to extract the product, and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to obtain compound 3 (280 mg, 79.5% yield).

[0495] Step 2): [ka] Compound 3 (280 mg, 1.3 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of compound 4 (430 mg, 2.0 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. When a new compound was detected by thin-layer chromatography, the reaction mixture was centrifuged. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24887 (weight 220 mg, yield 47.9%).

[0496] Compound AB24887 1 H NMR(400MHz,DMSO,d6)δ 9.28(s,1H),8.47(s,1H),8.32(s,1H),8.15(s,1H),7.95(d,J=7.6Hz,2H),7.44( d,J=7.7Hz,2H),7.34(s,5H),7.17(s,1H),6.37(s,2H),5.66(s,2H),2.41(s,3H). ESI-MS: Theoretical value [M-Br] + 341.43, Observed: 341.25.

[0497] Example 14 Preparation of compound AB24888 Step 1): [ka] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (DMF) (20 mL), NaH (203 mg, 5.07 mmol) was added in an ice bath, and the mixture was stirred at 0 °C for 30 min. Compound 2 (318 mg, 1.86 mmol) was then added and the mixture was stirred at room temperature for 3 h. After detecting a new compound by thin-layer chromatography, water (30 mL) and ethyl acetate (30 mL x 3) were added to extract the product, and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to obtain compound 3 (280 mg, 79.5% yield).

[0498] Step 2): [ka] Compound 3 (250 mg, 1.2 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of compound 4 (440 mg, 1.8 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Thin-layer chromatography revealed a new compound, which was then filtered off. The filter cake was washed three times with acetonitrile (3 mL) and centrifuged to obtain compound AB24888 (300 mg, 67.1% yield).

[0499] Compound AB24888 1 H NMR(400MHz,DMSO,d6)δ 9.26(s,1H),8.73(s,1H),8.58(d,J=8.1Hz,1H),8.46(t,J=7.4Hz,2H),8.35(d,J=6.8Hz,1 H),8.16(s,1H),7.94(t,J=7.9Hz,1H),7.33(s,5H),7.19(s,1H),6.47(s,2H),5.66(s,2H). ESI-MS: Theoretical value [M-Br] + 372.40, Observed: 372.25.

[0500] Example 15 Preparation of compound AB24895 Step 1): [ka] Compound 1 (500 mg, 4.23 mmol), iodobenzene (963 mg, 4.23 mmol), cuprous iodide (16.2 mg, 0.085 mmol), potassium phosphate tripotassium (1.79 g, 8.46 mmol), and cyclohexanediamine (99 mg, 0.87 mmol) were dissolved in N,N-dimethylformamide (DMF) (20 mL). The atmosphere was then flushed with nitrogen three times, and the temperature was raised to 110 °C and the mixture was stirred for 16 h. Thin-layer chromatography revealed a new compound, and the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound 3 (weight: 580 mg).

[0501] Step 2): [ka] Compound 3 (290 mg, 1.49 mmol) and compound 4 (477 mg, 2.24 mmol) were dissolved in acetonitrile (10 mL), then flushed with nitrogen three times and stirred at room temperature for 3 hours. When a new compound was detected by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24895 (weight 377 mg, yield 77.3%).

[0502] Compound AB24895: 1H NMR(400MHz,DMSO-d6)δ 9.45(s,1H),8.56(d,J=5.9Hz,1H),8.31(s,1H),8.14(d,J=6.5Hz,1H),7.96(d,J=7.3Hz,2H),7.70(dd, J=22.8,7.0Hz,4H),7.57(d,J=6.7Hz,1H),7.43(d,J=7.3Hz,2H),7.36(s,1H),6.50(s,2H),2.40(s,3H). ESI-MS: Theoretical value [M-Br] + 327.41, Observed: 327.20.

[0503] Example 16 Preparation of compound AB24833A Step 1): [ka] Compound 1 (2.0 g, 15.5 mmol), compound 2 (5.6 g, 46.6 mmol), bis(dibenzylideneacetone)palladium (771.0 mg, 0.5 mmol), tri-tert-butylphosphine tetrafluoroborate (451.0 mg, 1 mmol), and triethylenediamine (5.24 g, 30 mmol) were dissolved in N,N-dimethylformamide (DMF) (50 mL), and the mixture was purged with nitrogen three times. After stirring at 120 °C for 16 hours, a new compound was detected by thin-layer chromatography. The mixture was cooled to room temperature, and water and ethyl acetate (100 mL x 3) were added to extract the product. After the organic phases were combined, the product was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether=66.6%) to give compound 3 (weight 70 mg, yield 2.16%).

[0504] Step 2): [ka] Compound 3 (70 mg, 0.336 mmol) and compound 4 (157 mg, 0.673 mmol) were dissolved in acetonitrile (10 mL) ando The mixture was stirred at room temperature for 3 hours. When a new compound was detected by thin layer chromatography, the reaction solution was cooled to room temperature, and the reaction mixture was immediately filtered and the filter cake was washed with ethyl acetate to obtain compound AB24833A (weight 40 mg, yield 32.8%).

[0505] Compound AB24833A 1 H NMR(399MHz,DMSO-d6)δ 12.76(s,1H),9.26(s,1H),8.36(d,J=7.0Hz,1H),8.06(s,2H),8.02(d,J=7.2Hz,1H),7 .82(s,1H),7.75(s,2H),7.29(d,J=7.8Hz,4H),7.18(s,1H),6.33(s,2H),4.14(s,2H). ESI-MS: Theoretical value [M-CF3COO] + 361.85, Observed: 361.25.

[0506] Example 17 Preparation of compound AB24916 Step 1): [ka] Compound 1 (480 mg, 3.0 mmol) was dissolved in acetic acid (7 mL). Liquid bromine (480 mg, 3.0 mmol) was added to the mixture, and two drops of aqueous hydrobromic acid were added. The mixture was then stirred at room temperature for 3 hours. After detecting a new compound by thin-layer chromatography, ice water (30 mL) was added, followed by ethyl acetate (30 mL x 3) to extract the product. After the organic phases were combined, the product was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding compound 2 (400 mg, 55.8% yield).

[0507] Step 2): [ka] Compound 2 (150 mg, 0.63 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 3 (150 mg, 0.82 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Thin-layer chromatography revealed a new compound, which was then filtered off. The filter cake was washed three times with acetonitrile (2 mL) and centrifuged to obtain compound AB24916 (50 mg, 23.1% yield).

[0508] Compound AB24916: 1 H NMR (400MHz, DMSO-d6) δ 9.55(s,1H),8.26(d,J=7.0Hz,1H),8.15(d,J=7.1Hz,1H),7.69(s,1H),7.47(d, J=7.6Hz,1H),7.35(dd,J=20.0,5.6Hz,6H),7.07(d,J=7.0Hz,1H),6.98(d,J=6. 7Hz,1H),5.69(d,J=10.6Hz,1H),4.57(d,J=5.5Hz,2H),3.21(d,J=12.6Hz,1H), 3.11(d,J=16.3Hz,1H),2.75(d,J=10.4Hz,1H),2.46-2.41(m,1H),2.32(s,3H). ESI-MS: Theoretical value [M-Br] + 343.44, Observed: 343.10.

[0509] Example 18 Preparation of compound AB24913 Step 1): [ka] Compound 1 (500 mg, 2.77 mmol) was dissolved in acetic acid (7 mL). Liquid bromine (443 mg, 2.77 mmol) was added to the mixture, and two drops of aqueous hydrobromic acid were added. The mixture was then stirred at room temperature for 3 hours. After detecting a new compound by thin-layer chromatography, ice water (30 mL) was added, followed by ethyl acetate (30 mL x 3) to extract the product. After the organic phases were combined, the product was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding compound 2 (200 mg, 27.8% yield).

[0510] Step 2): [ka] Compound 3 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), followed by the addition of compound 4 (5 g, 53.13 mmol). The mixture was then flushed with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 h. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to 0 °C, sodium borohydride (4.01 g, 106.2 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. When a new compound was detected by thin-layer chromatography, the product was diluted with water (200 mL), and the product was extracted with ethyl acetate (200 mL x 3). After the organic phases were combined, the product was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 5 (2.6 g, 26.8% yield).

[0511] Step 3): [ka] Compound 2 (200 mg, 0.77 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 5 (212 mg, 1.12 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Thin-layer chromatography revealed a new compound, which was then filtered off. The filter cake was washed three times with acetonitrile (2 mL) and centrifuged to obtain compound AB24913 (50 mg, 17.5% yield).

[0512] Compound AB24913: 1 H NMR(400MHz,DMSO,d6)δ 9.34(s,1H),8.22(s,1H),8.12(d,J=6.5Hz,1H),7.82(s,1H),7.72(d,J=8.0Hz,1H),7.50(d,J=7.9Hz,1H),7.34(d,J=25.3 Hz,5H),7.01(d,J=6.4Hz,2H),5.68(d,J=14.0Hz,1H),4.57(d,J=5.3Hz,2H),3.19(t,J=17.3Hz,3H),2.77(d,J=9.0Hz,1H). ESI-MS: Theoretical value [M-Br-]+363.86, Observed value: 363.30.

[0513] Example 19 Preparation of compound AB24841A Step 1): [ka] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), followed by the addition of compound 2 (5 g, 53.13 mmol). The mixture was then flushed with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 h. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to 0 °C, sodium borohydride (4.01 g, 106.2 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. When a new compound was detected by thin-layer chromatography, the product was diluted with water (200 mL), and ethyl acetate (200 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g, 26.8% yield).

[0514] Step 2): [ka] Dissolve compound 4 (500 mg, 2.7 mmol) in acetic acid (50 mL). Add liquid bromine (442 mg, 2.7 mmol) and two drops of aqueous hydrobromic acid. Stir for 3 hours at room temperature. After detecting a new compound by thin-layer chromatography, add ice water (30 mL) and ethyl acetate (30 mL x 3). Extract the product. After combining the organic phases, wash the product with saturated brine (30 mL), dry over anhydrous sodium sulfate, and concentrate the solution under reduced pressure to remove the organic solvent, yielding compound 5 (700 mg, 97.3% yield).

[0515] Step 3): [ka] Compound 5 (400 mg, 1.5 mmol) and compound 3 (200 mg, 1.1 mmol) were dissolved in acetonitrile (10 mL), then flushed with nitrogen three times and stirred at room temperature for 5 hours. When a new compound was detected by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24841A (weight 37 mg, yield 9.3%).

[0516] Compound AB24841A: 1 H NMR(400MHz,CDCl3)δ 9.96(s,1H),7.90-7.52(m,3H),7.25(s,8H),6.50(s,1H),5.50(s,1H),4.43(s,2H),3.34(s,1H),3.05(s,1H),2.50(d,J=38.1Hz,2H). ESI-MS: Theoretical value [M-CF3COO] + 363.86, Observed: 363.25.

[0517] Example 20 Preparation of compound AB24920 Step 1): [ka] Compound 1 (500 mg, 2.6 mmol) was dissolved in tetrahydrofuran (10 mL), and then liquid bromine (418 mg, 2.6 mmol) was added at 0 °C and stirred for 2 h at 0 °C. When a new compound was detected by thin-layer chromatography, the product was diluted with 2 M aqueous sodium bicarbonate (40 mL) and ethyl acetate (40 mL), and the organic phase was centrifuged to obtain compound 2 (weight: 400 mg, Crude).

[0518] Step 2): [ka] Compound 2 (200 mg, 0.70 mmol) and compound 3 (130 mg, 0.70 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 4 hours. After detecting a new compound by thin-layer chromatography, the reaction mixture was centrifuged and purified by column chromatography (DCM:MeOH = 10:1) to give compound AB24920 (weight 41 mg, yield 14.8%).

[0519] Compound AB24920: 1 H NMR(400MHz,DMSO,d6)δ=9.44(s,1H),8.54(s,1H),8.46(d,J=8.1,1H),8.26(d,J=6.5,1H),8.14(d,J=6.0,1H),7.76(d,J=8.3 ,1H),7.37(s,4H),7.31(s,1H),7.04(s,2H),5.79(d,J=12.9,1H),5.73(s,1H),4.58(d,J=4.9,2H),2.83(s,1H),2.51(s,1H). ESI-MS: Theoretical value [M-Br] + 374.41, Observed: 374.30.

[0520] Example 21 Preparation of compound AB24923 Step 1): [ka] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), followed by the addition of compound 2 (5 g, 53.13 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 h. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to 0 °C, sodium borohydride (4.01 g, 106.2 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. When a new compound was detected by thin-layer chromatography, the product was diluted with water (200 mL), and then ethyl acetate (200 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g, 26.8% yield).

[0521] Step 2): [ka] Dissolve compound 4 (300 mg, 2.03 mmol) in acetic acid (10 mL). Add liquid bromine (326 mg, 2.03 mmol) and two drops of aqueous hydrobromic acid. Stir for 3 hours at room temperature. After detecting a new compound by thin-layer chromatography, add ice water (30 mL) and ethyl acetate (30 mL x 3). Extract the product. After combining the organic phases, wash the product with saturated brine (30 mL), dry over anhydrous sodium sulfate, and concentrate the solution under reduced pressure to remove the organic solvent, yielding compound 5 (400 mg, 86.7% yield).

[0522] Step 3): [ka] Compound 5 (200 mg, 0.88 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 3 (109 mg, 0.59 mmol), followed by three nitrogen flushes. A new compound was detected by thin-layer chromatography, and compound AB24923 (25 mg, 8.6% yield) was obtained via centrifugal dewatering.

[0523] Compound AB24923: 1 H NMR(400MHz,CD3OD)δ 8.68(s,1H),8.14(d,J=6.6Hz,1H),8.06(t,J=6.7Hz,3H),7.71(s,1H),7.37(s,7H),7.31(d,J=3.5Hz,1H),6.97(dd,J= 26.9,6.0Hz,3H),4.93-4.91(m,2H),4.60(s,2H),3.44(d,J=13.3Hz,1H),2.85(t,J=9.2Hz,1H),2.64(d,J=10.5Hz,1H). ESI-MS: Theoretical value [M-CF3COO-] + 330.40, Observed: 330.30.

[0524] Example 22 Preparation of compound AB24840A Step 1): [ka] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), followed by the addition of compound 2 (5 g, 53.13 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 h. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to 0 °C, sodium borohydride (4.01 g, 106.2 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. When a new compound was detected by thin-layer chromatography, the product was diluted with water (200 mL), and then ethyl acetate (200 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g, 26.8% yield).

[0525] Step 2): [ka] Compound 4 (500 mg, 3.0 mmol) was dissolved in acetic acid (50 mL). Liquid bromine (480 mg, 3.0 mmol) was added to the mixture, and two drops of aqueous hydrobromic acid were added. The mixture was then stirred at room temperature for 3 hours. After detecting a new compound by thin-layer chromatography, ice water (30 mL) was added, followed by ethyl acetate (30 mL x 3) to extract the product. After the organic phases were combined, the product was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding compound 5 (600 mg, 38.46% yield).

[0526] Step 3): [ka] Compound 5 (300 mg, 1.2 mmol) and compound 3 (200 mg, 1.1 mmol) were dissolved in acetonitrile (10 mL), then flushed with nitrogen three times and stirred at room temperature for 5 hours. When a new compound was detected by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24840A (weight 27.6 mg, yield 7.2%).

[0527] Compound AB24840A: 1 H NMR(400MHz,DMSO,d6)δ 9.38(s,1H),8.31(d,J=7.1Hz,1H),8.16(d,J=7.0Hz,1H),7.84-7.75(m,2H),7.60(d,J=8.1Hz,1H),7.34(dd,J=23.4,6. 5Hz,5H),6.99(d,J=6.6Hz,2H),5.62(t,J=6.7Hz,1H),4.58(d,J=5.4Hz,2H),3.85(dd,J=17.3,8.2Hz,1H),3.45(s,1H). ESI-MS: Theoretical value [M-CF3COO] + 349.84, Observed: 349.20.

[0528] Example 23 Preparation of compound AB24904 Step 1): [ka] Compound 1 (146 mg, 1.0 mmol) was dissolved in acetic acid (5 mL). Liquid bromine (160 mg, 1.0 mmol) was added to the mixture, and two drops of aqueous hydrobromic acid were added. The mixture was then stirred at room temperature for 3 hours. After detecting a new compound by thin-layer chromatography, ice water (30 mL) was added, followed by ethyl acetate (30 mL x 3) to extract the product. After the organic phases were combined, the product was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding compound 2 (180 mg, 97.3% yield).

[0529] Step 2): [ka] Compound 2 (180 mg, 0.79 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 3 (161 mg, 0.87 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Thin-layer chromatography revealed a new compound, which was then filtered off. The filter cake was washed three times with acetonitrile (2 mL) and centrifuged to obtain compound AB24904 (40 mg, 15.4% yield).

[0530] Compound AB24904: 1 H NMR(400MHz, DMSO-d6)δ 9.76(s,1H),8.34(d,J=6.1Hz,1H),8.20(d,J=6.0Hz,1H),7.64(d,J=6.7Hz,1H),7.45(d,J=6.7Hz,1H),7.37(s,4H),7.30(d ,J=5.3Hz,2H),7.11(s,1H),6.97(s,1H),5.67(s,1H),4.57(s,2H),3.77(dd,J=16.2,8.1Hz,1H),2.53(s,3H),2.48(s,1H). ESI-MS: Theoretical value [M-Br] + 329.42, Observed: 329.50.

[0531] Example 24 Preparation of compound AB24905 Step 1): [ka] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), followed by the addition of compound 2 (5 g, 53.13 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 h. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to 0 °C, sodium borohydride (4.01 g, 106.2 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. When a new compound was detected by thin-layer chromatography, the product was diluted with water (200 mL), and then ethyl acetate (200 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g, 26.8% yield).

[0532] Step 2): [ka] Compound 4 (300 mg, 2.05 mmol) was dissolved in acetic acid (10 mL). Liquid bromine (328 mg, 2.05 mmol) was added to the mixture, followed by two drops of aqueous hydrobromic acid. The mixture was then stirred at room temperature for 3 hours. After detecting a new compound by thin-layer chromatography, ice water (30 mL) was added, followed by ethyl acetate (30 mL x 3). The product was extracted. After the organic phases were combined, the product was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 0-20%) to obtain compound 5 (300 mg, 65% yield).

[0533] Step 3): [ka] Compound 5 (200 mg, 0.89 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 3 (110 mg, 0.60 mmol). The mixture was then flushed with nitrogen three times and stirred at room temperature overnight. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to obtain compound AB24905 (weight: 110 mg, yield: 56%).

[0534] Compound AB24905: 1 H NMR(400MHz,DMSO-d6)δ 9.43(s,1H),8.30(d,J=6.9Hz,1H),8.15(d,J=6.8Hz,1H),7.63(d,J=7.6Hz,1H),7.55(d,J=8.9Hz,2H),7.36(s,4H),7.30(d,J =5.6Hz,1H),6.99(t,J=8.0Hz,2H),5.62(s,1H),4.57(d,J=5.5Hz,2H),3.78(dd,J=16.7,8.4Hz,1H),3.37(s,1H),2.38(s,3H). ESI-MS: Theoretical value [M-Br] + 329.41, Observed: 329.25.

[0535] Example 25 Preparation of compound AB24883 Step 1): [ka] Compound 1 (1.06 g, 10 mmol) was dissolved in ethanol (50 mL), followed by the addition of compound 2 (1.37 g, 10 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 h. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to 0 °C, sodium borohydride (1.13 g, 30 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. When a new compound was detected by thin-layer chromatography, the product was diluted with water (20 mL), and then ethyl acetate (20 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to obtain compound 3 (600 mg, 26.4% yield).

[0536] Step 2): [ka] Compound 3 (50 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (DMF) (5 mL). 2-(7-azinebenzotriazole)-N,N,N',N'-hexafluorophosphate tetramethylurea (125.55 mg, 0.33 mmol), N,N-diisopropylethylamine (85.2 mg, 0.66 mmol), and compound 4 (25.9 mg, 0.24 mmol) were added. The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Upon detecting a new compound by thin-layer chromatography, the product was extracted with water (10 mL) and ethyl acetate (10 mL), followed by three ethyl acetate extractions. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane=0-10%) to obtain compound AB24883 (weight 27.9 mg, yield 36.7%).

[0537] Compound AB24883 1H NMR(400MHz,DMSO,d6)δ 8.79(s,1H),8.70(d,J=8.2Hz,1H),7.94(d,J=8.4Hz,2H),7.77(s,1H),7.62( s,1H),7.36(s,4H),7.26(s,1H),6.78(d,J=8.1Hz,2H),4.43(d,J=5.0Hz,2H). ESI-MS: Theoretical value [M+1] + 348.30, Observed: 348.20.

[0538] Example 26 Preparation of compound AB24851 Step 1): [ka] Compound 1 (3.0 g, 18.3 mmol) was dissolved in methylbenzene (50 mL), followed by the addition of compound 2 (5.8 g, 54.8 mmol), cesium carbonate (12.0 g, 36.5 mmol), tri-(diphenylene-base acetone)dipalladium (334 mg, 0.36 mmol), and 2-dicyclohexylhexylphosphorus-2,4,6-triisopropylbiphenyl (262 mg, 0.54 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 110 °C and stirred for 16 h. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to room temperature, the product was diluted with water (50 mL), and the product was extracted with ethyl acetate (50 mL x 3). After the organic phases were combined, the product was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane=10:1) to give compound 3 (weight 150 mg, yield 4.4%).

[0539] Step 2): [ka] Compound 3 (150 mg, 0.78 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of compound 4 (151 mg, 0.71 mmol). The mixture was then flushed with nitrogen three times, the temperature was raised to 80 °C, and the mixture was stirred overnight. When a new compound was detected by thin-layer chromatography, the mixture was cooled to room temperature, and the reaction mixture was centrifuged to obtain compound AB24851 (10 mg, 3.9% yield).

[0540] Compound AB24851: 1 H NMR(400MHz,CD3OD)δ 7.93(d,J=7.8Hz,2H),7.34(dd,J=47.3,19.8Hz,9H),4.58(s,2H),4.37(s,2H),2.45(s,3H). ESI-MS: Theoretical value [M-CF3COO] + 323.43, Observed: 323.20.

[0541] Example 27 Preparation of compound AB24850 Step 1): [ka] Compound 1 (2 g, 5.91 mmol), compound 2 (2.51 g, 7.09 mmol), and sodium methoxide (958 mg, 17.73 mmol) were dissolved in absolute ethanol (30 mL) and stirred at room temperature for 16 h. After detecting a new compound by thin-layer chromatography, the mixture was cooled to room temperature and water (50 mL) and ethyl acetate (50 mL x 3) were added to extract the product. After the organic phases were combined, the product was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 0-30%) to obtain compound 3 (2.1 g, 86.24% yield).

[0542] Step 2): [ka] Compound 3 (1.2 g, 2.91 mmol) was dissolved in tetrahydrofuran (6 mL) and water (6 mL), and then concentrated hydrochloric acid (3 mL) was added. The mixture was then stirred at 100°C for 3 hours. When a new compound was detected by thin-layer chromatography, the mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added to adjust the pH, and ethyl acetate (50 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure to remove the organic solvent, yielding compound 4 (500 mg, 83.21% yield).

[0543] Step 3): [ka] Compound 4 (200 mg, 1.17 mmol) and compound 5 (249 mg, 1.17 mmol) were dissolved in acetonitrile (10 mL), triethylamine (356 mg, 3.51 mmol) was added, and the mixture was stirred at 80 °C for 16 hours. When a new compound was detected by thin-layer chromatography, the mixture was cooled to room temperature and centrifuged to obtain compound AB24850 (40 mg, 11.32% yield).

[0544] Compound AB24850: 1 H NMR(400MHz,CD3OD)δ 8.83(s,0H),7.93(d,J=7.4Hz,1H),7.43-7.27(m,2H),7.22(s,0H),6.99(s,0H),6.48(s,0H),5.84(s,1H),2.44(s,3H). ESI-MS: Theoretical value [M+1] + 303.14, Observed: 303.00.

[0545] Example 28 Preparation of compound AB24885 Step 1): [ka] Compound 1 (519 mg, 3 mmol) was dissolved in tetrahydrofuran (30 mL), and then compound 2 (481 mg, 4.5 mmol) and methanesulfonate (2-dicyclohexylhexylphosphorine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-group) palladium(II) (163 mg, 0.18 mmol) were added successively. The reaction temperature was lowered to 0°C, and then ditrimethylsilylamine lithium was injected. After the temperature reached 40°C, the mixture was purged with nitrogen three times. ℃ The mixture was heated to 500°C and stirred for 16 hours. Thin-layer chromatography revealed a new compound. The product was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to obtain compound 3 (80 mg, 13% yield).

[0546] Step 2): [ka] Compound 3 (160 mg, 0.8 mmol) was dissolved in n-tert-butanol (10 mL), followed by the successive addition of triethyl formate (296 mg, 2 mmol) and formate (37 mg, 0.8 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 110 °C and stirred for 18 h. Upon detecting a new compound by thin-layer chromatography, the solution was immediately concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography to give compound 4 (weight: 100 mg, yield: 63.8%).

[0547] Step 3): [ka] Compound 4 (100 mg, 0.5 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 5 (127 mg, 0.6 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Upon detecting a new compound by thin-layer chromatography, the solution was immediately concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography to give compound AB24885 (weight 20 mg, yield 9.4%).

[0548] Compound AB24885: 1 H NMR(400MHz,DMSO-d6)δ 9.39(s,1H),8.92(s,1H),8.54(d,J=6.4Hz,1H),8.17(d,J=6.9Hz,1H),7.99(d,J =7.7Hz,2H),7.42(d,J=10.2Hz,7H),5.72(s,2H),4.85-4.84(m,2H),2.46(s,3H). ESI-MS: Theoretical value [M-Br] + 342.41, Observed: 342.30.

[0549] Example 29 Preparation of compound AB24898 Step 1): [ka] Compound 2 (53.5 mL, 150 mmol, 3N) was dissolved in tetrahydrofuran, followed by the addition of compound 1 (6.25 g, 50 mmol) at 0 °C and stirring at 0 °C to room temperature for 16 hours. When a new compound was detected by thin-layer chromatography, saturated ammonium chloride was added at 0 °C and the mixture was quenched. The product was filtered through diatomaceous earth and extracted with ethyl acetate. The solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to give compound 3 (4.2 g, 41.37% yield).

[0550] Step 2): [ka] Compound 3 (4.06 g, 20 mmol) was dissolved in tetrahydrofuran, and then Dess-Martin oxidant (10.17 g, 24 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 2 hours. A new compound was detected by thin-layer chromatography, and the product was purified by column chromatography (ethyl acetate:petroleum ether = 1:3) to give compound 4 (4.0 g, 99.0% yield).

[0551] Step 3): [ka] Compound 4 (402 mg, 2 mmol) was dissolved in ethanol, and then hydrazine hydrate (200 mg, 4 mmol) was added, followed by stirring at 90° C. for 16 hours. A new compound was detected by thin-layer chromatography, and the product was immediately purified by column chromatography (ethyl acetate:petroleum ether=1:1) via centrifugal dewatering to give compound 5 (weight: 60 mg, yield: 15.30%).

[0552] Step 4): [ka] Compound 5 (100 mg, 0.51 mmol) and compound 6 (123.93 mg, 0.51 mmol) were dissolved in acetonitrile (5 mL) and then stirred at room temperature for 3 hours. When a new compound was detected by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-30%) to obtain compound AB24898 (weight 100 mg, yield 54.61%).

[0553] Compound AB24898: 1H NMR(400MHz,DMSO-d6)δ 9.77(s,1H),8.89(d,J=6.4Hz,1H),8.78(s,1H),8.65-8.47(m,3H),8.11 (d,J=7.4Hz,2H),7.97(t,J=7.9Hz,1H),7.65-7.50(m,3H),6.65(s,2H). ESI-MS: Theoretical value [M-Br - ] + 359.36, Observed: 359.25.

[0554] Example 30 Preparation of compound AB24839B Step 1): [ka] Compound 1 (2.1 g, 20 mmol) was dissolved in ammonia and ethanol (40:40 mL), then stirred at -78 to -10 °C for 3 h. Compound 2 (6.72 g, 40 mmol) was added and stirred at room temperature overnight. After detecting a new compound by thin-layer chromatography, concentrated hydrochloric acid was added to adjust the pH to 1, and the product was extracted with water and ethyl acetate (80 mL). The pH of the aqueous phase was adjusted to 14 with 50% sodium hydroxide, and the product was extracted with water and dichloromethane (2 x 80 mL). The organic phase was centrifuged to obtain compound 3 (1.6 g, 54.42% yield).

[0555] Step 2): [ka] Compound 3 (5 g, 28.57 mmol), compound 4 (21 g, 142.85 mmol), and triethylamine (28.85 g, 285.7 mmol) were dissolved in acetonitrile (60 mL) and then stirred at 80 °C for 16 h. After detecting a new compound by thin-layer chromatography, the product was extracted with water and ethyl acetate (200 mL x 2). The organic phase was centrifuged and purified by column chromatography (PE:EA = 5:1) to give compound 5 (weight 2.2 g, yield 25.41%).

[0556] Step 3): [ka] Compound 5 (2.2 g, 7.26 mmol), compound 6 (1.68 g, 10.89 mmol), sodium carbonate (2.1 g, 19.8 mmol), and [1,1'-di(diphenylphosphine)dicyclopentadienyliron]palladium dichloride (495.6 mg, 0.66 mmol) were dissolved in dioxane and water (21:7 mL) and stirred in a sealed tube at 95 °C for 16 h. Thin-layer chromatography revealed a new compound, which was then extracted with water and ethyl acetate (200 mL x 2). The organic phase was centrifuged and purified by column chromatography (PE:EA = 3:1) to give compound 7 (200 mg, 11.02% yield).

[0557] Step 4): [ka] Compound 7 (500 mg, 2 mmol), dimethylaminopyridine (48.8 mg, 0.4 mmol), triethylamine (404 mg, 4 mmol), and trifluoroacetic anhydride (2.1 g, 10 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 h. After detecting a new compound by thin-layer chromatography, the product was extracted with water and dichloromethane (50 mL x 2). The organic phase was centrifuged and purified by column chromatography (PE:EA = 3:1) to give compound 8 (200 mg, 28.82% yield).

[0558] Step 5): [ka] Compound 8 (300 mg, 0.86 mmol) and Grubbs Catalyst 2ND (100 mg) were dissolved in dichloromethane (10 mL) and stirred at 40 °C for 16 hours. Then, aqueous potassium hydroxide (1N, 5 mL) was added and the mixture was stirred for 1 hour. A new compound was detected by thin-layer chromatography, and the product was extracted with water and dichloromethane (50 mL x 2). The organic phase was centrifuged and purified by column chromatography (DCM:MeOH = 10:1) to give compound 9 (120 mg, 62.57% yield).

[0559] Step 6): [ka] Compound 9 (60 mg, 0.25 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of compound 10 (57 mg, 0.25 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. A new compound was detected by thin-layer chromatography. The reaction mixture was centrifuged and the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24839B (6 mg, yield 9.94%).

[0560] Compound AB24839B: 1 H NMR(400MHz,CD3OD)δ 8.16(s,1H),8.05(d,J=7.1Hz,2H),7.83(s,1H),7.62(d,J=7.3Hz,2H),7.37(d,J=13.9Hz,6H),7.09(d,J=6.1Hz ,1H),6.40(d,J=11.0Hz,1H),6.20(s,1H),4.80-4.74(m,2H),3.62(s,1H),3.03(s,1H),2.81(d,J=10.6Hz,1H). ESI-MS: Theoretical value [M-Br] + 375.87, Observed: 375.30.

[0561] Example 31 Preparation of compound AB24959 Step 1): [ka] Compound 1 (294 mg, 2 mmol) was dissolved in dimethyl sulfoxide (10 mL), followed by the addition of cesium carbonate (1.64 g, 5 mmol) and cuprous iodide (76.2 mg, 0.4 mmol). Five drops of N,N-methylethylenediamine were added, and the reaction mixture was stirred at room temperature for 10 min. Compound 2 (650 mg, 3 mmol) was added, and the reaction mixture was heated to 120 °C and stirred for 2 h. After detecting a new compound by thin-layer chromatography, the product was extracted with water and ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain the residue. Finally, the residue was purified by thin-layer chromatography (methanol:dichloromethane = 10%) to obtain compound 3 (200 mg, 47.62% yield).

[0562] Step 2): [ka] Compound 3 (200 mg, 0.89 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 4 (189.57 mg, 0.89 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Thin layer chromatography revealed a new compound. The precipitated solid was filtered and washed with acetonitrile (5 mL) to give compound AB24959 (70 mg, 22.03% yield).

[0563] Compound AB24959: 1 H NMR(400MHz, DMSO-d6)δ 8.83(d,J=5.4Hz,2H),8.27(d,J=5.5Hz,2H),8.04(d,J=7.2Hz,1H),7.95(d,J=7.2Hz,2H) ,7.63(s,1H),7.45(d,J=5.7Hz,4H),6.31(s,2H),4.24(s,2H),3.21(s,2H),2.42(s,3H). ESI-MS: Theoretical value [M-Br]+ 357.43, Observed value: 357.10.

[0564] Example 32 Preparation of compound AB24938 Step 1): [ka] Compound 1 (2 g, 23 mmol) and compound 2 (2.5 g, 19 mmol) were dissolved in N,N-dimethylformamide (DMF) (30 mL). Triethylenediamine (6.5 g, 58 mmol), bis(dibenzylideneacetone)palladium (890 mg, 0.97 mmol), and tri-tert-butylphosphine tetrafluoroborate (561 mg, 1.94 mmol) were added and the mixture was stirred in a sealed tube at 120 °C for 16 h. Thin-layer chromatography revealed a new compound. The product was extracted with water and ethyl acetate (10 mL), and the organic phase was concentrated under reduced pressure to give the residue. Finally, the residue was purified by column chromatography (methanol:dichloromethane = 5%) to give compound 3 (800 mg, 26.1% yield).

[0565] Step 2): [ka] Compound 3 (100 mg, 0.625 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of compound 4 (200 mg, 0.938 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. A new compound was detected by thin-layer chromatography. The reaction mixture was centrifuged and the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24938 (weight 78 mg, yield 39.8%).

[0566] Compound AB24938: 1 H NMR(400MHz,DMSO-d6)δ 9.14(s,1H),8.23(d,J=9.1Hz,3H),8.08(s,1H),8.00(d,J=7.0Hz,1H),7.84(d,J= 7.3Hz,1H),7.68(t,J=7.1Hz,1H),6.39(s,2H),3.14(s,1H),1.33(d,J=5.7Hz,6H). ESI-MS: Theoretical value [M-Br] + 313.80, Observed: 313.25.

[0567] Example 33 Preparation of compound AB24821 Step 1): [ka] Compound 1 (2.7 g, 20 mmol) was dissolved in N,N-dimethylformamide (DMF) (50 mL). Compound 1-1 (5.3 g, 40 mmol), 2-(7-azinebenzotriazole)-N,N,N',N'-hexafluorophosphate tetramethylurea (11.4 g, 30 mmol), and N,N-diisopropylethylamine (9 g, 70 mmol) were then added and stirred at room temperature for 1 h. After detecting the new compound by thin-layer chromatography, water (50 mL) and ethyl acetate (50 mL x 3) were added to extract the product. After the organic phases were combined, the product was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 0-30%) to obtain compound 2 (3.6 g, 91.1% yield).

[0568] Step 2): [ka] Compound 2 (200 mg, 1 mmol) was dissolved in dry tetrahydrofuran (5 mL) and then 1N methylmagnesium bromide in tetrahydrofuran (2 mL) was added at 0 °C. The mixture was stirred at 0 °C for 3 hours. When a new compound was detected by thin layer chromatography, saturated aqueous sodium bicarbonate (6 mL), water (20 mL), and ethyl acetate (20 mL x 3) were added to extract the product. After the organic phases were combined, the product was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding compound 3 (67 mg, 37.4% yield).

[0569] Step 3): [ka] Dissolve compound 3 (363 mg, 3 mmol) in acetic acid (5 mL). Add liquid bromine (383 mg, 3.8 mmol) and two drops of aqueous hydrobromic acid. Stir for 3 hours at room temperature. After detecting a new compound by thin-layer chromatography, add ice water (30 mL) and ethyl acetate (30 mL x 3). Extract the product. After combining the organic phases, wash the product with saturated brine (30 mL), dry over anhydrous sodium sulfate, and concentrate the solution under reduced pressure to remove the organic solvent, yielding compound 4 (100 mg, 97.3% yield).

[0570] Step 4): [ka] Compound 5 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), followed by the addition of compound 6 (5 g, 53.13 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 h. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to 0 °C, sodium borohydride (4.01 g, 106.2 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. When a new compound was detected by thin-layer chromatography, the product was diluted with water (200 mL), and then ethyl acetate (200 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 7 (2.6 g, 26.8% yield).

[0571] Step 5): [ka] Compound 4 (100 mg, 0.46 mmol) and compound 7 (86 mg, 0.46 mmol) were dissolved in acetonitrile (10 mL) and then stirred at room temperature for 5 hours. When a new compound was detected by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to obtain compound AB24821 (weight 15 mg, yield 10.1%).

[0572] Compound AB24821 1 H NMR(400MHz,DMSO-d6)δ 9.45(s,1H),9.03(s,1H),8.77(s,1H),8.16(d,J=7.0Hz,1H),8.05(d,J=7.1Hz,1H),7.36(s,4H),7.30 (s,1H),7.05(d,J=8.3Hz,1H),7.01(d,J=7.3Hz,1H),5.92(s,2H),4.56(d,J=5.4Hz,2H),2.63(s,3H). ESI-MS: Theoretical value [M-Br] + 319.38, Observed: 319.30.

[0573] Example 34 Preparation of compound AB24839 Step 1): [ka] Compound 1 (2.1 g, 20 mmol) was dissolved in ammonia and ethanol (40:40 mL). After stirring at -78 °C to -10 °C for 3 hours, compound 2 (6.72 g, 40 mmol) was added and stirred at room temperature overnight. After detecting a new compound by thin-layer chromatography, the pH was adjusted to 1 with concentrated hydrochloric acid, and the product was extracted with water and ethyl acetate (80 mL). The pH of the aqueous phase was adjusted to 14 with 50% sodium hydroxide, and the product was extracted with water and dichloromethane (2 x 80 mL). The organic phase was centrifuged to obtain compound 3 (1.6 g, 54.42% yield).

[0574] Step 2): [ka] Compound 3 (5 g, 28.57 mmol), compound 4 (21 g, 142.85 mmol), and triethylamine (28.85 g, 285.7 mmol) were dissolved in acetonitrile (60 mL) and then stirred at 80 °C for 16 h. After detecting a new compound by thin-layer chromatography, the product was extracted with water and ethyl acetate (200 mL x 2). The organic phase was centrifuged and purified by column chromatography (PE:EA = 5:1) to give compound 5 (weight 2.2 g, yield 25.41%).

[0575] Step 3): [ka] Compound 5 (2.2 g, 7.26 mmol), compound 6 (1.68 g, 10.89 mmol), sodium carbonate (2.1 g, 19.8 mmol), and [1,1'-di(diphenylphosphine)dicyclopentadienyliron]palladium dichloride (495.6 mg, 0.66 mmol) were dissolved in dioxane and water (21:7 mL) and stirred in a sealed tube at 95 °C for 16 h. Thin-layer chromatography revealed a new compound, which was then extracted with water and ethyl acetate (200 mL x 2). The organic phase was centrifuged and purified by column chromatography (PE:EA = 3:1) to give compound 7 (200 mg, 11.02% yield).

[0576] Step 4): [ka] Compound 7 (500 mg, 2 mmol), dimethylaminopyridine (48.8 mg, 0.4 mmol), triethylamine (404 mg, 4 mmol), and trifluoroacetic anhydride (2.1 g, 10 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 h. After detecting a new compound by thin-layer chromatography, the product was extracted with water and dichloromethane (50 mL x 2). The organic phase was centrifuged and purified by column chromatography (PE:EA = 3:1) to give compound 8 (200 mg, 28.82% yield).

[0577] Step 5): [ka] Compound 8 (300 mg, 0.86 mmol) and Grubbs Catalyst 2ND (100 mg) were dissolved in dichloromethane (10 mL) and stirred at 40 °C for 16 hours. Then, aqueous potassium hydroxide (1N, 5 mL) was added and the mixture was stirred for 1 hour. A new compound was detected by thin-layer chromatography, and the product was extracted with water and dichloromethane (50 mL x 2). The organic phase was centrifuged and purified by column chromatography (DCM:MeOH = 10:1) to give compound 9 (120 mg, 62.57% yield).

[0578] Step 6): [ka] Compound 9 (120 mg, 0.53 mmol) was dissolved in tetrahydrofuran (5 mL) and then palladium on carbon (12 mg) was added. The mixture was stirred under hydrogen for 4 hours. A new compound was detected by thin-layer chromatography. The product was filtered through diatomaceous earth, and the filtrate was centrifuged to give compound 10 (20 mg, 16.77% yield).

[0579] Step 7): [ka] Compound 10 (20 mg, 0.08 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of compound 11 (20.71 mg, 0.08 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. A new compound was detected by thin-layer chromatography. The reaction mixture was centrifuged and the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24839 (weight 3.1 mg, yield 9.94%).

[0580] Compound AB24839: 1 H NMR(400MHz,CD3OD)δ 8.05(d,J=7.7Hz,2H),7.92-7.82(m,2H),7.62(d,J=7.7Hz,2H),7.40(dd,J=30.0,8.5Hz,6H),6.92 (d,J=6.7Hz,1H),5.80(s,2H),5.21(d,J=10.2Hz,1H),2.69-2.45(m,2H),2.13(s,2H),1.99(s,2H). ESI-MS: Theoretical value [M-Br]+ 377.89, Observed value: 377.25.

[0581] Example 35 Preparation of compound AB27130 Step 1): [ka] Compound 1 (200 mg, 1.01 mmol) and triphenylphosphine (400 mg, 3.54 mmol) were dissolved in tetrahydrofuran (10 mL), and the mixture was purged with nitrogen three times. The temperature was raised to 80 °C and the mixture was stirred for 16 h. When a new compound was detected by thin-layer chromatography, the mixture was cooled to room temperature, filtered, and washed three times with tetrahydrofuran to give crude compound 2 (weight 350 mg, yield 91.1%).

[0582] Step 2): [ka] Compound 2 (200 mg, 0.52 mmol) and compound 3 (108 mg, 0.46 mmol) were dissolved in tetrahydrofuran (10 mL), triethylamine (2 mL) was added, and the mixture was then purged with nitrogen three times. The temperature was then raised to 70 °C and the mixture was stirred for 16 h. When a new compound was detected by thin-layer chromatography, the mixture was cooled to room temperature and the solution was concentrated under reduced pressure. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound 4 (weight 150 mg, yield 89%).

[0583] Step 3): [ka] Dissolve compound 4 (200 mg, 0.61 mmol) in saturated ethyl acetate solution (5 mL) of hydrochloride and stir at room temperature for 3 h. When a new compound was detected by thin layer chromatography, concentrate the solution under reduced pressure to give crude compound 5 (weight: 210 mg).

[0584] Step 4): [ka] Compound 5 (200 mg, 0.97 mmol) was dissolved in ethanol (5 mL), followed by the addition of palladium on carbon (20 mg). The mixture was then purged with hydrogen three times and stirred overnight at room temperature. A new compound was detected by thin-layer chromatography, followed by filtration and concentration of the solution under reduced pressure. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound 6 (weight 60 mg, yield 29.5%).

[0585] Step 5): [ka] Compound 7 (200 mg, 1.11 mmol) was dissolved in dichloromethane (10 mL) and then CH 18Add N2O2HBr3 (456 mg, 1.11 mmol) and stir at room temperature for 1 hour. A new compound is detected by thin layer chromatography. The reaction mixture is centrifuged and purified by thin layer chromatography to obtain compound 8 (weight 250 mg, yield 87.29%).

[0586] Step 6): [ka] Compound 6 (100 mg, 0.48 mmol) and compound 8 (148 mg, 0.57 mmol) were dissolved in acetonitrile (10 mL), and potassium carbonate (66 mg, 0.48 mmol) was added and stirred at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to obtain compound AB27130 (weight: 55 mg, yield: 29.4%).

[0587] Compound AB27130: 1 H NMR(400MHz,DMSO-d6)δ 9.37(s,1H),8.18(s,1H),8.09(s,1H),7.79(d,J=45.7Hz,2H),7.53(s,1H),7.38(d,J=20.0Hz,5H),6.93(s ,1H),5.71(d,J=9.8Hz,1H),4.77(s,1H),3.22(s,2H),2.79(s,2H),2.52(s,2H),2.10(s,1H),1.89(s,1H). ESI-MS: Theoretical value [M-Br] + 389.90, Observed: 389.10.

[0588] Example 36 Preparation of compound AB27141 Step 1): [ka] Compound 1 (240 mg, 2 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (10 mL), followed by the addition of compound 2 (555 mg, 1.5 mmol) and triethylamine (606.0 mg, 6.0 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. After detecting a new compound by thin-layer chromatography, the product was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (ethyl acetate:petroleum ether = 0-50%) to give compound 3 (260 mg, 58.47% yield).

[0589] Step 2): [ka] Compound 3 (111 mg, 0.50 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 4 (130 mg, 0.5 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Upon detecting a new compound by thin-layer chromatography, the solution was filtered and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (ethanol:dichloromethane = 0-10%) to give compound AB27141 (weight 40 mg, yield 19.95%).

[0590] Compound AB27141 1H NMR(400MHz,DMSO-d6)δ 9.67(s,1H),8.75(d,J=6.4Hz,1H),8.22(d,J=6.5Hz,1H),8.05(s,1H),7.80(s,1H),7.73(d,J=7.8Hz,1H),7.57-7.50(m,3H),7.40(dd,J=12 .0,7.2Hz,4H),7.14(s,1H),6.25-6.15(m,2H),3.43(d,J=43.7Hz,2H),3.20(d,J=16.7Hz,1H),2.95(d,J=10.2Hz,1H),2.06(d,J=6.2Hz,3H). ESI-MS: Theoretical value [M-Br] + 401.91, Observed: 401.10.

[0591] Example 37 Preparation of compound AB24957 Step 1): [ka] Compound 1 (300 mg, 3.15 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 2 (671 mg, 2.35 mmol). The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new compound was detected by thin-layer chromatography. The reaction mixture was centrifuged and purified by thin-layer chromatography to obtain compound 3 (600 mg, 83.54% yield).

[0592] Step 2): [ka] Compound 3 (200 mg, 0.87 mmol) was dissolved in phosphorus oxychloride (10 mL), and the mixture was then purged with nitrogen three times and stirred at 90° C. for 2 hours. A new compound was detected by thin-layer chromatography, and the reaction mixture was centrifuged to give compound 4 (weight 215 mg, crude product), which was then directly used in the next step.

[0593] Step 3): [ka] Compound 4 (215 mg, 0.88 mmol) was dissolved in N,N-dimethylformamide (DMF) (10 mL), followed by the successive addition of compound 5 (117 mg, 0.88 mmol) and triethylamine (267 mg, 2.64 mmol), followed by three nitrogen purges and overnight stirring at 80° C. A new compound was detected by thin layer chromatography, yielding compound AB24957 (weight 80 mg, yield 26.50%).

[0594] Compound AB24957: 1 H NMR(400MHz,DMSO,d6)δ 8.30(s,2H),7.95(d,J=8.2Hz,2H),7.45(d,J=8.1Hz,1H),7.38(s,1H),7.32-7.27(m,2 H),6.00(s,2H),4.85(s,2H),3.86(t,J=6.0Hz,2H),3.04(t,J=5.9Hz,2H),2.44(s,2H). ESI-MS: Theoretical value [M-Br]+ 343.18, Observed value: 343.30.

[0595] Example 38 Preparation of compound AB24989 Step 1): [ka] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (DMF) (20 mL), NaH (203 mg, 5.07 mmol) was added, and the mixture was stirred in an ice bath for 30 minutes. Compound 2 (289 mg, 1.86 mmol) was then added and the mixture was stirred at room temperature for 3 hours. After detecting a new compound by thin-layer chromatography, water (10 mL) and ethyl acetate (10 mL) were added to extract the product. Extraction with ethyl acetate was repeated three times, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 0-10%) to give compound 3 (260 mg, 73.8% yield).

[0596] Step 2): [ka] Compound 3 (300 mg, 1.44 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 4 (577 mg, 2.16 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Thin layer chromatography revealed a new compound, and the precipitated solid was filtered to give compound AB24989 (weight 30 mg, yield 5.3%).

[0597] Compound AB24989: 1 H NMR(400MHz,DMSO,d6)δ 9.25(s,1H),8.45(s,1H),8.33(s,3H),8.16(s,2H),7.90(s,1H),7.34(s,5H),7.20(s,1H),6.44(s,2H),5.67(s,2H). ESI-MS: Theoretical value [M-Br] + 395.40, Observed: 395.30.

[0598] Example 39 Preparation of compound AB24906 Step 1): [ka] Compound 1 (438 mg, 3 mmol) was dissolved in acetic acid (5 mL), and one drop of hydrobromic acid was added. Then, liquid bromine (384 mg, 2.4 mmol) was added to acetic acid (2 mL), and the mixture was injected. The mixture was then purged with nitrogen three times and stirred at room temperature for 3 hours. A new compound was detected by thin-layer chromatography. The solution was filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain compound 2 (400 mg, 59.51% yield).

[0599] Step 2): [ka] Compound 2 (200 mg, 0.9 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 3 (171 mg, 0.9 mmol). The mixture was then flushed with nitrogen three times and stirred at room temperature for 3 hours. Upon detecting a new compound by thin-layer chromatography, the solution was filtered and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (dichloromethane:ethanol = 10:1) to obtain compound AB24906 (weight: 100 mg, yield: 27.23%).

[0600] Compound AB24906: 1 H NMR(400MHz,DMSO-d6)δ 9.54(s,1H),8.30(d,J=7.0Hz,1H),8.15(d,J=7.0Hz,1H),7.66(d,J=7.6Hz,1H),7.48(s,1H),7.33(d,J=25.3Hz,6H) ),7.00(dd,J=22.7,6.8Hz,2H),5.62(s,1H),4.57(d,J=4.8Hz,2H),3.76(d,J=8.3Hz,1H),3.39(s,1H),2.44(s,3H). ESI-MS: Theoretical value [M-Br] + 329.16, Observed: 329.16.

[0601] Example 40 Preparation of compound AB24949 Step 1): [ka] Compound 1 (200 mg, 1.22 mmol) was dissolved in acetic acid (5 mL), and one drop of hydrobromic acid was added. Then, liquid bromine (193 mg, 1.22 mmol) was added to acetic acid (2 mL), and the mixture was injected. The mixture was then purged with nitrogen three times and stirred at room temperature for 3 hours. A new compound was detected by thin-layer chromatography. The solution was filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain compound 2 (300 mg, 101% yield).

[0602] Step 2): [ka] Compound 3 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), followed by the addition of compound 4 (5 g, 53.13 mmol). The mixture was then flushed with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 h. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to 0 °C, sodium borohydride (4.01 g, 106.2 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. When a new compound was detected by thin-layer chromatography, the product was diluted with water (200 mL), and then ethyl acetate (200 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 5 (2.6 g, 26.8% yield).

[0603] Step 3): [ka] Compound 6 (300 mg, 1.24 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 5 (228 mg, 1.24 mmol). The mixture was then flushed with nitrogen three times and stirred at room temperature for 3 hours. Upon detecting a new compound by thin-layer chromatography, the solution was filtered and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (dichloromethane:ethanol = 10:1) to give compound AB24949 (weight 35 mg, yield 12.5%).

[0604] Compound AB24949: 1 H NMR(400MHz,CD3OD)δ 8.16-7.98(m,3H),7.35(d,J=21.1Hz,5H),7.16(s,2H),6.95(d,J=12.6Hz, 2H),4.59(s,2H),3.39(s,1H),3.24-3.19(m,1H),2.76(s,1H),2.59(s,1H). ESI-MS: Theoretical value [M-Br] +347.40, Observed: 347.10.

[0605] Example 41 Preparation of compound AB24954 Step 1): [ka] Compound 1 (176 mg, 1.0 mmol) was dissolved in acetic acid (7 mL). Liquid bromine (160 mg, 1.0 mmol) was added to the mixture, and two drops of aqueous hydrobromic acid were added. The mixture was then stirred at room temperature for 3 hours. After detecting a new compound by thin-layer chromatography, ice water (30 mL) was added, followed by ethyl acetate (30 mL x 3) to extract the product. After the organic phases were combined, the product was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding compound 2 (200 mg, 78.43% yield).

[0606] Step 2): [ka] Compound 2 (200 mg, 0.78 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 3 (150 mg, 0.82 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Thin-layer chromatography revealed a new compound. The precipitated solid was filtered, washed three times with acetonitrile (2 mL), and centrifuged to obtain compound AB24954 (20 mg, 7.14% yield).

[0607] Compound AB24954: 1H NMR(400MHz,CD3OD)δ 8.11(d,J=7.4Hz,1H),8.03(d,J=7.3Hz,1H),7.58(d,J=8.0Hz,1H),7.37(s,5H),7.32(s,1H),7.26(d,J=7.3Hz,1H),6.98(d,J=7.2Hz,1H),6 .92(d,J=7.3Hz,1H),4.86-4.84(m,1H),4.59(s,2H),3.90(s,3H),3.40(d,J=18.1Hz,1H),3.00(t,J=12.3Hz,1H),2.69(s,1H),2.60(s,1H). ESI-MS: Theoretical value [M-CF3COO] + 359.45, Observed: 359.10.

[0608] Example 42 Preparation of compound AB24963 Step 1): [ka] Compound 1 (8 g, 83.33 mmol) was dissolved in phosphorus oxychloride (40 mL), then purged with nitrogen three times, heated to 90 °C, and stirred overnight. After detecting a new compound by thin-layer chromatography, the phosphorus oxychloride was centrifuged. Dichloromethane (50 mL) was added in an ice bath, and ice water (50 mL) was slowly added dropwise. Dichloromethane (50 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 30-80%) to obtain compound 2 (5 g, 52.17% yield).

[0609] Step 2): [ka] Compound 2 (2.5 g, 21.73 mmol) was dissolved in N,N-dimethylformamide (DMF) (50 mL), followed by the addition of compound 3 (7.43 g, 65.22 mmol) and potassium carbonate (9.01 g, 65.22 mmol). The mixture was then flushed with nitrogen three times and heated to 80 °C with stirring overnight. After detecting a new compound by thin-layer chromatography, water (50 mL) and ethyl acetate (50 mL x 3) were added to extract the product. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 0-30%) to give compound 4 (2.1 g, 52.24% yield).

[0610] Step 3): [ka] Compound 4 (200 mg, 1.08 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 5 (371 mg, 1.62 mmol). The mixture was then flushed with nitrogen three times and stirred at room temperature overnight. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB24963 (weight 20 mg, yield 5.54%).

[0611] Compound AB24963 1 H NMR(400MHz,DMSO,d6)δ 10.18(s,1H),8.77(s,1H),8.14(s,1H),7.98(d,J=8.2Hz,2H),7.33(d,J=22.3Hz ,5H),7.13(d,J=8.2Hz,2H),6.97(s,1H),5.83(s,2H),4.73(s,2H),3.86(s,3H). ESI-MS: Theoretical value [M-Br] + 334.16, Observed: 334.25.

[0612] Example 43 Preparation of compound AB24964 Step 1): [ka] Compound 1 (8 g, 83.33 mmol) was dissolved in phosphorus oxychloride (40 mL), then purged with nitrogen three times, heated to 90 °C, and stirred overnight. After detecting a new compound by thin-layer chromatography, the phosphorus oxychloride was centrifuged. Dichloromethane (50 mL) was added in an ice bath, and ice water (50 mL) was slowly added dropwise. Dichloromethane (50 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 30-80%) to obtain compound 2 (5 g, 52.17% yield).

[0613] Step 2): [ka] Compound 2 (2.5 g, 21.73 mmol) was dissolved in N,N-dimethylformamide (DMF) (50 mL), followed by the addition of compound 3 (7.43 g, 65.22 mmol) and potassium carbonate (9.01 g, 65.22 mmol). The mixture was then flushed with nitrogen three times and heated to 80 °C with stirring overnight. After detecting a new compound by thin-layer chromatography, water (50 mL) and ethyl acetate (50 mL x 3) were added to extract the product. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 0-30%) to give compound 4 (2.1 g, 52.24% yield).

[0614] Step 3): [ka] Compound 4 (200 mg, 1.08 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 5 (446 mg, 1.62 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. A new compound was detected by thin-layer chromatography. The reaction mixture was centrifuged and the product was purified by column chromatography (methanol:dichloromethane = 10%) to give compound AB24964 (30 mg, 7.3% yield).

[0615] Compound AB24964: 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),8.79(s,1H),8.12(d,J=25.9Hz,3H),7.94(d,J=6.7Hz,2H),7.77(s,2H),7 .51(s,1H),7.44(s,1H),7.35(d,J=17.5Hz,3H),6.97(s,1H),5.92(s,2H),4.74(s,1H). ESI-MS: Theoretical value [M-CF3COO] + 380.46, Observed: 380.30.

[0616] Example 44 Preparation of compound AB24967 Step 1): [ka] Compound 1 (8 g, 83.33 mmol) was dissolved in phosphorus oxychloride (40 mL), then purged with nitrogen three times, heated to 90 °C, and stirred overnight. After detecting a new compound by thin-layer chromatography, the phosphorus oxychloride was centrifuged. Dichloromethane (50 mL) was added in an ice bath, and ice water (50 mL) was slowly added dropwise. Dichloromethane (50 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 30-80%) to obtain compound 2 (5 g, 52.17% yield).

[0617] Step 2): [ka] Compound 1 (2.5 g, 21.73 mmol) was dissolved in N,N-dimethylformamide (DMF) (50 mL), followed by the addition of compound 3 (7.43 g, 65.22 mmol) and potassium carbonate (9.01 g, 65.22 mmol). The mixture was then flushed with nitrogen three times and heated to 80 °C with stirring overnight. After detecting a new compound by thin-layer chromatography, water (50 mL) and ethyl acetate (50 mL x 3) were added to extract the product. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 0-30%) to give compound 4 (2.1 g, 52.24% yield).

[0618] Step 3): [ka] Compound 4 (200 mg, 1.08 mmol) was dissolved in acetonitrile (15 mL), followed by the addition of compound 5 (367 mg, 1.29 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB24967 (weight 30 mg, yield 7.16%).

[0619] Compound AB24967: 1 H NMR(400MHz,DMSO,d6)δ 10.29(s,1H),8.75(s,1H),8.14(s,1H),8.05(s,1H),7.92(s,1H),7.78(s,2 H),7.33(d,J=23.1Hz,6H),6.99(d,J=6.7Hz,1H),5.90(s,2H),4.73(s,2H). ESI-MS: Theoretical value [M-Br]+ 388.13, Observed: 388.25.

[0620] Example 45 Preparation of compound AB24991 Step 1): [ka] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (DMF) (20 mL), NaH (203 mg, 5.07 mmol) was added in an ice bath, and the mixture was stirred at 0 °C for 30 min. Compound 2 (318 mg, 1.86 mmol) was then added and the mixture was stirred at room temperature for 3 h. After detecting a new compound by thin-layer chromatography, water (30 mL) and ethyl acetate (30 mL x 3) were added to extract the product, and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to obtain compound 3 (200 mg, 56.9% yield).

[0621] Step 2): [ka] Compound 3 (200 mg, 0.96 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 4 (337 mg, 1.44 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to obtain compound AB24991 (weight 100 mg, yield 28.86%).

[0622] Compound AB24991: 1H NMR(400MHz,DMSO,d6)δ 9.26(s,1H),8.41(d,J=42.8Hz,2H),8.06(dd,J=48.7,20.6Hz,3H),7.85(d,J=6. 8Hz,1H),7.69(d,J=7.0Hz,1H),7.27(d,J=60.4Hz,6H),6.40(s,2H),5.67(s,2H). ESI-MS: Theoretical value [M-Br] + 361.11, Observed: 361.05.

[0623] Example 46 Preparation of compound AB27106 Step 1): [ka] Compound 1 (80 mg, 0.38 mmol) and compound 2 (103 mg, 0.385 mmol) were dissolved in acetonitrile (5 mL) and stirred at room temperature for 3 hours. When a new compound was detected by thin-layer chromatography, the precipitated solid was filtered under reduced pressure, washed three times with acetonitrile (2 mL), and centrifuged to obtain compound AB27106 (57 mg, 37.97% yield).

[0624] Compound AB27106: 1H NMR(400MHz,DMSO-d6)δ 13.53(s,1H),9.29(s,1H),8.33-8.25(m,4H),8.14(d,J=6.7Hz,1H),8.05(d,J=8.3H) z,2H),7.38-7.28(m,4H),7.21(dd,J=7.2,4.0,1.4Hz,1H),6.53(s,2H),4.22(s,2H). ESI-MS: Theoretical value [M-Br] + 395.40, Observed: 395.05.

[0625] Example 47 Preparation of compound AB27107 Step 1): [ka] Compound 1 (100 mg, 0.50 mmol) and compound 2 (141 mg, 0.5 mmol) were dissolved in acetonitrile (5 mL) and stirred at room temperature for 3 hours. When a new compound was detected by thin-layer chromatography, the precipitated solid was filtered under reduced pressure, washed three times with acetonitrile (2 mL), and centrifuged to obtain compound AB27107 (65 mg, 31.55% yield).

[0626] Compound AB27107: 1 H NMR(400MHz,DMSO-d6)δ 13.10(s,1H),9.24(s,1H),8.41-8.12(m,5H),7.67(d,J=8.3Hz,2H),7.40-7.27(m,4H),7.21(t,J=7.1Hz,1H),6.48(s,2H),4.22(s,2H). ESI-MS: Theoretical value [M-Br] + 411.40, Observed: 411.05.

[0627] Example 48 Preparation of compound AB27114 Step 1): [ka] Compound 1 (4.4 g, 20 mmol) was dissolved in N,N-dimethylformamide (DMF) (20 mL), followed by the sequential addition of compound 2 (4.28 g, 42 mmol), cuprous iodide (0.19 g, 1 mmol), N,N-diisopropylethylamine (8.24 g, 64 mmol), and bistriphenylphosphine palladium dichloride (190 mg, 0.6 mmol). The mixture was then purged with nitrogen three times and stirred at room temperature for 16 h. Upon detecting a new compound by thin-layer chromatography, the product was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether=2:1) ​​to obtain compound 3 (weight 3.5 g, yield 84.13%).

[0628] Step 2): [ka] Compound 3 (1.5 g, 7.2 mmol) was dissolved in 1,4-dioxane (40 mL), followed by the addition of potassium t-butoxide (2.4 mg, 21.6 mmol). The mixture was then flushed with nitrogen three times, and the temperature was raised to 100 °C and stirred overnight. Upon detecting a new compound by thin-layer chromatography, the solution was immediately concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 10:1) to give compound 4 (weight: 1.1 g, yield: 73.45%).

[0629] Step 3): [ka] Compound 4 (104 mg, 0.5 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 5 (160 mg, 0.6 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Upon detecting a new compound by thin-layer chromatography, the solution was immediately concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 10:1) to give compound AB27114 (weight: 141 mg, yield: 59.49%).

[0630] Compound AB27114: 1 H NMR(400MHz,DMSO-d6)δ 13.04(s,1H),9.11(s,1H),8.35(d,J=6.0Hz,1H),8.24(d,J=7.2Hz,2H),8.03(d,J=7.2Hz,2 H),7.96(d,J=6.2Hz,1H),7.33(s,2H),7.26(s,1H),6.82(s,1H),6.41(s,2H),4.24(s,2H). ESI-MS: Theoretical value [M-Br] + 395.14, Observed: 395.14.

[0631] Example 49 Preparation of compound AB27124 Step 1): [ka] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (DMF) (20 mL), and NaH (203 mg, 5.07 mmol) was added in an ice bath. ℃The mixture was stirred at rt for 30 min, then compound 2 (318 mg, 1.86 mmol) was added and stirred at room temperature for 3 h. After detecting a new compound by thin-layer chromatography, water (30 mL) and ethyl acetate (30 mL x 3) were added to extract the product, and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to obtain compound 3 (weight: 200 mg, yield: 56.9%).

[0632] Step 2): [ka] Compound 4 (200 mg, 1.11 mmol) was dissolved in dichloromethane (10 mL), and then compound 5 (456 mg, 1.11 mmol) was added and stirred at room temperature for 1 hour. A new compound was detected by thin-layer chromatography. The reaction mixture was centrifuged and purified by thin-layer chromatography to obtain compound 6 (weight: 250 mg, yield: 87.29%).

[0633] Step 3): [ka] Compound 3 (150 mg, 0.58 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 6 (100 mg, 0.48 mmol). The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new compound was detected by thin-layer chromatography. The reaction mixture was centrifuged and purified by thin-layer chromatography to obtain compound AB27124 (65 mg, 34.99% yield).

[0634] Compound AB27124: 1H NMR(400MHz,DMSO,d6)δ 9.45(s,1H),8.62(s,1H),8.40(d,J=6.8Hz,1H),8.21(d,J=2.5Hz,1H),7.88(d,J=2.0Hz,1H),7.79(dd,J=8.3,2.3Hz,1H),7.58(d,J =8.3Hz,1H),7.42-7.31(m,5H),7.19(d,J=3.3Hz,1H),5.71(s,2H),3.30(s,3H),3.04(dd,J=13.2,4.6Hz,1H),2.69(d,J=8.9Hz,1H). ESI-MS: Theoretical value [M-Br] + 387.13, Observed: 387.20.

[0635] Example 50 Preparation of compound AB27127 Steps): [ka] Compound 1 (100 mg, 0.42 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 2 (77.73 mg, 0.42 mmol). The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new compound was detected by thin-layer chromatography. The reaction mixture was centrifuged and purified by thin-layer chromatography to obtain compound AB27127 (15 mg, 9.73% yield).

[0636] Compound AB27127: 1 H NMR(400MHz,DMSO-d6)δ 9.50(s,1H),8.65(s,1H),8.40(d,J=6.5Hz,1H),8.20(s,1H),7.72(s,1H),7.49(s,1H),7.41-7.26(m,6H),7.14(s,1H) ,6.36(d,J=11.1Hz,1H),5.70(s,2H),3.31(s,1H),3.21-3.06(m,1H),2.95(t,J=30.6Hz,1H),2.65(s,1H),2.33(s,3H). ESI-MS: Theoretical value [M-Br]+ 367.47, Observed value: 367.25.

[0637] Example 51 Preparation of compound AB24924 Step 1): [ka] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), followed by the addition of compound 2 (5 g, 53.13 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 h. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to 0 °C, sodium borohydride (4.01 g, 106.2 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. When a new compound was detected by thin-layer chromatography, the product was diluted with water (200 mL), and then ethyl acetate (200 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g, 26.8% yield).

[0638] Step 2): [ka] Compound 4 (400 mg, 2.1 mmol) was dissolved in acetic acid (10 mL). Liquid bromine (348 mg, 2.17 mmol) was added to the mixture, and two drops of aqueous hydrobromic acid were added. The mixture was then stirred at room temperature for 3 h. Thin-layer chromatography revealed a new compound. The precipitated solid was filtered under reduced pressure, and the filter cake was washed with dichloromethane (5 mL) to remove the organic solvent, yielding compound 5 (400 mg, 81.3% yield).

[0639] Step 3): [ka] Compound 5 (300 mg, 1.16 mmol) and compound 3 (107 mg, 0.58 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 3 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10%) to obtain compound AB24924 (weight 15 mg, yield 3.9%).

[0640] Compound AB24924: 1 H NMR (400 MHz, CD3OD) δ 8.96(s,1H),8.57(d,J=5.3Hz,1H),8.05(dd,J=7.5,1.9Hz,1H),7.97(dd,J=7.4 ,1.9Hz,1H),7.41(d,J=5.3Hz,1H),7.29(t,J=4.6Hz,4H),7.27-7.20(m,1H),6. 92(dd,J=7.4,2.9Hz,1H),6.86(dd,J=7.5,2.9Hz,1H),4.52(s,2H),3.35(s,1H) ,3.24-3.21(m,1H),3.20-3.17(m,1H),2.72(d,J=4.5Hz,1H),2.56-2.48(m,1H). ESI-MS: Theoretical value [M-CF3COO] + 330.41, Observed: 330.30.

[0641] Example 52 Preparation of compound AB24996 Step 1): [ka] Compound 1 (22 g, 100 mmol) was dissolved in tetrahydrofuran (200 mL), followed by the addition of compound 2 (10.5 g, 150 mmol). The mixture was then added with n-butyllithium (80 mL, 2.5 mol / L) at -78 °C and stirred at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 50:1) to obtain compound 3 (12 g, 55.2% yield).

[0642] Step 2): [ka] Compound 3 (12 g, 55.6 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), and then silver nitrate (1.89 g, 11.12 mmol) and potassium persulfate (37 g, 139 mmol) were added and stirred at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 4 (weight 3.1 g, yield 26.05%).

[0643] Step 3): [ka] Compound 4 (1.5 mg, 6.9 mmol) was dissolved in dichloromethane (20 mL) and then CH 18 Add N2O2HBr3 (2.9 g, 6.9 mmol) and stir at room temperature for 1 hour. A new compound is detected by thin layer chromatography. The reaction mixture is centrifuged and purified by thin layer chromatography to obtain compound 5 (weight 2.2 g, yield 85.48%).

[0644] Step 4): [ka] Compound 5 (150 mg, 0.5 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of compound 6 (104 mg, 0.5 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB24996 (weight 40 mg, yield 16.0%).

[0645] Compound AB24996: 1 H NMR(400MHz,DMSO-d6)δ 9.38(s,1H),8.56(d,J=6.7Hz,1H),8.36(d,J=6.9Hz,1H),8.17(s,1H),8.11(d,J=8.0Hz,1H),7.94(s,1H),7.80(d, J=8.1Hz,1H),7.35(s,5H),7.17(s,1H),6.20(d,J=9.8Hz,1H),5.67(s,2H),3.40(s,3H),3.06(s,1H),2.68(s,1H). ESI-MS: Theoretical value [M-Br] + 421.15, Observed: 421.15.

[0646] Example 53 Preparation of compound AB27111 Step 1): [ka] Compound 1 (36.3 g, 150 mmol) was dissolved in tetrahydrofuran (120 mL), followed by the addition of compound 2 (12.6 g, 180 mmol). The mixture was then added with n-butyllithium (120 mL, 2.5 mol / L) at -78 °C and stirred at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to obtain compound 3 (weight 6.72 g, yield 18.66%).

[0647] Step 2): [ka] Compound 3 (6.72 g, 28 mmol) was dissolved in dichloromethane (200 mL) and water (200 mL), followed by the addition of silver nitrate (952 mg, 5.6 mmol) and potassium persulfate (18.9 g, 70 mmol) and stirring at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 4 (weight: 2.35 g, yield: 36.33%).

[0648] Step 3): [ka] Compound 4 (2.0 g, 8.69 mmol) was dissolved in dichloromethane (50 mL) and then CH 18 Add N2O2HBr3 (2.9 g, 6.9 mmol) and stir at room temperature for 1 hour. A new compound is detected by thin-layer chromatography. The reaction mixture is centrifuged and purified by thin-layer chromatography (petroleum ether: ethyl acetate = 0-10%) to obtain compound 5 (weight 2.5 g, yield 93.10%).

[0649] Step 4): [ka] Compound 5 (240 mg, 0.78 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 6 (150 mg, 0.78 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB27111 (weight 88 mg, yield 27.31%).

[0650] Compound AB27111: 1 H NMR(400MHz,DMSO-d6)δ 9.72(s,1H),8.27(d,J=6.8Hz,1H),8.17(d,J=6.7Hz,1H),8.02(d,J=8.5Hz,1H),7.48(s,1H),7.40(d,J=11.9Hz,5H),7.29(s,1H),7.11 (d,J=5.7Hz,1H),6.99(d,J=5.6Hz,1H),5.81(d,J=10.7Hz,1H),4.57(d,J=4.9Hz,2H),3.25(s,2H),3.21(s,1H),2.81(d,J=9.3Hz,1H). ESI-MS: Theoretical value [M-Br] + 413.42, Observed: 413.20.

[0651] Example 54 Preparation of compound AB27112 Step 1): [ka] Compound 1 (8 g, 83.33 mmol) was dissolved in phosphorus oxychloride (40 mL), then purged with nitrogen three times, heated to 90 °C, and stirred overnight. After detecting a new compound by thin-layer chromatography, the phosphorus oxychloride was centrifuged. Dichloromethane (50 mL) was added in an ice bath, and ice water (50 mL) was slowly added dropwise. Dichloromethane (50 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 30-80%) to obtain compound 2 (5 g, 52.17% yield).

[0652] Step 2): [ka] Compound 1 (2.5 g, 21.73 mmol) was dissolved in N,N-dimethylformamide (DMF) (50 mL), followed by the addition of compound 3 (7.43 g, 65.22 mmol) and potassium carbonate (9.01 g, 65.22 mmol). The mixture was then flushed with nitrogen three times and heated to 80 °C with stirring overnight. After detecting a new compound by thin-layer chromatography, water (50 mL) and ethyl acetate (50 mL x 3) were added to extract the product. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (ethyl acetate:petroleum ether = 0-30%) to give compound 4 (2.1 g, 52.24% yield).

[0653] Step 3): [ka] Compound 4 (100 mg, 0.54 mmol) was dissolved in acetonitrile (10 mL), and then compound 5 (173 mg, 0.65 mmol) was added and stirred at room temperature for 16 hours. When a new compound was detected by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to obtain compound AB27112 (weight: 40 mg, yield: 19.9%).

[0654] Compound AB27112: 1 H NMR(400MHz,DMSO-d6)δ 10.47(s,1H),8.79(s,1H),8.20(s,3H),8.01(d,J=6.7Hz,2H),7.37(s,5H),7.06(d,J=6.5Hz,1H),5.97(s,2H),4.73(s,2H). ESI-MS: Theoretical value [M-Br] + 372.36, Observed: 372.10.

[0655] Example 55 Preparation of compound AB27125 Step 1): [ka] Compound 1 (22 g, 100 mmol) was dissolved in tetrahydrofuran (200 mL), followed by the addition of compound 2 (10.5 g, 150 mmol). The mixture was then added with n-butyllithium (80 mL, 2.5 mol / L) at -78 °C and stirred at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain compound 3 (weight: 13 g, yield: 60.3%).

[0656] Step 2): [ka] Compound 3 (6.48 g, 30 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), and then silver nitrate (1 g, 6 mmol) and potassium persulfate (20 g, 270 mmol) were added and stirred at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 4 (weight: 584 mg, yield: 9.0%).

[0657] Step 3): [ka] Compound 4 (584 mg, 1.98 mmol) was dissolved in dichloromethane (20 mL) and then CH 18 Add N2O2HBr3 (820 mg, 1.98 mmol) and stir at room temperature for 1 hour. A new compound is detected by thin layer chromatography. The reaction mixture is centrifuged and purified by thin layer chromatography to obtain compound 5 (weight 670 mg, yield 94.7%).

[0658] Step 4): [ka] Compound 5 (200 mg, 0.65 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of compound 6 (100 mg, 0.65 mmol). The mixture was then flushed with nitrogen three times and stirred at room temperature overnight. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB27125 (weight 53 mg, yield 16.3%).

[0659] Compound AB27125: 1 H NMR(400MHz,DMSO-d6)δ 9.40(s,1H),8.58(d,J=6.0Hz,1H),8.37(d,J=6.2Hz,1H),8.15(d,J=17.0Hz,2H),8.06(d,J=7.5Hz,1 H),7.76(d,J=7.5Hz,1H),7.35(s,5H),7.17(s,1H),6.24(d,J=12.0Hz,1H),5.68(s,2H),3.39(s,2H). ESI-MS: Theoretical value [M-Br] + 421.15, Observed: 421.15.

[0660] Example 56 Preparation of compound AB27126 Step 1): [ka] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (DMF) (20 mL), and NaH (203 mg, 5.07 mmol) was added in an ice bath. ℃The mixture was stirred at rt for 30 min, then compound 2 (318 mg, 1.86 mmol) was added and stirred at room temperature for 3 h. After detecting a new compound by thin-layer chromatography, water (30 mL) and ethyl acetate (30 mL x 3) were added to extract the product, and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to obtain compound 3 (weight: 200 mg, yield: 56.9%).

[0661] Step 2): [ka] Compound 4 (30 g, 124 mmol) was dissolved in tetrahydrofuran (200 mL), followed by the addition of compound 5 (10.46 g, 149 mmol). The mixture was then flushed with nitrogen three times, and n-butyllithium (80 mL, 2.5 mol / L) was added at -78 °C. The mixture was then stirred at room temperature for 16 hours. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 6 (weight: 11.2 g, yield: 38.93%).

[0662] Step 3): [ka] Compound 6 (11.2 g, 48 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), followed by the addition of silver nitrate (1.65 g, 9.7 mmol) and potassium persulfate (32.6 g, 121 mmol) and stirring at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 7 (weight 930 mg, yield 8.42%).

[0663] Step 4): [ka] Compound 7 (930 mg, 4.04 mmol) was dissolved in dichloromethane (20 mL) and then CH 18 N2O2HBr3 (1.68 g, 4.04 mmol) was added and stirred at room temperature for 1 hour. A new compound was detected by thin layer chromatography. The reaction mixture was centrifuged and purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 8 (weight 800 mg, yield 64.50%).

[0664] Step 5): [ka] Compound 8 (200 mg, 0.65 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of compound 3 (100 mg, 0.65 mmol). The mixture was then flushed with nitrogen three times and stirred at room temperature overnight. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB27126 (weight 20 mg, yield 7.04%).

[0665] Compound AB27126: 1 H NMR(400MHz,DMSO-d6)δ 9.41(s,1H),8.58(s,1H),8.37(d,J=5.9Hz,1H),8.18(s,1H),7.70(dd,J=33.1,12.2Hz,3H),7.3 5(s,5H),7.16(s,1H),6.25(s,1H),5.68(s,2H),3.48(s,2H),3.04(d,J=9.3Hz,1H),2.65(s,1H). ESI-MS: Theoretical value [M-Br] + 437.15, Observed: 437.20.

[0666] Example 57 Preparation of compound AB27131 Step 1): [ka] Compound 1 (22 g, 100 mmol) was dissolved in tetrahydrofuran (200 mL), followed by the addition of compound 2 (10.5 g, 150 mmol). The mixture was then added with n-butyllithium (80 mL, 2.5 mol / L) at -78 °C and stirred at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain compound 3 (13 g, 60.1% yield).

[0667] Step 2): [ka] Compound 3 (6.48 g, 30 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), and then silver nitrate (1 g, 6 mmol) and potassium persulfate (20 g, 270 mmol) were added and stirred at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 4 (weight: 584 mg, yield: 9.0%).

[0668] Step 3): [ka] Compound 4 (584 mg, 1.98 mmol) was dissolved in dichloromethane (20 mL) and then CH 18 Add N2O2HBr3 (820 mg, 1.98 mmol) and stir at room temperature for 1 hour. A new compound is detected by thin layer chromatography. The reaction mixture is centrifuged and purified by thin layer chromatography to obtain compound 5 (weight 670 mg, yield 94.7%).

[0669] Step 4): [ka] Compound 5 (150 mg, 0.5 mmol) and compound 6 (105 mg, 0.5 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 3 hours. When a new compound was detected by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 10%) to give compound AB27131 (weight 30 mg, yield 11.9%).

[0670] Compound AB27131: 1 H NMR(400MHz,DMSO-d6)δ 9.29(s,1H),8.15(d,J=14.3Hz,2H),8.05(dd,J=14.3,7.1Hz,2H),7.73(d,J=7.4Hz,1H),7.45-7.30(m,5H),6 .90(d,J=6.3Hz,1H),5.70(d,J=12.1Hz,1H),4.77(s,1H),2.81(s,2H),2.59(s,4H),2.10(s,1H),1.88(s,1H). ESI-MS: Theoretical value [M-Br] + 423.17, Observed: 423.17.

[0671] Example 58 Preparation of compound AB27133 Step 1): [ka] Compound 1 (160 g, 1 mmol) was dissolved in dichloromethane (50 mL) and then CH 18 N2O2HBr3 (414 mg, 1 mmol) was added and stirred at room temperature for 1 hour. A new compound was detected by thin layer chromatography. The reaction mixture was centrifuged and purified by thin layer chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 2 (weight 240 mg, yield 100%).

[0672] Step 2): [ka] Compound 2 (240 mg, 1.0 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 3 (210 mg, 1.0 mmol). The mixture was then flushed with nitrogen three times and stirred at room temperature overnight. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-30%) to obtain compound AB27133 (weight 70.0 mg, yield 18.97%).

[0673] Compound AB27133: 1 H NMR(400MHz,DMSO-d6)δ 9.47(s,1H),8.20(s,1H),8.12(d,J=6.4Hz,1H),7.71(s,1H),7.48(d,J=7.2Hz,1H ),7.39(d,J=6.3Hz,2H),7.34(d,J=6.5Hz,4H),6.98(d,J=6.7Hz,1H),5.72(d,J=11 .3Hz,1H),4.77(s,1H),3.33-3.27(m,1H),3.23(d,J=12.8Hz,1H),3.12(d,J=15.4 Hz,1H),2.77(d,J=9.3Hz,2H),2.57(s,1H),2.33(s,3H),2.08(s,1H),1.88(s,1H). ESI-MS: Theoretical value [M-Br] + 369.49, Observed: 369.15.

[0674] Example 59 Preparation of compound AB27142 Step 1): [ka] Compound 1 (5.0 g, 22.72 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (100 mL). Compound 2 (7.65 g, 68.16 mmol), dimethylferrocene palladium dichloride (1.0 g, 1.2 mmol), lithium chloride (0.96 mg, 22.72 mmol), and sodium carbonate (4.8 g, 45.44 mmol) were added, and the mixture was stirred overnight at room temperature after flushing with nitrogen three times. Upon detecting a new compound by thin-layer chromatography, the product was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin layer chromatography (ethyl acetate:petroleum ether=0-50%) to give compound 3 (weight 2.65 g, yield 56.89%).

[0675] Step 2): [ka] Compound 3 (2.65 g, 12.99 mmol) was dissolved in ethanol (100 mL), sodium hydroxide (15.59 g, 389.70 mmol) was added, and the mixture was then flushed with nitrogen three times. The temperature was raised to 90 °C and the mixture was stirred overnight. After detecting a new compound by thin-layer chromatography, the product was diluted with water (20 mL) and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound 4 (1.1 g, 63.66% yield).

[0676] Step 3): [ka] Compound 4 (260 mg, 2 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (10 mL), followed by the addition of compound 5 (253 mg, 1.5 mmol) and potassium carbonate (830 mg, 6 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. After detecting a new compound by thin-layer chromatography, the product was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (ethyl acetate:petroleum ether = 0-50%) to give compound 6 (100 mg, 22.52% yield).

[0677] Step 4): [ka] Compound 6 (100 mg, 0.45 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 7 (116 mg, 0.45 mmol). The mixture was then flushed with nitrogen three times and stirred at room temperature overnight. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound AB27142 (weight 12.1 g, yield 6.70%).

[0678] Compound AB27142: 1 H NMR(400MHz,CD3OD-d6)δ 9.25(s,1H),8.38(d,J=6.2Hz,1H),8.06-7.96(m,2H),7.66(d,J=14.5Hz,2H),7.48(d,J=7.8Hz,1H),7.33(d,J= 16.3Hz,5H),5.57(s,2H),3.47(t,J=13.4Hz,1H),3.33(s,1H),3.04(s,1H),2.75(d,J=10.2Hz,1H),2.44(s,4H). ESI-MS: Theoretical value [M-Br] +401.91, Observed: 401.10.

[0679] Example 60 Preparation of compound AB27144 Step 1): [ka] Compound 1 (22 g, 100 mmol) was dissolved in tetrahydrofuran (200 mL), followed by the addition of compound 2 (10.5 g, 150 mmol). The mixture was then added with n-butyllithium (80 mL, 2.5 mol / L) at -78 °C and stirred at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain compound 3 (13 g, 60.1% yield).

[0680] Step 2): [ka] Compound 3 (6.48 g, 30 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), and then silver nitrate (1 g, 6 mmol) and potassium persulfate (20 g, 270 mmol) were added and stirred at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 4 (weight: 584 mg, yield: 9.0%).

[0681] Step 3): [ka] Compound 4 (584 mg, 1.98 mmol) was dissolved in dichloromethane (20 mL) and then CH 18Add N2O2HBr3 (820 mg, 1.98 mmol) and stir at room temperature for 1 hour. A new compound is detected by thin layer chromatography. The reaction mixture is centrifuged and purified by thin layer chromatography to obtain compound 5 (weight 670 mg, yield 94.7%).

[0682] Step 4): [ka] Compound 5 (150 mg, 0.5 mmol) and compound 6 (92 mg, 0.5 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 3 hours. When a new compound was detected by thin layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin layer chromatography (dichloromethane:methanol = 10:1) to obtain compound AB27144 (weight 30 mg, yield 12.6%).

[0683] Compound AB27144: 1 H NMR(400MHz,DMSO-d6)δ 9.33(s,1H),8.25(d,J=6.3Hz,1H),8.12(d,J=11.7Hz,2H),8.03(d,J=7.2Hz,1H),7.71(d,J=7.9Hz,1H),7.34(d, J=24.9Hz,5H),7.02(s,2H),5.72(d,J=10.7Hz,1H),4.58(d,J=4.9Hz,2H),3.39(s,1H),2.83(s,1H),2.50(s,2H). ESI-MS: Theoretical value [M-Br] + 397.15, Observed: 397.15.

[0684] Example 61 Preparation of compound AB27156 Step 1): [ka] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), followed by the addition of compound 2 (5 g, 53.13 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 h. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to 0 °C, sodium borohydride (4.01 g, 106.2 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. When a new compound was detected by thin-layer chromatography, the product was diluted with water (200 mL), and then ethyl acetate (200 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g, 26.8% yield).

[0685] Step 2): [ka] Compound 4 (30 g, 124 mmol) was dissolved in tetrahydrofuran (200 mL), followed by the addition of compound 5 (10.46 g, 149 mmol). The mixture was then flushed with nitrogen three times, and n-butyllithium (100 mL, 2.5 mol / L) was added at -78 °C, followed by stirring at room temperature for 16 hours. A new compound was detected by thin-layer chromatography, and the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 6 (weight: 11.2 g, yield: 38.93%).

[0686] Step 3): [ka] Compound 6 (11.2 g, 48 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), followed by the addition of silver nitrate (1.65 g, 9.7 mmol) and potassium persulfate (32.6 g, 121 mmol) and stirring at room temperature for 16 hours. After detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 7 (weight 930 mg, yield 8.42%).

[0687] Step 4): [ka] Compound 7 (930 mg, 4.04 mmol) was dissolved in dichloromethane (20 mL) and then CH 18 N2O2HBr3 (1.68 g, 4.04 mmol) was added and stirred at room temperature for 1 hour. A new compound was detected by thin layer chromatography. The reaction mixture was centrifuged and purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 8 (weight 800 mg, yield 64.50%).

[0688] Step 5): [ka] Compound 8 (200 mg, 0.65 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of compound 3 (100 mg, 0.65 mmol). The mixture was then flushed with nitrogen three times and stirred at room temperature overnight. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB27156 (weight 12 mg, yield 4.5%).

[0689] 1H NMR(400MHz,DMSO-d6)δ 9.50(s,1H),8.25(d,J=6.7Hz,1H),8.14(d,J=6.6Hz,1H),7.76-7.66(m,2H),7.61(d,J=8.2Hz,1H),7.34(d,J=24.9Hz ,5H),7.03(dd,J=16.4,6.5Hz,2H),5.75(d,J=10.8Hz,1H),4.58(d,J=4.8Hz,2H),3.24(s,3H),2.81(d,J=8.6Hz,1H). ESI-MS: Theoretical value [M-Br] + 413.41, Observed: 413.30.

[0690] Example 62 Preparation of compound AB27128 Step 1): [ka] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (DMF) (20 mL), and NaH (203 mg, 5.07 mmol) was added in an ice bath. ℃ The mixture was stirred at rt for 30 min, then compound 2 (318 mg, 1.86 mmol) was added and stirred at room temperature for 3 h. After detecting a new compound by thin-layer chromatography, water (30 mL) and ethyl acetate (30 mL x 3) were added to extract the product, and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-10%) to obtain compound 3 (weight: 200 mg, yield: 56.9%).

[0691] Step 2): [ka] Compound 4 (200 mg, 1.05 mmol) was dissolved in dichloromethane (10 mL) and then CH 18Add N2O2HBr3 (434 mg, 1.05 mmol) and stir at room temperature for 1 hour. A new compound is detected by thin layer chromatography. The reaction mixture is centrifuged and purified by thin layer chromatography to obtain compound 5 (weight 260 mg, yield 92.05%).

[0692] Step 3): [ka] Compound 3 (125 mg, 0.65 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 5 (260 mg, 0.96 mmol). The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new compound was detected by thin-layer chromatography. The reaction mixture was centrifuged and purified by thin-layer chromatography to obtain compound AB27128 (20 mg, 7.73% yield).

[0693] Compound AB27128 1 H NMR(400MHz,DMSO-d6)δ 9.45(s,1H),8.61(dd,J=10.6,4.8Hz,2H),8.52(dd,J=8.5,2.5Hz,1H),8.41(d,J=7.1Hz,1H),8.21(d,J=3.3Hz,1H),7.83(d,J=8.5Hz,1H) ),7.42-7.31(m,5H),7.21(d,J=3.2Hz,1H),6.34(d,J=14.0Hz,1H),5.71(s,2H),3.47(s,2H),3.09(dd,J=13.3,5.7Hz,1H),2.73(s,1H). ESI-MS: Theoretical value [M-Br]+ 398.15, Observed value: 398.25.

[0694] Example 63 Preparation of compound AB27169 Step 1): [ka] Compound 1 (200 mg, 1.85 mmol) was dissolved in absolute ethanol (30 mL), followed by the addition of compound 2 (236 mg, 236 mmol). The mixture was then flushed with nitrogen three times and stirred at 90 °C overnight. When a new compound was detected by thin-layer chromatography, sodium borohydride (210 mg, 5.55 mmol) was added and the mixture was stirred at room temperature for 3 hours. When a new compound was detected by thin-layer chromatography, the mixture was quenched with water (20 mL), followed by the addition of ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound 3 (100 mg, 27.16% yield).

[0695] Step 2): [ka] Compound 3 (100 mg, 0.5 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 4 (160 mg, 0.75 mmol). The mixture was then flushed with nitrogen three times and stirred at 80 °C overnight. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB27169 (weight 25 mg, yield 15.10%).

[0696] 1 H NMR(400MHz,DMSO-d6)δ 8.65(s,1H),8.10(s,2H),7.87(s,2H),7.38(d,J=12.9Hz,8H),7.27(s ,1H),6.89(s,1H),5.86(s,2H),4.64(s,2H),2.39(s,4H),2.20(s,3H). ESI-MS: Theoretical value [M-Br]+ 331.18, Observed value: 331.30.

[0697] Example 64 Preparation of compound AB27166 Step 1): [ka] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), followed by the addition of compound 2 (5 g, 53.13 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 h. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to 0 °C, sodium borohydride (4.01 g, 106.2 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. When a new compound was detected by thin-layer chromatography, the product was diluted with water (200 mL), and then ethyl acetate (200 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g, 26.8% yield).

[0698] Step 2): [ka] Compound 3 (184 mg, 1 mmol) was dissolved in N,N-dimethylformamide (DMF) (5 mL), triethylamine (303 mg, 3 mmol) was added, and the mixture was then purged with nitrogen three times. The mixture was stirred at 0 °C for 30 minutes, and compound 4 (157 mg, 2 mmol) was added at 0 °C, and the reaction was carried out at room temperature. When a new compound was detected by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to obtain compound 5 (weight: 180 mg, yield: 79.2%).

[0699] Step 3): [ka] Compound 5 (180 mg, 0.8 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 6 (426 mg, 2 mmol). The mixture was then flushed with nitrogen three times and stirred at room temperature overnight. Upon detecting a new compound by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified to give compound AB27166 (weight: 40 mg, yield: 10.5%).

[0700] 1 H NMR(400MHz,DMSO-d6)δ 8.78(d,J=6.3Hz,2H),8.16(d,J=6.3Hz,2H),7.91(d,J=7.6Hz,2H),7.43(d,J=7.6Hz,2H),7.3 5(d,J=7.1Hz,1H),7.27(d,J=7.2Hz,3H),6.29(s,2H),5.32(s,2H),2.40(s,3H),2.38(s,2H). ESI-MS: Theoretical value [M-CF3COO]+ 359.44, Observed value: 359.20.

[0701] Example 65 Preparation of compound AB27170 Step 1): [ka] Compound 1 (1 g, 9.26 mmol) was dissolved in ethanol (10 mL), followed by the addition of compound 2 (2.9 g, 27.78 mmol). The mixture was then flushed with nitrogen three times, and the temperature was raised to 90 °C and stirred overnight. When a new compound was detected by thin-layer chromatography, the reaction temperature was lowered to 0 °C, sodium borohydride (422 mg, 11.11 mmol) was slowly added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. When a new compound was detected by thin-layer chromatography, the product was diluted with water (30 mL), and then ethyl acetate (20 mL x 3) was added to extract the product. After the organic phases were combined, the product was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (1.5 g, 81.4% yield).

[0702] Step 2): [ka] Compounds 3 (100 mg, 0.51 mmol) and 4 (108 mg, 0.51 mmol) were dissolved in acetonitrile (10 mL) and stirred at 80 °C for 16 h. When a new compound was detected by thin-layer chromatography, the solution was concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by column chromatography (methanol:dichloromethane = 10%) to give compound AB27170 (weight 75 mg, yield 29.4%).

[0703] 1 H NMR(400MHz,DMSO-d6)δ 9.20(d,J=24.3Hz,1H),8.07(dd,J=48.5,6.5Hz,1H),7.92(d,J=6.8Hz,2H),7.40(dd,J=22.1,7.3Hz ,5H),7.31(s,1H),7.03-6.84(m,2H),5.96(s,2H),4.55(s,2H),2.40(s,3H),2.32(d,J=7.7Hz,3H). ESI-MS: Theoretical value [M-Br]+ 331.43, Observed value: 331.25.

[0704] Example 66 Preparation of compound AB24917 Step 1): [ka] Compound 1 (160 mg, 1 mmol) was dissolved in acetic acid (7 mL). Liquid bromine (160 mg, 1.0 mmol) was added to the mixture, and two drops of aqueous hydrobromic acid were added. The mixture was then stirred at room temperature for 3 hours. After detecting a new compound by thin-layer chromatography, ice water (30 mL) was added, followed by ethyl acetate (30 mL x 3) to extract the product. After the organic phases were combined, the product was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding compound 2 (260 mg, 90.0% yield).

[0705] Step 2): [ka] Compound 2 (260 mg, 0.9 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 3 (165 mg, 0.9 mmol). The mixture was then flushed with nitrogen three times and stirred overnight at room temperature. Thin layer chromatography revealed a new compound. The precipitated solid was filtered, washed three times with acetonitrile (2 mL), and centrifuged to obtain compound AB24917 (45 mg, 14.57% yield).

[0706] 1H NMR(400MHz,DMSO-d6)δ 9.76(s,1H),8.30(d,J=7.2Hz,1H),8.20(d,J=7.0Hz,1H),7.82(d,J=7.8Hz,1H) ,7.45-7.37(m,4H),7.34-7.30(m,1H),7.26(d,J=10.1Hz,2H),7.17-7.11(m,1H) ,7.03-6.97(m,1H),5.76(dd,J=13.8,4.1Hz,1H),4.60(d,J=5.4Hz,2H),3.33-3 .22(m,2H),3.12(d,J=16.4Hz,1H),2.83-2.72(m,1H),2.46(s,1H),2.38(s,3H). ESI-MS: Theoretical value [M-Br]+ 343.45, Observed value: 343.10.

[0707] Example 67 Preparation of compound AB24956 Step 1): [ka] Compound 1 (300 mg, 3.15 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 2 (671 mg, 2.35 mmol). The mixture was then purged with nitrogen three times and stirred at room temperature overnight. A new compound was detected by thin-layer chromatography, and the reaction mixture was centrifuged and purified by thin-layer chromatography to obtain compound 3 (600 mg, 83.54% yield).

[0708] Step 2): [ka] Compound 3 (200 mg, 0.87 mmol) was dissolved in phosphorus oxychloride (10 mL), and the mixture was then purged with nitrogen three times and stirred at 90° C. for 2 hours. A new compound was detected by thin-layer chromatography, and the reaction mixture was centrifuged to give compound 4 (weight 215 mg, crude product), which was then directly used in the next step.

[0709] Step 3): [ka] Compound 4 (215 mg, 0.88 mmol) was dissolved in N,N-dimethylformamide (DMF) (10 mL), followed by the sequential addition of compound 5 (137 mg, 0.88 mmol) and triethylamine (267 mg, 2.64 mmol). The mixture was then purged with nitrogen three times and stirred overnight at 80 °C. A new compound was detected by thin-layer chromatography, and the reaction mixture was centrifuged to obtain compound AB24956 (weight: 20 mg, yield: 6.91%).

[0710] 1 H NMR(400MHz,DMSO-d6)δ 8.27(s,2H),7.92(d,J=6.6Hz,2H),7.40(d,J=18.2Hz,6H),7.08(s,2H),5.96(s,2H),4.95(s,4H),2.41(s,3H). ESI-MS: Theoretical value [M-CF3COO]+ 329.16, Observed value: 329.25.

[0711] Example 68 Preparation of compound AB27176 Step 1): [ka] Compound 1 (100 mg, 0.76 mmol) was dissolved in N,N-dimethylformamide (DMF) (10 mL), NaH (61 mg, 1.56 mmol) was added, and the mixture was stirred in an ice bath for 10 minutes. Compound 2 (130 mg, 0.76 mmol) was then added, followed by three flushes with nitrogen and stirring at room temperature for 5 hours. Upon detecting a new compound by thin-layer chromatography, the product was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound 3 (90 mg, 53.1% yield).

[0712] Step 2): [ka] Compound 3 (90 mg, 0.4 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 4 (116 mg, 0.48 mmol). The mixture was then flushed with nitrogen three times and stirred at 70 °C overnight. Upon detecting a new compound by thin-layer chromatography, the solution was filtered and concentrated under reduced pressure to remove the organic solvent. Finally, the product was purified by thin-layer chroma...

Claims

1. A compound of formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof. 【Chemical 1】 (i) (in Formula I, ring A represents a substituted or unsubstituted pyridine ring, where "substituted" means that one, two, or three hydrogen atoms on the ring are replaced with a substituent selected from the group consisting of a C1-C4 alkyl group; Ring B represents a substituted or unsubstituted pyrrole ring, where "substituted" means that one, two, or three hydrogen atoms on the ring are replaced with a substituent selected from the group consisting of a C1-C4 alkyl group; R １ teeth 【Chemistry 2】 represents; R ２ represents a hydrogen atom; R ３ represents a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted C6-C10 aryl group-C1-C4 alkyl group-, or a substituted or unsubstituted 5-10 membered heteroaryl group-C1-C4 alkyl group, where "substituted" means that one, two, or three hydrogen atoms on the atomic group are replaced by substituents selected from the group consisting of C1-C6 alkyl groups; Ring C represents a substituted or unsubstituted C6-C10 aromatic ring or a substituted or unsubstituted 3- to 10-membered heteroaromatic ring, where "substituted" means that one, two, or three hydrogen atoms on the ring are replaced by a substituent selected from the group consisting of a C1-C6 alkyl group, a C1-C6 haloalkyl group, a halogen, a nitro group, a C1-C6 haloalkoxyl group, and a C1-C6 haloalkylthio group; R ７ represents a hydrogen atom or a C1-C4 alkyl group; R ８ and R ９ are linked to form a cyclopentane or cyclohexane ring; The heterocyclic rings of the heteroaryl group and heteroaromatic ring each independently contain 1, 2, or 3 heteroatoms selected from N, O, and S. or (ii) (In Formula I, ring A represents a pyridine ring, and "substituted" here means that one, two, or three hydrogen atoms on the ring are replaced with a substituent selected from the group consisting of a C1-C4 alkyl group; Ring B represents a substituted or unsubstituted pyrrole ring, where "substituted" means that one, two, or three hydrogen atoms on the ring are replaced with a substituent selected from the group consisting of a C1-C4 alkyl group; R １ teeth 【Chemistry 3】 represents; R ２ represents a hydrogen atom; R ３ represents a C1-C6 alkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted C6-C10 aryl group-C1-C4 alkyl group-, or a substituted or unsubstituted 5-10 membered heteroaryl group-C1-C4 alkyl group, where "substituted" means that one, two, or three hydrogen atoms on the atomic group are replaced by a substituent selected from the group consisting of a C1-C6 alkyl group and a halogen; R ４ and R ５ each independently represents a hydrogen atom or a C1-C6 alkyl group; R ６ represents a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, where "substituted" means that one, two or three hydrogen atoms on the atomic group are replaced by a substituent selected from the group consisting of a C1-C6 alkyl group, a C1-C6 haloalkyl group, a halogen, a nitro group, a C1-C6 haloalkoxyl group and a C1-C6 haloalkylthio group; n represents 1; The heterocyclic ring of said heteroaryl group has 1, 2 or 3 heteroatoms each independently selected from N, O and S.

2. (i) In Formula I, ring A represents a substituted or unsubstituted pyridine ring, where "substituted" means that one, two, or three hydrogen atoms on the ring are replaced with a substituent selected from the group consisting of a C1-C4 alkyl group; Ring B represents a substituted or unsubstituted pyrrole ring, where "substituted" means that one, two, or three hydrogen atoms on the ring are replaced with a substituent selected from the group consisting of a C1-C4 alkyl group; R １ teeth 【Chemistry 4】 represents; R ２ represents a hydrogen atom; R ３ represents a C1-C4 alkyl group, a C3-C8 cycloalkyl group, a C6-C8 aryl group-C1-C2 alkyl group-, or a 5-8 membered heteroaryl group-C1-C2 alkyl group-; R ７ represents a hydrogen atom or a C1-C4 alkyl group; R ８ and R ９ are linked to form a cyclopentene or cyclohexene ring; Ring C represents a substituted or unsubstituted benzene ring or pyridine ring, where "substituted" means that one, two, or three hydrogen atoms on the ring are replaced with a substituent selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, halogen, a nitro group, a C1-C4 haloalkoxyl group, and a C1-C4 haloalkylthio group; The heterocyclic ring of the heteroaryl group has 1, 2 or 3 heteroatoms selected from N, O and S; or (ii) In Formula I, ring A represents a substituted or unsubstituted pyridine ring, where "substituted" means that one, two, or three hydrogen atoms on the ring are replaced with a substituent selected from the group consisting of a C1-C4 alkyl group; Ring B represents a substituted or unsubstituted pyrrole ring, where "substituted" means that one, two, or three hydrogen atoms on the ring are replaced with a substituent selected from the group consisting of a C1-C4 alkyl group; R １ teeth 【Chemistry 5】 represents; R ２ represents a hydrogen atom; R ３ represents a C1-C4 alkyl group, a substituted or unsubstituted C6-C8 aryl group, a substituted or unsubstituted 5-8 membered heteroaryl group, a substituted or unsubstituted C6-C8 aryl group-C1-C2 alkyl group, or a substituted or unsubstituted 5-8 membered heteroaryl group-C1-C2 alkyl group, where "substituted" means that one, two, or three hydrogen atoms on the atomic group are replaced by a substituent selected from the group consisting of C1-C4 alkyl or halogen; R ４ and R ５ each independently represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, or a butyl group; R ６ represents a substituted or unsubstituted phenyl group, the substituted or unsubstituted phenyl group being a monosubstituted or unsubstituted phenyl, the substitution being ortho-, para- or meta-substitution of the phenyl group, and the substituents being halogen, nitro group, C1-C4 alkyl group, F ３ C- or F ３ C—O—; n represents 1; The heterocyclic ring of the heteroaryl group has 1, 2 or 3 heteroatoms selected from N, O and S; 2. The compound according to claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

3. (i) In formula I, ring A represents a pyridine ring; Ring B represents a substituted or unsubstituted pyrrole ring, where "substituted" means that one, two, or three hydrogen atoms on the ring are replaced with a substituent selected from the group consisting of a C1-C4 alkyl group; R １ teeth 【Chemistry 6】 represents; R ２ represents a hydrogen atom; R ３ represents phenyl-methyl, phenyl-ethyl, a methyl group, an ethyl group, a propyl group or a cyclopropyl group; R ７ represents a hydrogen atom; R ８ and R ９ are linked to form a cyclohexene ring; Ring C represents a substituted or unsubstituted benzene ring, where "substituted" means that one, two, or three hydrogen atoms on the ring are replaced with a methyl group, a halogen, a nitro group, or -CF ３ , -OCF ３ means substituted by a substituent selected from the group consisting of or (ii) In formula I, ring A represents a pyridine ring; Ring B represents a pyrrole ring; R １ teeth 【Chemistry 7】 represents; R ２ represents a hydrogen atom; R ３ represents a phenyl-methyl, propyl group, or a substituted or unsubstituted phenyl group, the substituted or unsubstituted phenyl group being a monosubstituted or unsubstituted phenyl, the substitution being ortho-, para- or meta-substitution of the phenyl group, and the substituent being a C1-C4 alkyl group or a halogen; R ４ and R ５ each independently represents a hydrogen atom; R ６ is a meta-nitrophenyl group, an ortho-nitrophenyl group, a para-nitrophenyl group, a para-methylphenyl group, an ortho-methylphenyl group, a meta-methylphenyl group, a meta-trifluoromethoxyphenyl group, a para-trifluoromethoxyphenyl group, an ortho-trifluoromethoxyphenyl group, a para-halogenated phenyl group, an ortho-halogenated phenyl group, a meta-halogenated phenyl group, a para-trifluoromethylphenyl group, an ortho-trifluoromethylphenyl group, or a meta-trifluoromethylphenyl group; n represents 1, 2. The compound according to claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

4. In formula I, R １ is attached to a heteroatom on the ring of ring A; R ２ is attached to a carbon atom on the ring A; and / or R ３ is bonded to a heteroatom or carbon atom on the ring B; 2. The compound according to claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

5. Compounds of formula I have the structure of formula I-9: 【Chemistry 8】 R ３ represents a C6-C10 aryl group, a C6-C10 aryl group-C1-C4 alkyl group, a 5-10 membered heteroaryl group, or a 5-10 membered heteroaryl group-C1-C4 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a substituted or unsubstituted C6-C10 aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group, where "substituted" means that one, two or three hydrogen atoms on the atomic group are replaced with a substituent selected from the group consisting of halogen; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-10: 【Chemistry 9】 R ３ represents a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted C6-C10 aryl group-C1-C4 alkyl group, a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted 5-10 membered heteroaryl-C1-C4 alkyl group, or a C1-C6 alkyl group; here, "substituted" means that one, two, or three hydrogen atoms on the atomic group are replaced with a substituent selected from the group consisting of a C1-C6 alkyl group and a halogen; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a substituted or unsubstituted C6-C10 aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group, where "substituted" means that one, two or three hydrogen atoms on the atomic group are replaced by a substituent selected from the group consisting of a C1-C6 alkyl group, a C1-C6 haloalkyl group, a halogen, a nitro group, and a C1-C6 haloalkoxy group; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-11: 【Chemistry 10】 R ３ represents a C6-C10 aryl group-C1-C4 alkyl group, or a 5-10 membered heteroaryl group-C1-C4 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a substituted or unsubstituted C6-C10 aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group, where "substituted" means that one, two or three hydrogen atoms on the atomic group are replaced with a substituent selected from the group consisting of C1-C6 alkyl groups; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-15: 【Chemistry 11】 R ３ represents a C6-C10 aryl group, a C6-C10 aryl group-C1-C4 alkyl group, a 5-10 membered heteroaryl group, or a 5-10 membered heteroaryl group-C1-C4 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a substituted or unsubstituted C6-C10 aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group, where "substituted" means that one, two or three hydrogen atoms on the atomic group are replaced by a substituent selected from the group consisting of a halogen, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group and a C1-C6 haloalkoxy group; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-16: 【Chemistry 12】 R ３ represents a C6-C10 aryl group-C1-C4 alkyl group, or a 5-10 membered heteroaryl group-C1-C4 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a substituted or unsubstituted C6-C10 aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group, where "substituted" means that one, two or three hydrogen atoms on the atomic group are replaced with a substituent selected from the group consisting of halogen and a C1-C6 haloalkyl group; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-17: 【Chemistry 13】 R ３ is a C6-C10 aryl group, a C1-C4 alkyl group, or a 5-10 membered heteroaryl group represents a C1-C4 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a substituted or unsubstituted C6-C10 aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group, where "substituted" means that one, two or three hydrogen atoms on the atomic group are replaced with a substituent selected from the group consisting of halogen; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-34: 【Chemistry 14】 R ３ represents a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C6-C10 aryl group-C1-C4 alkyl group, or a 5- to 10-membered heteroaryl group-C1-C4 alkyl group; R １４ , R １５ , R １６ and R １７ are each independently a hydrogen atom, a halogen atom, a methyl group, a nitro group, or —OCF ３ , or -CF ３ represents; a represents 1; R １８ represents a hydrogen atom or a C1-C4 alkyl group; In any of the foregoing compounds, the heterocyclic ring of the heteroaryl group has 1, 2, or 3 heteroatoms selected from N, O, and S.

2. The compound according to claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

6. Compounds of formula I have the structure of formula I-9: 【Chemistry 15】 R ３ represents a C6-C10 aryl group, or a C6-C10 aryl group-C1-C4 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a substituted or unsubstituted phenyl group, the substituted or unsubstituted phenyl group being a monosubstituted or unsubstituted phenyl group, the substitution being ortho-, para- or meta-substitution of the phenyl group, and the substituent being a halogen; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-10: 【Chemistry 16】 R ３ represents a substituted or unsubstituted C6-C10 aryl group, C6-C10 aryl group-C1-C4, or C1-C6 alkyl group; where "substituted" means that one, two, or three hydrogen atoms on the atomic group are replaced with a substituent selected from the group consisting of a C1-C4 alkyl group and a halogen; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a substituted or unsubstituted phenyl group, the substituted or unsubstituted phenyl group being a monosubstituted or unsubstituted phenyl group, the substitution being ortho-, para- or meta-substitution of the phenyl group, and the substituents being halogen, nitro group, C1-C4 alkyl group, F ３ C- or F ３ C—O—; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-11: 【Chemistry 17】 R ３ represents a C6-C10 aryl group-C1-C4 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a substituted or unsubstituted phenyl group, the substituted or unsubstituted phenyl group being a monosubstituted or unsubstituted phenyl group, the substitution being ortho-, para- or meta-substitution of the phenyl group, and the substituent being a C1-C4 alkyl group; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-15: 【Chemistry 18】 R ３ represents a C6-C10 aryl group, or a C6-C10 aryl group-C1-C4 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a substituted or unsubstituted phenyl group, the substituted or unsubstituted phenyl group being a monosubstituted or unsubstituted phenyl group, the substitution being ortho-, para- or meta-substitution of the phenyl group, and the substituents being halogen, nitro group, C1-C4 alkyl group, F ３ C- or F ３ C—O—; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-16: 【Chemistry 19】 R ３ represents a C6-C10 aryl group-C1-C4 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a substituted or unsubstituted phenyl group, the substituted or unsubstituted phenyl group being a monosubstituted or unsubstituted phenyl group, the substitution being ortho-, para- or meta-substitution of the phenyl group, and the substituent being a halogen or F. ３ C-; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-17: 【Chemistry 20】 R ３ represents a C6-C10 aryl group-C1-C4 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a substituted or unsubstituted phenyl group, the substituted or unsubstituted phenyl group being a monosubstituted or unsubstituted phenyl group, the substitution being ortho-, para- or meta-substitution of the phenyl group, and the substituent being a halogen; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-34: 【Chemical 21】 R ３ represents a C1-C6 alkyl group, a C3-C8 cycloalkyl group, or a C6-C10 aryl group-C1-C4 alkyl group; R １４ , R １５ , R １６ and R １７ are each independently a hydrogen atom, a halogen atom, a methyl group, a nitro group, or —OCF ３ , or -CF ３ represents; a represents 1; R １８ represents a hydrogen atom or a C1-C4 alkyl group; 2. The compound according to claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

7. Compounds of formula I have the structure of formula I-9: 【Chemical 22】 R ３ represents a C6-C8 aryl group, or a C6-C8 aryl group-C1-C2 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a para-halogenated phenyl, an ortho-halogenated phenyl, or a meta-halogenated phenyl; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-10: 【Chemical 23】 R ３ represents a substituted or unsubstituted C6-C8 aryl group, C6-C8 aryl group-C1-C2 or C1-C4 alkyl group; where "substituted" means that one hydrogen atom on the atomic group is replaced with a substituent selected from the group consisting of C1-C4 alkyl groups and halogens; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a para-halogenated phenyl, ortho-halogenated phenyl, meta-halogenated phenyl, para-methylphenyl, ortho-methylphenyl, meta-methylphenyl, para-nitrophenyl, ortho-nitrophenyl, meta-nitrophenyl, meta-trifluoromethylphenyl, para-trifluoromethylphenyl, or meta-trifluoromethylphenyl group; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-11: 【Chemistry 24】 R ３ represents a C6-C8 aryl group-C1-C2 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a para-methylphenyl group, an ortho-methylphenyl group, or a meta-methylphenyl group; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-15: 【Chemistry 25】 R ３ represents a C6-C8 aryl group, or a C6-C8 aryl group-C1-C2 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents para-halogenated phenyl, ortho-halogenated phenyl, meta-halogenated phenyl, para-methylphenyl, ortho-methylphenyl, meta-methylphenyl, para-nitrophenyl, ortho-nitrophenyl, meta-nitrophenyl, meta-trifluoromethylphenyl, para-trifluoromethylphenyl, ortho-trifluoromethylphenyl, meta-trifluoromethoxyphenyl, para-trifluoromethoxyphenyl, or ortho-trifluoromethoxyphenyl; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-16: 【Chemical 26】 R ３ represents a C6-C8 aryl group-C1-C2 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents para-halogenated phenyl, ortho-halogenated phenyl, meta-halogenated phenyl, para-trifluoromethylphenyl, ortho-trifluoromethylphenyl, or meta-trifluoromethylphenyl; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-17: 【Chemical 27】 R ３ represents a C6-C8 aryl group-C1-C2 alkyl group; R ４ and R ５ each independently represents a hydrogen atom; R ６ represents a para-halogenated phenyl, an ortho-halogenated phenyl, or a meta-halogenated phenyl; n represents 1; a represents 0; Or, Compounds of formula I have the structure of formula I-34: 【Chemical formula 28】 R ３ represents a C1-C4 alkyl group, a C3-C8 cycloalkyl group, or a C6-C8 aryl group-C1-C2 alkyl group; R １４ , R １５ , R １６ and R １７ are each independently a hydrogen atom, a halogen atom, a methyl group, a nitro group, or —OCF ３ , or -CF ３ represents; a represents 1; R １８ represents a hydrogen atom or a C1-C4 alkyl group; 2. The compound according to claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

8. 2. The compound of claim 1, having the following structure: or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof. 【Chemical 29】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

9. (a) a compound of formula I according to claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier thereof. A drug composition characterized by:

10. Use of a compound of formula I according to claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, for preparing a composition or formulation for use in the prevention and / or treatment of tumors.

11. The tumor is a human tumor; and / or the tumor is selected from lung cancer, pancreatic cancer, breast cancer, lymphoma, prostate cancer, brain cancer, leukemia, liver cancer, melanoma, intestinal cancer, kidney cancer, colon cancer, or a combination thereof.

11. Use according to claim 10.

12. the colon cancer comprises colon adenocarcinoma; the breast cancer comprises triple-negative breast cancer; The liver cancer is undifferentiated or poorly differentiated liver cancer; The leukemia comprises acute myeloid leukemia; the lung cancer is selected from non-small cell lung cancer, small cell lung cancer, or a combination thereof; the lymphoma comprises a B-cell lymphoma; the intestinal cancer comprises rectal adenocarcinoma; the brain tumor is selected from glioblastoma, medulloblastoma, or a combination thereof; and / or the kidney cancer comprises renal clear cell adenocarcinoma.

12. Use according to claim 11.

13. The leukemia comprises M4 acute myeloid leukemia; and / or the rectal adenocarcinoma comprises Dukes' type C, grade IV rectal adenocarcinoma.

13. The use according to claim 12.

14. The tumor comprises a tumor in which the mitochondrial oxidative phosphorylation pathway is upregulated; The tumor comprises a tumor in which the mitochondrial permeability transition pore is hypoactive; The tumor includes a tumor in which the NNMT gene is underexpressed or not expressed; The tumor comprises a tumor in which a nucleotide site in the NNMT gene is hypermethylated; and / or the cancer comprises a tumor in which DNA CpG sites in the NNMT gene region are hypermethylated.

11. Use according to claim 10.

15. The upregulation of the mitochondrial oxidative phosphorylation pathway refers to a ratio (E1 / E0) between the level or expression level E1 of the mitochondrial oxidative phosphorylation pathway in tumor cells and the level or expression level E0 of the mitochondrial oxidative phosphorylation pathway in normal cells or similar cells of >1.0; The tumor in which the mitochondrial permeability transition pore is hypoactive refers to a tumor in which the ratio (A1 / A0) between the activity or expression level A1 of the mitochondrial permeability transition pore in tumor cells and the activity or expression level A0 of the mitochondrial permeability transition pore in normal cells or similar cells is <1.0; The tumor in which the NNMT gene is under-expressed or not expressed refers to a tumor in which the ratio (E1 / E0) between the expression level E1 of the NNMT gene in tumor cells and the expression level E0 of the NNMT gene in the same cells or normal cells is <1.0; A tumor in which the nucleotide site of the NNMT gene is hypermethylated refers to a tumor in which the ratio (L1 / L0) between the methylation level L1 of the nucleotide site of the NNMT gene in tumor cells and the methylation level L0 of the nucleotide site of the NNMT gene in the same cells or normal cells is >1.0; and / or A tumor in which the DNA CpG site of the NNMT gene region is hypermethylated refers to a tumor in which the ratio (W1 / W0) between the methylation level W1 of the DNA CpG site of the NMT gene region in tumor cells and the methylation level W0 of the DNA CpG site of the NMT gene region in the same cells or normal cells is >1.

0.

15. Use according to claim 14.

16. said expression includes protein expression and / or mRNA expression; The identical cells refer to similar tumor cells in which the mitochondrial oxidative phosphorylation pathway is normally expressed; The identical cells refer to similar tumor cells in which the activity of the mitochondrial permeability transition pore is normally expressed; The same cells refer to similar cells, even similar tumor cells in which the NNMT gene is normally expressed; The identical cells refer to similar tumor cells in which the nucleotide site of the NNMT gene is normally methylated; The identical cells refer to similar tumor cells in which the DNA CpG sites in the NNMT gene region are normally methylated; The normal cells refer to normal tissue cells in which the mitochondrial oxidative phosphorylation pathway is normally expressed; The normal cells refer to normal tissue cells in which the activity of the mitochondrial permeability transition pore is normally expressed; The normal cells refer to normal tissue cells in which the NNMT gene is normally expressed; The normal cells refer to normal tissue cells in which the nucleotide sites of the NNMT gene are normally methylated; and / or The normal cells refer to normal tissue cells in which the DNA CpG sites in the NNMT gene region are normally methylated.

16. Use according to claim 15.

17. A tumor in which the nucleotide site of the NNMT gene is hypermethylated has a methylation level M% of the nucleotide site of the NNMT gene in tumor cells of ≧3% and ≦100%; The methylation level of the nucleotide site of the NNMT gene refers to the ratio between the number of methylated nucleotides in the NNMT gene region and the number of all nucleotides in the NNMT gene region; The methylation level of the nucleotide site of the NNMT gene includes the methylation level of the nucleotide site of the NNMT gene promoter region; The methylation level of the nucleotide site of the NNMT gene includes the methylation level of the nucleotide site within a region from 1050 bp before the transcription start site of the NNMT gene to 499 bp after the transcription start site; The methylation level of the nucleotide site of the NNMT gene includes the methylation level of the nucleotide site within a region from 1050 bp before the transcription start site of the NNMT gene to 193 bp before the transcription start site; A tumor in which the DNA CpG site of the NNMT gene region is hypermethylated has a methylation level M% of the DNA CpG site of the NNMT gene region in tumor cells of ≥ 3% and ≤ 100%; The methylation level of the DNA CpG site in the NNMT gene region refers to the ratio between the number of methylated CpG nucleotides in the NNMT gene region and the number of all nucleotides in the NNMT gene region; The methylation level of the DNA CpG site in the NNMT gene region refers to the ratio between the number of methylated CpG nucleotides in the DNA of the NNMT gene region and the number of all CpG nucleotides in the DNA of the NNMT gene region; The methylation level of the DNA CpG site in the NNMT gene region includes the methylation level of the DNA CpG site in the NNMT gene promoter region; The methylation level of DNA CpG sites in the NNMT gene region includes the methylation level of DNA CpG sites in the region from 1050 bp before the transcription start site of the NNMT gene to 499 bp after the transcription start site; and / or The methylation level of the DNA CpG site in the NNMT gene region includes the methylation level of the DNA CpG site in the region from 1050 bp before the transcription start site of the NNMT gene to 193 bp before the transcription start site.

15. Use according to claim 14.

18. said M% being 95%; The nucleotide sequence of the NNMT gene promoter region is shown in SEQ ID NO: 1; The region from 1050 bp before the transcription start site to 499 bp after the transcription start site of the NNMT gene is from positions 951 to 2500 of the nucleotide sequence set forth in SEQ ID NO: 1; and / or The region from 1050 bp before the transcription start site to 193 bp before the transcription start site of the NNMT gene corresponds to positions 951 to 1808 of the nucleotide sequence shown in SEQ ID NO:

1.

18. Use according to claim 17.

19. the composition is a drug composition; The composition or formulation further comprises a pharmaceutically acceptable carrier; The composition or formulation is in solid, liquid or semi-solid form; and / or The composition or preparation is an oral preparation, an external preparation, or an injectable preparation.

11. Use according to claim 10.

20. (1) a first active ingredient serving as an anticancer agent, which is a compound of formula I according to claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof; (2) A second active ingredient that acts as an inhibitor of the mitochondrial membrane permeability transition pore. A drug composition characterized by:

21. (A) a first formulation comprising a first active ingredient as an anticancer agent, which is the compound of formula I according to claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof; (B) a second preparation containing a second active ingredient that acts as an inhibitor of the mitochondrial permeability transition pore.

22. The tumor is as claimed in any one of claims 11 to 18; and / or the inhibitor of the mitochondrial permeability transition pore is selected from Cyclosporin A, a CyP-D protein inhibitor, a peroxide scavenger, or a combination thereof.

21. The pharmaceutical composition of claim 20.

23. The tumor is as described in any one of claims 11 to 18; and / or the inhibitor of the mitochondrial permeability transition pore is selected from Cyclosporin A, a CyP-D protein inhibitor, a peroxide scavenger, or a combination thereof.

22. The medical kit of claim 21.

24. (i) a detection reagent used to detect the level of the mitochondrial oxidative phosphorylation pathway, the level of the mitochondrial permeability transition pore, the expression level of the NNMT gene, the methylation level of the nucleotide site of the NNMT gene and / or the methylation level of the DNA CpG site in the NNMT gene region; (ii) a compound of formula I according to claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof. A medical kit characterized by:

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