A benzene ring compound and application thereof

Abstract

The present application relates to a benzene ring compound and application thereof. Specifically, the present application provides a compound of formula I, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof. The compound described in the present application has excellent therapeutic effect on tumors.

Description

[0001] This application is a divisional application of the invention application filed on December 17, 2021, with application number 202180007785.3 and title "A Benzene Ring Compound and Its Application". Technical Field

[0002] This invention relates to the field of pharmaceuticals, and more specifically to a benzene ring compound and its applications. Background Technology

[0003] Cancer is a common disease that seriously threatens human health, and the mortality rate of malignant tumors continues to rise. Due to the heterogeneity of tumors and individual differences among patients, simply using the same treatment method or the same drug based on their origin or pathological characteristics can easily lead to inappropriate treatment, wasting valuable treatment time and opportunities for patients. Therefore, personalized treatment tailored to each patient's specific situation is essential. With the development of biological technology, cancer treatment has entered the era of precision medicine, and more and more alterations in the expression of tumor-related genes have been discovered. These alterations play an important role in the development of malignant tumors. The discovery and application of biomarkers will provide precise guidance for the application of related drugs, making personalized cancer treatment possible, thereby achieving targeted drug delivery and significantly improving treatment outcomes.

[0004] Therefore, there is an urgent need in this field to develop a drug that can provide precise treatment for tumors. Summary of the Invention

[0005] The purpose of this invention is to provide a safe and effective compound for inhibiting cancer and its applications.

[0006] Another objective of this invention is to provide biomarkers for determining whether cancer patients are suitable for prevention and / or treatment using the compounds described herein, based on the levels of mitochondrial oxidative phosphorylation pathway, mitochondrial membrane permeability transition pore, NNMT gene, and / or NNMT gene region DNA CpG site methylation. The compounds described herein exhibit significantly superior therapeutic effects against tumors with upregulated mitochondrial oxidative phosphorylation pathway, low activity of the mitochondrial membrane permeability transition pore, low or no expression of the NNMT gene, and / or high levels of NNMT gene region DNA CpG site methylation.

[0007] In a first aspect, the present invention provides a compound of formula I, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0008]

[0009] in,

[0010] Ring A is a substituted or unsubstituted C6-C16 aromatic ring, a substituted or unsubstituted C3-C16 cycloalkane ring, a substituted or unsubstituted 3-16 membered heterocyclic alkane ring, or a substituted or unsubstituted 3-16 membered heteroaromatic ring;

[0011] Ring B is an unsubstituted or substituted C6-C16 aromatic ring, a substituted or unsubstituted C3-C16 cycloalkane ring, a substituted or unsubstituted 3-16 membered heterocyclic alkane ring, or a substituted or unsubstituted 3-16 membered heteroaromatic ring.

[0012] R1 is

[0013] R2 is hydrogen.

[0014] R3 is free, hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, F3C-, F3C-O-, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C6-C16 aryl, substituted or unsubstituted 5-12 heteroaryl, substituted or unsubstituted C6-C16 aryl-substituted or unsubstituted C1-C10 alkyl-, substituted or unsubstituted 5-12 heteroaryl-substituted or unsubstituted C1-C10 alkyl;

[0015] R4 and R5 are each independently hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C6-C16 aryl, or substituted or unsubstituted 5-12 heteroaryl.

[0016] R6 is a substituted or unsubstituted C6-C16 aryl, or a substituted or unsubstituted 5-12-membered heteroaryl, a substituted or unsubstituted 3-16-membered cycloalkyl, or a substituted or unsubstituted 3-16-membered heterocycloalkyl.

[0017] n is 0, 1, 2, 3, 4, 5, or 6;

[0018] The ring C is an unsubstituted or substituted C6-C16 aromatic ring, a substituted or unsubstituted C3-C16 cycloalkane ring, a substituted or unsubstituted 3-16 membered heterocyclic alkane ring, or a substituted or unsubstituted 3-16 membered heteroaromatic ring;

[0019] R7 is hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C6-C16 aryl, or substituted or unsubstituted 5-12 heteroaryl.

[0020] R8 and R9 are linked to form substituted or unsubstituted 3-16 membered cycloalkane rings, or substituted or unsubstituted 3-16 membered heterocycloalkane rings;

[0021] R 10 and R 11 Each of these can be independently hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, F3C-O-, F3C-, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C6-C16 aryl, or substituted or unsubstituted 5-12 heteroaryl, substituted or unsubstituted C6-C16 aryl-substituted or unsubstituted C1-C10 alkyl-, or substituted or unsubstituted 5-12 heteroaryl-substituted or unsubstituted C1-C10 alkyl-, substituted or unsubstituted C1-C6 alkyl-C(O)-; or R 10 and R 11 Linkage forms substituted or unsubstituted 3-16 membered heterocyclic alkyl rings, or substituted or unsubstituted 3-16 membered heteroaromatic rings;

[0022] R 12 and R 13 Each of these can be independently hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, F3C-, F3C-O-, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C6-C16 aryl, substituted or unsubstituted 5-12 heteroaryl, substituted or unsubstituted C6-C16 aryl-substituted or unsubstituted C1-C10 alkyl-, substituted or unsubstituted 5-12 heteroaryl-substituted or unsubstituted C1-C10 alkyl-;

[0023] Any “substitution” refers to the substitution of one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on a ring or group by a substituent selected from the group consisting of: C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C3-C8 halocycloalkyl, halogen, nitro, -CN, hydroxyl, mercapto, amino, F3C-O-, F3C-, C1-C4 carboxyl, C2-C4 ester, C2-C4 amide, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, C6-C12 aryl, 5-10 heteroaryl, 5-10 heterocyclic alkyl;

[0024] The heterocyclic alkyl, heteroaryl, heterocyclic alkyl, and heteroaromatic rings each have 1 to 4 (preferably 1, 2, 3, or 4) heteroatoms selected from N, O, and S.

[0025] In another preferred embodiment, any “substitution” refers to one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on a ring or group being replaced by a substituent selected from the group consisting of: C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C8 halocycloalkyl, halogen, nitro, -CN, hydroxyl, mercapto, amino, F3C-O-, F3C-, C1-C4 carboxyl, C2-C4 ester, C2-C4 amide, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkylthio, C6-C12 aryl, 5-10 heteroaryl, 5-10 heterocyclic alkyl.

[0026] In another preferred embodiment, any “substitution” refers to one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on a ring or group being replaced by a substituent selected from the group consisting of: C1-C4 alkyl, C3-C8 cycloalkyl, C1-C4 haloalkyl, C3-C8 halocycloalkyl, halogen, nitro, -CN, hydroxyl, mercapto, amino, F3C-O-, F3C-, C1-C4 carboxyl, C2-C4 ester, C2-C4 amide, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 haloalkoxy, C1-C4 haloalkylthio, C6-C12 aryl, 5-10 heteroaryl, 5-10 heterocyclic alkyl.

[0027] In another preferred embodiment, each of the heterocyclic alkyl, heteroaryl, heterocyclic alkyl, and heteroaromatic rings has 1 to 4 (preferably 1, 2, 3, or 4) heteroatoms selected from N, O, and S.

[0028] In another preferred embodiment, the halogen is F, Cl, Br or I.

[0029] In another preferred embodiment, the cycloalkane ring has one, two, or three C=C ring double bonds.

[0030] In another preferred embodiment, the heterocyclic alkyl ring has 1, 2, or 3 C=C ring double bonds. In another preferred embodiment, each of the heterocyclic alkyl, heteroaryl, heterocyclic alkyl, and heteroaryl rings independently has 1 to 4 (preferably 1, 2, 3, or 4) heteroatoms selected from N, O, and S.

[0031] In another preferred embodiment, ring A is a substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted C3-C12 cycloalkane ring, a substituted or unsubstituted 3-12 membered heterocyclic alkyl ring, or a substituted or unsubstituted 3-12 membered heteroaromatic ring.

[0032] In another preferred embodiment, ring A is a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted C3-C10 cycloalkane ring, a substituted or unsubstituted 3-10 membered heterocyclic alkyl ring, or a substituted or unsubstituted 3-10 membered heteroaromatic ring.

[0033] In another preferred embodiment, ring A is a substituted or unsubstituted C6-C8 aromatic ring, a substituted or unsubstituted C3-C8 cycloalkane ring, a substituted or unsubstituted 3-8 membered heterocyclic alkyl ring, or a substituted or unsubstituted 5-8 membered heteroaromatic ring.

[0034] In another preferred embodiment, ring A is an unsubstituted or substituted 5-membered heterocyclic alkyl ring, a substituted or unsubstituted 6-membered heterocyclic alkyl ring, a substituted or unsubstituted 7-membered heterocyclic alkyl ring, a substituted or unsubstituted 8-membered heterocyclic alkyl ring, a substituted or unsubstituted 5-membered heteroaromatic ring, a substituted or unsubstituted 6-membered heteroaromatic ring, a substituted or unsubstituted 7-membered heteroaromatic ring, or a substituted or unsubstituted 8-membered heteroaromatic ring.

[0035] In another preferred embodiment, ring A is a substituted or unsubstituted 5-membered heteroaromatic ring, a substituted or unsubstituted 6-membered heteroaromatic ring, a substituted or unsubstituted 7-membered heteroaromatic ring, or a substituted or unsubstituted 8-membered heteroaromatic ring.

[0036] In another preferred embodiment, ring A is a substituted or unsubstituted aridine ring, a substituted or unsubstituted pyrimidine ring, a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted thiazole ring, a substituted or unsubstituted imidazole ring, or a substituted or unsubstituted pyrrole ring.

[0037] In another preferred embodiment, ring A is a pyrimidine ring, a benzene ring, a naphthalene ring, a thiazole ring, or an imidazole ring.

[0038] In another preferred embodiment, R1 is attached to a cyclic heteroatom of ring A.

[0039] In another preferred embodiment, R1 is attached to a ring N, O, or S atom of ring A.

[0040] In another preferred embodiment, R1 is attached to the ring N atom of ring A.

[0041] In another preferred embodiment, R2 is attached to the cyclic carbon atom of ring A.

[0042] In another preferred embodiment, ring B is an unsubstituted or substituted C6-C12 aromatic ring, a substituted or unsubstituted C3-C12 cycloalkane ring, a substituted or unsubstituted 3-12 membered heterocyclic alkyl ring, or a substituted or unsubstituted 3-12 membered heteroaromatic ring.

[0043] In another preferred embodiment, ring B is an unsubstituted or substituted C6-C10 aromatic ring, a substituted or unsubstituted C3-C10 cycloalkane ring, a substituted or unsubstituted 3-10 membered heterocyclic alkyl ring, or a substituted or unsubstituted 3-10 membered heteroaromatic ring.

[0044] In another preferred embodiment, ring B is an unsubstituted or substituted C6-C8 aromatic ring, a substituted or unsubstituted C5-C8 cycloalkane ring, a substituted or unsubstituted 5-8 membered heterocyclic alkyl ring, or a substituted or unsubstituted 5-8 membered heteroaromatic ring.

[0045] In another preferred embodiment, ring B is an unsubstituted or substituted 5-membered heterocyclic alkyl ring, a substituted or unsubstituted 6-membered heterocyclic alkyl ring, a substituted or unsubstituted 7-membered heterocyclic alkyl ring, a substituted or unsubstituted 8-membered heterocyclic alkyl ring, a substituted or unsubstituted 5-membered heteroaromatic ring, a substituted or unsubstituted 6-membered heteroaromatic ring, a substituted or unsubstituted 7-membered heteroaromatic ring, or a substituted or unsubstituted 8-membered heteroaromatic ring.

[0046] In another preferred embodiment, the heterocyclic ring has one, two, or three carbon-carbon double bonds.

[0047] In another preferred embodiment, ring B is an unsubstituted or substituted tetrahydropyridine ring, a substituted or unsubstituted pyrrole ring, a substituted or unsubstituted dihydropyrrole ring, a substituted or unsubstituted imidazole ring, or a substituted or unsubstituted pyrazole ring.

[0048] In another preferred embodiment, ring B is absent, a tetrahydropyridine ring, a piperidine ring, a pyrrole ring, a dihydropyrrole ring, a tetrahydropyrrole ring, an imidazole ring, a pyrazole ring, or a pyridine ring. ring, ring.

[0049] In another preferred embodiment, R3 is attached to the cyclic carbon atom of ring B.

[0050] In another preferred embodiment, R3 is attached to a cyclic heteroatom of ring B.

[0051] In another preferred embodiment, R3 is attached to a ring N, O, or S atom of ring B.

[0052] In another preferred embodiment, R3 is attached to the ring N atom of ring B.

[0053] In another preferred embodiment, the described The connection method with ring A is as follows

[0054] In another preferred embodiment, the described The connection method with ring A is as follows

[0055] In another preferred embodiment, the tetrahydropyridine ring is a 1,2,3,4-tetrahydropyridine ring.

[0056] In another preferred embodiment, the pyrrole ring is a 1-hydropyrrole ring.

[0057] In another preferred embodiment, the dihydropyrrole ring is a 2,3-dihydropyrrole ring.

[0058] In another preferred embodiment, ring B is absent.

[0059] It should be understood in this invention that when ring B is absent, the structure of the compound of formula I is as shown in structure I-1 below:

[0060]

[0061] In another preferred embodiment, the compound of formula I is a compound of formula I-1:

[0062]

[0063] In another preferred embodiment, ring B is absent, and R2 is...

[0064] In another preferred embodiment, ring B is a substituted or unsubstituted C6-C16 aromatic ring, a substituted or unsubstituted C3-C16 cycloalkane ring, a substituted or unsubstituted 3-16 membered heterocyclic alkyl ring, or a substituted or unsubstituted 3-16 membered heteroaromatic ring, and R2 is hydrogen.

[0065] In another preferred embodiment, R1 is

[0066] In another preferred embodiment, R1 is

[0067] In another preferred embodiment, R2 is hydrogen,

[0068] In another preferred embodiment, R2 is hydrogen,

[0069] In another preferred embodiment, R3 is hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, F3C-O-, F3C-, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C8 alkyl-, or substituted or unsubstituted 5-10 heteroaryl-substituted or unsubstituted C1-C8 alkyl-.

[0070] In another preferred embodiment, R3 is hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, F3C-O-, F3C-, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C6-C10 aryl-substituted or unsubstituted C1-C4 alkyl-, or substituted or unsubstituted 5-10 heteroaryl-substituted or unsubstituted C1-C4 alkyl-.

[0071] In another preferred embodiment, R3 is hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, F3C-O-, F3C-, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylthio, substituted or unsubstituted C6-C8 aryl, or substituted or unsubstituted 5-8 heteroaryl, substituted or unsubstituted C6-C8 aryl-substituted or unsubstituted C1-C2 alkyl-, or substituted or unsubstituted 5-8 heteroaryl-substituted or unsubstituted C1-C2 alkyl-.

[0072] In another preferred embodiment, R3 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyl-methyl-, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridyl-methyl-, substituted or unsubstituted phenyl-ethyl-, or substituted or unsubstituted pyridyl-ethyl-.

[0073] In another preferred embodiment, R3 is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyl-methyl-, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridyl-methyl-, substituted or unsubstituted phenyl-ethyl-, or substituted or unsubstituted pyridyl-ethyl-.

[0074] In another preferred embodiment, R3 is hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyl-methyl-, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridyl-methyl-, substituted or unsubstituted phenyl-ethyl-, or substituted or unsubstituted pyridyl-ethyl-.

[0075] In another preferred embodiment, the substituted or unsubstituted phenyl group is a monosubstituted or unsubstituted phenyl group.

[0076] In another preferred embodiment, the substituted or unsubstituted phenyl group is a monosubstituted or unsubstituted phenyl group, and the substitution is an ortho, para, or meta substitution of the phenyl group.

[0077] In another preferred embodiment, in the substituted or unsubstituted phenyl group, the substituted or unsubstituted phenyl group is a monosubstituted or unsubstituted phenyl group, and the substitution is an ortho, para, or meta substitution of the phenyl group, wherein the substituent is a halogen (such as chlorine), nitro, amino, C1-C4 alkyl (such as methyl), C1-C4 alkoxy, C1-C4 alkylthio, F3C-, F3C-O-.

[0078] In another preferred embodiment, in the substituted or unsubstituted phenyl-methyl-, the substituted or unsubstituted phenyl is a monosubstituted or unsubstituted phenyl.

[0079] In another preferred embodiment, in the substituted or unsubstituted phenyl-methyl-, the substituted or unsubstituted phenyl is a monosubstituted or unsubstituted phenyl, and the substitution is an ortho, para, or meta substitution of the phenyl.

[0080] In another preferred embodiment, in the substituted or unsubstituted phenyl-methyl-, the substituted or unsubstituted phenyl is a monosubstituted or unsubstituted phenyl, and the substitution is an ortho, para, or meta substitution of the phenyl, and the substituent is a halogen (such as chlorine), nitro, amino, C1-C4 alkyl (such as methyl), C1-C4 alkoxy, C1-C4 alkylthio, F3C-, F3C-O-.

[0081] In another preferred embodiment, the substituted phenyl group is a monosubstituted phenyl group.

[0082] In another preferred embodiment, R4 and R5 are each independently hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 heteroaryl.

[0083] In another preferred embodiment, R4 and R5 are each independently hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 heteroaryl.

[0084] In another preferred embodiment, R4 and R5 are each independently hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylthio, substituted or unsubstituted C6-C8 aryl, or substituted or unsubstituted 5-8 heteroaryl.

[0085] In another preferred embodiment, R4 and R5 are each independently hydrogen, methyl, ethyl, propyl, or butyl.

[0086] In another preferred embodiment, n is 0, 1, 2, 3, 4, 5, or 6.

[0087] In this invention, it should be understood that when n is 0, for

[0088] In another preferred embodiment, R6 is a substituted or unsubstituted C6-C12 aryl, or a substituted or unsubstituted 5-12 heteroaryl, a substituted or unsubstituted 3-12 cycloalkyl, or a substituted or unsubstituted 3-12 heterocycloalkyl.

[0089] In another preferred embodiment, R6 is a substituted or unsubstituted C6-C10 aryl, or a substituted or unsubstituted 5-10 heteroaryl, a substituted or unsubstituted 3-8 cycloalkyl, or a substituted or unsubstituted 3-8 heterocycloalkyl.

[0090] In another preferred embodiment, R6 is a substituted or unsubstituted C6-C8 aryl, or a substituted or unsubstituted 5-8 membered heteroaryl, a substituted or unsubstituted 3-8 membered cycloalkyl, or a substituted or unsubstituted 3-8 membered heterocycloalkyl.

[0091] In another preferred embodiment, R6 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, or a substituted or unsubstituted pyrazinyl group.

[0092] In another preferred embodiment, the substituted or unsubstituted phenyl group is a monosubstituted or unsubstituted phenyl group.

[0093] In another preferred embodiment, the substituted or unsubstituted phenyl group is a monosubstituted or unsubstituted phenyl group, and the substitution is an ortho, para, or meta substitution of the phenyl group.

[0094] In another preferred embodiment, the substituted or unsubstituted phenyl group is a monosubstituted or unsubstituted phenyl group, and the substitution is an ortho, para, or meta substitution of the phenyl group, wherein the substituent is a halogen, nitro, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, F3C-, F3C-O-, C6-C12 aryl, or 5-10 heteroaryl.

[0095] In another preferred embodiment, the substituted or unsubstituted phenyl group is a monosubstituted or unsubstituted phenyl group, and the substitution is an ortho, para, or meta substitution of the phenyl group, wherein the substituent is a halogen, nitro, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, F3C-, F3C-O-, or phenyl.

[0096] In another preferred embodiment, the substituted phenyl group is a monosubstituted phenyl group.

[0097] In another preferred embodiment, R6 is m-nitrophenyl, o-nitrophenyl, p-nitrophenyl, phenyl, p-methylphenyl, o-methylphenyl, m-methylphenyl, m-aminophenyl, p-aminophenyl, o-aminophenyl, m-methoxyphenyl, p-methoxyphenyl, o-methoxyphenyl, m-trifluoromethoxyphenyl, p-trifluoromethoxyphenyl, o-trifluoromethoxyphenyl, p-halophenyl, o-halophenyl, m-halophenyl, p-trifluoromethylphenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, p-phenylphenyl, o-phenylphenyl, m-phenylphenyl, pyridyl, Pyrazinyl, monomethyl-substituted pyrazinyl.

[0098] In another preferred embodiment, R7 is hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 heteroaryl.

[0099] In another preferred embodiment, R7 is hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C4 alkylthio, substituted or unsubstituted C6-C8 aryl, or substituted or unsubstituted 5-8 heteroaryl.

[0100] In another preferred embodiment, R7 is hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C4 alkylthio, substituted or unsubstituted C6-C8 aryl, or substituted or unsubstituted 5-8 heteroaryl.

[0101] In another preferred embodiment, R7 is hydrogen.

[0102] In another preferred embodiment, R8 and R9 are connected to form a substituted or unsubstituted 3-12 membered cycloalkane ring or a substituted or unsubstituted 3-12 membered heterocycloalkane ring.

[0103] In another preferred embodiment, R8 and R9 are connected to form a substituted or unsubstituted 3-10 membered cycloalkane ring or a substituted or unsubstituted 3-10 membered heterocycloalkane ring.

[0104] In another preferred embodiment, R8 and R9 are connected to form a substituted or unsubstituted 3-8 membered cycloalkane ring or a substituted or unsubstituted 3-8 membered heterocycloalkane ring.

[0105] In another preferred embodiment, R8 and R9 are connected to form a substituted or unsubstituted 5-8 membered cycloalkane ring or a substituted or unsubstituted 5-8 membered heterocycloalkane ring.

[0106] In another preferred embodiment, R8 and R9 are connected to form a substituted or unsubstituted 5-6 membered cycloalkane ring or a substituted or unsubstituted 5-6 membered heterocycloalkane ring.

[0107] In another preferred embodiment, R8 and R9 are connected to form a substituted or unsubstituted 5-membered cycloalkane ring or a substituted or unsubstituted 6-membered cycloalkane ring.

[0108] In another preferred embodiment, the cycloalkane ring has one, two, or three carbon-carbon double bonds (C=C).

[0109] In another preferred embodiment, R8 and R9 are connected to form a substituted or unsubstituted cyclopentene ring or cyclohexene ring.

[0110] In another preferred embodiment, the ring C is an unsubstituted or substituted C6-C12 aromatic ring, a substituted or unsubstituted C3-C12 cycloalkane ring, a substituted or unsubstituted 3-12 membered heterocyclic alkyl ring, or a substituted or unsubstituted 3-12 membered heteroaromatic ring.

[0111] In another preferred embodiment, the ring C is an unsubstituted or substituted C6-C10 aromatic ring, a substituted or unsubstituted C3-C10 cycloalkane ring, a substituted or unsubstituted 3-10 membered heterocyclic alkyl ring, or a substituted or unsubstituted 3-10 membered heteroaromatic ring.

[0112] In another preferred embodiment, the ring C is an unsubstituted or substituted C6-C8 aromatic ring, a substituted or unsubstituted C5-C10 cycloalkane ring, a substituted or unsubstituted 5-10 membered heterocyclic alkyl ring, or a substituted or unsubstituted 5-8 membered heteroaromatic ring.

[0113] In another preferred embodiment, ring C is a substituted or unsubstituted benzene ring, and ring C is a substituted or unsubstituted arsenic ring.

[0114] In another preferred embodiment, ring C is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted arsenic ring, wherein any “substitution” is the substitution of 1, 2 or 3 hydrogen atoms on the group by a substituent selected from the group consisting of: methyl, halogen, nitro, -CN, hydroxy, mercapto, amino, F3C-O-, F3C-, methoxy-.

[0115] In another preferred embodiment, R 10 and R 11 Each of these can be independently hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, F3C-O-, F3C-, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-12 heteroaryl, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C8 alkyl-, or substituted or unsubstituted 5-12 heteroaryl-substituted or unsubstituted C1-C8 alkyl-, substituted or unsubstituted C1-C4 alkyl-C(O)-; or R 10 and R 11 They can be linked to form substituted or unsubstituted 3-12 membered heterocyclic alkyl rings or substituted or unsubstituted 3-12 membered heteroaromatic rings.

[0116] In another preferred embodiment, R 10 and R 11 Each of these can be independently hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, F3C-O-, F3C-, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted C6-C8 aryl, or substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C6-C10 aryl-substituted or unsubstituted C1-C4 alkyl-, or substituted or unsubstituted 5-10 heteroaryl-substituted or unsubstituted C1-C4 alkyl-, substituted or unsubstituted C1-C4 alkyl-C(O)-; or R 10 and R 11 They can be linked to form substituted or unsubstituted 5-12 membered heterocyclic alkyl rings or substituted or unsubstituted 5-12 membered heteroaromatic rings.

[0117] In another preferred embodiment, R 10 and R 11 Each of these can be independently hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, F3C-O-, F3C-, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylthio, substituted or unsubstituted C6-C8 aryl, or substituted or unsubstituted 5-8 heteroaryl, substituted or unsubstituted C6-C8 aryl-substituted or unsubstituted C1-C2 alkyl-, or substituted or unsubstituted 5-8 heteroaryl-substituted or unsubstituted C1-C2 alkyl-, substituted or unsubstituted C1-C4 alkyl-C(O)-; or R 10 and R 11 They can be linked to form substituted or unsubstituted 5-12 membered heterocyclic alkyl rings or substituted or unsubstituted 5-12 membered heteroaromatic rings.

[0118] In another preferred embodiment, the substituted or unsubstituted 3-12 membered heterocyclic alkyl ring is a substituted or unsubstituted C6-C8 aromatic ring and a substituted or unsubstituted monocyclic C5-C8 heterocyclic alkyl ring.

[0119] In another preferred embodiment, the substituted or unsubstituted 5-12 membered heterocyclic alkyl ring is a substituted or unsubstituted C6-C8 aromatic ring and a substituted or unsubstituted monocyclic C5-C8 heterocyclic alkyl ring.

[0120] In another preferred embodiment, R 10 and R 11 Each of these can be independently hydrogen, methyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyl-C1-C2 alkyl-, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridyl-C1-C2 alkyl-, substituted or unsubstituted C1-C3 alkyl-C(O)-; or R 10 and R 11 The rings are linked to form substituted or unsubstituted isoquinoline rings, substituted or unsubstituted quinoline rings, substituted or unsubstituted tetrahydroisoquinoline rings, substituted or unsubstituted tetrahydroquinoline rings, and substituted or unsubstituted dihydroisoquinoline-1 one rings.

[0121] In another preferred embodiment, the tetrahydroquinoline ring is a 1,2,3,4-tetrahydroquinoline ring.

[0122] In another preferred embodiment, the dihydroisoquinoline-1 one ring is a 3,4-dihydroisoquinoline-1 one ring.

[0123] In another preferred embodiment, the substituted or unsubstituted phenyl-C1-C2 alkyl- is a substituted or unsubstituted phenyl-methyl- or a substituted or unsubstituted phenyl-ethyl-.

[0124] In another preferred embodiment, in the substituted or unsubstituted phenyl-C1-C2 alkyl-, the substituted or unsubstituted phenyl is a monosubstituted or unsubstituted phenyl.

[0125] In another preferred embodiment, in the substituted or unsubstituted phenyl-C1-C2 alkyl-, the substituted or unsubstituted phenyl is a monosubstituted or unsubstituted phenyl, and the substitution is an ortho, para, or meta substitution of the phenyl.

[0126] In another preferred embodiment, in the substituted or unsubstituted phenyl-C1-C2 alkyl-, the substituted or unsubstituted phenyl is a monosubstituted or unsubstituted phenyl, and the substitution is an ortho, para, or meta substitution of the phenyl, and the substituent is a halogen, nitro, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, F3C-, or F3C-O-.

[0127] In another preferred embodiment, the substituted phenyl group is a monosubstituted phenyl group.

[0128] In another preferred embodiment, the substituted or unsubstituted phenyl-C1-C2 alkyl- is a substituted or unsubstituted phenyl-methyl- or a substituted or unsubstituted phenyl-ethyl-.

[0129] In another preferred embodiment, R 12 and R 13 Each of these can be independently hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, F3C-, F3C-O-, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-12 heteroaryl, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C6 alkyl-, or substituted or unsubstituted 5-12 heteroaryl-substituted or unsubstituted C1-C6 alkyl-.

[0130] In another preferred embodiment, R 12 and R 13 Each of these can be independently hydrogen, halogen, -CN, hydroxyl, mercapto, nitro, amino, F3C-, F3C-O-, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylthio, substituted or unsubstituted C6-C8 aryl, or substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C6-C8 aryl-substituted or unsubstituted C1-C2 alkyl-, or substituted or unsubstituted 5-8 heteroaryl-substituted or unsubstituted C1-C2 alkyl-.

[0131] In another preferred embodiment, R 12 and R 13 Each can be independently classified as hydrogen, halogen, or phenyl.

[0132] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-2 below:

[0133]

[0134] R4, R5, R6 and n are defined as above.

[0135] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-3 below:

[0136]

[0137] R4, R5, R6 and n are defined as above.

[0138] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-4 below:

[0139]

[0140] Among them, R4, R5, R6, R 10 R 11 And n is as defined above.

[0141] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-5 below:

[0142]

[0143] Among them, R4, R5, R6, R 10 R 11 And n is as defined above.

[0144] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-6 below:

[0145]

[0146] R3, R4, R5, R6 and n are defined as above.

[0147] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-7 below:

[0148]

[0149] R3 is defined as above;

[0150] R 15 R 16 and R17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3.

[0151] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-8 below:

[0152]

[0153] R3 is defined as above;

[0154] R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl), methyl, nitro, or phenyl.

[0155] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-9 below:

[0156]

[0157] R3, R4, R5, R6 and n are defined as above;

[0158] a is 0, 1, or 2;

[0159] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0160] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-10 below:

[0161]

[0162] R3, R4, R5, R6 and n are defined as above;

[0163] a is 0, 1, or 2;

[0164] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0165] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-11 below:

[0166]

[0167] R3, R4, R5, R6 and n are defined as above;

[0168] a is 0, 1, or 2;

[0169] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0170] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-12 below:

[0171]

[0172] R3, R4, R5, R6 and n are defined as above;

[0173] a can be 0, 1, 2, or 3;

[0174] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0175] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-13 below:

[0176]

[0177] R3, R4, R5, R6 and n are defined as above;

[0178] a can be 0, 1, 2, 3, or 4;

[0179] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0180] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-14 below:

[0181]

[0182]

[0183] R3, R4, R5, R6 and n are defined as above;

[0184] a can be 0, 1, 2, or 3;

[0185] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0186] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-15 below:

[0187]

[0188] R3, R4, R5, R6 and n are defined as above;

[0189] a is 0, 1, or 2;

[0190] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0191] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-16 below:

[0192]

[0193] R3, R4, R5, R6 and n are defined as above;

[0194] a is 0, 1, or 2;

[0195] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0196] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-17 below:

[0197]

[0198] R3, R4, R5, R6 and n are defined as above;

[0199] a is 0, 1, or 2;

[0200] Each R 18It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0201] In another preferred embodiment, the structure of the compound of formula I is as shown in structure I-18:

[0202]

[0203] R3, R4, R5, R6 and n are defined as above.

[0204] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-19 below:

[0205]

[0206] R3 is defined as above.

[0207] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-20 below:

[0208]

[0209] R3, R4, R5, R6 and n are defined as above;

[0210] a can be 0, 1, 2, 3, 4, or 5;

[0211] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0212] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-21 below:

[0213]

[0214] R3 is defined as above;

[0215] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3;

[0216] a can be 0, 1, 2, 3, 4, or 5;

[0217] Each R18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0218] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-22 below:

[0219]

[0220] R3 is defined as above;

[0221] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3;

[0222] a is 1, 2, 3, 4 or 5;

[0223] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0224] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-23 below:

[0225]

[0226] R3, R4, R5, R6 and n are defined as above;

[0227] a is 1, 2, 3, 4 or 5;

[0228] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0229] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-24 below:

[0230]

[0231] R3 is defined as above;

[0232] a can be 0, 1, 2, 3, 4, or 5;

[0233] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3;

[0234] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0235] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-25 below:

[0236]

[0237] R3 is defined as above;

[0238] a can be 0, 1, 2, 3, 4, or 5;

[0239] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3;

[0240] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0241] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-26 below:

[0242]

[0243] Among them, R 10 R 11 And ring C is as defined above.

[0244] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-27 below:

[0245]

[0246] Among them, R 10 R11 And ring C is as defined above.

[0247] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-28 below:

[0248]

[0249] Among them, R 10 and R 11 As defined above;

[0250] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3.

[0251] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-29 below:

[0252]

[0253] Among them, R 10 and R 11 As defined above;

[0254] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3.

[0255] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-30 below:

[0256]

[0257] Among them, R 10 and R 11 As defined above;

[0258] R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3.

[0259] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-31 below:

[0260]

[0261]

[0262] Among them, R 10 and R 11 As defined above;

[0263] R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3.

[0264] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-32 below:

[0265]

[0266] R3 is defined as above;

[0267] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3;

[0268] a can be 0, 1, 2, or 3;

[0269] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0270] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-33 below:

[0271]

[0272] R3 is defined as above;

[0273] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3;

[0274] a can be 0, 1, 2, or 3;

[0275] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0276] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-34 below:

[0277]

[0278] R3 is defined as above;

[0279] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3;

[0280] a can be 0, 1, 2, or 3;

[0281] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0282] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-35 below:

[0283]

[0284] R3 is defined as above;

[0285] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3;

[0286] a can be 0, 1, 2, or 3;

[0287] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0288] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-36 below:

[0289]

[0290] R3 is defined as above;

[0291] R14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3;

[0292] a can be 0, 1, 2, or 3;

[0293] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0294] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-37 below:

[0295]

[0296] R3 is defined as above;

[0297] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3;

[0298] a can be 0, 1, 2, or 3;

[0299] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0300] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-38 below:

[0301]

[0302] R3, R4, R5, R6 and n are defined as above;

[0303] a can be 0, 1, 2, or 3;

[0304] Each R 18 It is independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 heterocyclic alkyl, or substituted or unsubstituted 5-8 heteroaryl.

[0305] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-39 below:

[0306]

[0307] in,

[0308] R 10 and R 11 As defined above;

[0309] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3, -CF3.

[0310] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-40 below:

[0311]

[0312] Among them, R4, R5, R6, R 10 R 11 and n are as defined above;

[0313] R 19 It is hydrogen, substituted or unsubstituted C1-C6 alkyl.

[0314] In another preferred embodiment, R 19 It is hydrogen, substituted or unsubstituted C1-C4 alkyl (such as methyl).

[0315] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-41 below:

[0316]

[0317] Among them, R4, R5, R6, R 10 R 11 and n are as defined above;

[0318] R 20 It consists of hydrogen and halogens.

[0319] In another preferred embodiment, R 19 It is hydrogen, substituted or unsubstituted C1-C4 alkyl (such as methyl).

[0320] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-42 below:

[0321]

[0322] R4, R5, R6 and n are defined as above.

[0323] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-43 below:

[0324]

[0325] R3 is defined as above;

[0326] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, -CF3, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3;

[0327] R 19 It is hydrogen, substituted or unsubstituted C1-C6 alkyl.

[0328] In another preferred embodiment, R 19 It is hydrogen, substituted or unsubstituted C1-C4 alkyl (such as methyl).

[0329] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-44 below:

[0330]

[0331] R3 is defined as above;

[0332] R 14 R 15 R 16 and R 17 Each can be independently hydrogen, -CF3, halogen (such as Cl, F), methyl, nitro, phenyl, -OCF3;

[0333] R 19 It is hydrogen, substituted or unsubstituted C1-C6 alkyl.

[0334] In another preferred embodiment, R 19 It is hydrogen, substituted or unsubstituted C1-C4 alkyl (such as methyl).

[0335] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-45 below:

[0336]

[0337] Among them, R4, R5, R6, R 10 R 11 And n is as defined above.

[0338] In another preferred embodiment, the structure of the compound of formula I is shown in structure I-46 below:

[0339]

[0340] Among them, R4, R5, R6, R 10 R 11 And n is as defined above.

[0341] In another preferred embodiment, 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 the group consisting of: hydrochloric acid, mucoic 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, glutamic acid, or combinations thereof.

[0342] In another preferred embodiment, the compound of formula I has the following structure:

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371] In a second aspect, the present invention provides a pharmaceutical composition comprising (a) a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.

[0372] A third aspect of the present invention provides the use of a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a composition or formulation for the prevention and / or treatment of cancer.

[0373] In another preferred embodiment, the cancer is selected from the group consisting of: lung cancer, pancreatic cancer, breast cancer, lymphoma, prostate cancer, brain cancer, leukemia, liver cancer, melanoma, intestinal cancer, kidney cancer, colon cancer, or combinations thereof.

[0374] In another preferred embodiment, the tumor is a human tumor.

[0375] In another preferred embodiment, the tumor is a human tumor.

[0376] In another preferred embodiment, the colon cancer includes colonic adenocarcinoma.

[0377] In another preferred embodiment, the mitochondrial membrane permeability transition pores in the cancer cells are of low activity.

[0378] In another preferred embodiment, the cancer includes cancers in which the mitochondrial membrane permeability transition pore is of low activity.

[0379] In another preferred embodiment, the low activity of the mitochondrial membrane permeability transition pore refers to the ratio (A1 / A0) of the activity level or expression level A1 of the mitochondrial membrane permeability transition pore in a certain cell (such as a cancer cell) to the activity level or expression level A0 of the mitochondrial membrane permeability transition pore in normal cells (of the same type of cell) < 1.0, preferably ≤ 0.8, more preferably ≤ 0.7, more preferably ≤ 0.6, more preferably ≤ 0.5, more preferably ≤ 0.4, more preferably ≤ 0.3, more preferably ≤ 0.2, more preferably ≤ 0.1, and most preferably ≤ 0.05.

[0380] In another preferred embodiment, the same cell refers to a cell in which the activity of the mitochondrial membrane permeability transition pore is normally expressed (such as a type of cancer cell).

[0381] In another preferred embodiment, the same cell refers to cells of the same species but with normal expression of mitochondrial membrane permeability transition pore activity.

[0382] In another preferred embodiment, the normal cells refer to normal tissue cells (such as tumor cell origin cells, tumor-adjacent cells, or adjacent cancer cells) that exhibit normal expression of mitochondrial membrane permeability transition pore activity.

[0383] In another preferred embodiment, the breast cancer includes triple-negative breast cancer.

[0384] In another preferred embodiment, the liver cancer is anaplastic poorly differentiated liver cancer.

[0385] In another preferred embodiment, the leukemia includes acute myeloid leukemia.

[0386] In another preferred embodiment, the leukemia includes M4 type acute myeloid leukemia.

[0387] In another preferred embodiment, the lung cancer is selected from the group consisting of small cell lung cancer, non-small cell lung cancer, or a combination thereof.

[0388] In another preferred embodiment, the lymphoma includes B-cell lymphoma.

[0389] In another preferred embodiment, the colorectal cancer includes colorectal adenocarcinoma.

[0390] In another preferred embodiment, the colorectal adenocarcinoma includes Dukes' type C, grade IV colorectal adenocarcinoma.

[0391] In another preferred embodiment, the brain cancer is selected from the group consisting of medulloblastoma, glioblastoma, or a combination thereof.

[0392] In another preferred embodiment, the renal cell carcinoma includes clear cell adenocarcinoma of the kidney.

[0393] In another preferred embodiment, the mitochondrial oxidative phosphorylation pathway is modulated and / or the mitochondrial membrane permeability transition pore activity is reduced in the cancer cells of the said cancer.

[0394] In another preferred embodiment, the mitochondrial oxidative phosphorylation pathway is upregulated in the cancer cells of the said cancer.

[0395] In another preferred embodiment, the cancer includes cancers in which the mitochondrial oxidative phosphorylation pathway is upregulated.

[0396] In another preferred embodiment, the mitochondrial membrane permeability transition pores in the cancer cells of the said cancer are low in activity.

[0397] In another preferred embodiment, the upregulation of the mitochondrial oxidative phosphorylation pathway refers to the ratio (E1 / E0) of the mitochondrial oxidative phosphorylation pathway level or expression E1 in a certain cell (such as a cancer cell) to the mitochondrial oxidative phosphorylation pathway level or expression E0 in normal cells (the same type of cells) being >1.0, preferably ≥1.2, more preferably ≥1.5, more preferably ≥2, more preferably ≥3, and more preferably ≥5.

[0398] In another preferred embodiment, the same cell refers to a cell that normally expresses the mitochondrial oxidative phosphorylation pathway (such as a type of cancer cell).

[0399] In another preferred embodiment, the same cell refers to cells of the same species but with normal expression of the mitochondrial oxidative phosphorylation pathway.

[0400] In another preferred embodiment, the normal cells refer to normal tissue cells (such as tumor cell origin cells, tumor-adjacent cells, or adjacent normal tissue cells) that express the mitochondrial oxidative phosphorylation pathway normally.

[0401] In another preferred embodiment, the normal cells (isocytocytes) include cells insensitive to the compound of formula I, its optical isomer or racemate, its solvate, or its pharmaceutically acceptable salt.

[0402] In another preferred embodiment, the low activity of the mitochondrial membrane permeability transition pore refers to the ratio (A1 / A0) of the activity level or expression level A1 of the mitochondrial membrane permeability transition pore in a certain cell (such as a cancer cell) to the activity level or expression level A0 of the mitochondrial membrane permeability transition pore in normal cells (of the same type of cell) < 1.0, preferably ≤ 0.8, more preferably ≤ 0.7, more preferably ≤ 0.6, more preferably ≤ 0.5, more preferably ≤ 0.4, more preferably ≤ 0.3, more preferably ≤ 0.2, more preferably ≤ 0.1, and most preferably ≤ 0.05.

[0403] In another preferred embodiment, the cancer patient is given an inhibitor of mitochondrial membrane permeability transition pores to reduce the activity of mitochondrial membrane permeability transition pores in cancer cells.

[0404] In another preferred embodiment, the mitochondrial membrane permeability transition pore is rendered inactive by administering an inhibitor of the mitochondrial membrane permeability transition pore.

[0405] In another preferred embodiment, the level is the protein level and / or mRNA level.

[0406] In another preferred embodiment, the expression is protein expression and / or mRNA expression.

[0407] In another preferred embodiment, the mitochondrial membrane permeability transition pore inhibitor is selected from the group consisting of Cyclosporin A, CyP-D protein inhibitors, peroxide scavengers, or combinations thereof.

[0408] In another preferred embodiment, the tumor (cancer) includes tumors with low or no expression of the NNMT gene.

[0409] In another preferred embodiment, the tumor (cancer) includes tumors with high levels of methylation at NNMT gene nucleotide sites and / or high levels of methylation at NNMT gene region DNA CpG sites.

[0410] In another preferred embodiment, the tumor comprises a tumor with a high level of methylation at the NNMT gene nucleotide site.

[0411] In another preferred embodiment, the tumor (cancer) includes tumors with high levels of methylation at the CpG site of the NNMT gene region DNA.

[0412] In another preferred embodiment, the NNMT gene is a human NNMT gene.

[0413] In another preferred embodiment, the NNMT gene is the human NNMT gene.

[0414] In another preferred embodiment, the tumor with low or no NNMT gene expression refers to a tumor from which 1 μg of protein extracted from the tumor is undetectable by an NNMT antibody, more preferably, it refers to a tumor from which 5 μg of protein extracted from the tumor is undetectable by an NNMT antibody, more preferably, it refers to a tumor from which 10 μg of protein extracted from the tumor is undetectable by an NNMT antibody, more preferably, it refers to a tumor from which 100 μg of protein extracted from the tumor is undetectable by an NNMT antibody, and it refers to a tumor from which 1000 μg of protein extracted from the tumor is undetectable by an NNMT antibody.

[0415] In another preferred embodiment, the tumor with low or no NNMT gene expression refers to a tumor cell whose NNMT gene expression level is lower than that in the same cell or normal cells (such as adjacent normal tissue cells).

[0416] In another preferred embodiment, the tumor with low or no NNMT gene expression refers to the ratio (E1 / E0) of the NNMT gene expression level E1 in tumor cells to the NNMT gene expression level E0 in the same cell or normal cells (such as adjacent normal tissue cells).

[0417] In another preferred embodiment, the low or no expression of the NNMT gene means that the ratio (E1 / E0) of the expression E1 of the NNMT gene in a certain cell (such as a cancer cell) to the expression E0 of the NNMT gene in the same cell or normal cells (such as adjacent normal tissue cells) is <1.0, preferably ≤0.7, more preferably ≤0.6, more preferably ≤0.5, more preferably ≤0.4, more preferably ≤0.3, more preferably ≤0.2, more preferably ≤0.1, more preferably ≤0.05, more preferably ≤0.01, more preferably ≤0.005, more preferably ≤0.001, more preferably ≤0.0001, more preferably ≤0.00001, more preferably ≤0.000001, more preferably ≤0.000001.

[0418] In another preferred embodiment, the same cell refers to cells of the same species but with normal expression of the NNMT gene (such as a type of cancer cell).

[0419] In another preferred embodiment, the same cell refers to cells of the same species but with normal expression of the NNMT gene.

[0420] In another preferred embodiment, the normal cells refer to normal tissue cells that express the NNMT gene normally (such as cancer cell origin cells, tumor-adjacent cells, or neighboring cells).

[0421] In another preferred embodiment, E0 represents the expression level of the NNMT gene in cells that normally express the NNMT gene.

[0422] In another preferred embodiment, the cells that normally express the NNMT gene include cells that are insensitive to the compound of formula I, its optical isomer or racemate, its solvate, or its pharmaceutically acceptable salt.

[0423] In another preferred embodiment, a high methylation level of the NNMT gene nucleotide site means that the methylation level of the NNMT gene nucleotide site in a certain cell (such as a tumor cell) is greater than that in the same cell or normal cells (such as adjacent normal tissue cells).

[0424] In another preferred embodiment, a high NNMT gene nucleotide site methylation level means that the ratio (L1 / L0) of the NNMT gene nucleotide site methylation level L1 in a certain cell (such as a tumor cell) to the NNMT gene nucleotide site methylation level L0 in the same cell or normal cells (such as adjacent tumor tissue cells) is >1.0, preferably ≥1.2, preferably ≥1.5, more preferably ≥2, more preferably ≥3, more preferably ≥5, more preferably ≥8, more preferably ≥10, more preferably ≥15, more preferably ≥20, more preferably ≥30, and more preferably ≥50.

[0425] In another preferred embodiment, a high methylation level of the NNMT gene nucleotide site means that the methylation level of the NNMT gene nucleotide site in a certain cell (such as a tumor cell) is ≥1%, preferably ≥3%, preferably ≥5%, preferably ≥10%, preferably ≥15%, preferably ≥20%, more preferably ≥25%, more preferably ≥30%, more preferably ≥40%, and more preferably ≥50%.

[0426] In another preferred embodiment, the same cell refers to a cell with a normal level of methylation at the NNMT gene nucleotide site (such as a type of tumor cell).

[0427] In another preferred embodiment, the same cell refers to cells of the same species but with normal methylation levels at the NNMT gene nucleotide sites.

[0428] In another preferred embodiment, the normal cells refer to normal tissue cells (such as tumor cell origin cells, tumor-adjacent cells, or adjacent normal tissue cells) with normal methylation levels at the NNMT gene nucleotide sites.

[0429] In another preferred embodiment, cells with normal methylation levels at the NNMT gene nucleotide sites include cells insensitive to compounds of formula I, or their optical isomers or racemates, or their solvates or pharmaceutically acceptable salts.

[0430] In another preferred embodiment, a high methylation level of the NNMT gene nucleotide site means that the methylation level (M%) of the NNMT gene nucleotide site in a certain cell (such as a tumor cell) is ≥3% and less than or equal to M1, where M1 is any positive integer between 3 and 100.

[0431] In another preferred embodiment, M1 is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95 or 100.

[0432] In another preferred embodiment, the methylation level of the NNMT gene nucleotide site refers to the ratio of the number of methylated nucleotides in the NNMT gene region to the total number of nucleotides in the NNMT gene region.

[0433] In another preferred embodiment, the nucleotide site methylation level of the NNMT gene includes the nucleotide site methylation level of the NNMT gene promoter region.

[0434] In another preferred embodiment, the nucleotide sequence of the NNMT gene promoter region is shown in SEQ ID NO:1.

[0435] In another preferred embodiment, the nucleotide site methylation level of the NNMT gene includes the nucleotide site methylation level in the region from 1050 bp before the transcription start site to 499 bp after the transcription start site of the NNMT gene.

[0436] In another preferred embodiment, the 1050 bp before the transcription start site of the NNMT gene to the 499 bp after the transcription start site are positions 951-2500 of the nucleotide sequence shown in SEQ ID NO:1.

[0437] In another preferred embodiment, the nucleotide site methylation level of the NNMT gene includes the nucleotide site methylation level in the region from 1050 bp before the transcription start site to 193 bp before the transcription start site of the NNMT gene.

[0438] In another preferred embodiment, the 1050 bp to 193 bp before the transcription start site of the NNMT gene is positions 951-1808 of the nucleotide sequence shown in SEQ ID NO:1.

[0439] In another preferred embodiment, a high methylation level of the NNMT gene region DNA CpG site means that the methylation level of the NNMT gene region DNA CpG site in a certain cell (such as a tumor cell) is greater than the methylation level of the NNMT gene region DNA CpG site in the same cell or normal cells (such as adjacent normal tissue cells).

[0440] In another preferred embodiment, a high methylation level of the NNMT gene region DNA CpG site means that the ratio (W1 / W0) of the methylation level W1 of the NNMT gene region DNA CpG site in a certain cell (such as a tumor cell) to the methylation level W0 of the NNMT gene region DNA CpG site in the same cell or normal cells (such as adjacent tumor tissue cells) is >1.0, preferably ≥1.2, preferably ≥1.5, more preferably ≥2, more preferably ≥3, more preferably ≥5, more preferably ≥8, more preferably ≥10, more preferably ≥15, more preferably ≥20, more preferably ≥30, and more preferably ≥50.

[0441] In another preferred embodiment, a high methylation level of the NNMT gene region DNA CpG site means that the methylation level of the NNMT gene region DNA CpG site in a certain cell (such as a tumor cell) is ≥1%, preferably ≥3%, preferably ≥5%, preferably ≥10%, preferably ≥15%, preferably ≥20%, more preferably ≥25%, more preferably ≥30%, more preferably ≥40%, and more preferably ≥50%.

[0442] In another preferred embodiment, the same cell refers to a cell with a normal level of methylation at the CpG site of the NNMT gene region DNA (such as a type of tumor cell).

[0443] In another preferred embodiment, the same cell refers to a cell of the same species but with a normal level of methylation at the CpG site of the NNMT gene region DNA.

[0444] In another preferred embodiment, the normal cells refer to normal tissue cells (such as tumor cell origin cells, tumor-adjacent cells, or adjacent cancer cells) with normal methylation levels at the DNA CpG sites in the NNMT gene region.

[0445] In another preferred embodiment, cells with normal methylation levels at the DNA CpG sites in the NNMT gene region include cells insensitive to compound of formula I, its optical isomer or racemate, its solvate, or its pharmaceutically acceptable salts.

[0446] In another preferred embodiment, a high methylation level of the NNMT gene region DNA CpG site means that the methylation level (M%) of the NNMT gene region DNA CpG site in a certain cell (such as a tumor cell) is ≥3% and less than or equal to M2%, where M2 is any positive integer between 3 and 100.

[0447] 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.

[0448] In another preferred embodiment, the CpG site methylation level refers to the ratio of the number of methylated CpG nucleotides in a gene region to the total number of nucleotides in that gene region.

[0449] In another preferred embodiment, the methylation level of the DNA CpG sites in the NNMT gene region refers to the ratio of the number of methylated CpG nucleotides in the NNMT gene region to the total number of nucleotides in the NNMT gene region.

[0450] In another preferred embodiment, the CpG site methylation level refers to the ratio of the number of methylated CpG nucleotides in a gene region to the total number of CpG nucleotides in that gene region.

[0451] In another preferred embodiment, the methylation level of the DNA CpG sites in the NNMT gene region refers to the ratio of the number of methylated CpG nucleotides in the NNMT gene region to the total number of CpG nucleotides in the NNMT gene region.

[0452] In another preferred embodiment, the DNA CpG site methylation level refers to the ratio of the number of methylated CpG sites in a certain region of DNA to the total number of CpG sites in that region of DNA.

[0453] In another preferred embodiment, the DNA CpG site methylation level refers to the ratio of the number of methylated CpG nucleotides in a certain region of DNA to the total number of nucleotides in that region of DNA.

[0454] In another preferred embodiment, the DNA CpG site methylation level refers to the ratio of the number of methylated CpG nucleotides in a certain region of DNA to the total number of CpG nucleotides in that region of DNA.

[0455] In another preferred embodiment, the methylation level of the NNMT gene region DNA CpG sites refers to the ratio of the number of methylated CpG sites in the NNMT gene region DNA to the total number of CpG sites in the NNMT gene region DNA.

[0456] In another preferred embodiment, the methylation level of the NNMT gene region DNA CpG sites refers to the ratio of the number of methylated CpG nucleotides in the NNMT gene region DNA to the total number of CpG nucleotides in the NNMT gene region DNA.

[0457] In another preferred embodiment, the methylation level of the NNMT gene region DNA CpG site includes the methylation level of the NNMT gene promoter region DNA CpG site.

[0458] In another preferred embodiment, the nucleotide sequence of the NNMT gene promoter region is shown in SEQ ID NO:1.

[0459] 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 to 499 bp after the transcription start site.

[0460] In another preferred embodiment, the 1050 bp before the transcription start site of the NNMT gene to the 499 bp after the transcription start site are positions 951-2500 of the nucleotide sequence shown in SEQ ID NO:1.

[0461] In another preferred embodiment, the DNA CpG site methylation level of the NNMT gene region includes the DNA CpG site methylation level in the region from 1050 bp before the NNMT gene transcription start site to 193 bp before the gene transcription start site.

[0462] In another preferred embodiment, the 1050 bp to 193 bp before the transcription start site of the NNMT gene is positions 951-1808 of the nucleotide sequence shown in SEQ ID NO:1.

[0463] In another preferred embodiment, the tumor is selected from the group consisting of: lung cancer, kidney cancer, breast cancer, colon cancer, lymphoma, leukemia, pancreatic cancer, liver cancer, prostate cancer, or combinations thereof.

[0464] In another preferred embodiment, the expression includes protein expression and / or mRNA expression.

[0465] In another preferred embodiment, the composition is a pharmaceutical composition.

[0466] In another preferred embodiment, the composition or formulation further includes a pharmaceutically acceptable carrier.

[0467] In another preferred embodiment, the expression is mRNA or protein expression.

[0468] In another preferred embodiment, the dosage form of the composition or formulation is a solid dosage form, a liquid dosage form, or a semi-solid dosage form. In another preferred embodiment, the dosage form of the composition or formulation is an oral dosage form, a topical dosage form, or an injectable dosage form.

[0469] In another preferred embodiment, the dosage form of the composition or preparation is a tablet, injection, infusion, ointment, gel, solution, microsphere, or film.

[0470] In another preferred embodiment, the composition is a pharmaceutical composition.

[0471] In another preferred embodiment, the composition or formulation further includes a pharmaceutically acceptable carrier.

[0472] In a fourth aspect, the present invention provides the use of a mitochondrial membrane permeability transition pore inhibitor for preparing a composition or formulation, said composition or formulation for enhancing the anticancer effect of an anticancer drug.

[0473] In another preferred embodiment, the anticancer drug is a compound of formula I as described in the first aspect of the invention, or an optical isomer thereof, a racemic mixture thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0474] In another preferred embodiment, the cancer is as described in the first aspect of the invention.

[0475] In another preferred embodiment, the mitochondrial membrane permeability transition pore inhibitor is selected from the group consisting of Cyclosporin A, CyP-D protein inhibitors, peroxide scavengers, or combinations thereof.

[0476] In another preferred embodiment, the CyP-D protein inhibitors include SfA, BKA, and ADP (small molecules that regulate ANT protein activity).

[0477] In another preferred embodiment, the peroxide scavenger is selected from the group consisting of Propofol, pyruvate, MCI-186, or combinations thereof.

[0478] In a fifth aspect, the present invention provides an active ingredient combination comprising the following components:

[0479] (1) A first active ingredient, wherein the first active ingredient is an anticancer drug; and

[0480] (2) The second active ingredient is a mitochondrial membrane permeability transition pore inhibitor.

[0481] In another preferred embodiment, the molar ratio of the first active ingredient to the second active ingredient is 0.01-600:1, more preferably 0.05-500:1, more preferably 0.1-400:1, more preferably 0.2-200:1, more preferably 0.5-100:1, more preferably 0.5-80:1, and most preferably 1-50:1.

[0482] In another preferred embodiment, at least one of the active ingredients in the combination of active ingredients is independent.

[0483] In another preferred embodiment, the first active ingredient and the second active ingredient in the combination of active ingredients are independent of each other.

[0484] In a sixth aspect, the present invention provides a composition comprising:

[0485] (1) A first active ingredient, wherein the first active ingredient is an anticancer drug; and

[0486] (2) The second active ingredient is a mitochondrial membrane permeability transition pore inhibitor.

[0487] In another preferred embodiment, the composition is a pharmaceutical composition.

[0488] In another preferred embodiment, the pharmaceutical composition further includes a pharmaceutically acceptable carrier.

[0489] In another preferred embodiment, the content of the first active ingredient is 0.01-99.99 wt%, more preferably 0.1-99.9 wt%, more preferably 1-99 wt%, more preferably 10-99 wt%, and most preferably 20-99 wt%, based on the total weight of the active ingredients in the composition.

[0490] In another preferred embodiment, the content of the second active ingredient is 0.01-99.99 wt%, more preferably 0.1-99.9 wt%, more preferably 1-99 wt%, more preferably 10-99 wt%, and most preferably 20-99 wt%, based on the total weight of the active ingredients in the composition.

[0491] In a seventh aspect, the present invention provides a medicine box, the medicine box comprising:

[0492] (A) A first formulation containing a first active ingredient, wherein the first active ingredient is an anticancer drug; and

[0493] (B) A second formulation containing a second active ingredient, wherein the second active ingredient is a mitochondrial membrane permeability transition pore inhibitor.

[0494] In another preferred embodiment, the medicine box also includes an instruction manual.

[0495] In another preferred embodiment, the first and second formulations are independent formulations.

[0496] In another preferred embodiment, the first and second formulations are combined formulations.

[0497] In another preferred embodiment, the instructions for use specify that the first and second formulations are used in combination to enhance the antitumor activity of the anticancer drug.

[0498] In another preferred embodiment, the combined method involves first administering a second formulation containing a mitochondrial membrane permeability transition pore inhibitor, followed by administering an anticancer drug.

[0499] An eighth aspect of the present invention provides a method for in vitro non-therapeutic and non-diagnostic inhibition of cancer cells, the method comprising the step of contacting cancer cells with a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof or a racemic mixture thereof, or a solvate thereof or a pharmaceutically acceptable salt thereof, thereby inhibiting cancer cells.

[0500] In another preferred embodiment, the contact is an in vitro culture contact.

[0501] A ninth aspect of the present invention provides a method for preventing and / or treating cancer, the method comprising the steps of: administering to a desired subject a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a combination of active ingredients as described in the fifth aspect of the present invention, or a composition as described in the sixth aspect of the present invention, or a medicament as described in the seventh aspect of the present invention, thereby preventing and / or treating cancer.

[0502] In another preferred embodiment, the object is a human or non-human mammal (rodents, rabbits, monkeys, livestock, dogs, cats, etc.).

[0503] In a tenth aspect, the present invention provides a biomarker for determining whether a cancer patient is suitable for prevention and / or treatment of cancer using the compound of formula I described in the first aspect of the present invention, or its optical isomer or racemic mixture, or its solvate or pharmaceutically acceptable salt thereof, wherein the biomarker includes the mitochondrial oxidative phosphorylation pathway, mitochondrial membrane permeability transition pore, NNMT gene, methylation level of NNMT gene nucleotide sites and / or methylation level of NNMT gene region DNA CpG sites.

[0504] In another preferred embodiment, the biomarkers include mitochondrial oxidative phosphorylation pathway expression levels, mitochondrial membrane permeability transition pore activity, NNMT gene expression levels, NNMT gene nucleotide site methylation levels, and / or NNMT gene region DNA CpG site methylation levels.

[0505] In another preferred embodiment, the methylation level of the NNMT gene region DNA CpG site includes the methylation level of the NNMT gene promoter region DNA CpG site.

[0506] In another preferred embodiment, the DNA CpG site methylation level in the NNMT gene region includes the DNA CpG site methylation level in the region from 1050 bp before the NNMT gene transcription start site to 499 bp after the transcription start site.

[0507] In another preferred embodiment, the methylation level of DNA CpG sites in the NNMT gene region includes the methylation level of DNA CpG sites within the region from 1050 bp before the NNMT gene transcription start site to 193 bp before the transcription start site. In another preferred embodiment, when the mitochondrial oxidative phosphorylation pathway is upregulated in the tumor cells of a tumor patient, the tumor patient is suitable for prophylaxis and / or treatment with the compound of Formula I described in the first aspect of the invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0508] In another preferred embodiment, when the mitochondrial membrane permeability transition pores of a tumor patient are inactive, the tumor patient is suitable for prevention and / or treatment with the compound of formula I described in the first aspect of the invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0509] In another preferred embodiment, when the tumor cells of a tumor patient have low or no expression of the NNMT gene, high methylation levels at NNMT gene nucleotide sites, and / or high methylation levels at NNMT gene region DNA CpG sites, the tumor patient is suitable for prevention and / or treatment using the compound of Formula I described in the first aspect of the present invention, or its optical isomer or racemic mixture, or its solvate, or its pharmaceutically acceptable salt.

[0510] In another preferred embodiment, when the tumor cells of a tumor patient have high expression of the NNMT gene, low methylation levels of NNMT gene nucleotide sites, and / or low methylation levels of NNMT gene region DNA CpG sites, the tumor patient is not suitable for prevention and / or treatment using 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.

[0511] Eleventh aspect of the present invention provides a detection kit, the detection kit comprising:

[0512] (i) Detection reagents for detecting mitochondrial oxidative phosphorylation pathway levels, mitochondrial membrane permeability transition pore levels, NNMT gene expression, and / or methylation levels of CpG sites in the NNMT gene region DNA.

[0513] In another preferred embodiment, the levels include protein levels and / or mRNA levels.

[0514] In another preferred embodiment, the test sample of the test kit includes tumor cells.

[0515] In another preferred embodiment, NNMT gene expression refers to the expression of the gene mRNA and the protein;

[0516] 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.

[0517] In another preferred embodiment, the DNA CpG site methylation level in the NNMT gene region refers to the DNA CpG site methylation level in the region from 1050 bp before the transcription start site to 499 bp after the transcription start site of the NNMT gene.

[0518] In another preferred embodiment, the DNA CpG site methylation level in the NNMT gene region refers to the DNA CpG site methylation level in the region from 1050 bp before the transcription start site to 193 bp before the transcription start site of the NNMT gene.

[0519] In a twelfth aspect of the present invention, there is a use of the test kit as described in the twelfth aspect of the invention for preparing a companion diagnostic kit, said companion diagnostic kit for determining whether a cancer patient is suitable for prevention and / or treatment with the compound of formula I as described in the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0520] In another preferred embodiment, the companion diagnostic kit also includes instructions or labels.

[0521] In another preferred embodiment, the instruction manual or label states:

[0522] When the mitochondrial oxidative phosphorylation pathway is upregulated in the tumor cells of a cancer patient, the cancer patient is suitable for prevention and / or treatment with the compound of Formula I as described in the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0523] In another preferred embodiment, the instruction manual or label states:

[0524] When the mitochondrial membrane permeability transition pores of tumor cells in a cancer patient are inactive, the cancer patient is suitable for prevention and / or treatment with the compound of Formula I as described in the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0525] In another preferred embodiment, the instruction manual or label states:

[0526] When a tumor patient's tumor cells have low or no expression of the NNMT gene, high methylation levels at NNMT gene nucleotide sites, and / or high methylation levels at NNMT gene region DNA CpG sites, the tumor patient is suitable for prevention and / or treatment using the compound of Formula I described in the first aspect of this invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0527] In another preferred embodiment, the instruction manual or label states:

[0528] When a tumor patient's tumor cells have high expression of the NNMT gene, low methylation levels at NNMT gene nucleotide sites, and / or low methylation levels at NNMT gene region DNA CpG sites, the tumor patient is not suitable for prevention and / or treatment using the compound of Formula I described in the first aspect of this invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0529] According to a thirteenth aspect of the present invention, a medicine box is provided, the medicine box comprising:

[0530] (i) Detection reagents for measuring mitochondrial oxidative phosphorylation pathway levels, mitochondrial membrane permeability transition pore levels, NNMT gene expression, NNMT gene nucleotide site methylation levels, and / or NNMT gene region DNA CpG site methylation levels; and

[0531] (ii) A compound of formula I as described in the first aspect of the invention, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0532] In another preferred embodiment, the medicine box also includes instructions or labels.

[0533] In another preferred embodiment, the instruction manual or label states:

[0534] When the mitochondrial oxidative phosphorylation pathway is upregulated in the tumor cells of a cancer patient, the cancer patient is suitable for prevention and / or treatment with the compound of Formula I as described in the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0535] In another preferred embodiment, the instruction manual or label states:

[0536] When the mitochondrial membrane permeability transition pores of tumor cells in a cancer patient are inactive, the cancer patient is suitable for prevention and / or treatment with the compound of Formula I as described in the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0537] In another preferred embodiment, the instruction manual or label states:

[0538] When a tumor patient's tumor cells have low or no expression of the NNMT gene, high methylation levels at NNMT gene nucleotide sites, and / or high methylation levels at NNMT gene region DNA CpG sites, the tumor patient is suitable for prevention and / or treatment with the compound of Formula I as described in the first aspect of this invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0539] In another preferred embodiment, when the tumor cells of a tumor patient have high expression of the NNMT gene, low methylation levels of NNMT gene nucleotide sites, and / or low methylation levels of NNMT gene DNACpG sites, the tumor patient is not suitable for prevention and / or treatment using 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.

[0540] In a fourteenth aspect of the present invention, a method for preventing and / or treating tumors is provided by administering to a desired subject a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0541] In another preferred embodiment, the tumor is as described in the first aspect of the invention.

[0542] In another preferred embodiment, the mitochondrial oxidative phosphorylation pathway is modulated and / or the mitochondrial membrane permeability transition pore activity is reduced in the cancer cells of the said cancer.

[0543] In another preferred embodiment, the tumor of the object includes tumors with low or no expression of the NNMT gene.

[0544] In another preferred embodiment, the tumor of the object includes tumors with high levels of methylation at the NNMT gene nucleotide sites.

[0545] In another preferred embodiment, the tumor of the object includes tumors with high levels of methylation at the CpG site of the NNMT gene region DNA.

[0546] In another preferred embodiment, the object is a human or non-human mammal (rodents, rabbits, monkeys, livestock, dogs, cats, etc.).

[0547] According to a fifteenth aspect of the present invention, an apparatus or system is provided, the apparatus or system comprising:

[0548] (i) Detection module, wherein the detection module is used to detect the level of mitochondrial oxidative phosphorylation pathway, the level of mitochondrial membrane permeability transition pore, NNMT gene expression and / or the methylation level of DNA CpG sites in the NNMT gene region;

[0549] (ii) an output module, wherein the output module includes outputting the following information:

[0550] When the mitochondrial oxidative phosphorylation pathway is upregulated in the tumor cells of a cancer patient, the cancer patient is suitable for prevention and / or treatment with the compound of Formula I as described in the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0551] In another preferred embodiment, when the mitochondrial membrane permeability transition pores of a tumor patient are inactive, the tumor patient is suitable for prevention and / or treatment with the compound of Formula I as described in the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0552] When a tumor patient's tumor cells show low or no expression of the NNMT gene, high methylation levels at NNMT gene nucleotide sites, and / or high methylation levels at NNMT gene region DNA CpG sites, then the tumor patient is suitable for prophylaxis and / or treatment with the compound of Formula I as described in the first aspect of this invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt; and / or

[0553] When a tumor patient's tumor cells have high expression of the NNMT gene, low methylation levels at NNMT gene nucleotide sites, and / or low methylation levels at NNMT gene region DNA CpG sites, the tumor patient is not suitable for prevention and / or treatment using the compound of Formula I described in the first aspect of this invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt.

[0554] In another preferred embodiment, the device includes a gene analyzer or a protein analyzer.

[0555] In another preferred embodiment, the device or system further includes a sample introduction module.

[0556] In another preferred embodiment, the injection module is used to inject tumor cell extracts.

[0557] In another preferred embodiment, the device or system further includes a data processing module.

[0558] In another preferred embodiment, the data processing module processes data to obtain the expression level of the NNMT gene and / or the methylation level of the CpG site in the NNMT gene region DNA.

[0559] In another preferred embodiment, the data processing module processes data to obtain the expression level of the NNMT gene and / or the methylation level of the DNA CpG site in the NNMT gene promoter region.

[0560] In another preferred embodiment, the data processing module processes the data to obtain the expression level of the NNMT gene and / or the methylation level 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.

[0561] In another preferred embodiment, the data processing module processes the data to obtain the expression level of the NNMT gene and / or the methylation level of DNA CpG sites in the region from 1050 bp before the transcription start site to 193 bp before the transcription start site of the NNMT gene.

[0562] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0563] Attached Figure

[0564] Figure 1 The expression status of NNMT gene in sensitive and insensitive tumor cells.

[0565] Figure 2 The methylation level of the CpG site in the promoter region of the NNMT gene in sensitive and insensitive tumor cells.

[0566] Figure 3 The methylation level of CpG sites in the DNA region from 1050 bp before the transcription start site to 499 bp after the transcription start site in sensitive and insensitive tumor cells.

[0567] Figure 4 The methylation level of CpG sites in the DNA region between 1050 bp and 193 bp before the transcription start site of the NNMT gene in sensitive and insensitive tumor cells. Detailed Implementation

[0568] Through long-term and in-depth research and extensive screening, the inventors unexpectedly discovered that a specific class of compounds (compounds of formula I, or their optical isomers, racemates, solvates, or pharmaceutically acceptable salts) can effectively inhibit tumors. Furthermore, it was unexpectedly found that the compounds of this invention can significantly inhibit the activity of tumor cells with inactive mitochondrial oxidative phosphorylation pathway (mPTP) even at low concentrations (IC50). This indicates that the compounds of this invention have a stronger inhibitory effect on tumor cells with low or inactive mPTP, while their inhibitory effect on cells with high mPTP activity is relatively weak. Normal somatic cells typically have high mPTP activity, meaning that the compounds of this invention have relatively little effect on normal somatic cells and exhibit good drug safety.

[0569] The inventors also unexpectedly discovered for the first time that the compounds of this invention have a significant inhibitory effect on tumor cells with low (or no) NNMT gene expression, high NNMT gene nucleotide site methylation levels, and / or high NNMT gene region DNA CpG site methylation levels. NNMT gene expression levels, NNMT gene nucleotide site methylation levels, and / or NNMT gene promoter region DNA CpG site methylation levels can serve as biomarkers for determining whether tumor patients are suitable for prevention and / or treatment using the compounds of this invention. Based on this, the inventors completed this invention.

[0570] the term

[0571] As used herein, the terms “comprising,” “including,” and “containing” are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, the terms include “consisting of” and “substantially consisting of”.

[0572] The terms "anticancer drugs" and "antitumor drugs" are used interchangeably.

[0573] The terms “cancer,” “tumor,” “tumor,” and “carcinoma” are used interchangeably.

[0574] As used in this article, the term "a cell" refers to a single cell (such as a single cancer cell) or a group of cells containing multiple similar cells (such as a tumor tissue).

[0575] The term "IC50" stands for half-inhibiting concentration, which is the concentration of the inhibitor at which 50% inhibition is achieved.

[0576] As used herein, the terms "IC50" and "IC" are distinct. 50 "Interchangeable" refers to half-inhibiting concentration, which is the concentration of the inhibitor that achieves a 50% inhibitory effect.

[0577] The term "mitochondrial membrane permeability transition pore" is abbreviated as mPTP (mitochondria permeability transition pore).

[0578] The term "oxidative phosphorylation pathway" is abbreviated as OXPHOS (Oxidative Phosphorylation), also known as oxidative phosphorylation.

[0579] As used in this article, the terms “high level of DNA CpG site methylation”, “high level of DNA CpG site methylation”, and “high methylation of DNA CpG site” are used interchangeably.

[0580] As used in this article, the terms “low level of DNA CpG site methylation”, “low level of DNA CpG site methylation”, and “low methylation of DNA CpG site” are used interchangeably.

[0581] As used in this article, the term "DNA CpG site methylation level" refers to the proportion of methylated CpG sites in a DNA region relative to the total number of CpG sites in that region.

[0582] As used herein, the terms “CpG site methylation”, “CpG nucleotide methylation” and “CpG methylation” are used interchangeably.

[0583] As used herein, "suitable for use by cancer patients" includes cancer patients whose tumors are sensitive to the compounds of the present invention.

[0584] As used herein, "cancer patients are not suitable for use with the compounds of the present invention" includes cancer patients whose tumors are not sensitive to the compounds of the present invention.

[0585] As used in this article, the English name for the term "NNMT" is Nicotinamide N-Methyltransferase.

[0586] As used in this article, the term "bp" refers to a base pair.

[0587] As used in this article, the term "SST" refers to the transcription start site.

[0588] It should be understood that those skilled in the art can select the substituents and substitution patterns on the compounds of the present invention to produce chemically stable compounds that can be synthesized using techniques known in the art and the methods described below. If substituted by more than one (or more) substituent groups, it should be understood that these groups can be on the same carbon or on different carbons, as long as a stable structure is produced.

[0589] As used herein, the term “substitution” or “substituted” refers to a compound in which a hydrogen atom on a group is replaced by a non-hydrogen group, but the substitution must satisfy the valence requirement and the substitution produces a chemically stable compound, i.e., a compound that does not spontaneously undergo transformations such as cyclization or elimination.

[0590] As used in this article, "R1", "R1", and "R" are... 1 The meanings of "" are the same and they can be used interchangeably. Other similar definitions have the same meaning.

[0591] As used in this article, " "" indicates the linking site of a functional group.

[0592] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched groups. When an alkyl group is preceded by a carbon number qualifier (e.g., C1-C6 alkyl), it means that the alkyl group contains 1-6 carbon atoms. For example, C1-C4 alkyl means an alkyl group containing 1-4 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0593] As used herein, the term "C2-C4 alkenyl" refers to a hydrocarbon group formed by removing one hydrogen atom from a straight-chain or branched olefin molecule with 2-4 carbon atoms having one or more double bonds, such as vinyl (CH2=CH-), (C(CH3)2=CH-), or similar groups.

[0594] As used herein, the term “C2-C4 ynyl” refers to a straight-chain or branched ynyl molecule with 2-4 carbon atoms having one or more triple bonds, with one hydrogen atom missing from the triple bond to form a hydrocarbon group, such as ethynyl (CH≡CH-), (H3C-C≡CH-), or similar groups.

[0595] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0596] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0597] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more (preferably 1, 2, 3 or 4) hydrogen atoms are replaced by a halogen, the alkyl group and the halogen being as defined above. When an alkyl group is preceded by a carbon number limit (e.g., C1-C8 haloalkyl), it means that the alkyl group contains 1 to 8 carbon atoms. For example, C1-C6 haloalkyl refers to a haloalkyl group containing 1 to 6 carbon atoms. Representative examples include, but are not limited to, -CF3, -CHF2, monofluoroisopropyl, difluorobutyl, or similar groups.

[0598] As used herein, the term "cycloalkane ring" refers to a monocyclic or polycyclic (fused, bridged, or spirocyclic) ring system that is saturated or partially saturated. When a cycloalkane ring is preceded by a carbon number limit (e.g., C3-C12), it means that the cycloalkane ring has 3-12 ring carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkane ring" refers to a saturated or partially saturated monocyclic or bicyclic alkane ring having 3-8 ring carbon atoms, including cyclopropane, cyclobutane, cyclopentane, cycloheptane, or similar rings. "Spirocycloalkane ring" refers to a bicyclic or polycyclic ring in which the monocyclic rings share a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Fused cycloalkane rings" refer to bicyclic or polycyclic rings in which each ring shares a pair of adjacent carbon atoms with the other rings in the system. One or more rings may contain one or more double bonds, but the shared pair of adjacent carbon atoms connecting the parent ring is a pair of adjacent carbon atoms on a bicyclic or polycyclic ring with non-conjugated π-electron systems. "Bridged cycloalkane rings" refer to polycyclic rings in which any two rings share two non-directly connected carbon atoms. These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Representative examples of cycloalkane rings are as follows, including but not limited to: cyclopropyl rings, cyclobutane rings, cyclopentane rings, cycloheptane rings, or similar rings.

[0599] As used herein, the term "cycloalkyl" refers to a cyclic group having a saturated or partially saturated monocyclic ring, bicyclic or polycyclic (fused, bridged, or spirocyclic) ring system. When a cycloalkyl group is preceded by a carbon number limitation (e.g., C3-C12), it means that the cycloalkyl group has 3-12 ring carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3-8 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Fused cycloalkyl" refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but the point of connection to the parent ring must be on a carbon atom of a ring with a non-conjugated π-electron system. "Bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. These groups may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Representative examples of cycloalkyl groups are as follows, including but not limited to:

[0600]

[0601] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group in which one or more (preferably 1, 2, 3, or 4) hydrogen atoms are replaced by a halogen, the cycloalkyl group and the halogen being as defined above. When a carbon number limitation is specified before the cycloalkyl group (e.g., C3-C8 haloalkyl), it means that the cycloalkyl group contains 3-8 cyclic carbon atoms. For example, C3-C8 haloalkyl refers to a halocycloalkyl group containing 3-6 carbon atoms. Representative examples include, but are not limited to, monofluorocyclopropyl, monochlorocyclobutyl, monofluorocyclopentyl, difluorocycloheptyl, or similar groups.

[0602] The term "alkoxy" refers to an RO- group, where R is an alkyl group, and the alkyl group is as defined above herein. When the alkoxy group is preceded by a carbon number qualifier, such as C1-C8 alkoxy groups, it means that the alkyl group in the alkoxy group has 1-8 carbon atoms. Representative examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or similar groups.

[0603] As used herein, the term "alkathio" refers to an RO- group, where R is an alkyl group, and the alkyl group is as defined above. When the alkathio group is preceded by a carbon number qualifier, such as C1-C8 alkathio, it means that the alkyl group in the alkathio group has 1-8 carbon atoms. Representative examples of alkathio groups include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, or similar groups.

[0604] As used herein, the term "haloalkoxy" refers to a haloalkyl group -O-, as defined above. For example, C1-C6 haloalkoxy refers to a haloalkoxy group containing 1-6 carbon atoms, and representative examples include, but are not limited to, monofluoromethoxy, monofluoroethoxy, difluorobutoxy, or similar groups.

[0605] As used herein, the term "haloalkylthio" refers to a haloalkyl-S-, as defined above, for example, C1-C6 haloalkylthio refers to a haloalkylthio containing 1-4 carbon atoms, representative examples including but not limited to, monofluoromethylthio, monofluoroethylthio, difluorobutylthio, or similar groups.

[0606] The term "heterocyclic alkane," also known as "heterocycle," refers to a fully saturated or partially unsaturated ring (including, but not limited to, 3-7 membered monocyclic rings, 7-11 membered bicyclic rings, or 8-16 membered tricyclic systems), in which at least one heteroatom is present in a ring with at least one carbon atom. When a member is specified before "heterocycle," it refers to the number of ring atoms in the heterocycle; for example, a 3-16 membered heterocycle refers to a heterocycle with 3-16 ring atoms. Each heterocycle containing heteroatoms may have one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom can be oxidized or quaternized. Heterocycles can be attached to any heteroatom or carbon residue in a ring or ring system molecule. Typical monocyclic heterocyclic alkane rings include, but are not limited to, azathiobutane rings, oxacyclobutane rings, imidazoline rings, imidazoline rings, tetrahydrofuran rings, piperidine rings, piperazine rings, 2-oxopiperazine rings, 2-oxopiperidine rings, 4-piperidinone rings, tetrahydropyran rings, morpholine rings, thiomorpholine rings, thiomorpholine sulfoxide rings, thiomorpholine sulfone rings, 1,3-dioxane rings, and tetrahydro-1,1-dioxothiophene rings. Polycyclic heterocyclic alkane rings include spirocyclic, fused, and bridged heterocyclic rings; the spirocyclic, fused, and bridged heterocyclic rings involved may optionally be connected to other rings by single bonds, or further cyclically linked to other cycloalkane rings, heterocyclic rings, aromatic rings, or heteroaromatic rings by any two or more atoms on the ring. The point of connection to the parent ring must be a carbon atom or heteroatom on a ring with a non-conjugated π-electron system.

[0607] The term "heterocyclic alkyl" refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3-7 membered monocyclic, 7-11 membered bicyclic, or 8-16 membered tricyclic systems) in which at least one heteroatom is present in a ring with at least one carbon atom. When a heterocyclic alkyl group is preceded by a number, it refers to the number of ring atoms in the heterocyclic alkyl group; for example, a 3-16 membered heterocyclic alkyl group refers to a heterocyclic alkyl group having 3-16 ring atoms. Each heterocyclic ring containing a heteroatom may have one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized. Heterocyclic alkyl groups may be attached to any heteroatom or carbon atom residue in a ring or cyclic molecule. Typical monocyclic heterocyclic alkyl groups include, but are not limited to, azazolinyl, oxazolinyl, imidazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinosulfone, 1,3-dioxane, and tetrahydro-1,1-dioxothiophene. Polycyclic heterocyclic alkyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; the spirocyclic, fused-ring, and bridged-ring heterocyclic alkyl groups involved may optionally be connected to other groups by single bonds, or further cyclically linked to other cycloalkane rings or heterocycles by any two or more atoms on the ring. Polycyclic heterocyclic alkyl groups may have fused aromatic rings, but the point of connection to the parent group must be a carbon atom or heteroatom on a ring with a non-conjugated π-electron system.

[0608] The term "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic ring (i.e., a ring sharing adjacent carbon atom pairs) with a conjugated π-electron system. It is an aromatic cyclic hydrocarbon compound. When the aromatic ring is preceded by a carbon atom number limit, such as a C6-C12 aromatic ring, it means that the aromatic ring has 6-12 ring carbon atoms, such as benzene and naphthalene rings. The aromatic ring can be fused to other carbon rings (including saturated or unsaturated rings), but it cannot contain heteroatoms such as nitrogen, oxygen, or sulfur. The point of connection to the parent ring must be on a carbon atom of a ring with a conjugated π-electron system. Representative aromatic rings are benzene and naphthalene rings, or similar rings.

[0609] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon pairs) group with a conjugated π-electron system. It is an aromatic cyclic hydrocarbon compound group. When the aryl group is preceded by a carbon number limit, such as C6-C12 aryl, it means that the aryl group has 6-12 ring carbon atoms, for example, phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated or unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur. The point of attachment to the parent group must be on a carbon atom of a ring with a conjugated π-electron system. The following are representative examples of aryl groups, including but not limited to:

[0610]

[0611] The term "heteroaromatic ring" refers to an aromatic heterocycle having one to several (preferably 1, 2, 3, or 4) heteroatoms. It can be a monocyclic ring (monocyclic) or a polycyclic ring (bicyclic, tricyclic, or polycyclic) fused together or covalently linked. Each heterocycle containing heteroatoms may have one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen. When a member is specified before "heteroaromatic ring," it refers to the number of ring atoms in the heteroaromatic ring. For example, a 5-12 member heteroaromatic ring refers to a heteroaromatic ring having 5-12 ring atoms. Representative examples include, but are not limited to: pyrrole rings, pyrazole rings, imidazole rings, oxazole rings, isoxazole rings, thiazole rings, thiadiazole rings, isothiazole rings, furan rings, pyridine rings, pyrazine rings, pyrimidine rings, pyridazine rings, triazine rings, triazole rings, and tetrazolium rings.

[0612] The term "heteroaryl" refers to an aromatic heterocyclic group having one to several (preferably 1, 2, 3, or 4) heteroatoms. These heteroatoms can be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic, or polycyclic) fused together or covalently linked. Each heterocycle containing a heteroatom may have one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen. When a member is specified before "heteroaryl," it refers to the number of ring atoms in the heteroaryl group. For example, a 5-12 member heteroaryl refers to a heteroaryl group having 5-12 ring atoms. Representative examples include, but are not limited to: pyrrole, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl.

[0613] As used herein, the term “carboxyl” refers to a group having a -COOH group or an alkyl-COOH group, where alkyl is as defined above, for example, “C2-C4 carboxyl” refers to a group with a -C1-C3 alkyl-COOH structure. Representative examples of carboxyl groups include (but are not limited to): -COOH, -CH2COOH, -C2H4COOH, or similar groups.

[0614] As used herein, the term "ester group" refers to an R-CO-O- or -CO-OR group, where R is an alkyl group and the alkyl group is as defined above herein. For example, "C2-C4 ester group" refers to a group with a C1-C3 alkyl-CO-O- structure or a group with a -CO-O-C1-C3 alkyl structure. Representative examples of ester groups include, but are not limited to: CH3COO-, C2H5COO-, C3H8COO-, (CH3)2CHCOO-, -COOCH3, -COOC2H5, -COOC3H8, or similar groups.

[0615] As used herein, the term "amide group" refers to an R-CO-N- or -CO-NR group, where R is an alkyl group and the alkyl group is as defined above herein. For example, "C2-C4 amide group" refers to a group with a C1-C3 alkyl-CO-N- structure or a group with a -CO-N-C1-C3 alkyl structure. Representative examples of amide groups include, but are not limited to: CH3CO-N-, C2H5CO-N-, C3H8CO-N-, (CH3)2CHCO-N-, -CO-N-CH3, -CO-N-C2H5, -CO-N-C3H8, or similar groups.

[0616] As used herein, the term "amino" means -NH2, either alone or as part of other substituents.

[0617] As used herein, the term "nitro" means -NO2, either alone or as part of other substituents.

[0618] As used herein, the term "cyano" means -CN, either alone or as part of other substituents.

[0619] As used herein, the term "hydroxyl" means -OH, either alone or as part of other substituents.

[0620] As used herein, the term "thiol" means -SH, either alone or as part of other substituents.

[0621] In this specification, all substituents should be interpreted as unsubstituted unless explicitly described herein as "substituted". The term "substituted" means that one or more hydrogen atoms on a particular group are replaced by a particular substituent. The particular substituent is the substituent described accordingly above, or the substituent appearing in the various examples. Preferably, the substitution means that one or more (preferably 1, 2, 3, 4, 5, 6, 7, or 8) hydrogen atoms on a ring or group are replaced by a substituent selected from the group consisting of: C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C3-C8 halocycloalkyl, halogen, nitro, -CN, hydroxyl, mercapto, amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amide, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, C6-C12 aryl, 5-10 heteroaryl, 5-10 heterocyclic alkyl. Unless otherwise specified, any substituted group may have a substituent selected from a particular group at any substituted site of the group, and the substituents may be the same or different at each position.

[0622] In this invention, the term "prevention" refers to a method of preventing the onset of a disease and / or its accompanying symptoms or protecting a subject from acquiring a disease. As used herein, "prevention" also includes delaying the onset of a disease and / or its accompanying symptoms and reducing the subject's risk of contracting the disease.

[0623] The “treatment” described in this invention includes delaying and halting the progression of disease, or eliminating disease, and does not require 100% inhibition, eradication, and reversal. In some embodiments, compared to levels observed in the absence of the compositions, packaging, food packaging, or health product packaging, or combination of active ingredients described in this invention, the compositions or pharmaceutical compositions of this invention reduce, inhibit, and / or reverse tumors by, for example, at least about 10%, at least about 30%, at least about 50%, or at least about 80%.

[0624] In this invention, the term "prevention" means a method of preventing the onset of a disease and / or its accompanying symptoms or protecting a subject from acquiring a disease.

[0625] The “treatment” described in this invention includes delaying and halting the progression of a disease, or eliminating the disease, and does not require 100% inhibition, eradication, or reversal. In some embodiments, compared to levels observed in the absence of the compounds described in this invention, the compounds of this invention reduce, inhibit, and / or reverse the associated disease (such as tumor) and its complications by, for example, at least about 10%, at least about 30%, at least about 50%, or at least about 80%, at least about 90%, or 100%.

[0626] Mitochondrial oxidative phosphorylation pathway and mitochondrial membrane permeability transition pore

[0627] Oxidative phosphorylation (OXPHOS) is one of the most important pathways in mitochondria. This pathway utilizes NADH and FADH, derived from pathways such as the tricarboxylic acid cycle and lipid oxidation, to synthesize ATP. The mitochondrial oxidative phosphorylation pathway consists of more than 90 proteins, which form five protein complexes: complexes I, II, III, IV, and V.

[0628] The mitochondrial oxidative phosphorylation pathway is regulated by the mitochondrial membrane permeability transition pore (mPTP), and the compounds of this invention have a better inhibitory effect in cells with inactive mPTP.

[0629] As used herein, the terms "upregulated mitochondrial oxidative phosphorylation pathway" and "positive mitochondrial oxidative phosphorylation pathway" are used interchangeably, referring to a higher level or expression of mitochondrial oxidative phosphorylation pathway in a cell (such as cancer cells) than in normal cells (of the same cell type). Preferably, the terms "upregulated mitochondrial oxidative phosphorylation pathway" or "positive mitochondrial oxidative phosphorylation pathway" refer to a ratio (E1 / E0) of mitochondrial oxidative phosphorylation pathway level or expression E1 in a cell (such as tumor cells) to that in normal cells (of the same cell type) > 1.0, more preferably ≥ 1.2, more preferably ≥ 1.5, more preferably ≥ 2, more preferably ≥ 3, and more preferably ≥ 5.

[0630] In this invention, "upregulation of the mitochondrial oxidative phosphorylation pathway" and "positive mitochondrial oxidative phosphorylation pathway" can be characterized by the activity of mPTP. Inactive mPTP indicates "upregulation of the mitochondrial oxidative phosphorylation pathway" or "positive mitochondrial oxidative phosphorylation pathway". For example, when the ratio (A1 / A0) of the mPTP activity level or expression level A1 in a certain cell (such as a cancer cell) to the mPTP activity level or expression level A0 in normal cells (of the same type of cells) is less than 1.0, preferably ≤0.8, more preferably ≤0.7, more preferably ≤0.6, more preferably ≤0.5, more preferably ≤0.4, more preferably ≤0.3, more preferably ≤0.2, more preferably ≤0.1, and most preferably ≤0.05, the cell can be considered to be a cell with upregulation or positive mitochondrial oxidative phosphorylation pathway.

[0631] In a preferred embodiment of the invention, the level is the protein level and / or mRNA level.

[0632] In a preferred embodiment of the present invention, the expression is protein expression and / or mRNA expression.

[0633] In this invention, the level or expression of the oxidative phosphorylation pathway and the activity or expression level of mPTP can be determined using conventional methods, such as measuring the activity of mPTP or measuring the expression level of mPTP at the protein or mRNA level.

[0634] NNMT gene

[0635] In this invention, NNMT is called Nicotinamide N-Methyltransferase. Different databases have different identification numbers for the NNMT gene: HGNC:7861; Entrez Gene:4837; Ensembl:ENSG00000166741; OMIM:600008; UniProtKB:P40261.

[0636] According to the human genome version GCF_000001405.25 (GRCh37.p13), the NNMT gene region is located on human chromosome 11 from position 114,128,528 to 114,184,258, a DNA sequence with a total length of 55,731 bp, including the NNMT gene promoter region, NNMT gene exon region, and NNMT gene intron region. The transcription start site of the NNMT gene is position 114,166,535.

[0637] The NNMT gene promoter region is the nucleotide sequence from position 114,164,535 bp to position 114,167,034 bp on human chromosome 11. Specifically, it comprises the sequence from the 2000 bp before the transcription start site (bold portion) to the transcription start site itself and the following 499 bp (underlined portion), a total length of 2500 bp. The nucleotide sequence of the NNMT gene promoter region is shown in SEQ ID NO:1 below:

[0638]

[0639]

[0640] In this invention, the 1050bp before the transcription start site of the NNMT gene to the 499bp after the transcription start site is position 951-2500 of the nucleotide sequence shown in SEQ ID NO:1.

[0641] In this invention, the 1050bp to 193bp before the transcription start site of the NNMT gene is the nucleotide sequence 951-1808 shown in SEQ ID NO:1.

[0642] DNA methylation

[0643] DNA methylation is a form of DNA chemical modification that can alter genetic expression without changing the DNA sequence. DNA methylation refers to the covalent bonding of a methyl group to the 5th carbon position of the cytosine of a CpG dinucleotide in the genome, under the action of DNA methyltransferases. Numerous studies have shown that DNA methylation can induce changes in chromatin structure, DNA conformation, DNA stability, and the way DNA interacts with proteins, thereby regulating gene expression.

[0644] DNA methylation is one of the earliest discovered and most thoroughly studied epigenetic regulatory mechanisms. In a broad sense, DNA methylation refers to the chemical modification process in which a specific base on the DNA sequence acquires a methyl group through covalent bonding, catalyzed by DNA methyltransferase (DNMT), using S-adenosyl methionine (SAM) as the methyl donor. This DNA methylation modification can occur at sites such as the C-5 position of cytosine, the N-6 position of adenine, and the N-7 position of guanine. Generally, the DNA methylation involved in research mainly refers to the methylation process occurring at the 5th carbon atom of cytosine in CpG dinucleotides, the product of which is called 5-methylcytosine (5-mC), the main form of DNA methylation in eukaryotes such as plants and animals. As a relatively stable modification state, DNA methylation can be inherited by newly formed daughter DNA during DNA replication under the action of DNA methyltransferase, making it an important epigenetic mechanism.

[0645] DNA methylation reactions are classified into two types. One type involves the methylation of DNA in which both strands are unmethylated, known as de novo methylation. The other type involves the methylation of one strand of a double-stranded DNA while the other unmethylated strand is methylated; this type is called maintenance methylation.

[0646] Typically, DNA methylation is the methylation of DNA CpG sites. The distribution of CpG dinucleotides in the human genome is highly uneven, with some regions maintaining or exceeding normal probabilities of CpG. CpG-rich regions (also known as CpG islands) are mainly located in the promoter and exon regions of genes, and are regions rich in CpG dinucleotides; approximately 60% or more of the gene promoters contain CpG islands. Here, CpG is an abbreviation for cytosine (C)-phosphate (p)-guanine (G).

[0647] Intracellular gene expression is regulated by multiple signal transduction pathways, transcription factors, and epigenetic modifications. DNA methylation is an important way in which epigenetic modifications regulate gene expression; the level of DNA methylation in a specific gene region often affects the expression level of that gene. Compared to the regulation of gene expression by signal transduction pathways and transcription factors, the effect of DNA methylation on gene expression is more stable and less affected by the extracellular environment. Furthermore, DNA methylation modifications are easily and accurately detected using existing technologies, making them a relatively ideal biomarker.

[0648] Formula I compound

[0649] As used herein, the terms "compound of the present invention," "compound of formula I of the present invention," or "compound of formula I" are used interchangeably to refer to a compound having the structure of formula I, or an optical isomer thereof, a racemic mixture thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. It should be understood that the term also includes mixtures of the foregoing components.

[0650]

[0651] Specifically, the compound of formula I is as described in the first aspect of the present invention above.

[0652] Representatively, the compounds of Formula I described in this invention are specific compounds prepared as described in Examples 1-105 of this invention (including their salt-forming form or free form after removing the salt radical).

[0653] In this invention, it should be understood that when ring B is absent, R3 is also absent, that is, when ring B is absent, the compound of formula I has the following structure:

[0654]

[0655] The compounds of Formula I described herein can be prepared by organic synthesis methods known in the art.

[0656] The compounds of this invention exhibit excellent inhibitory effects on tumor cells, with even better inhibitory effects on tumor cells with upregulated mitochondrial oxidative phosphorylation pathways or low mPTP activity, particularly on tumor cells where mPTP remains permanently switched off. Simultaneously, because normal somatic cells have high mPTP activity, the compounds of this invention exhibit weaker inhibitory effects on normal somatic cells and fewer toxic side effects. Therefore, the compounds of this invention can be developed into relatively safe and effective anticancer drugs.

[0657] The term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are salts formed by the compounds of the present invention with acids, including (but not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic 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. A preferred class of salts are metal salts formed by the compounds of the present invention with bases, including (but 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.

[0658] The compounds of Formula I described in this invention can be converted into their pharmaceutically acceptable salts by conventional methods. For example, a solution of the corresponding acid can be added to a solution of the above-mentioned compound, and after complete salt formation, the solvent can be removed to obtain the corresponding salt of the compound described in this invention.

[0659] The compounds described in this invention are preferably prepared as described in the embodiments of this invention.

[0660] cancer

[0661] The present invention demonstrates that the compounds of the present invention have excellent inhibitory effects on tumor cells, especially on tumor cells with upregulated mitochondrial oxidative phosphorylation pathway, low mPTP activity, low or no expression of NNMT gene, high methylation level of NNMT gene nucleotide sites, and / or high methylation level of NNMT gene DNA CpG sites.

[0662] Specifically, the tumor described in this invention is as described in the first aspect of this invention above.

[0663] anticancer drugs

[0664] In this invention, the anticancer drug may be a compound of formula I as described in this invention, or an optical isomer or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0665] Inhibitors of mitochondrial membrane permeability transition pore and their uses

[0666] In this invention, the mitochondrial membrane permeability transition pore inhibitors include, but are not limited to: Cyclosporin A, CyP-D protein inhibitors, peroxide scavengers, or combinations thereof.

[0667] Representative examples include CyP-D protein inhibitors such as SfA, BKA, and ADP (small molecules that regulate ANT protein activity).

[0668] Typically, the peroxide scavengers include, but are not limited to: Propofol, pyruvate, MCI-186, or combinations thereof.

[0669] markers

[0670] The present invention also provides a biomarker for determining whether a cancer patient is suitable for prevention and / or treatment using the compounds described herein. The biomarker includes the mitochondrial oxidative phosphorylation pathway, mitochondrial membrane permeability transition pore, NNMT gene, high methylation level of NNMT gene nucleotide sites, and / or methylation level of NNMT gene region DNA CpG sites.

[0671] Compositions or formulations, combinations of active ingredients, and packaging and administration methods

[0672] The present invention also provides a composition or formulation, a combination of active ingredients, and a medicine box, wherein the composition or formulation, the combination of active ingredients, and the medicine box can be used for the prevention and / or treatment of cancer.

[0673] The compositions described in this invention are preferably pharmaceutical compositions. The compositions described in this invention may include pharmaceutically acceptable carriers.

[0674] As used herein, "pharmaceutically acceptable carrier" refers to one or more compatible solid, semi-solid, liquid, or gel fillers that are suitable for human or animal use and must have sufficient purity and sufficiently low toxicity. "Compatibility" refers to the ability of the components in a pharmaceutical composition and the active ingredient of the drug, as well as their interactions, to not significantly reduce the efficacy of the drug.

[0675] It should be understood that, in this invention, there are no particular limitations on the pharmaceutically acceptable carriers used. Materials commonly used in the art can be selected, or they can be prepared using conventional methods or purchased from the market. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium dodecyl sulfate), buffers, chelating agents, thickeners, pH adjusters, transdermal penetration enhancers, colorants, flavoring agents, stabilizers, antioxidants, preservatives, antibacterial agents, pyrogen-free water, etc.

[0676] In in vitro studies and in vivo administration (such as intratumoral administration), mitochondrial membrane permeability transition pore inhibitors enhance the therapeutic effect of antitumor drugs by reducing mPTP activity in tumor cells and upregulating the mitochondrial oxidative phosphorylation pathway. Therefore, antitumor drugs and mPTP inhibitors can exert a synergistic antitumor effect.

[0677] This invention provides a combination of active ingredients, a composition, and a kit containing an antitumor drug and an mPTP inhibitor for synergistic antitumor effects.

[0678] The present invention also provides an active ingredient combination, the active ingredient combination comprising the following components:

[0679] (1) A first active ingredient, wherein the first active ingredient is an anticancer drug; and

[0680] (2) The second active ingredient is a mitochondrial membrane permeability transition pore inhibitor.

[0681] In another preferred embodiment, at least one of the active ingredients in the combination of active ingredients is independent.

[0682] In another preferred embodiment, the first active ingredient and the second active ingredient in the combination of active ingredients are independent of each other.

[0683] The present invention also provides a composition comprising:

[0684] (1) A first active ingredient, wherein the first active ingredient is an anticancer drug; and

[0685] (2) The second active ingredient is a mitochondrial membrane permeability transition pore inhibitor.

[0686] In another preferred embodiment, the pharmaceutical composition further includes a pharmaceutically acceptable carrier.

[0687] In another preferred embodiment, the content of the first active ingredient is 0.01-99.99 wt%, more preferably 0.1-99.9 wt%, more preferably 1-99 wt%, more preferably 10-99 wt%, and most preferably 20-99 wt%, based on the total weight of the active ingredients in the composition.

[0688] In another preferred embodiment, the content of the second active ingredient is 0.01-99.99 wt%, more preferably 0.1-99.9 wt%, more preferably 1-99 wt%, more preferably 10-99 wt%, and most preferably 20-99 wt%, based on the total weight of the active ingredients in the composition.

[0689] The present invention also provides a medicine box, the medicine box comprising:

[0690] (A) A first formulation containing a first active ingredient, wherein the first active ingredient is an anticancer drug; and

[0691] (B) A second formulation containing a second active ingredient, wherein the second active ingredient is a mitochondrial membrane permeability transition pore inhibitor.

[0692] In another preferred embodiment, the medicine box also includes an instruction manual.

[0693] In another preferred embodiment, the first and second formulations are independent formulations.

[0694] In another preferred embodiment, the first and second formulations are combined formulations.

[0695] In another preferred embodiment, the instructions for use specify that the first and second formulations are used in combination to enhance the antitumor activity of the anticancer drug.

[0696] In another preferred embodiment, the combined method involves first administering a second formulation containing a mitochondrial membrane permeability transition pore inhibitor, followed by administering an anticancer drug.

[0697] Preferably, in the combination, composition and / or flask of the active ingredients described in this invention, the molar ratio of the first active ingredient to the second active ingredient is 0.01-600:1, more preferably 0.05-500:1, more preferably 0.1-400:1, more preferably 0.2-200:1, more preferably 0.5-100:1, more preferably 0.5-80:1, and most preferably 1-50:1.

[0698] In this invention, the dosage forms of the compositions and formulations include, but are not limited to, oral formulations, injectable formulations, and topical formulations.

[0699] Representatively, the dosage forms of compounds and preparations include, but are not limited to: tablets, injections, infusions, ointments, gels, solutions, microspheres, and films.

[0700] Typically, the injectable is an intratumoral injectable.

[0701] Pharmaceutical formulations should be matched with the route of administration, preferably oral or injectable (e.g., intratumoral injection). When used, a therapeutically effective amount of the drug is administered to the desired subject (e.g., human or non-human mammal). As used herein, the term "therapeutically effective amount" refers to an amount that is functionally or activityably produced in humans and / or animals and is acceptable to humans and / or animals. Those skilled in the art will understand that the "therapeutically effective amount" can vary depending on the form of the pharmaceutical composition, the route of administration, the excipients used, the severity of the disease, and whether it is used in combination with other drugs.

[0702] In one administration method, the safe and effective daily dose of the first active ingredient is generally at least about 0.1 mg, and in most cases does not exceed about 2500 mg. Preferably, this dose is 1 mg to 500 mg; the safe and effective amount of the second active ingredient is generally at least about 0.01 mg, and in most cases does not exceed 2500 mg. Preferably, this dose range is 0.1 mg to 2500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

[0703] The main advantages of this invention include:

[0704] This invention is the first to develop a novel compound that can efficiently and safely inhibit tumor cells, especially tumor cells with upregulated mitochondrial oxidative phosphorylation pathway or low mPTP activity. In addition, it has a significant inhibitory effect on tumors with low or no NNMT gene expression and / or tumors with high methylation levels at the DNA CpG site in the NNMT gene region.

[0705] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0706] Example 1

[0707] Preparation of compound AB24831A

[0708] Step 1):

[0709]

[0710] Compound 1 (440 mg, 2 mmol) was dissolved in dry N,N-dimethylformamide (20 mL), followed by compound 2 (428.4 mg, 4.2 mmol), bis(triphenylphosphine)palladium dichloride (42 mg, 0.06 mmol), N,N-diisopropylethylamine (825 mg, 6.4 mmol), and cuprous iodide (19 mg, 0.1 mmol). The mixture was then purged with nitrogen three times and stirred overnight at room temperature. Upon the appearance of a new spot on a TLC plate, the mixture 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, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound 3 (130 mg). Yield: 33%.

[0711] Step 2):

[0712]

[0713] Compound 3 (130 mg, 0.47 mmol) was dissolved in dioxane (6 mL), followed by the addition of potassium tert-butoxide (336.6 mg, 3 mmol). The mixture was then purged three times with nitrogen, and stirred at 110 °C for 16 hours. Upon the appearance of a new spot on a TLC plate, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to obtain compound 4 (50 mg). Yield: 50%.

[0714] Step 3):

[0715]

[0716] Compound 4 (100 mg, 0.67 mmol) was dissolved in acetonitrile (10 mL), and compound 5 (312 mg, 1.34 mmol) was added. The mixture was then purged with nitrogen three times, heated to 80 °C, and stirred overnight. A new spot was observed on a TLC plate. The mixture was diluted with water (50 mL), and then 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. Compound AB24831A (25.2 mg) was obtained by preparative purification. Yield: 8.1%.

[0717] Compound AB24831A:

[0718] 1H NMR (400MHz, DMSO-d6) δ13.53(s,1H),9.06(s,1H),8.24(d,J=7.1Hz,1H),8.14(d,J=6.5Hz,1 H),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).

[0719] MS-ESI: Theoretical value [M-CF3COO] + 347.82, measured value: 347.25.

[0720] Example 2

[0721] Preparation of compound AB24828A

[0722] Step 1):

[0723]

[0724] Compound 1 (140 mg, 0.66 mmol) was dissolved in dry N,N-dimethylformamide (10 mL), followed by the addition of compound 2 (161.4 mg, 1.39 mmol), bis(triphenylphosphine)palladium dichloride (14 mg, 0.02 mmol), N,N-diisopropylethylamine (272 mg, 2.11 mmol), and cuprous iodide (5.7 mg, 0.03 mmol). The mixture was then purged with nitrogen three times and stirred overnight at room temperature. Upon the appearance of a new spot on a TLC plate, the mixture 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, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound 3 (100 mg). Yield: 75.7%.

[0725] Step 2):

[0726]

[0727] Compound 3 (100 mg, 0.47 mmol) was dissolved in dioxane (30 mL), followed by the addition of potassium tert-butoxide (160 mg, 1.43 mmol). The mixture was then purged three times with nitrogen and stirred at 110 °C for 1 hour. A new spot was observed on a TLC plate. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound 4 (50 mg). Yield: 50%.

[0728] Step 3):

[0729]

[0730] Compound 4 (50 mg, 0.67 mmol) was dissolved in acetonitrile (10 mL), and then compound 5 (312 mg, 1.34 mmol) was added. The mixture was then purged with nitrogen three times, heated to 80 °C, and stirred overnight. A new spot appeared on a TLC plate. The organic solvent was removed by direct concentration under reduced pressure, and compound AB24828A (34.7 mg) was obtained through preparative purification. Yield: 10.9%.

[0731] Compound AB24828A:

[0732] 1H NMR (400MHz, DMSO-d6) δ13.15(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).

[0733] MS-ESI: Theoretical value [M-CF3COO] + 361.84, measured value 361.25.

[0734] Example 3

[0735] Preparation of compound AB24861

[0736] step:

[0737]

[0738] Compounds 1 (100 mg, 0.48 mmol) and 2 (123 g, 0.577 mmol) were dissolved in acetonitrile (10 mL). The mixture was stirred at room temperature for 4 hours. New spots were observed by TLC. The reaction mixture was directly filtered, and the filter cake was washed with acetonitrile to give compound AB24861 (110.0 mg). Yield: 67.2%.

[0739] Compound AB24861:

[0740] 1 H NMR (400MHz, DMSO-d6) δ12.96(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=7.1H z,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).

[0741] MS-ESI: Theoretical value [M-Br] + 341.43, measured value 341.30.

[0742] Example 4

[0743] Preparation of compound AB24859

[0744] Step 1):

[0745]

[0746] Compound 1 (2.0 g, 15.5 mmol), compound 2 (5.6 g, 46.6 mmol), bis(dibenzylacetone)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-dimethylacetamide (50 mL). The mixture was then purged with nitrogen three times, stirred at 120 °C for 16 hours, and the reaction was detected by TLC to identify new spots. The mixture was then cooled to room temperature, extracted with water and ethyl acetate (100 mL x 3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 66.6%) to give compound 3 (70 mg). Yield: 2.16%.

[0747] Step 2):

[0748]

[0749] Compounds 3 (97 mg, 0.5 mmol) and 4 (244 g, 1 mmol) were dissolved in acetonitrile (10 mL). The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The reaction mixture was directly filtered, and the filter cake was washed with acetonitrile to give compound AB24859 (89 mg). Yield: 52.1%.

[0750] Compound AB24859:

[0751] 1 H NMR (400MHz, DMSO-d6) δ12.98(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).

[0752] MS-ESI: Theoretical value [M-Br] + 341.43, measured value 341.30.

[0753] Example 5

[0754] Preparation of compound AB24835A

[0755] Step 1):

[0756]

[0757] Compound 1 (1.28 g, 10 mmol), compound 2 (4.02 g, 30 mmol), bis(dibenzylacetone)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-dimethylacetamide (50 mL). The mixture was then purged with nitrogen three times, stirred at 120 °C for 16 hours, and the reaction was detected by TLC to identify new spots. The mixture was then cooled to room temperature, extracted with water and ethyl acetate (100 mL x 3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 66.6%) to give compound 3 (1.1 g). Yield: 52.88%. MS-ESI: Theoretical value [M+1] + 208.26, measured value: 209.30.

[0758] Step 2):

[0759]

[0760] Compounds 3 (208 mg, 1 mmol) and 4 (233.5 mg, 1 mmol) were dissolved in acetonitrile (10 mL). The mixture was stirred at 80 °C for 3 hours. New spots were observed by TLC, and the mixture was then cooled to room temperature. The reaction solution was directly filtered, and the filter cake was washed with ethyl acetate to give compound AB24835A (150 mg). Yield: 41.55%.

[0761] Compound AB24835A:

[0762] 1 H NMR(400MHz,DMSO-d6)δ12.98(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).

[0763] MS-ESI: Theoretical value [M-Br] + 361.84, measured value 361.30.

[0764] Example 6

[0765] Preparation of compound AB24863

[0766] Step 1):

[0767]

[0768] Compound 1 (3.86 g, 30 mmol) was dissolved in N,N-dimethylacetamide (250 mL), followed by compound 2 (12.1 g, 90 mmol), then triethylenediamine (10.1 g, 90 mmol), then tri-tert-butylphosphine tetrafluoroborate (870 mg, 3 mmol), and finally bis(di-benzylacetone)palladium (1.37 g, 1.5 mmol). The mixture was then purged with nitrogen three times, heated to 120 °C, and stirred overnight for 2 hours. New spots were detected by TLC. The mixture was diluted with water (200 mL), then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.0 g). Yield: 32%.

[0769] Step 2):

[0770]

[0771] Compound 3 (100 mg, 0.5 mmol) was dissolved in acetonitrile (10 mL), and then compound 4 (244 mg, 1 mmol) was added. The mixture was then purged with nitrogen three times, heated to 80 °C, and stirred overnight. A new spot appeared on a TLC plate. The organic solvent was removed by direct concentration under reduced pressure, and the solution was purified by thin-layer chromatography (methanol:dichloromethane = 10:1) to obtain compound AB24863 (140 mg). Yield: 59.8%.

[0772] Compound AB24863:

[0773] 1 H NMR (400MHz, DMSO-d6) δ13.01(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).

[0774] MS-ESI: Theoretical value [M-Br] + 388.40, measured value 388.25.

[0775] Example 7

[0776] Preparation of compound AB24878

[0777] Step 1):

[0778]

[0779] Compounds 1 (2.7 g, 23 mmol) and 2 (2.5 g, 19 mmol) were dissolved in N,N-dimethylacetamide (30 mL). Triethylenediamine (6.5 g, 58 mmol), bis(diphenylacetone)palladium (890 mg, 0.97 mmol), and tri-tert-butylphosphine tetrafluoroborate (561 mg, 1.94 mmol) were added. The mixture was stirred at 120 °C for 16 hours under sealed conditions. New spots were observed by TLC. The mixture was extracted with water and ethyl acetate (60 mL), and the organic phase was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (methanol:dichloromethane = 5%) to give compound 3 (800 mg). Yield: 17.9%.

[0780] Step 2):

[0781]

[0782] Compounds 3 (92 mg, 0.5 mmol) and 4 (244 g, 1 mmol) were dissolved in acetonitrile (10 mL). The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The reaction mixture was directly filtered, and the filter cake was washed with acetonitrile to give compound AB24878 (116.2 mg). Yield: 53.02%.

[0783] Compound AB24878:

[0784] 1 H NMR (400MHz, DMSO-d6) δ9.28(s,1H),8.77(d,J=11.6Hz,2H),8.59(d,J=8.2Hz,1H),8.48(s,2H),8.37(d,J=6.3 Hz,1H),7.96(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).

[0785] MS-ESI: Theoretical value [M-Br] + 358.37, measured value 358.30.

[0786] Example 8

[0787] Preparation of compound AB24872

[0788] Step 1):

[0789]

[0790] Compound 1 (500 mg, 3.6 mmol) was dissolved in dichloromethane (20 mL), and Dysmartin oxidant (2.02 g, 4.7 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 2 hours. New spots were observed by TLC. The filtrate was concentrated under reduced pressure to remove the organic solvent, and then subjected to column chromatography (ethyl acetate: petroleum ether = 0-10%) to give compound 2 (340 mg). Yield: 69.1%.

[0791] Step 2):

[0792]

[0793] Compounds 2 (340 mg, 2.67 mmol), 3 (286 mg, 2.22 mmol), bis(dibenzylacetone)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-dimethylacetamide (50 mL). The mixture was then purged with nitrogen three times, stirred at 120 °C for 16 hours, and the reaction was detected by TLC to identify new spots. The mixture was then cooled to room temperature, extracted with water and ethyl acetate (100 mL x 3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 66.6%) to give compound 4 (200 mg). Yield: 37.9%.

[0794] Step 3):

[0795]

[0796] Compound 4 (200 mg, 0.96 mmol) and compound 5 (245 mg, 1.15 mmol) were dissolved in acetonitrile (10 mL). The mixture was purged with nitrogen three times and stirred at room temperature for 5 hours. New spots were detected by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24872 (92.6 mg). Yield: 28.3%.

[0797] Compound AB24872:

[0798] 1H NMR (400MHz, CD3OD) δ10.11(s,1H),9.54(s,1H),9.20(dd,J=39.1,6.4Hz,2H),8.78(d,J=7.5Hz,2H),8.4 6–8.36(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).

[0799] MS-ESI: Theoretical value [M-Br] + 341.43, measured value 341.25.

[0800] Example 9

[0801] Preparation of compound AB24854

[0802] Step 1):

[0803]

[0804] Compound 1 (8 g, 47.1 mmol) was dissolved in tetrahydrofuran (80 mL). A 2.5 N solution of lithium aluminum hydride in tetrahydrofuran (56 mL, 141.2 mmol) was added dropwise under ice bath conditions. The mixture was stirred at room temperature for 30 minutes, then refluxed at 75 °C overnight. New spots were observed by TLC. The mixture was then cooled to room temperature, and water (56 mL) was added dropwise under ice-water bath conditions, followed by 15% sodium hydroxide aqueous solution (56 mL), and then water (158 mL). The mixture was filtered through a diatomaceous earth filter to remove the aluminum salts. Ethyl acetate (100 mL x 3) was added for extraction. 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, yielding compound 2 (5.6 g). Yield: 75.76%.

[0805] Step 2):

[0806]

[0807] Compound 2 (3 g, 17.64 mmol) was dissolved in dichloromethane (50 mL), and Dysmartin oxidant (8.97 g, 21.18 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 1 hour, and a new spot was observed on a TLC plate. Then, dichloromethane (50 mL) was added, and the mixture was filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure to remove the organic solvent, and then subjected to column chromatography (ethyl acetate: petroleum ether = 0-10%) to give compound 3 (2.4 g). Yield: 80.9%.

[0808] Step 3):

[0809]

[0810] Compounds 3-1 (1.67 g, 12.99 mmol) and 3 (2.4 g, 14.29 mmol) were dissolved in N,N-dimethylacetamide (30 mL), followed by the addition of triethylenediamine (4.37 g, 38.97 mmol), bis(diphenylacetone)palladium (595 mg, 0.65 mmol), and tri-tert-butylphosphine tetrafluoroborate (377 mg, 1.31 mmol). The mixture was stirred at 120 °C for 16 hours. New spots were observed by TLC. The mixture was extracted with water and ethyl acetate (10 mL), and the organic phase was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (methanol:dichloromethane = 10%) to give compound 4 (1.2 g) (50% crude product).

[0811] Step 4):

[0812]

[0813] Compound 4 (500 mg, 2.06 mmol) was dissolved in acetonitrile (5 mL), then compound 5 (660 mg, 3.09 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was observed on a TLC plate. The reaction solution was evaporated to dryness, and the crude product was sent to prepare compound AB24854 (20 mg). Yield: 2.59%.

[0814] Compound AB24854:

[0815] 1 H NMR(400MHz,CD3OD)δ9.02(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).

[0816] MS-ESI: Theoretical value [M-CF3COO] + 375.12, measured value 375.20.

[0817] Example 10

[0818] Preparation of compound AB24945

[0819] Step 1):

[0820]

[0821] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydride (203 mg, 5.07 mmol) was added under ice bath conditions, and the mixture was stirred for 30 minutes under ice bath conditions. Then, compound 2 (289 mg, 1.86 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Upon detection of a new spot on TLC, the reaction was extracted with water (10 mL) and ethyl acetate (10 mL). The ethyl acetate extraction was performed three times, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate: petroleum ether = 0-10%) to give compound 3 (260 mg). Yield: 73.8%.

[0822] Step 2):

[0823]

[0824] Compound 3 (130 mg, 0.625 mmol) was dissolved in acetonitrile (10 mL), and then compound 4 (200 mg, 0.94 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared on a TLC plate, indicating the precipitation of a solid. The solid was filtered to obtain compound AB24945 (70 mg). Yield: 32.8%.

[0825] Compound AB24945:

[0826] 1 H NMR (400MHz, CDCl3) δ10.96 (s, 1H), 8.05 (d, J = 7.4Hz, 2H), 7.87 (s, 2H), 7.78 (s, 1H) ,7.42(s,2H),7.36–7.28(m,5H),6.81(d,J=11.9Hz,3H),5.70(s,2H),2.41(s,3H).

[0827] MS-ESI: Theoretical value [M-Br] + 341.43, measured value 341.10.

[0828] Example 11

[0829] Preparation of compound AB24837

[0830] Step 1):

[0831]

[0832] Compound 1 (440 mg, 2 mmol) was dissolved in dry N,N-dimethylformamide (20 mL), followed by compound 2 (428.4 mg, 4.2 mmol), bis(triphenylphosphine)palladium dichloride (42 mg, 0.06 mmol), N,N-diisopropylethylamine (825 mg, 6.4 mmol), and cuprous iodide (19 mg, 0.1 mmol). The mixture was then purged with nitrogen three times and stirred overnight at room temperature. Upon the appearance of a new spot on a TLC plate, the mixture 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, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound 3 (130 mg). Yield: 33%.

[0833] Step 2):

[0834]

[0835] Compound 3 (130 mg, 0.47 mmol) was dissolved in dioxane (6 mL), followed by the addition of potassium tert-butoxide (336.6 mg, 3 mmol). The mixture was then purged three times with nitrogen, and stirred at 110 °C for 16 hours. Upon the appearance of a new spot on a TLC plate, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to obtain compound 4 (50 mg). Yield: 50%.

[0836] Step 3):

[0837]

[0838] Compound 4 (340 mg, 1.75 mmol) was dissolved in acetic acid (5 mL), followed by the addition of palladium on carbon (100 mg, 3 mmol). The mixture was then purged three times with hydrogen and stirred at room temperature for 12 hours. New spots were detected by TLC. The solution was filtered, evaporated to dryness, and sent to prepare compound 5 (50 mg). Yield: 50%

[0839] Step 4):

[0840]

[0841] 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 purged with nitrogen three times, heated to 80 °C, and stirred overnight. A new spot was observed on a TLC plate. The mixture was diluted with water (50 mL), then 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 concentrated under reduced pressure to remove the organic solvent. Compound AB24837 (30 mg) was obtained through preparative purification. Yield: 33.71%.

[0842] Compound AB24837:

[0843] 1 H NMR (400MHz, DMSO-d6) δ9.40(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).

[0844] MS-ESI: Theoretical value [M-CF3COO] + 349.84, measured value 349.00.

[0845] Example 12

[0846] Preparation of compound AB24827A

[0847] Step 1):

[0848]

[0849] Compound 1 (440 mg, 2 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by compound 2 (486 mg, 4.2 mmol), then cuprous iodide (19 mg, 0.1 mmol), then N,N-diisopropylethylamine (824 mg, 6.4 mmol), and finally palladium dichloride bis(triphenylphosphine) (42 mg, 0.06 mmol). The mixture was then purged with nitrogen three times and stirred at room temperature for 16 hours. Once a new spot appeared on a TLC plate, the mixture was diluted with water (50 mL), then extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 10:1) to give compound 3 (332 mg). Yield: 79.8%.

[0850] Step 2):

[0851]

[0852] Compound 3 (332 mg, 1.6 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the addition of potassium tert-butoxide (538 mg, 4.8 mmol). The mixture was then purged three times with nitrogen and heated to 100 °C with stirring overnight. A new spot appeared on TLC. The mixture was then concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 10:1) to give compound 4 (189 mg). Yield: 56.7%.

[0853] Step 3)

[0854]

[0855] Compound 4 (189 mg, 0.9 mmol) was dissolved in acetonitrile (10 mL), and compound 5 (233 mg, 1.1 mmol) was added. The mixture was then purged with nitrogen three times, heated to 80 °C, and stirred overnight. A new spot appeared on a TLC plate. The mixture was then concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 10:1) to give compound AB24827A. The yield was 9.3%.

[0856] Compound AB24827A:

[0857] 1H NMR (400MHz, DMSO-d6) δ13.00(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).

[0858] MS-ESI: Theoretical value [M-CF3COO] + 361.84, measured value 361.25.

[0859] Example 13

[0860] Preparation of compound AB24887

[0861] Step 1):

[0862]

[0863] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (20 mL), and NaH (203 mg, 5.07 mmol) was added under ice bath conditions. The mixture was stirred at 0 °C for 30 minutes. Then, compound 2 (318 mg, 1.86 mmol) was slowly added, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on TLC. The mixture was extracted with water (30 mL) and ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then subjected to column chromatography (methanol:dichloromethane = 0-10%) to give compound 3 (280 mg). Yield: 79.5%.

[0864] Step 2):

[0865]

[0866] Compound 3 (280 mg, 1.3 mmol) was dissolved in acetonitrile (5 mL), then compound 4 (430 mg, 2.0 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was observed on TLC. The reaction mixture was evaporated to dryness and subjected to column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24887 (220 mg). Yield: 47.9%.

[0867] Compound AB24887:

[0868] 1H NMR(400MHz,DMSO,d6)δ9.28(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).

[0869] MS-ESI: Theoretical value [M-Br] + 341.43, measured value 341.25.

[0870] Example 14

[0871] Preparation of compound AB24888

[0872] Step 1):

[0873]

[0874] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (20 mL), and NaH (203 mg, 5.07 mmol) was added under ice bath conditions. The mixture was stirred at 0 °C for 30 minutes. Compound 2 (318 mg, 1.86 mmol) was then slowly added, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on TLC. The mixture was extracted with water (30 mL) and ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The resulting solution was obtained by column chromatography (methanol:dichloromethane = 0-10%), yielding compound 3 (280 mg). Yield: 79.5%

[0875] Step 2):

[0876]

[0877] Compound 3 (250 mg, 1.2 mmol) was dissolved in acetonitrile (5 mL), then compound 4 (440 mg, 1.8 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared on a TLC plate, indicating the precipitation of a solid. The mixture was filtered, and the filter cake was washed three times with acetonitrile (3 mL). The solution was then evaporated to dryness to give compound AB24888 (300 mg). Yield: 67.1%.

[0878] Compound AB24888:

[0879] 1H NMR (400MHz, DMSO, d6) δ9.26 (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,1H),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).

[0880] MS-ESI: Theoretical value [M-Br] + 372.40, measured value 372.25.

[0881] Example 15

[0882] Preparation of compound AB24895

[0883] Step 1):

[0884]

[0885] Compound 1 (500 mg, 4.23 mmol), iodobenzene (963 mg, 4.23 mmol), cuprous iodide (16.2 mg, 0.085 mmol), potassium phosphate (1.79 g, 8.46 mmol), and cyclohexanediamine (99 mg, 0.87 mmol) were dissolved in N,N-dimethylacetamide (20 mL). The mixture was purged with nitrogen three times, heated to 110 °C, and stirred for 16 hours. New spots were detected by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound 3 (580 mg).

[0886] Step 2):

[0887]

[0888] Compound 3 (290 mg, 1.49 mmol) and compound 4 (477 mg, 2.24 mmol) were dissolved in acetonitrile (10 mL). The mixture was purged with nitrogen three times and stirred at room temperature for 3 hours. New spots were detected by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24895 (377 mg). Yield: 77.3%.

[0889] Compound AB24895:

[0890] 1H NMR (400MHz, DMSO-d6) δ9.45(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).

[0891] MS-ESI: Theoretical value [M-Br] + 327.41, measured value 327.20.

[0892] Example 16

[0893] Preparation of compound AB24833A

[0894] Step 1):

[0895]

[0896] Compounds 1 (2.0 g, 15.5 mmol), 2 (5.6 g, 46.6 mmol), bis(dibenzylacetone)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-dimethylacetamide (50 mL). The mixture was then purged with nitrogen three times, stirred at 120 °C for 16 hours, and the reaction was detected by TLC to identify new spots. The mixture was then cooled to room temperature, extracted with water and ethyl acetate (100 mL x 3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 66.6%) to give compound 3 (70 mg). Yield: 2.16%.

[0897] Step 2):

[0898]

[0899] Compounds 3 (70 mg, 0.336 mmol) and 4 (157 mg, 0.673 mmol) were dissolved in acetonitrile (10 mL). The mixture was stirred at 80 °C for 3 hours. New spots were observed by TLC, and the mixture was then cooled to room temperature. The reaction solution was directly filtered, and the filter cake was washed with ethyl acetate to give compound AB24833A (40 mg). Yield: 32.8%.

[0900] Compound AB24833A:

[0901] 1 H NMR (399MHz, DMSO-d6) δ12.76(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).

[0902] MS-ESI: Theoretical value [M-CF3COO] + 361.85, measured value 361.25.

[0903] Example 17

[0904] Preparation of compound AB24916

[0905] Step 1):

[0906]

[0907] Compound 1 (480 mg, 3.0 mmol) was dissolved in acetic acid (7 mL). Liquid bromine (480 mg, 3.0 mmol) and two drops of hydrobromic acid aqueous solution were added to the mixture, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on a TLC plate. Ice water (30 mL) was added, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, 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). Yield: 55.8%.

[0908] Step 2):

[0909]

[0910] Compound 2 (150 mg, 0.63 mmol) was dissolved in acetonitrile (10 mL), and then compound 3 (150 mg, 0.82 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared on a TLC plate, indicating the precipitation of a solid. The mixture was filtered, and the filter cake was washed three times with acetonitrile (2 mL). The solution was then evaporated to dryness to give compound AB24916 (50 mg). Yield: 23.1%.

[0911] Compound AB24916:

[0912] 1H NMR (400MHz, DMSO-d6) δ9.55(s,1H),8.26(d,J=7.0Hz,1H),8.15(d,J=7.1Hz,1H),7.6 9(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).

[0913] MS-ESI: Theoretical value [M-Br] + 343.44, measured value 343.10.

[0914] Example 18

[0915] Preparation of compound AB24913

[0916] Step 1):

[0917]

[0918] Compound 1 (500 mg, 2.77 mmol) was dissolved in acetic acid (7 mL). Liquid bromine (443 mg, 2.77 mmol) and two drops of hydrobromic acid aqueous solution were added to the mixture, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on a TLC plate. Ice water (30 mL) was added, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, 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). Yield: 27.8%.

[0919] Step 2):

[0920]

[0921] Compound 3 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), and then compound 4 (5 g, 53.13 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 hours. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (4.01 g, 106.2 mmol) was slowly added. The system was allowed to rise naturally to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (200 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 5 (2.6 g). Yield: 26.8%.

[0922] Step 3):

[0923]

[0924] Compound 2 (200 mg, 0.77 mmol) was dissolved in acetonitrile (10 mL), and compound 5 (212 mg, 1.12 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared on a TLC plate, indicating the precipitation of a solid. The mixture was filtered, and the filter cake was washed three times with acetonitrile (2 mL). The solution was then evaporated to dryness to give compound AB24913 (50 mg). Yield: 17.5%.

[0925] Compound AB24913:

[0926] 1 H NMR(400MHz,DMSO,d6)δ9.34(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),7.3 4(d,J=25.3Hz,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).

[0927] MS-ESI: Theoretical value [M-Br] - ] + 363.86, measured value 363.30.

[0928] Example 19

[0929] Preparation of compound AB24841A

[0930] Step 1):

[0931]

[0932] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), and then compound 2 (5 g, 53.13 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 hours. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (4.01 g, 106.2 mmol) was slowly added. The system was allowed to rise naturally to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (200 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g). Yield: 26.8%.

[0933] Step 2):

[0934]

[0935] Compound 4 (500 mg, 2.7 mmol) was dissolved in acetic acid (50 mL). Liquid bromine (442 mg, 2.7 mmol) and two drops of hydrobromic acid aqueous solution were added to the mixture, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on a TLC plate. Ice water (30 mL) was added, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding compound 5 (700 mg). Yield: 97.3%.

[0936] Step 3):

[0937]

[0938] Compound 5 (400 mg, 1.5 mmol) and compound 3 (200 mg, 1.1 mmol) were dissolved in acetonitrile (10 mL). The mixture was purged with nitrogen three times and stirred at room temperature for 5 hours. New spots were detected by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24841A (37 mg). Yield: 9.3%.

[0939] Compound AB24841A:

[0940] 1H NMR(400MHz, CDCl3)δ9.96(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).

[0941] MS-ESI: Theoretical value [M-CF3COO] + 363.86, measured value 363.25.

[0942] Example 20

[0943] Preparation of compound AB24920

[0944] Step 1):

[0945]

[0946] Compound 1 (500 mg, 2.6 mmol) was dissolved in tetrahydrofuran (10 mL). Liquid bromine (418 mg, 2.6 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 2 hours. New spots were observed by TLC. The solution was diluted with 2 M sodium bicarbonate aqueous solution (40 mL) and ethyl acetate (40 mL), and the organic phase was evaporated to dryness to give compound 2 (400 mg, Crude).

[0947] Step 2):

[0948]

[0949] Compound 2 (200 mg, 0.70 mmol) and compound 3 (130 mg, 0.70 mmol) were dissolved in acetonitrile (10 mL). The mixture was stirred at room temperature for 4 hours. New spots were observed by TLC. The reaction solution was evaporated to dryness and then subjected to column chromatography (DCM:MeOH = 10:1) to give compound AB24920 (41 mg). Yield: 14.8%.

[0950] Compound AB24920:

[0951] 1H 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).

[0952] MS-ESI: Theoretical value [M-Br] + 374.41, measured value 374.30.

[0953] Example 21

[0954] Preparation of compound AB24923

[0955] Step 1):

[0956]

[0957] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), and then compound 2 (5 g, 53.13 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 hours. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (4.01 g, 106.2 mmol) was slowly added. The system was allowed to rise naturally to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (200 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g). Yield: 26.8%.

[0958] Step 2):

[0959]

[0960] Compound 4 (300 mg, 2.03 mmol) was dissolved in acetic acid (10 mL). Liquid bromine (326 mg, 2.03 mmol) and two drops of hydrobromic acid aqueous solution were added to the mixture, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on a TLC plate. Ice water (30 mL) was added, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding compound 5 (400 mg). Yield: 86.7%.

[0961] Step 3):

[0962]

[0963] Compound 5 (200 mg, 0.88 mmol) was dissolved in acetonitrile (10 mL), and then compound 3 (109 mg, 0.59 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was observed on a TLC plate, and the solution was evaporated to dryness to obtain compound AB24923 (25 mg). Yield: 8.6%.

[0964] Compound AB24923:

[0965] 1 H NMR (400MHz, CD3OD) δ8.68(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).

[0966] MS-ESI: Theoretical value [M-CF3COO-] + 330.40, measured value 330.30.

[0967] Example 22

[0968] Preparation of compound AB24840A

[0969] Step 1):

[0970]

[0971] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), and then compound 2 (5 g, 53.13 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 hours. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (4.01 g, 106.2 mmol) was slowly added. The system was allowed to rise naturally to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (200 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g). Yield: 26.8%.

[0972] Step 2):

[0973]

[0974] Compound 4 (500 mg, 3.0 mmol) was dissolved in acetic acid (50 mL). Liquid bromine (480 mg, 3.0 mmol) and two drops of hydrobromic acid aqueous solution were added to the mixture, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on a TLC plate. Ice water (30 mL) was added, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, 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). Yield: 38.46%.

[0975] Step 3):

[0976]

[0977] Compound 5 (300 mg, 1.2 mmol) and compound 3 (200 mg, 1.1 mmol) were dissolved in acetonitrile (10 mL). The mixture was purged with nitrogen three times and stirred at room temperature for 5 hours. New spots were detected by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24840A (27.6 mg). Yield: 7.2%.

[0978] Compound AB24840A:

[0979] 1H NMR(400MHz,DMSO,d6)δ9.38(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).

[0980] MS-ESI: Theoretical value [M-CF3COO] + 349.84, measured value 349.20.

[0981] Example 23

[0982] Preparation of compound AB24904

[0983] Step 1):

[0984]

[0985] Compound 1 (146 mg, 1.0 mmol) was dissolved in acetic acid (5 mL). Liquid bromine (160 mg, 1.0 mmol) and two drops of hydrobromic acid aqueous solution were added to the mixture, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on a TLC plate. Ice water (30 mL) was added, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, 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). Yield: 97.3%.

[0986] Step 2):

[0987]

[0988] Compound 2 (180 mg, 0.79 mmol) was dissolved in acetonitrile (10 mL), and then compound 3 (161 mg, 0.87 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared on a TLC plate, indicating the precipitation of a solid. The mixture was filtered, and the filter cake was washed three times with acetonitrile (2 mL). The solution was then evaporated to dryness to obtain compound AB24904 (40 mg). Yield: 15.4%.

[0989] Compound AB24904:

[0990] 1H NMR (400MHz, DMSO-d6) δ9.76(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).

[0991] MS-ESI: Theoretical value [M-Br] + 329.42, measured value 329.50.

[0992] Example 24

[0993] Preparation of compound AB24905

[0994] Step 1):

[0995]

[0996] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), and then compound 2 (5 g, 53.13 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 hours. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (4.01 g, 106.2 mmol) was slowly added. The system was allowed to rise naturally to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (200 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g). Yield: 26.8%.

[0997] Step 2):

[0998]

[0999] Compound 4 (300 mg, 2.05 mmol) was dissolved in acetic acid (10 mL). Liquid bromine (328 mg, 2.05 mmol) and two drops of hydrobromic acid aqueous solution were added to the mixture, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on a TLC plate. Ice water (30 mL) was added, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The solution was purified by column chromatography (ethyl acetate: petroleum ether = 0-20%) to give compound 5 (300 mg). Yield: 65%.

[1000] Step 3):

[1001]

[1002] Compound 5 (200 mg, 0.89 mmol) was dissolved in acetonitrile (10 mL), and then compound 3 (110 mg, 0.60 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was detected by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24905 (110 mg). Yield: 56%.

[1003] Compound AB24905:

[1004] 1 H NMR (400MHz, DMSO-d6) δ9.43(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).

[1005] MS-ESI: Theoretical value [M-Br] + 329.41, measured value 329.25.

[1006] Example 25

[1007] Preparation of compound AB24883

[1008] Step 1):

[1009]

[1010] Compound 1 (1.06 g, 10 mmol) was dissolved in ethanol (50 mL), and then compound 2 (1.37 g, 10 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 hours. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (1.13 g, 30 mmol) was slowly added. The system was allowed to rise naturally to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (20 mL), and then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (600 mg). Yield: 26.4%.

[1011] Step 2):

[1012]

[1013] Compound 3 (50 mg, 0.22 mmol) was dissolved in N'N-dimethylformamide (5 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (125.55 mg, 0.33 mmol), N'N-diisopropylethylamine (85.2 mg, 0.66 mmol), and compound 4 (25.9 mg, 0.24 mmol). The mixture was then purged with nitrogen three times and stirred overnight at room temperature. New spots were observed on TLC. The mixture was extracted three times with water (10 mL) and ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24883 (27.9 mg). Yield: 36.7%.

[1014] Compound AB24883

[1015] 1 H NMR(400MHz,DMSO,d6)δ8.79(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).

[1016] MS-ESI: Theoretical value [M+1] + 348.30, measured value 348.20.

[1017] Example 26

[1018] Preparation of compound AB24851

[1019] Step 1):

[1020]

[1021] Compound 1 (3.0 g, 18.3 mmol) was dissolved in toluene (50 mL), followed by the addition of compound 2 (5.8 g, 54.8 mmol), cesium carbonate (12.0 g, 36.5 mmol), tris-(diphenylene-BASE-acetone)dipalladium (334 mg, 0.36 mmol), and 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (262 mg, 0.54 mmol). The mixture was then purged with nitrogen three times, heated to 110 °C, and stirred for 16 hours. After the appearance of a new spot on a TLC plate, the reaction temperature was lowered to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (150 mg). Yield: 4.4%.

[1022] Step 2):

[1023]

[1024] Compound 3 (150 mg, 0.78 mmol) was dissolved in acetonitrile (5 mL), then compound 4 (151 mg, 0.71 mmol) was added. The mixture was then purged with nitrogen three times, heated to 80 °C, and stirred overnight. A new spot was observed on a TLC plate. The mixture was then cooled to room temperature, and the solution was evaporated to dryness to prepare compound AB24851 (10 mg). Yield: 3.9%.

[1025] Compound AB24851:

[1026] 1 H NMR (400MHz, CD3OD) δ7.93(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).

[1027] MS-ESI: Theoretical value [M-CF3COO] + 323.43, measured value 323.20.

[1028] Example 27

[1029] Preparation of compound AB24850

[1030] Step 1):

[1031]

[1032] Compounds 1 (2 g, 5.91 mmol), 2 (2.51 g, 7.09 mmol), and sodium methoxide (958 mg, 17.73 mmol) were dissolved in anhydrous ethanol (30 mL) and stirred at room temperature for 16 hours. New spots were observed by TLC. The mixture was then cooled to room temperature and extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 0-30%) to give compound 3 (2.1 g), yield: 86.24%.

[1033] Step 2):

[1034]

[1035] Compound 3 (1.2 g, 2.91 mmol) was dissolved in tetrahydrofuran (6 mL) and water (6 mL), followed by the addition of concentrated hydrochloric acid (3 mL). The mixture was stirred at 100 °C for 3 hours. A new spot was observed on a TLC plate. The mixture was then cooled to room temperature, and the solution was adjusted to alkali with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding compound 4 (500 mg), in 83.21% yield.

[1036] Step 3):

[1037]

[1038] Compound 4 (200 mg, 1.17 mmol) and compound 5 (249 mg, 1.17 mmol) were dissolved in acetonitrile (10 mL), and then triethylamine (356 mg, 3.51 mmol) was added. The mixture was stirred at 80 °C for 16 hours. New spots were observed by TLC. The mixture was then cooled to room temperature, and the solution was evaporated to dryness to prepare AB24850 (40 mg). Yield: 11.32%.

[1039] Compound AB24850:

[1040] 1 H NMR (400MHz, CD3OD) δ8.83(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).

[1041] MS-ESI: Theoretical value [M+1] + 303.14, measured value: 303.00.

[1042] Example 28

[1043] Preparation of compound AB24885

[1044] Step 1):

[1045]

[1046] Compound 1 (519 mg, 3 mmol) was dissolved in tetrahydrofuran (30 mL), followed by compound 2 (481 mg, 4.5 mmol), and then methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (163 mg, 0.18 mmol). The mixture was cooled to 0 °C, and then bis(trimethylsilylamino)lithium (7.5 mL) was injected. The mixture was then purged with nitrogen three times, heated to 40 °C, and stirred for 16 hours. New spots appeared on TLC. The mixture was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to obtain compound 3 (80 mg). Yield: 13%.

[1047] Step 2):

[1048]

[1049] Compound 3 (160 mg, 0.8 mmol) was dissolved in 10 mL of n-tert-butanol, followed by the addition of triethyl orthoformate (296 mg, 2 mmol) and formic acid (37 mg, 0.8 mmol). The mixture was then purged with nitrogen three times, heated to 110 °C, and stirred for 18 hours. A new spot appeared upon TLC detection. The mixture was then concentrated under reduced pressure to remove the organic solvent, and compound 4 (100 mg) was obtained by thin-layer chromatography. Yield: 63.8%.

[1050] Step 3):

[1051]

[1052] 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 purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared upon TLC detection. The organic solvent was removed by direct concentration under reduced pressure, and compound AB24885 (20 mg) was obtained by thin-layer chromatography. Yield: 9.4%.

[1053] Compound AB24885:

[1054] 1 H NMR (400MHz, DMSO-d6) δ9.39(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).

[1055] MS-ESI: Theoretical value [M-Br] + 342.41, measured value 342.30.

[1056] Example 29

[1057] Preparation of compound AB24898

[1058] Step 1):

[1059]

[1060] Compound 2 (53.5 mL, 150 mmol, 3 N) was dissolved in tetrahydrofuran, and compound 1 (6.25 g, 50 mmol) was added at 0 °C. The mixture was stirred for 16 hours from 0 °C to room temperature. New spots were observed by TLC, quenched with saturated ammonium chloride at 0 °C, filtered with diatomaceous earth, and extracted with ethyl acetate. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to give compound 3 (4.2 g). Yield: 41.37%.

[1061] Step 2):

[1062]

[1063] Compound 3 (4.06 g, 20 mmol) was dissolved in tetrahydrofuran, and Desmartin oxidant (10.17 g, 24 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 2 hours. New spots were observed by TLC, and the compound was purified by column chromatography (ethyl acetate; petroleum ether = 1:3) to give compound 4 (4.0 g). Yield: 99.0%.

[1064] Step 3):

[1065]

[1066] Compound 4 (402 mg, 2 mmol) was dissolved in ethanol, and then hydrazine hydrate (200 mg, 4 mmol) was added. The mixture was stirred at 90 °C for 16 hours. New spots were observed by TLC, and the compound was purified by column chromatography (ethyl acetate; petroleum ether = 1:1) to give compound 5 (60 mg). Yield: 15.30%.

[1067] Step 4):

[1068]

[1069] Compound 5 (100 mg, 0.51 mmol) and compound 6 (123.93 mg, 0.51 mmol) were dissolved in acetonitrile (5 mL). The solution was stirred at room temperature for 3 hours. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB24898 (100 mg). Yield: 54.61%.

[1070] Compound AB24898:

[1071] 1 H NMR(400MHz, DMSO-d6)δ9.77(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).

[1072] MS-ESI: Theoretical value [M-Br] - ] + 359.36, measured value 359.25.

[1073] Example 30

[1074] Preparation of compound AB24839B

[1075] Step 1):

[1076]

[1077] Compound 1 (2.1 g, 20 mmol) was dissolved in ammonia and ethanol (40:40 mL). The solution was stirred at -78°C to -10°C for 3 hours. Then, compound 2 (6.72 g, 40 mmol) was added, and the mixture was stirred overnight at room temperature. A new spot was observed by TLC. The pH was adjusted to 1 with concentrated hydrochloric acid, and the mixture was extracted with water and ethyl acetate (80 mL). The aqueous phase was then adjusted to pH 14 with 50% sodium hydroxide, and extracted again with water and dichloromethane (2 x 80 mL). The organic phase was evaporated to dryness to give compound 3 (1.6 g). Yield: 54.42%.

[1078] Step 2):

[1079]

[1080] 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). The mixture was stirred at 80 °C for 16 hours. New spots were observed by TLC. The mixture was extracted with water and ethyl acetate (200 mL x 2). The organic phase was then subjected to rotary evaporation and column chromatography (PE:EA = 5:1) to give compound 5 (2.2 g). Yield: 25.41%.

[1081] Step 3):

[1082]

[1083] 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'-bis(diphenylphosphine)ferrocene]palladium dichloride (495.6 mg, 0.66 mmol) were dissolved in dioxane:water (21:7 mL). The mixture was stirred at 95 °C for 16 hours. New spots were observed by TLC. Extraction was performed with water and ethyl acetate (200 mL x 2). The organic phase was then subjected to rotary evaporation followed by column chromatography (PE:EA = 3:1) to give compound 7 (200 mg). Yield: 11.02%.

[1084] Step 4):

[1085]

[1086] 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). The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The mixture was extracted with water and dichloromethane (50 mL x 2), and the organic phase was evaporated by rotary chromatography (PE:EA = 3:1) to give compound 8 (200 mg). Yield: 28.82%.

[1087] Step 5):

[1088]

[1089] Compound 8 (300 mg, 0.86 mmol) and Grubbs Catalyst 2ND (100 mg) were dissolved in dichloromethane (10 mL). The mixture was stirred at 40 °C for 16 hours. A potassium hydroxide aqueous solution (1 N, 5 mL) was then added and stirred for 1 hour. New spots were observed on TLC. The mixture was extracted with water and dichloromethane (50 mL x 2). The organic phase was evaporated by rotary chromatography (DCM:MeOH = 10:1) to give compound 9 (120 mg). Yield: 62.57%.

[1090] Step 6):

[1091]

[1092] Compound 9 (60 mg, 0.25 mmol) was dissolved in acetonitrile (5 mL), then compound 10 (57 mg, 0.25 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was observed on TLC. The reaction mixture was evaporated to dryness and subjected to column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24839B (6 mg). Yield: 9.94%.

[1093] Compound AB24839B:

[1094] 1 H NMR (400MHz, CD3OD) δ8.16(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).

[1095] MS-ESI: Theoretical value [M-Br] + 375.87, measured value 375.30.

[1096] Example 31

[1097] Preparation of compound AB24959

[1098] Step 1):

[1099]

[1100] Compound 1 (294 mg, 2 mmol) was dissolved in dimethyl sulfoxide (10 mL), and cesium carbonate (1.64 g, 5 mmol), cuprous iodide (76.2 mg, 0.4 mmol), and five drops of N,N-2-methylethylenediamine were added. The reaction mixture was stirred at room temperature for 10 minutes. Compound 2 (650 mg, 3 mmol) was added; the reaction mixture was heated to 120°C and stirred for 2 hours. New spots were observed by TLC. The mixture was extracted with water and ethyl acetate (10 mL), and the organic phase was concentrated under reduced pressure to obtain the residue. The residue was purified by TLC (methanol:dichloromethane = 10%) to obtain compound 3 (200 mg). Yield: 47.62%.

[1101] Step 2):

[1102]

[1103] Compound 3 (200 mg, 0.89 mmol) was dissolved in acetonitrile (10 mL), then compound 4 (189.57 mg, 0.89 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. TLC showed the formation of new spots and the precipitation of solids. The solids were filtered and washed with acetonitrile (5 mL) to give compound AB24959 (70 mg). Yield: 22.03%.

[1104] Compound AB24959:

[1105] 1 H NMR (400MHz, DMSO-d6) δ8.83(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).

[1106] MS-ESI: Theoretical value [M-Br] + 357.43, measured value 357.10.

[1107] Example 32

[1108] Preparation of compound AB24938

[1109] Step 1):

[1110]

[1111] Compound 1 (2 g, 23 mmol) and compound 2 (2.5 g, 19 mmol) were dissolved in N,N-dimethylacetamide (30 mL). Triethylenediamine (6.5 g, 58 mmol), bis(diphenylacetone)palladium (890 mg, 0.97 mmol), and tri-tert-butylphosphine tetrafluoroborate (561 mg, 1.94 mmol) were added, and the mixture was stirred at 120 °C for 16 hours under sealed conditions. New spots were observed by TLC. The mixture was extracted with water and ethyl acetate (10 mL), and the organic phase was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (methanol:dichloromethane = 5%) to give compound 3 (800 mg). Yield: 26.1%.

[1112] Step 2):

[1113]

[1114] Compound 3 (100 mg, 0.625 mmol) was dissolved in acetonitrile (5 mL), then compound 4 (200 mg, 0.938 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was observed on TLC. The reaction mixture was evaporated to dryness and subjected to column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24938 (78 mg). Yield: 39.8%.

[1115] Compound AB24938:

[1116] 1 H NMR(400MHz,DMSO-d6)δ9.14(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).

[1117] MS-ESI: Theoretical value [M-Br] + 313.80, measured value 313.25.

[1118] Example 33

[1119] Preparation of compound AB24821

[1120] Step 1):

[1121]

[1122] Compound 1 (2.7 g, 20 mmol) was dissolved in N,N-dimethylformamide (50 mL), and compound 1-1 (5.3 g, 40 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (11.4 g, 30 mmol), and N,N-diisopropylethylamine (9 g, 70 mmol) were added. The mixture was stirred at room temperature for 1 hour. New spots were observed on TLC. The mixture was extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 0-30%) to give compound 2 (3.6 g). Yield: 91.1%.

[1123] Step 2):

[1124]

[1125] Compound 2 (200 mg, 1 mmol) was dissolved in dry tetrahydrofuran (5 mL), and a solution of 1N methylmagnesium bromide in tetrahydrofuran (2 mL) was added at 0 °C. The mixture was stirred at 0 °C for 3 hours. A new spot was observed by TLC. The mixture was extracted with saturated sodium bicarbonate aqueous solution (6 mL), water (20 mL), and ethyl acetate (20 mL x 3). The organic phases were combined, 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). Yield: 37.4%.

[1126] Step 3):

[1127]

[1128] Compound 3 (363 mg, 3 mmol) was dissolved in acetic acid (5 mL). Liquid bromine (383 mg, 3.8 mmol) and two drops of hydrobromic acid aqueous solution were added to the mixture, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on a TLC plate. Ice water (30 mL) was added, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding compound 4 (100 mg). Yield: 97.3%.

[1129] Step 4):

[1130]

[1131] Compound 5 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), and then compound 6 (5 g, 53.13 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 hours. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (4.01 g, 106.2 mmol) was slowly added. The system was allowed to rise naturally to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (200 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 7 (2.6 g). Yield: 26.8%.

[1132] Step 5):

[1133]

[1134] Compound 4 (100 mg, 0.46 mmol) and compound 7 (86 mg, 0.46 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 5 hours. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24821 (15 mg). Yield: 10.1%.

[1135] Compound AB24821:

[1136] 1 H NMR (400MHz, DMSO-d6) δ9.45(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).

[1137] MS-ESI: Theoretical value [M-Br] + 319.38, measured value 319.30.

[1138] Example 34

[1139] Preparation of compound AB24839

[1140] Step 1):

[1141]

[1142] Compound 1 (2.1 g, 20 mmol) was dissolved in ammonia and ethanol (40:40 mL). The solution was stirred at -78°C to -10°C for 3 hours. Then, compound 2 (6.72 g, 40 mmol) was added, and the mixture was stirred overnight at room temperature. A new spot was observed by TLC. The pH was adjusted to 1 with concentrated hydrochloric acid, and the mixture was extracted with water and ethyl acetate (80 mL). The aqueous phase was then adjusted to pH 14 with 50% sodium hydroxide, and extracted again with water and dichloromethane (2 x 80 mL). The organic phase was evaporated to dryness to give compound 3 (1.6 g). Yield: 54.42%.

[1143] Step 2):

[1144]

[1145] 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). The mixture was stirred at 80 °C for 16 hours. New spots were observed by TLC. The mixture was extracted with water and ethyl acetate (200 mL x 2). The organic phase was then subjected to rotary evaporation and column chromatography (PE:EA = 5:1) to give compound 5 (2.2 g). Yield: 25.41%.

[1146] Step 3):

[1147]

[1148] 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'-bis(diphenylphosphine)ferrocene]palladium dichloride (495.6 mg, 0.66 mmol) were dissolved in dioxane:water (21:7 mL). The mixture was stirred at 95 °C for 16 hours. New spots were observed by TLC. Extraction was performed with water and ethyl acetate (200 mL x 2). The organic phase was then subjected to rotary evaporation followed by column chromatography (PE:EA = 3:1) to give compound 7 (200 mg). Yield: 11.02%.

[1149] Step 4):

[1150]

[1151] 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). The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The mixture was extracted with water and dichloromethane (50 mL x 2), and the organic phase was evaporated by rotary chromatography (PE:EA = 3:1) to give compound 8 (200 mg). Yield: 28.82%.

[1152] Step 5):

[1153]

[1154] Compound 8 (300 mg, 0.86 mmol) and Grubbs Catalyst 2ND (100 mg) were dissolved in dichloromethane (10 mL). The mixture was stirred at 40 °C for 16 hours. A potassium hydroxide aqueous solution (1 N, 5 mL) was then added and stirred for 1 hour. New spots were observed on TLC. The mixture was extracted with water and dichloromethane (50 mL x 2). The organic phase was evaporated by rotary chromatography (DCM:MeOH = 10:1) to give compound 9 (120 mg). Yield: 62.57%.

[1155] Step 6):

[1156]

[1157] Compound 9 (120 mg, 0.53 mmol) was dissolved in tetrahydrofuran (5 mL). Palladium on carbon (12 mg) was added, and the mixture was stirred under hydrogen atmosphere for 4 hours. New spots were observed by TLC. The solution was filtered through diatomaceous earth, and the filtrate was evaporated to dryness to give compound 10 (20 mg). Yield: 16.77%.

[1158] Step 7):

[1159]

[1160] Compound 10 (20 mg, 0.08 mmol) was dissolved in acetonitrile (5 mL), then compound 11 (20.71 mg, 0.08 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was observed on TLC. The reaction mixture was evaporated to dryness and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB24839 (3.1 mg). Yield: 9.94%.

[1161] Compound AB24839:

[1162] 1H NMR (400MHz, CD3OD) δ8.05(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).

[1163] MS-ESI: Theoretical value [M-Br] + 377.89, measured value 377.25.

[1164] Example 35

[1165] Preparation of compound AB27130

[1166] Step 1):

[1167]

[1168] Compound 1 (200 mg, 1.01 mmol) and triphenylphosphine (400 mg, 3.54 mmol) were dissolved in tetrahydrofuran (10 mL), then purged with nitrogen three times, and stirred at 80 °C for 16 hours. New spots were observed by TLC, and the mixture was then cooled to room temperature, filtered, and washed three times with tetrahydrofuran to obtain crude compound 2 (350 mg). Yield: 91.1%.

[1169] Step 2):

[1170]

[1171] Compound 2 (200 mg, 0.52 mmol) and compound 3 (108 mg, 0.46 mmol) were dissolved in tetrahydrofuran (10 mL), followed by the addition of triethylamine (2 mL). The mixture was then purged three times with nitrogen, and stirred at 70 °C for 16 hours. New spots were observed on TLC, and the mixture was then cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound 4 (150 mg). Yield: 89%.

[1172] Step 3):

[1173]

[1174] Compound 4 (200 mg, 0.61 mmol) was dissolved in ethyl acetate and hydrochloric acid gas (5 mL) and stirred at room temperature for 3 hours. New spots were observed by TLC, and the solution was concentrated under reduced pressure to give crude compound 5 (210 mg).

[1175] Step 4):

[1176]

[1177] Compound 5 (200 mg, 0.97 mmol) was dissolved in ethanol (5 mL), palladium on carbon (20 mg) was added, and hydrogen was purged three times. The mixture was stirred overnight at room temperature. New spots were detected by TLC. The solution was filtered, concentrated under reduced pressure, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound 6 (60 mg). Yield: 29.5%.

[1178] Step 5):

[1179]

[1180] Compound 7 (200 mg, 1.11 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of bis(N,N-dimethylacetamide)dibromobromate (456 mg, 1.11 mmol). The mixture was stirred at room temperature for 1 hour. New spots were observed on TLC. The reaction solution was evaporated to dryness, and compound 8 (250 mg) was obtained by thin-layer chromatography. Yield: 87.29%.

[1181] Step 6):

[1182]

[1183] Compound 6 (100 mg, 0.48 mmol) and compound 8 (148 mg, 0.57 mmol) were dissolved in acetonitrile (10 mL), and then potassium carbonate (66 mg, 0.48 mmol) was added. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB27130 (55 mg). Yield: 29.4%.

[1184] Compound AB27130:

[1185] 1 H NMR (400MHz, DMSO-d6) δ9.37(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).

[1186] MS-ESI: Theoretical value [M-Br] + 389.90, measured value 389.10.

[1187] Example 36

[1188] Preparation of compound AB27141

[1189] Step 1):

[1190]

[1191] Compound 1 (240 mg, 2 mmol) was dissolved in dry N,N-dimethylformamide (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 purged with nitrogen three times and stirred overnight at room temperature. Upon the appearance of a new spot on a TLC plate, the mixture 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, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound 3 (260 mg). Yield: 58.47%.

[1192] Step 2):

[1193]

[1194] Compound 3 (111 mg, 0.50 mmol) was dissolved in acetonitrile (10 mL), and then compound 4 (130 mg, 0.5 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was detected by TLC. The solution was filtered, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound AB27141 (40 mg). Yield: 19.95%.

[1195] Compound AB27141:

[1196] 1H NMR(400MHz,DMSO-d6)δ9.67(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=43.7H z, 2H), 3.20 (d, J = 16.7Hz, 1H), 2.95 (d, J = 10.2Hz, 1H), 2.06 (d, J = 6.2Hz, 3H).

[1197] MS-ESI: Theoretical value [M-Br] + 401.91, measured value: 401.10.

[1198] Example 37

[1199] Preparation of compound AB24957

[1200] Step 1):

[1201]

[1202] Compound 1 (300 mg, 3.15 mmol) was dissolved in acetonitrile (10 mL), and then compound 2 (671 mg, 2.35 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. After the appearance of a new spot on a TLC plate, the reaction solution was evaporated to dryness, and compound 3 (600 mg) was obtained by thin-layer chromatography. Yield: 83.54%

[1203] Step 2):

[1204]

[1205] Compound 3 (200 mg, 0.87 mmol) was dissolved in phosphorus oxychloride (10 mL), then purged with nitrogen three times and stirred at 90°C for 2 h. After a new spot was detected by TLC, the reaction solution was evaporated to dryness, yielding compound 4 (215 mg crude product), which was directly added to the next step.

[1206] Step 3):

[1207]

[1208] Compound 4 (215 mg, 0.88 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by compound 5 (117 mg, 0.88 mmol), and then triethylamine (267 mg, 2.64 mmol). The mixture was then purged with nitrogen three times and stirred overnight at 80°C. A new spot was observed on a TLC plate, yielding compound AB24957 (80 mg). Yield: 26.50%.

[1209] Compound AB24957:

[1210] 1 H NMR (400MHz, DMSO, d6) δ8.30(s,2H),7.95(d,J=8.2Hz,2H),7.45(d,J=8.1Hz,1H),7.38(s,1H),7.3 2–7.27(m,2H),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).

[1211] MS-ESI: Theoretical value [M-Br] + 343.18, measured value 343.30.

[1212] Example 38

[1213] Preparation of compound AB24989

[1214] Step 1):

[1215]

[1216] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydride (203 mg, 5.07 mmol) was added under ice bath conditions, and the mixture was stirred for 30 minutes under ice bath conditions. Then, compound 2 (289 mg, 1.86 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Upon detection of a new spot on TLC, the reaction was extracted with water (10 mL) and ethyl acetate (10 mL). The ethyl acetate extraction was performed three times, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate: petroleum ether = 0-10%) to give compound 3 (260 mg). Yield: 73.8%.

[1217] Step 2):

[1218]

[1219] Compound 3 (300 mg, 1.44 mmol) was dissolved in acetonitrile (10 mL), and then compound 4 (577 mg, 2.16 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared on a TLC plate, indicating the precipitation of a solid. The solid was filtered to obtain compound AB24989 (30 mg). Yield: 5.3%.

[1220] Compound AB24989:

[1221] 1 H NMR (400MHz, DMSO, d6) δ9.25(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).

[1222] MS-ESI: Theoretical value [M-Br] + 395.40, measured value 395.30.

[1223] Example 39

[1224] Preparation of compound AB24906

[1225] Step 1):

[1226]

[1227] Compound 1 (438 mg, 3 mmol) was dissolved in acetic acid (5 mL), and one drop of hydrobromic acid was added. Liquid bromine (384 mg, 2.4 mmol) was added to acetic acid (2 mL) and then injected into the mixture. The mixture was then purged with nitrogen three times and stirred at room temperature for 3 hours. New spots were detected by TLC. The mixture was filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain compound 2 (400 mg). Yield: 59.51%.

[1228] Step 2):

[1229]

[1230] Compound 2 (200 mg, 0.9 mmol) was dissolved in acetonitrile (10 mL). Compound 3 (171 mg, 0.9 mmol) was added. The mixture was then purged with nitrogen three times and stirred at room temperature for 3 hours. New spots were detected by TLC. The solution was filtered, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound AB24906 (100 mg). Yield: 27.23%.

[1231] Compound AB24906:

[1232] 1 H NMR (400MHz, DMSO-d6) δ9.54(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).

[1233] MS-ESI: Theoretical value [M-Br] + 329.16, measured value 329.16.

[1234] Example 40

[1235] Preparation of compound AB24949

[1236] Step 1):

[1237]

[1238] Compound 1 (200 mg, 1.22 mmol) was dissolved in acetic acid (5 mL), and one drop of hydrobromic acid was added. Liquid bromine (193 mg, 1.22 mmol) was added to acetic acid (2 mL) and then injected into the mixture. The mixture was then purged with nitrogen three times and stirred at room temperature for 3 hours. New spots were detected by TLC. The mixture was filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain compound 2 (300 mg). Yield: 101%.

[1239] Step 2):

[1240]

[1241] Compound 3 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), and then compound 4 (5 g, 53.13 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 hours. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (4.01 g, 106.2 mmol) was slowly added. The system was allowed to rise naturally to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (200 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 5 (2.6 g). Yield: 26.8%.

[1242] Step 3):

[1243]

[1244] Compound 6 (300 mg, 1.24 mmol) was dissolved in acetonitrile (10 mL). Compound 5 (228 mg, 1.24 mmol) was added. The mixture was then purged with nitrogen three times and stirred at room temperature for 3 hours. New spots were detected by TLC. The solution was filtered, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound AB24949 (35 mg). Yield: 12.5%.

[1245] Compound AB24949:

[1246] 1 H NMR(400MHz,CD3OD)δ8.16–7.98(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).

[1247] MS-ESI: Theoretical value [M-Br] + 347.40, measured value: 347.10.

[1248] Example 41

[1249] Preparation of compound AB24954

[1250] Step 1):

[1251]

[1252] Compound 1 (176 mg, 1.0 mmol) was dissolved in acetic acid (7 mL). Liquid bromine (160 mg, 1.0 mmol) and two drops of hydrobromic acid aqueous solution were added to the mixture, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on a TLC plate. Ice water (30 mL) was added, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, 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). Yield: 78.43%.

[1253] Step 2):

[1254]

[1255] Compound 2 (200 mg, 0.78 mmol) was dissolved in acetonitrile (10 mL), and then compound 3 (150 mg, 0.82 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared on a TLC plate, indicating the precipitation of a solid. The mixture was filtered, and the filter cake was washed three times with acetonitrile (2 mL). The solution was then evaporated to dryness to obtain compound AB24954 (20 mg). Yield: 7.14%.

[1256] Compound AB24954:

[1257] 1 H NMR (400MHz, CD3OD) δ8.11(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).

[1258] MS-ESI: Theoretical value [M-CF3COO] + 359.45, measured value 359.10.

[1259] Example 42

[1260] Preparation of compound AB24963

[1261] Step 1):

[1262]

[1263] Compound 1 (8 g, 83.33 mmol) was dissolved in phosphorus oxychloride (40 mL), then purged with nitrogen three times, and heated to 90 °C with stirring overnight. A new spot was detected by TLC. The phosphorus oxychloride was evaporated to dryness, and dichloromethane (50 mL) was added under an ice-water bath. Ice water (50 mL) was slowly added dropwise, followed by extraction with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 30-80%) to give compound 2 (5 g), yield: 52.17%.

[1264] Step 2):

[1265]

[1266] Compound 2 (2.5 g, 21.73 mmol) was dissolved in N,N-dimethylformamide (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 purged with nitrogen three times and stirred overnight at 80 °C. A new spot was observed on TLC. The mixture was extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 0-30%) to give compound 4 (2.1 g), yield: 52.24%.

[1267] Step 3):

[1268]

[1269] 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 purged with nitrogen three times and stirred overnight at room temperature. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-30%) to obtain compound AB24963 (20 mg). Yield: 5.54%.

[1270] Compound AB24963

[1271] 1 H NMR (400MHz, DMSO, d6) δ10.18(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).

[1272] MS-ESI: Theoretical value [M-Br] + 334.16, measured value: 334.25.

[1273] Example 43

[1274] Preparation of compound AB24964

[1275] Step 1):

[1276]

[1277] Compound 1 (8 g, 83.33 mmol) was dissolved in phosphorus oxychloride (40 mL), then purged with nitrogen three times, and heated to 90 °C with stirring overnight. A new spot was detected by TLC. The phosphorus oxychloride was evaporated to dryness, and dichloromethane (50 mL) was added under an ice-water bath. Ice water (50 mL) was slowly added dropwise, followed by extraction with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 30-80%) to give compound 2 (5 g), yield: 52.17%.

[1278] Step 2):

[1279]

[1280] Compound 2 (2.5 g, 21.73 mmol) was dissolved in N,N-dimethylformamide (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 purged with nitrogen three times and stirred overnight at 80 °C. A new spot was observed on TLC. The mixture was extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 0-30%) to give compound 4 (2.1 g), yield: 52.24%.

[1281] Step 3):

[1282]

[1283] Compound 4 (200 mg, 1.08 mmol) was dissolved in acetonitrile (10 mL), and then compound 5 (446 mg, 1.62 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was observed on a TLC plate. The reaction mixture was evaporated to dryness and purified by column chromatography (methanol:dichloromethane = 10%) to give compound AB24964 (30 mg). Yield: 7.3%.

[1284] Compound AB24964:

[1285] 1H NMR (400MHz, DMSO-d6) δ10.13(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).

[1286] MS-ESI: Theoretical value [M-CF3COO] + 380.46, measured value: 380.30.

[1287] Example 44

[1288] Preparation of compound AB24967

[1289] Step 1):

[1290]

[1291] Compound 1 (8 g, 83.33 mmol) was dissolved in phosphorus oxychloride (40 mL), then purged with nitrogen three times, and heated to 90 °C with stirring overnight. A new spot was detected by TLC. The phosphorus oxychloride was evaporated to dryness, and dichloromethane (50 mL) was added under an ice-water bath. Ice water (50 mL) was slowly added dropwise, followed by extraction with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 30-80%) to give compound 2 (5 g), yield: 52.17%.

[1292] Step 2):

[1293]

[1294] Compound 2 (2.5 g, 21.73 mmol) was dissolved in N,N-dimethylformamide (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 purged with nitrogen three times and stirred overnight at 80 °C. A new spot was observed on TLC. The mixture was extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 0-30%) to give compound 4 (2.1 g), yield: 52.24%.

[1295] Step 3):

[1296]

[1297] Compound 4 (200 mg, 1.08 mmol) was dissolved in acetonitrile (15 mL), and then compound 5 (367 mg, 1.29 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB24967 (30 mg). Yield: 7.16%.

[1298] Compound AB24967:

[1299] 1 H NMR(400MHz,DMSO,d6)δ10.29(s,1H),8.75(s,1H),8.14(s,1H),8.05(s,1H),7.92(s,1H ),7.78(s,2H),7.33(d,J=23.1Hz,6H),6.99(d,J=6.7Hz,1H),5.90(s,2H),4.73(s,2H).

[1300] MS-ESI: Theoretical value [M-Br] + 388.13, measured value: 388.25.

[1301] Example 45

[1302] Preparation of compound AB24991

[1303] Step 1):

[1304]

[1305] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (20 mL), and NaH (203 mg, 5.07 mmol) was added under ice bath conditions. The mixture was stirred at 0 °C for 30 minutes. Then, compound 2 (318 mg, 1.86 mmol) was slowly added, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on TLC. The mixture was extracted with water (30 mL) and ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then subjected to column chromatography (methanol:dichloromethane = 0-10%) to give compound 3 (200 mg). Yield: 56.9%.

[1306] Step 2):

[1307]

[1308] 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 purged with nitrogen three times and stirred overnight at room temperature. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to obtain compound AB24991 (100 mg). Yield: 28.86%.

[1309] Compound AB24991:

[1310] 1 H NMR(400MHz,DMSO,d6)δ9.26(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).

[1311] MS-ESI: Theoretical value [M-Br] + 361.11, measured value: 361.05.

[1312] Example 46

[1313] Preparation of compound AB27106

[1314] step:

[1315]

[1316] Compound 1 (80 mg, 0.38 mmol) and compound 2 (103 mg, 0.385 mmol) were dissolved in acetonitrile (5 mL). The mixture was stirred at room temperature for 3 hours. A new spot was observed on a TLC plate, indicating the precipitation of a solid. The mixture was filtered, and the filter cake was washed three times with acetonitrile (2 mL). The solution was then evaporated to dryness to give compound AB27106 (57 mg). Yield: 37.97%.

[1317] Compound AB27106:

[1318] 1H NMR(400MHz,DMSO-d6)δ13.53(s,1H),9.29(s,1H),8.33–8.25(m,4H),8.14(d,J=6.7Hz,1H),8.0 5(d,J=8.3Hz,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).

[1319] MS-ESI: Theoretical value [M-Br] + 395.40, measured value 395.05.

[1320] Example 47

[1321] Preparation of compound AB27107

[1322] step:

[1323]

[1324] Compound 1 (100 mg, 0.50 mmol) and compound 2 (141 mg, 0.5 mmol) were dissolved in acetonitrile (5 mL). The mixture was stirred at room temperature for 3 hours. A new spot was observed on a TLC plate, indicating the precipitation of a solid. The mixture was filtered, and the filter cake was washed three times with acetonitrile (2 mL). The solution was then evaporated to dryness to give compound AB27107 (65 mg). Yield: 31.55%.

[1325] Compound AB27107:

[1326] 1 H NMR(400MHz,DMSO-d6)δ13.10(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).

[1327] MS-ESI: Theoretical value [M-Br] + 411.40, measured value 411.05.

[1328] Example 48

[1329] Preparation of compound AB27114

[1330] Step 1):

[1331]

[1332] Compound 1 (4.4 g, 20 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by compound 2 (4.28 g, 42 mmol), then cuprous iodide (0.19 g, 1 mmol), then N,N-diisopropylethylamine (8.24 g, 64 mmol), and finally palladium dichloride bis(triphenylphosphine) (190 mg, 0.6 mmol). The mixture was then purged with nitrogen three times and stirred at room temperature for 16 hours. A new spot was observed on a TLC plate. The mixture was diluted with water (100 mL), then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 2:1) to obtain compound 3 (3.5 g). Yield: 84.13%.

[1333] Step 2):

[1334]

[1335] Compound 3 (1.5 g, 7.2 mmol) was dissolved in 1,4-dioxane (40 mL), followed by the addition of potassium tert-butoxide (2.4 mg, 21.6 mmol). The mixture was then purged three times with nitrogen and heated to 100 °C with stirring overnight. A new spot appeared on TLC. The mixture was then concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 10:1) to give compound 4 (1.1 g). Yield: 73.45%.

[1336] Step 3)

[1337]

[1338] Compound 4 (104 mg, 0.5 mmol) was dissolved in acetonitrile (10 mL), and compound 5 (160 mg, 0.6 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared on a TLC plate. The mixture was then concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound AB27114 (141 mg). Yield: 59.49%.

[1339] Compound AB27114:

[1340] 1H NMR (400MHz, DMSO-d6) δ13.04(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,2H),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).

[1341] MS-ESI: Theoretical value [M-Br] + 395.14, measured value 395.14.

[1342] Example 49

[1343] Preparation of compound AB27124

[1344] Step 1):

[1345]

[1346] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (20 mL), and NaH (203 mg, 5.07 mmol) was added under ice bath conditions. The mixture was stirred at 0 °C for 30 minutes. Then, compound 2 (318 mg, 1.86 mmol) was slowly added, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on the TLC plate. The mixture was extracted with water (30 mL) and ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then subjected to column chromatography (methanol:dichloromethane = 0-10%) to obtain compound 3 (200 mg).

[1347] Yield: 56.9%

[1348] Step 2):

[1349]

[1350] Compound 4 (200 mg, 1.11 mmol) was dissolved in dichloromethane (10 mL), and then compound 5 (456 mg, 1.11 mmol) was added. The mixture was stirred at room temperature for 1 hour. New spots were observed on TLC. The reaction solution was evaporated to dryness, and compound 6 (250 mg) was obtained by thin-layer chromatography. Yield: 87.29%.

[1351] Step 3):

[1352]

[1353] Compound 3 (150 mg, 0.58 mmol) was dissolved in acetonitrile (10 mL), and then compound 6 (100 mg, 0.48 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was observed on a TLC plate. The reaction solution was evaporated to dryness, and compound AB27124 (65 mg) was obtained by thin-layer chromatography. Yield: 34.99%.

[1354] Compound AB27124:

[1355] 1 H NMR(400MHz,DMSO,d6)δ9.45(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).

[1356] MS-ESI: Theoretical value [M-Br] + 387.13, measured value 387.20.

[1357] Example 50

[1358] Preparation of compound AB27127

[1359] step:

[1360]

[1361] 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 spot was observed on a TLC plate. The reaction solution was evaporated to dryness, and the solution was purified by thin-layer chromatography to obtain compound AB27127 (15 mg). Yield: 9.73%.

[1362] Compound AB27127:

[1363] 1H NMR(400MHz, DMSO-d6)δ9.50(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).

[1364] MS-ESI: Theoretical value [M-Br] + 367.47, measured value 367.25.

[1365] Example 51

[1366] Preparation of compound AB24924

[1367] Step 1):

[1368]

[1369] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), and then compound 2 (5 g, 53.13 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 hours. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (4.01 g, 106.2 mmol) was slowly added. The system was allowed to rise naturally to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (200 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g). Yield: 26.8%.

[1370] Step 2):

[1371]

[1372] Compound 4 (400 mg, 2.1 mmol) was dissolved in acetic acid (10 mL). Liquid bromine (348 mg, 2.17 mmol) and two drops of hydrobromic acid aqueous solution were added to the mixture. The mixture was then purged with nitrogen three times and stirred at room temperature for 3 hours. TLC detection showed the formation of new spots and the precipitation of a solid. The solid was filtered, washed with dichloromethane (5 mL), and the filter cake was used to remove the organic solvent, yielding compound 5 (400 mg). Yield: 81.3%.

[1373] Step 3):

[1374]

[1375] Compound 5 (300 mg, 1.16 mmol) and compound 3 (107 mg, 0.58 mmol) were dissolved in acetonitrile (10 mL). The mixture was stirred at room temperature for 3 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10%) to give compound AB24924 (15 mg). Yield: 3.9%.

[1376] Compound AB24924:

[1377] 1 H NMR (400MHz, CD3OD) δ8.96 (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).

[1378] MS-ESI: Theoretical value [M-CF3COO] + 330.41, measured value 330.30.

[1379] Example 52

[1380] Preparation of compound AB24996

[1381] Step 1):

[1382]

[1383] Compound 1 (22 g, 100 mmol) was dissolved in tetrahydrofuran (200 mL), and compound 2 (10.5 g, 150 mmol) was added. Then, n-butyllithium (80 mL, 2.5 mol / L) was added dropwise at -78°C, and the mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 50:1) to give compound 3 (12 g). Yield: 55.2%.

[1384] Step 2):

[1385]

[1386] Compound 3 (12 g, 55.6 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), and silver nitrate (1.89 g, 11.12 mmol) and potassium persulfate (37 g, 139 mmol) were added. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 4 (3.1 g). Yield: 26.05%.

[1387] Step 3):

[1388]

[1389] Compound 4 (1.5 mg, 6.9 mmol) was dissolved in dichloromethane (20 mL), and then C8H was added. 18 N₂O₂HBr₃ (2.9 g, 6.9 mmol) was stirred at room temperature for 1 hour. New spots were observed by TLC. The reaction solution was evaporated to dryness, and compound 5 (2.2 g) was obtained by thin-layer chromatography. Yield: 85.48%.

[1390] Step 4):

[1391]

[1392] Compound 5 (150 mg, 0.5 mmol) was dissolved in acetonitrile (5 mL), then compound 6 (104 mg, 0.5 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was detected by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB24996 (40 mg). Yield: 16.0%.

[1393] Compound AB24996:

[1394] 1 H NMR (400MHz, DMSO-d6) δ9.38(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,1 H),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).

[1395] MS-ESI: Theoretical value [M-Br] + 421.15, measured value: 421.15.

[1396] Example 53

[1397] Preparation of compound AB27111

[1398] Step 1):

[1399]

[1400] Compound 1 (36.3 g, 150 mmol) was dissolved in tetrahydrofuran (120 mL), and compound 2 (12.6 g, 180 mmol) was added. Then, n-butyllithium (120 mL, 2.5 mol / L) was added dropwise at -78°C, and the mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 3 (6.72 g). Yield: 18.66%.

[1401] Step 2):

[1402]

[1403] Compound 3 (6.72 g, 28 mmol) was dissolved in dichloromethane (200 mL) and water (200 mL), and silver nitrate (952 mg, 5.6 mmol) and potassium persulfate (18.9 g, 70 mmol) were added. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 4 (2.35 g). Yield: 36.33%.

[1404] Step 3):

[1405]

[1406] Compound 4 (2.0 g, 8.69 mmol) was dissolved in dichloromethane (50 mL), followed by the addition of compound bis(N,N-dimethylacetamide)dibromobromate (3.65 g, 8.90 mmol). The mixture was stirred at room temperature for 1 hour. New spots were observed on TLC. The reaction mixture was evaporated to dryness and purified by thin-layer chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 5 (2.5 g). Yield: 93.10%.

[1407] Step 4):

[1408]

[1409] Compound 5 (240 mg, 0.78 mmol) was dissolved in acetonitrile (10 mL), then compound 6 (150 mg, 0.78 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared upon TLC detection. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB27111 (88 mg). Yield: 27.31%.

[1410] Compound AB27111:

[1411] 1 H NMR (400MHz, DMSO-d6) δ9.72(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).

[1412] MS-ESI: Theoretical value [M-Br] + 413.42, measured value: 413.20.

[1413] Example 54

[1414] Preparation of compound AB27112

[1415] Step 1):

[1416]

[1417] Compound 1 (8 g, 83.33 mmol) was dissolved in phosphorus oxychloride (40 mL), then purged with nitrogen three times, and heated to 90 °C with stirring overnight. A new spot was detected by TLC. The phosphorus oxychloride was evaporated to dryness, and dichloromethane (50 mL) was added under an ice-water bath. Ice water (50 mL) was slowly added dropwise, followed by extraction with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 30-80%) to give compound 2 (5 g), yield: 52.17%.

[1418] Step 2):

[1419]

[1420] Compound 2 (2.5 g, 21.73 mmol) was dissolved in N,N-dimethylformamide (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 purged with nitrogen three times and stirred overnight at 80 °C. Upon the appearance of a new spot on a TLC plate, the mixture was extracted with water (50 mL) and ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (ethyl acetate: petroleum ether = 0-30%) to give compound 4 (2.1 g), yield: 52.24%.

[1421] Step 3):

[1422]

[1423] Compound 4 (100 mg, 0.54 mmol) was dissolved in acetonitrile (10 mL), and compound 5 (173 mg, 0.65 mmol) was added. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB27112 (40 mg). Yield: 19.9%.

[1424] Compound AB27112:

[1425] 1 H NMR (400MHz, DMSO-d6) δ10.47(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).

[1426] MS-ESI: Theoretical value [M-Br] + 372.36, measured value: 372.10.

[1427] Example 55

[1428] Preparation of compound AB27125

[1429] Step 1):

[1430]

[1431] Compound 1 (22 g, 100 mmol) was dissolved in tetrahydrofuran (200 mL), and compound 2 (10.5 g, 150 mmol) was added. Then, n-butyllithium (80 mL, 2.5 mol / L) was added dropwise at -78°C, and the mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 50:1) to give compound 3 (13 g). Yield: 60.3%.

[1432] Step 2):

[1433]

[1434] Compound 3 (6.48 g, 30 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), and silver nitrate (1 g, 6 mmol) and potassium persulfate (20 g, 270 mmol) were added. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 4 (584 mg). Yield: 9.0%.

[1435] Step 3):

[1436]

[1437] Compound 4 (584 mg, 1.98 mmol) was dissolved in dichloromethane (20 mL), and then C8H was added. 18 N₂O₂HBr₃ (820 mg, 1.98 mmol) was stirred at room temperature for 1 hour. New spots were observed by TLC. The reaction solution was evaporated to dryness, and compound 5 (670 mg) was obtained by thin-layer chromatography. Yield: 94.7%.

[1438] Step 4):

[1439]

[1440] Compound 5 (200 mg, 0.65 mmol) was dissolved in acetonitrile (5 mL), then compound 6 (100 mg, 0.65 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was detected by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB27125 (53 mg). Yield: 16.3%.

[1441] Compound AB27125:

[1442] 1H NMR (400MHz, DMSO-d6) δ9.40(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,1H),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).

[1443] MS-ESI: Theoretical value [M-Br] + 421.15, measured value: 421.15.

[1444] Example 56

[1445] Preparation of compound AB27126

[1446] Step 1):

[1447]

[1448] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (20 mL), and NaH (203 mg, 5.07 mmol) was added under ice bath conditions. The mixture was stirred at 0 °C for 30 minutes. Compound 2 (318 mg, 1.86 mmol) was then slowly added, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on TLC. The mixture was extracted with water (30 mL) and ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The resulting solution was obtained by column chromatography (methanol:dichloromethane = 0-10%) to give compound 3 (200 mg). Yield: 56.9%

[1449] Step 2):

[1450]

[1451] Compound 4 (30 g, 124 mmol) was dissolved in tetrahydrofuran (200 mL), and compound 5 (10.46 g, 149 mmol) was added. The mixture was purged with nitrogen three times, and n-butyllithium (100 mL, 2.5 mol / L) was added dropwise at -78 °C. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 6 (11.2 g). Yield: 38.93%.

[1452] Step 3):

[1453]

[1454] Compound 6 (11.2 g, 48 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), and silver nitrate (1.65 g, 9.7 mmol) and potassium persulfate (32.6 g, 121 mmol) were added. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove water and organic solvents. The solution was purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 7 (930 mg). Yield: 8.42%.

[1455] Step 4):

[1456]

[1457] Compound 7 (930 mg, 4.04 mmol) was dissolved in dichloromethane (20 mL), and then bis(N,N-dimethylacetamide)dibromobromate (1.68 g, 4.04 mmol) was added. The mixture was stirred at room temperature for 1 hour. New spots were observed by TLC. The reaction solution was evaporated to dryness and purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 8 (800 mg). Yield: 64.50%.

[1458] Step 5):

[1459]

[1460] Compound 8 (200 mg, 0.65 mmol) was dissolved in acetonitrile (5 mL), then compound 3 (100 mg, 0.65 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared upon TLC detection. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB27126 (20 mg). Yield: 7.04%.

[1461] Compound AB27126:

[1462] 1 H NMR (400MHz, DMSO-d6) δ9.41(s,1H),8.58(s,1H),8.37(d,J=5.9Hz,1H),8.18(s,1H),7.70(dd,J=33.1,12.2 Hz,3H),7.35(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).

[1463] MS-ESI: Theoretical value [M-Br]+ 437.15, measured value: 437.20.

[1464] Example 57

[1465] Preparation of compound AB27131

[1466] Step 1):

[1467]

[1468] Compound 1 (22 g, 100 mmol) was dissolved in tetrahydrofuran (200 mL), and compound 2 (10.5 g, 150 mmol) was added. Then, n-butyllithium (80 mL, 2.5 mol / L) was added dropwise at -78°C, and the mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 50:1) to give compound 3 (13 g). Yield: 60.1%.

[1469] Step 2):

[1470]

[1471] Compound 3 (6.48 g, 30 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), and silver nitrate (1 g, 6 mmol) and potassium persulfate (20 g, 270 mmol) were added. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 4 (584 mg). Yield: 9.0%.

[1472] Step 3):

[1473]

[1474] Compound 4 (584 mg, 1.98 mmol) was dissolved in dichloromethane (20 mL), and then C8H was added. 18 N₂O₂HBr₃ (820 mg, 1.98 mmol) was stirred at room temperature for 1 hour. New spots were observed by TLC. The reaction solution was evaporated to dryness, and compound 5 (670 mg) was obtained by thin-layer chromatography. Yield: 94.7%.

[1475] Step 4):

[1476]

[1477] Compound 5 (150 mg, 0.5 mmol) and compound 6 (105 mg, 0.5 mmol) were dissolved in acetonitrile (10 mL). The mixture was stirred at room temperature for 3 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 10%) to give compound AB27131 (30 mg). Yield: 11.9%.

[1478] Compound AB27131:

[1479] 1 H NMR (400MHz, DMSO-d6) δ9.29 (s, 1H), 8.15 (d, J=14.3Hz, 2H), 8.05 (dd, J=

[1480] 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),5.7 0(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).

[1481] MS-ESI: Theoretical value [M-Br] + 423.17, Measured value: 423.17

[1482] Example 58

[1483] Preparation of compound AB27133

[1484] Step 1):

[1485]

[1486] Compound 1 (160 g, 1 mmol) was dissolved in dichloromethane (50 mL), and then compound bis(N,N-dimethylacetamide) dibromobromate (414 mg, 1 mmol) was added. The mixture was stirred at room temperature for 1 hour. New spots were observed on TLC. The reaction solution was evaporated to dryness, and compound 2 (240 mg) was obtained by thin-layer chromatography (petroleum ether: ethyl acetate = 0-10%). Yield: 100%.

[1487] Step 2):

[1488]

[1489] Compound 2 (240 mg, 1.0 mmol) was dissolved in acetonitrile (10 mL), then compound 3 (210 mg, 1.0 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was detected by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol and dichloromethane = 0-30%) to give compound AB27133 (70.0 mg). Yield: 18.97%.

[1490] Compound AB27133:

[1491] 1 H NMR (400MHz, DMSO-d6) δ9.47 (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 =15.4Hz,1H),2.77(d,J=9.3Hz,2H),2.57(s,1H),2.33(s,3H),2.08(s,1H),1.88(s,1H).

[1492] MS-ESI: Theoretical value [M-Br] + 369.49, measured value: 369.15.

[1493] Example 59

[1494] Preparation of compound AB27142

[1495] Step 1):

[1496]

[1497] Compound 1 (5.0 g, 22.72 mmol) was dissolved in dry N,N-dimethylformamide (100 mL), followed by 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). The mixture was then purged with nitrogen three times and stirred overnight at room temperature. Upon the appearance of a new spot on a TLC plate, the mixture 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, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound 3 (2.65 g). Yield: 56.89%.

[1498] Step 2):

[1499]

[1500] Compound 3 (2.65 g, 12.99 mmol) was dissolved in ethanol (100 mL), followed by the addition of sodium hydroxide (15.59 g, 389.70 mmol). The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C with stirring overnight. A new spot was observed on a TLC plate. The mixture was diluted with water (20 mL), and then extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound 4 (1.1 g). Yield: 63.66%.

[1501] Step 3):

[1502]

[1503] Compound 4 (260 mg, 2 mmol) was dissolved in dry N,N-dimethylformamide (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 purged with nitrogen three times and stirred overnight at room temperature. Upon the appearance of a new spot on a TLC plate, the mixture 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, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound 6 (100 mg). Yield: 22.52%.

[1504] Step 4):

[1505]

[1506] 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 purged with nitrogen three times and stirred overnight at room temperature. A new spot was detected by TLC. The solution was filtered, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound AB27142 (12.1 mg). Yield: 6.70%.

[1507] Compound 27142:

[1508] 1 H NMR (400MHz, CD3OD-d6) δ9.25(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).

[1509] MS-ESI: Theoretical value [M-Br] + 401.91, measured value: 401.10.

[1510] Example 60

[1511] Preparation of compound AB27144

[1512] Step 1):

[1513]

[1514] Compound 1 (22 g, 100 mmol) was dissolved in tetrahydrofuran (200 mL), and compound 2 (10.5 g, 150 mmol) was added. Then, n-butyllithium (80 mL, 2.5 mol / L) was added dropwise at -78°C, and the mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 50:1) to give compound 3 (13 g). Yield: 60.1%.

[1515] Step 2):

[1516]

[1517] Compound 3 (6.48 g, 30 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), and silver nitrate (1 g, 6 mmol) and potassium persulfate (20 g, 270 mmol) were added. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 4 (584 mg). Yield: 9.0%.

[1518] Step 3):

[1519]

[1520] Compound 4 (584 mg, 1.98 mmol) was dissolved in dichloromethane (20 mL), and then C8H was added. 18 N₂O₂HBr₃ (820 mg, 1.98 mmol) was stirred at room temperature for 1 hour. New spots were observed by TLC. The reaction solution was evaporated to dryness, and compound 5 (670 mg) was obtained by thin-layer chromatography. Yield: 94.7%.

[1521] Step 4):

[1522]

[1523] Compound 5 (150 mg, 0.5 mmol) and compound 6 (92 mg, 0.5 mmol) were dissolved in acetonitrile (10 mL). The mixture was stirred at room temperature for 3 hours. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound AB27144 (30 mg). Yield: 12.6%.

[1524] Compound AB27144:

[1525] 1 H NMR (400MHz, DMSO-d6) δ9.33(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,1 H),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).

[1526] MS-ESI: Theoretical value [M-Br] + 397.15, measured value: 397.15.

[1527] Example 61

[1528] Preparation of compound AB27156

[1529] Step 1):

[1530]

[1531] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), and then compound 2 (5 g, 53.13 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 hours. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (4.01 g, 106.2 mmol) was slowly added. The system was allowed to rise naturally to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (200 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g). Yield: 26.8%.

[1532] Step 2):

[1533]

[1534] Compound 4 (30 g, 124 mmol) was dissolved in tetrahydrofuran (200 mL), and compound 5 (10.46 g, 149 mmol) was added. The mixture was purged with nitrogen three times, and n-butyllithium (100 mL, 2.5 mol / L) was added dropwise at -78 °C. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 6 (11.2 g). Yield: 38.93%.

[1535] Step 3):

[1536]

[1537] Compound 6 (11.2 g, 48 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), and silver nitrate (1.65 g, 9.7 mmol) and potassium persulfate (32.6 g, 121 mmol) were added. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove water and organic solvents. The solution was purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 7 (930 mg). Yield: 8.42%.

[1538] Step 4):

[1539]

[1540] Compound 7 (930 mg, 4.04 mmol) was dissolved in dichloromethane (20 mL), and then bis(N,N-dimethylacetamide)dibromobromate (1.68 g, 4.04 mmol) was added. The mixture was stirred at room temperature for 1 hour. New spots were observed by TLC. The reaction solution was evaporated to dryness and purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 8 (800 mg). Yield: 64.50%.

[1541] Step 5):

[1542]

[1543] Compound 8 (200 mg, 0.65 mmol) was dissolved in acetonitrile (5 mL), then compound 3 (100 mg, 0.65 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was detected by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB27156 (12 mg). Yield: 4.5%.

[1544] 1 H NMR(400MHz, DMSO-d6)δ9.50(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).

[1545] MS-ESI: Theoretical value [M-Br] + 413.41, measured value: 413.30.

[1546] Example 62

[1547] Preparation of compound AB27128

[1548] Step 1):

[1549]

[1550] Compound 1 (200 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (20 mL), and NaH (203 mg, 5.07 mmol) was added under ice bath conditions. The mixture was stirred at 0 °C for 30 minutes. Then, compound 2 (318 mg, 1.86 mmol) was slowly added, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on the TLC plate. The mixture was extracted with water (30 mL) and ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then subjected to column chromatography (methanol:dichloromethane = 0-10%) to obtain compound 3 (200 mg).

[1551] Yield: 56.9%

[1552] Step 2):

[1553]

[1554] Compound 4 (200 mg, 1.05 mmol) was dissolved in dichloromethane (10 mL), and then bis(N,N-dimethylacetamide)dibromobromate (434 mg, 1.05 mmol) was added. The mixture was stirred at room temperature for 1 hour. New spots were observed on TLC. The reaction solution was evaporated to dryness, and compound 5 (260 mg) was obtained by thin-layer chromatography. Yield: 92.05%.

[1555] Step 3):

[1556]

[1557] 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 spot was observed on a TLC plate. The reaction mixture was evaporated to dryness and purified by thin-layer chromatography to obtain compound AB27128 (20 mg). Yield: 7.73%

[1558] 1 H NMR (400MHz, DMSO-d6) δ9.45(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).

[1559] MS-ESI: Theoretical value [M-Br]+398.15, measured value: 398.25.

[1560] Example 63

[1561] Preparation of compound AB27169

[1562] Step 1):

[1563]

[1564] Compound 1 (200 mg, 1.85 mmol) was dissolved in anhydrous ethanol (30 mL), then compound 2 (236 mg, 236 mmol) was added, followed by nitrogen purging three times and stirring overnight at 90°C. A new spot was detected by TLC, then sodium borohydride (210 mg, 5.55 mmol) was added, and the mixture was stirred at room temperature for 3 h. A new spot was detected by TLC, quenched with water (20 mL), and then 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, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound 3 (100 mg). Yield: 27.16%.

[1565] Step 2):

[1566]

[1567] Compound 3 (100 mg, 0.5 mmol) was dissolved in acetonitrile (10 mL), then compound 4 (160 mg, 0.75 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at 80°C. A new spot was observed on TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB27169 (25 mg). Yield: 15.10%.

[1568] 1 H NMR (400MHz, DMSO-d6) δ8.65(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).

[1569] MS-ESI: Theoretical value [M-Br] +331.18, measured value: 331.30.

[1570] Example 64

[1571] Preparation of compound AB27166

[1572] Step 1):

[1573]

[1574] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), and then compound 2 (5 g, 53.13 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 hours. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (4.01 g, 106.2 mmol) was slowly added. The system was allowed to rise naturally to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (200 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g). Yield: 26.8%.

[1575] Step 2):

[1576]

[1577] Compound 3 (184 mg, 1 mmol) was dissolved in N,N,dimethylhexamethylenetetramine (5 mL), followed by the addition of triethylamine (303 mg, 3 mmol). The mixture was then purged with nitrogen three times and stirred at 0°C for 30 minutes. Compound 4 (157 mg, 2 mmol) was added at 0°C, and the reaction was allowed to proceed at room temperature. The reaction was monitored by TLC, and the organic solvent was removed by concentration under reduced pressure. The mixture was then purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to obtain compound 5 (180 mg). Yield: 79.2%.

[1578] Step 3):

[1579]

[1580] Compound 5 (180 mg, 0.8 mmol) was dissolved in acetonitrile (10 mL), then compound 6 (426 mg, 2 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared upon TLC detection. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified to obtain compound AB27166 (40 mg). Yield: 10.5%.

[1581] 1H NMR (400MHz, DMSO-d6) δ8.78(d,J=6.3Hz,2H),8.16(d,J=6.3Hz,2H),7.91(d,J=7.6Hz,2H),7.43(d,J=7.6 Hz,2H),7.35(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).

[1582] MS-ESI: Theoretical value [M-CF3COO]+359.44, measured value: 359.20.

[1583] Example 65

[1584] Preparation of compound AB27170

[1585] Step 1):

[1586]

[1587] Compound 1 (1 g, 9.26 mmol) was dissolved in ethanol (10 mL), and then compound 2 (2.9 g, 27.78 mmol) was added. The mixture was then purged with nitrogen three times, heated to 90 °C, and stirred overnight. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (422 mg, 11.11 mmol) was slowly added. The system was allowed to warm to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (30 mL), and then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (1.5 g). Yield: 81.4%.

[1588] Step 2):

[1589]

[1590] Compound 3 (100 mg, 0.51 mmol) and compound 4 (108 mg, 0.51 mmol) were dissolved in acetonitrile (10 mL). The mixture was stirred at 80 °C for 16 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound AB27170 (75 mg). Yield: 29.4%.

[1591] 1H NMR (400MHz, DMSO-d6) δ9.20(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).

[1592] MS-ESI: Theoretical value [M-Br] +331.43, measured value: 331.25.

[1593] Example 66

[1594] Preparation of compound AB24917

[1595] Step 1):

[1596]

[1597] Compound 1 (160 mg, 1 mmol) was dissolved in acetic acid (7 mL). Liquid bromine (160 mg, 1.0 mmol) and two drops of hydrobromic acid aqueous solution were added to the mixture, and the mixture was stirred at room temperature for 3 hours. A new spot was observed on a TLC plate. Ice water (30 mL) was added, followed by extraction with ethyl acetate (30 mL x 3). The organic phases were combined, 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). Yield: 90.0%.

[1598] Step 2):

[1599]

[1600] Compound 2 (260 mg, 0.9 mmol) was dissolved in acetonitrile (10 mL), and then compound 3 (165 mg, 0.9 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared on a TLC plate, indicating the precipitation of a solid. The mixture was filtered, and the filter cake was washed three times with acetonitrile (2 mL). The solution was then evaporated to dryness to give compound AB24917 (45 mg). Yield: 14.57%

[1601] 1H NMR(400MHz, DMSO-d6)δ9.76(s,1H),8.30(d,J=7.2Hz,1H),8.20(d,J=7.0Hz,1H),7.8 2(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).

[1602] MS-ESI: Theoretical value [M-Br] +343.45, measured value: 343.10.

[1603] Example 67

[1604] Preparation of compound AB24956

[1605] Step 1):

[1606]

[1607] Compound 1 (300 mg, 3.15 mmol) was dissolved in acetonitrile (10 mL), and then compound 2 (671 mg, 2.35 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. After the appearance of a new spot on a TLC plate, the reaction solution was evaporated to dryness, and compound 3 (600 mg) was obtained by thin-layer chromatography. Yield: 83.54%

[1608] Step 2):

[1609]

[1610] Compound 3 (200 mg, 0.87 mmol) was dissolved in phosphorus oxychloride (10 mL), then purged with nitrogen three times and stirred at 90°C for 2 h. After a new spot was detected by TLC, the reaction solution was evaporated to dryness, yielding compound 4 (215 mg crude product), which was directly added to the next step.

[1611] Step 3):

[1612]

[1613] Compound 4 (215 mg, 0.88 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the 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 spot was observed on a TLC plate. The reaction solution was evaporated to dryness and sent to prepare compound AB24956 (20 mg).

[1614] Yield: 6.91%

[1615] 1 H NMR (400MHz, DMSO-d6) δ8.27(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).

[1616] MS-ESI: Theoretical value [M-CF3COO]+329.16, measured value: 329.25.

[1617] Example 68

[1618] Preparation of compound AB27176

[1619] Step 1):

[1620]

[1621] Compound 1 (100 mg, 0.76 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). Sodium hydride (61 mg, 1.56 mmol) was added under ice bath conditions, and the mixture was stirred for 10 minutes under ice bath conditions. Compound 2 (130 mg, 0.76 mmol) was then added, followed by nitrogen purging three times and incubation at room temperature for 5 hours. New spots were detected by TLC. The mixture 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, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to obtain compound 3 (90 mg). Yield: 53.1%.

[1622] Step 2):

[1623]

[1624] 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 purged with nitrogen three times and stirred overnight at 70 °C. A new spot was observed on a TLC plate. The solution was filtered, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to obtain compound AB27176 (40 mg). Yield: 26.2%.

[1625] 1 H NMR (400MHz, DMSO-d6) δ9.43(s,1H),8.54(s,1H),8.30(s,1H),7.89(s,1H),7.73(s,1H),7.50(s,1H),7.34(s,5H),6.13(d,J=1 2.3Hz,1H),5.59(s,2H),3.21(s,2H),3.03(d,J=11.6Hz,1H),2.62(s,1H),2.49(s,1H),2.48(s,3H),2.36(s,1H),2.34(s,3H).

[1626] MS-ESI: Theoretical value [M-Br] +381.49, measured value: 381.10.

[1627] Example 69

[1628] Preparation of compound AB27174

[1629] Step 1):

[1630]

[1631] Compound 1 (10.0 g, 25.44 mmol) was dissolved in dry N,N-dimethylformamide (100 mL), followed by compound 2 (15.3 g, 136 mmol), dimethylferrocene palladium dichloride (2.0 g, 2.4 mmol), lithium chloride (1.82 mg, 45 mmol), and sodium carbonate (9.6 g, 90 mmol). The mixture was then purged with nitrogen three times and stirred overnight at room temperature. Upon the appearance of a new spot on a TLC plate, the mixture 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, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound 3 (5.3 g). Yield: 56.89%.

[1632] Step 2):

[1633]

[1634] Compound 3 (3.2 g, 15.6 mmol) was dissolved in ethanol (100 mL), followed by the addition of sodium hydroxide (18.7 g, 468 mmol). The mixture was then purged three times with nitrogen and stirred overnight at 90 °C. A new spot was observed on a TLC plate. The mixture was diluted with water (20 mL), and then extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound 4 (1.9 g). Yield: 63.66%.

[1635] Step 3):

[1636]

[1637] Compound 4 (100 mg, 0.751 mmol) was dissolved in dry N,N-dimethylformamide (10 mL), followed by the addition of compound 5 (95 mg, 0.751 mmol) and potassium carbonate (311 mg, 2.25 mmol). The mixture was then purged with nitrogen three times and stirred overnight at room temperature. Upon the appearance of a new spot on a TLC plate, the mixture 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, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound 6 (60 mg). Yield: 35.8%.

[1638] Step 4):

[1639]

[1640] Compound 6 (60 mg, 0.269 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of compound 7 (78 mg, 0.269 mmol). The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was detected by TLC. The solution was filtered, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to obtain compound AB27174 (20 mg). Yield: 18.54%.

[1641] 1H NMR (400MHz, DMSO-d6) δ9.49(s,1H),8.60(d,J=6.5Hz,1H),8.34(d,J=6.5Hz,1H),8.14(s,1H),8.06(d,J=7.6Hz,1H),7.90(s,1H), 7.77(d,J=7.7Hz,1H),7.35(s,5H),6.37(d,J=11.0Hz,1H),5.61(s,2H),3.09(d,J=10.1Hz,1H),2.67(d,J=8.6Hz,1H),2.35(s,3H).

[1642] MS-ESI: Theoretical value [M-Br] +435.41, measured value: 435.35.

[1643] Example 70

[1644] Preparation of compound AB24948

[1645] Step 1):

[1646]

[1647] Compound 1 (5.6 g, 53.13 mmol) was dissolved in ethanol (10 mL), and then compound 2 (5 g, 53.13 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature was raised to 90 °C and stirred for 2 hours. A new spot appeared on TLC. The reaction temperature was lowered to 0 °C, and sodium borohydride (4.01 g, 106.2 mmol) was slowly added. The system was allowed to rise naturally to room temperature and stirred for 1 hour. A new spot appeared on TLC. The mixture was diluted with water (200 mL), and then extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 10:1) to give compound 3 (2.6 g). Yield: 26.8%.

[1648] Step 2):

[1649]

[1650] Compound 4 (200 mg, 1.22 mmol) was dissolved in dichloromethane (10 mL), and then bis(N,N-dimethylacetamide)dibromobromate (505 mg, 1.22 mmol) was added. The mixture was stirred at room temperature for 1 hour. New spots were observed on TLC. The reaction solution was evaporated to dryness, and compound 5 (270 mg) was obtained by thin-layer chromatography. Yield: 92.97%.

[1651] Step 3):

[1652]

[1653] Compound 3 (140 mg, 0.74 mmol) was dissolved in acetonitrile (10 mL), and then compound 5 (270 mg, 1.11 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot appeared on the TLC plate, indicating compound AB24948 (220 mg).

[1654] Yield: 75.47%

[1655] 1 H NMR (400MHz, CD3OD) δ10.19(s,1H),9.05(s,1H),8.94(s,1H),8.44–8.30(m,3H),8.15(d,J=25.3Hz,5 H),7.83(s,2H),6.52(s,1H),5.38(s,2H),4.03(d,J=15.5Hz,2H),3.95(s,1H),3.60(d,J=8.4Hz,1H).

[1656] MS-ESI: Theoretical value [M-Br]+347.16, measured value: 347.10.

[1657] Example 71

[1658] Preparation of compound AB27163

[1659] Step 1):

[1660]

[1661] Compound 1 (1.19 mg, 10 mmol) was dissolved in N,N,dimethylhexamethylenetetramine (50 mL), followed by the addition of sodium hydroxide (480 mg, 20 mmol). The mixture was then purged with nitrogen three times and stirred at 0°C for 30 minutes. Compound 2 (1.85 g, 10 mmol) was added at 0°C, and the reaction was allowed to proceed at room temperature. The reaction was monitored by TLC, and the organic solvent was removed by concentration under reduced pressure. The mixture was then purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound 3 (1.2 g). Yield: 53.8%.

[1662] Step 2):

[1663]

[1664] Compound 3 (100 mg, 0.45 mmol) was dissolved in acetonitrile (10 mL), then compound 4 (107.55 mg, 0.45 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was detected by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB27163 (30 mg). Yield: 17.49%.

[1665] 1 H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.54(s,1H),8.37–8.29(m,2H),7.72(s, 1H),7.51(d,J=7.5Hz,1H),7.42(d,J=7.0Hz,2H),7.37(d,J=8.0Hz,3H),7.30 (d,J=6.8Hz,1H),7.18(s,1H),6.14(dd,J=28.5,8.4Hz,2H),3.19(d,J=15.1H z,2H),2.98(d,J=9.9Hz,1H),2.64(s,1H),2.34(s,3H),1.97(d,J=6.4Hz,3H).

[1666] MS-ESI: Theoretical value [M-Br] +381.49, measured value: 381.20.

[1667] Example 72

[1668] Preparation of compound AB27184

[1669] Step 1):

[1670]

[1671] Compound 1 (360 mg, 2.25 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of compound C8H18N2O2HBr3 (929 mg, 2.25 mmol), and then one drop of methanol. The mixture was then purged three times with nitrogen and stirred at room temperature for 1 h. A new spot was detected by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 2 (470 mg). Yield: 64.48%.

[1672] Step 2):

[1673]

[1674] Compound 2 (116 mg, 0.5 mmol) was dissolved in acetonitrile (10 mL), then compound 3 (111 mg, 0.5 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at 80 °C. A new spot was observed on TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain compound AB27184 (104 mg). Yield: 46.73%.

[1675] 1 H NMR(400MHz,dmso-d6)δ9.37(s,1H),8.54(s,1H),8.33(d,J=11.0Hz,2H),7.81(d,J=6.6Hz,1H),7.31(dd,J=58.4, 33.6Hz,9H),6.17(s,1H),6.10(s,1H),3.18(d,J=18.2Hz,2H),2.98(s,1H),2.64(s,1H),2.38(s,3H),1.96(s,3H).

[1676] MS-ESI: Theoretical value [M-Br] +381.49, measured value: 381.30

[1677] Example 73

[1678] Preparation of compound AB27162

[1679] Step 1):

[1680]

[1681] Compound 1 (1.19 g, 10 mmol) was dissolved in N,N,dimethylhexamethylenetetramine (50 mL), followed by the addition of sodium hydroxide (480 mg, 20 mmol). The mixture was then purged with nitrogen three times and stirred at 0°C for 30 minutes. Compound 2 (1.85 g, 10 mmol) was added at 0°C, and the reaction was allowed to proceed at room temperature. The reaction was monitored by TLC, and the organic solvent was removed by concentration under reduced pressure. The mixture was then purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound 3 (1.2 g). Yield: 53.8%.

[1682] Step 2):

[1683]

[1684] Compound 4 (30 g, 124 mmol) was dissolved in tetrahydrofuran (200 mL), and compound 5 (10.46 g, 149 mmol) was added. The mixture was purged with nitrogen three times, and n-butyllithium (100 mL, 2.5 mol / L) was added dropwise at -78 °C. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 6 (11.2 g). Yield: 38.93%.

[1685] Step 3):

[1686]

[1687] Compound 6 (11.2 g, 48 mmol) was dissolved in dichloromethane (100 mL) and water (100 mL), and silver nitrate (1.65 g, 9.7 mmol) and potassium persulfate (32.6 g, 121 mmol) were added. The mixture was stirred at room temperature for 16 hours. New spots were observed by TLC. The solution was concentrated under reduced pressure to remove water and organic solvents. The solution was purified by column chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 7 (930 mg). Yield: 8.42%.

[1688] Step 4):

[1689]

[1690] Compound 7 (930 mg, 4.04 mmol) was dissolved in dichloromethane (20 mL), and then bis(N,N-dimethylacetamide)dibromobromate (1.68 g, 4.04 mmol) was added. The mixture was stirred at room temperature for 1 hour. New spots were observed by TLC. The reaction solution was evaporated to dryness and purified by column chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound 8 (800 mg). Yield: 64.50%.

[1691] Step 5):

[1692]

[1693] Compound 3 (100 mg, 0.45 mmol) was dissolved in acetonitrile (10 mL), then compound 8 (138 mg, 0.45 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at room temperature. A new spot was detected by TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-30%) to give compound AB27162 (30.0 mg). Yield: 14.78%.

[1694] 1H NMR(400MHz, DMSO-d6)δ9.39(s,1H),8.56(s,1H),8.36(s,2H),7.70(dd,J=33.7,12.2Hz,3H),7.46–7.26( m,5H),7.20(s,1H),6.19(s,2H),3.34(s,2H),3.02(d,J=10.4Hz,1H),2.64(s,1H),1.97(d,J=6.4Hz,3H).

[1695] MS-ESI: Theoretical value [M-Br]+451.16, measured value: 451.35.

[1696] Example 74

[1697] Preparation of compound AB27145

[1698] Step 1):

[1699]

[1700] Compound 1 (236 mg, 2.0 mmol) was dissolved in NN-dimethylformamide (10 mL). Sodium hydride (24 mg, 1.0 mmol) was added under ice bath conditions, followed by nitrogen purging three times. The mixture was stirred under ice bath conditions for 30 minutes, and then compound 2 (408 mg, 2.4 mmol) was slowly added dropwise under ice bath conditions. The mixture was stirred at room temperature for 90 minutes. A new spot appeared on the TLC plate. The mixture was diluted with ice water (20 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, concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography (methanol:dichloromethane = 0-10%) to give compound 3 (200 mg). Yield: 62.5%.

[1701] Step 2):

[1702]

[1703] Compound 3 (60 mg, 0.31 mmol) was dissolved in acetonitrile (10 mL), then compound 4 (100 mg, 0.31 mmol) was added. The mixture was then purged with nitrogen three times and stirred overnight at 60 °C. A new spot was observed on a TLC plate. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by thin-layer chromatography to obtain compound AB27145 (30 mg). Yield: 24.88%.

[1704] 1H NMR (400MHz, DMSO-d6) δ9.37(s,1H),8.57(d,J=6.7Hz,1H),8.34(d,J=6.6Hz,1H),8.07(s,1H),7.80–7.71(m,2H),7.67(d,J=8.1Hz,1H),7.1 3(s,1H),6.21(d,J=12.0Hz,1H),4.37(s,2H),3.33(s,2H),3.06(d,J=10.1Hz,1H),2.69(s,1H),1.84(d,J=7.0Hz,2H),0.84(t,J=6.8Hz,3H).

[1705] MS-ESI: Theoretical value [M-Br] +389.39, measured value: 389.05.

[1706] Example 75

[1707] Preparation of compound AB27129

[1708] Step 1):

[1709]

[1710] Compound 1 (5.5 g, 25 mmol) was dissolved in N,N-dimethylformamide (200 mL), compound 2 (52.5 mL) was added, followed by cuprous iodide (237 mg, 1.25 mmol), then N,N-diisopropylethylamine (10.0 g, 80 mmol), and finally palladium dichloride bis(triphenylphosphine) (525.75 mg, 0.75 mmol). The mixture was stirred at room temperature for 16 hours. New spots were observed on TLC. The solution was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound 3 (2.25 g). Yield: 67.67%.

[1711] Step 2):

[1712]

[1713] Compound 3 (2.25 g, 17 mmol) was dissolved in 1,4-dioxane (20 mL), and potassium tert-butoxide (51 mL) was added. The mixture was stirred at 110 °C for 16 hours. New spots were observed by TLC. The mixture was concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography (methanol:dichloromethane = 0-10%) to give compound 4 (1.2 g). Yield: 54.3%.

[1714] Step 3):

[1715]

[1716] Compound 4 (550 mg, 4.2 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound sodium hydride (304 mg, 12.7 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 3 hours. New spots were observed on TLC. The reaction solution was evaporated to dryness, and compound 5 (294 mg) was obtained by thin-layer chromatography. Yield: 31.53%.

[1717] Step 4):

[1718]

[1719] Compound 5 (100 mg, 0.5 mmol) was di...

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the compound of formula I is shown in structure I-10 below: ； R3 is a C1-C6 alkyl, a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted C6-C10 aryl-C1-C4 alkyl-, wherein any "substitution" means that 1, 2 or 3 hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: C1-C6 alkyl, halogen; R4 and R5 are each independently hydrogen; R6 is a substituted or unsubstituted phenyl group, where "substituted" means that one, two or three hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, halogen, nitro, and C1-C6 haloalkoxy. n is 1; a is 0; Alternatively, the structure of the compound of formula I is shown in structure I-9 below: ； R3 is C6-C10 aryl or C6-C10 aryl-C1-C4 alkyl-; R4 and R5 are each independently hydrogen; R6 is a substituted or unsubstituted phenyl group, where "substituted" means that one, two or three hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogens; n is 1; a is 0; Alternatively, the structure of the compound of formula I is shown in structure I-11 below: ； R3 is a C6-C10 aryl-C1-C4 alkyl-; R4 and R5 are each independently hydrogen; R6 is a substituted or unsubstituted phenyl group, where "substituted" means that one, two or three hydrogen atoms on the group are replaced by a substituent selected from the group consisting of C1-C6 alkyl groups. n is 1; a is 0 Alternatively, the structure of the compound of formula I is shown in structure I-15 below: ； R3 is C6-C10 aryl or C6-C10 aryl-C1-C4 alkyl-; R4 and R5 are each independently hydrogen; R6 is a substituted or unsubstituted phenyl group, where "substituted" means that one, two or three hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, halogen, nitro, and C1-C6 haloalkoxy. n is 1; a is 0; Alternatively, the structure of the compound of formula I is shown in structure I-16 below: ； R3 is a C6-C10 aryl-C1-C4 alkyl-; R4 and R5 are each independently hydrogen; R6 is a substituted or unsubstituted phenyl group, where "substituted" means that one, two or three hydrogen atoms on the group are replaced by substituents selected from the group consisting of C1-C6 haloalkyl groups and halogens. n is 1; a is 0; Alternatively, the structure of the compound of formula I is shown in structure I-17 below: ； R3 is a C6-C10 aryl-C1-C4 alkyl-; R4 and R5 are each independently hydrogen; R6 is a substituted or unsubstituted phenyl group, where "substituted" means that one, two or three hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogens; n is 1; a is 0.

2. A compound of formula I, or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the compound of formula I is shown in structure I-10 below: ； R3 is a C1-C4 alkyl, a substituted or unsubstituted C6-C8 aryl, a substituted or unsubstituted C6-C8 aryl-C1-C2 alkyl-, wherein any "substitution" means that 1, 2 or 3 hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: C1-C4 alkyl, halogen; R4 and R5 are each independently hydrogen; R6 is a substituted or unsubstituted phenyl group, where "substituted" means that one, two or three hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: C1-C4 alkyl, C1-C4 haloalkyl, halogen, nitro, and C1-C4 haloalkoxy. n is 1; a is 0; Alternatively, the structure of the compound of formula I is shown in structure I-9 below: ； R3 is C6-C8 aryl or C6-C8 aryl-C1-C2 alkyl-; R4 and R5 are each independently hydrogen; R6 is a substituted or unsubstituted phenyl group, where "substituted" means that one, two or three hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogens; n is 1; a is 0; Alternatively, the structure of the compound of formula I is shown in structure I-11 below: ； R3 is a C6-C8 aryl-C1-C2 alkyl-; R4 and R5 are each independently hydrogen; R6 is a substituted or unsubstituted phenyl group, where "substituted" means that one, two or three hydrogen atoms on the group are replaced by a substituent selected from the group consisting of C1-C4 alkyl groups. n is 1; a is 0 Alternatively, the structure of the compound of formula I is shown in structure I-15 below: ； R3 is C6-C8 aryl or C6-C8 aryl-C1-C2 alkyl-; R4 and R5 are each independently hydrogen; R6 is a substituted or unsubstituted phenyl group, where "substituted" means that one, two or three hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: C1-C4 alkyl, C1-C4 haloalkyl, halogen, nitro, and C1-C4 haloalkoxy. n is 1; a is 0; Alternatively, the structure of the compound of formula I is shown in structure I-16 below: ； R3 is a C6-C8 aryl-C1-C2 alkyl-; R4 and R5 are each independently hydrogen; R6 is a substituted or unsubstituted phenyl group, where "substituted" means that one, two or three hydrogen atoms on the group are replaced by substituents selected from the group consisting of: C1-C4 haloalkyl groups, halogens; n is 1; a is 0; Alternatively, the structure of the compound of formula I is shown in structure I-17 below: ； R3 is a C6-C8 aryl-C1-C2 alkyl-; R4 and R5 are each independently hydrogen; R6 is a substituted or unsubstituted phenyl group, where "substituted" means that one, two or three hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogens; n is 1; a is 0.

3. A compound of formula I, or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the compound of formula I is shown in structure I-10 below: ； R3 is propyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyl-methyl-, wherein the substituted or unsubstituted phenyl is a monosubstituted or unsubstituted phenyl, and the substitution is an ortho, para or meta substitution of the phenyl, and the substituent is a halogen or methyl. R4 and R5 are each independently hydrogen; R6 is m-nitrophenyl, o-nitrophenyl, p-nitrophenyl, p-methylphenyl, o-methylphenyl, m-methylphenyl, m-trifluoromethoxyphenyl, p-trifluoromethoxyphenyl, o-trifluoromethoxyphenyl, p-halophenyl, o-halophenyl, m-halophenyl, p-trifluoromethylphenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl; n is 1; a is 0; Alternatively, the structure of the compound of formula I is shown in structure I-9 below: ； R3 is phenyl or phenyl-methyl-; R4 and R5 are each independently hydrogen; R6 represents a para-halophenyl, ortho-halophenyl, or meta-halophenyl; n is 1; a is 0; Alternatively, the structure of the compound of formula I is shown in structure I-15 below: ； R3 is phenyl or phenyl-methyl-; R4 and R5 are each independently hydrogen; R6 is m-nitrophenyl, o-nitrophenyl, p-nitrophenyl, p-methylphenyl, o-methylphenyl, m-methylphenyl, m-trifluoromethoxyphenyl, p-trifluoromethoxyphenyl, o-trifluoromethoxyphenyl, p-halophenyl, o-halophenyl, m-halophenyl, p-trifluoromethylphenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl; n is 1; a is 0; Alternatively, the structure of the compound of formula I is shown in structure I-17 below: ； R3 is phenyl-methyl-; R4 and R5 are each independently hydrogen; R6 represents p-halophenyl, ortho-halophenyl, or meta-halophenyl; n is 1; a is 0.

4. A compound of formula I, or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the compound of formula I is shown in structure I-10 below: ； R3 is propyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenyl-methyl-, wherein the substituted or unsubstituted phenyl is a monosubstituted or unsubstituted phenyl, and the substitution is an ortho, para, or meta substitution of the phenyl, and the substituent is chloro or methyl. R4 and R5 are each independently hydrogen; R6 is m-nitrophenyl, p-nitrophenyl, p-methylphenyl, o-methylphenyl, p-trifluoromethoxyphenyl, p-chlorophenyl, m-chlorophenyl, or p-trifluoromethylphenyl; n is 1; a is 0; Alternatively, the structure of the compound of formula I is shown in structure I-15 below: ； R3 is phenyl or phenyl-methyl-; R4 and R5 are each independently hydrogen; R6 is m-nitrophenyl, p-methylphenyl, p-trifluoromethoxyphenyl, m-chlorophenyl, m-trifluoromethylphenyl, or p-trifluoromethylphenyl; n is 1; a is 0.

5. The compound of formula I as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that, Pharmaceutically acceptable salts of the compound of formula I are salts formed by the compound of formula I with an acid selected from the group consisting of: hydrochloric 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, glutamic acid, or combinations thereof.

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises (a) a compound of formula I as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, characterized in that, The dosage form of the pharmaceutical composition is an oral preparation, a topical preparation, or an injectable preparation.

8. Use of a compound of formula I as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that, For use in the preparation of compositions or formulations for the prevention and / or treatment of cancer, said cancer being selected from the group consisting of: lung cancer, pancreatic cancer, breast cancer, lymphoma, prostate cancer, brain cancer, leukemia, liver cancer, melanoma, colorectal cancer, kidney cancer, or combinations thereof.

9. The use as described in claim 8, characterized in that, The breast cancer mentioned is triple-negative breast cancer; The liver cancer described is anaplastic, poorly differentiated liver cancer; The leukemia mentioned is acute myeloid leukemia; The lung cancer mentioned is selected from the following group: small cell lung cancer, non-small cell lung cancer, or a combination thereof; The lymphoma mentioned is B-cell lymphoma; The colorectal cancer mentioned is colorectal adenocarcinoma; The brain cancer mentioned is selected from the group consisting of: medulloblastoma, glioblastoma, or a combination thereof; and / or The renal cell carcinoma mentioned is clear cell adenocarcinoma of the kidney.

10. The use as described in claim 9, characterized in that, The leukemia described is M4 type acute myeloid leukemia; and / or The colorectal adenocarcinoma mentioned is Dukes' type C, grade IV colorectal adenocarcinoma.

11. The use as described in claim 8, characterized in that, The cancer in question is one in which the mitochondrial oxidative phosphorylation pathway is upregulated; and / or The cancer in question is one in which the mitochondrial membrane permeability transition pore has low activity; and / or The cancer is a tumor with low or no expression of the NNMT gene; and / or The cancer in question is a tumor with a high level of methylation at the CpG site of the NNMT gene region DNA.

12. The use as described in claim 11, characterized in that, The cancer patients were given an inhibitor of mitochondrial membrane permeability transition pores to reduce the activity of mitochondrial membrane permeability transition pores in cancer cells.

13. The use as described in claim 12, characterized in that, The mitochondrial membrane permeability transition pore inhibitor is selected from the group consisting of Cyclosporin A, CyP-D protein inhibitors, peroxide scavengers, or combinations thereof.

14. The use as described in claim 11, characterized in that, The NNMT gene mentioned is the human NNMT gene.

15. The use as described in claim 11, characterized in that, The tumor with low or no NNMT gene expression refers to a tumor in which NNMT protein cannot be detected by NNMT antibody in 1 μg of protein extracted from the tumor.

16. The use as described in claim 8, characterized in that, The composition is a pharmaceutical composition.

17. The use as described in claim 8, characterized in that, The composition or formulation may also include a pharmaceutically acceptable carrier.

18. The use as described in claim 8, characterized in that, The dosage form of the composition or formulation is a solid dosage form, a liquid dosage form, or a semi-solid dosage form; and / or The dosage form of the composition or preparation is an oral preparation, a topical preparation, or an injectable preparation.

19. A composition, characterized in that, The composition comprises: (1) A first active ingredient, wherein the first active ingredient is an anticancer drug, the anticancer drug being a compound of formula I as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof; and (2) The second active ingredient is a mitochondrial membrane permeability transition pore inhibitor.

20. The composition of claim 19, characterized in that, The composition is a pharmaceutical composition.

21. The composition according to claim 20, characterized in that, The pharmaceutical composition also includes a pharmaceutically acceptable carrier.

22. A medicine box, characterized in that, The medicine box includes: (A) A first formulation containing a first active ingredient, wherein the first active ingredient is an anticancer drug, and the anticancer drug is a compound of formula I as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof; and (B) A second formulation containing a second active ingredient, wherein the second active ingredient is a mitochondrial membrane permeability transition pore inhibitor.

23. The medicine box as described in claim 22, characterized in that, The first and second formulations are independent formulations; or The first and second formulations are combined formulations.

24. A method for inhibiting cancer cells in vitro, non-therapeutic and non-diagnostic, characterized in that, The method includes the step of contacting cancer cells with a compound of formula I as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof, thereby inhibiting cancer cells; The cancer is as described in any one of claims 8-15.

25. A medicine box, characterized in that, The medicine box includes: (i) Detection reagents for detecting mitochondrial oxidative phosphorylation pathway levels, mitochondrial membrane permeability transition pore levels, NNMT gene expression, NNMT gene nucleotide site methylation levels, and / or NNMT gene region DNA CpG site methylation levels; and (ii) The compound of formula I as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof.

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