Phosphorus compound and its use

Abstract

The present invention relates to a phosphorus compound and its use. The compound of the present invention has a significantly excellent precision therapeutic effect on tumors having low expression, non-expression, low activation or inactivation of the mitochondrial membrane permeability transition pore, low expression, non-expression, low activation or inactivation of peptidylprolyl isomerase F, low expression or non-expression of the NNMT gene, high expression of DNA methylase, high expression of UHRF1, high methylation of nucleotide sites of the NNMT gene and / or high methylation of DNA CpG sites in the NNMT gene region. 【Solution means】The present invention provides a compound of formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof. JPEG2025518287000326.jpg50147

Description

Technical Field

[0001] The present invention relates to the technical field of drugs, and particularly to phosphorus compounds and their uses.

Background Art

[0002] Tumors are common diseases that seriously endanger human health, and the mortality rate due to malignant tumors has been showing an upward trend. Due to tumor heterogeneity, if the same treatment method or the same drug is simply used according to its origin and pathological characteristics, problems caused by inappropriate treatment are likely to appear, delaying the crucial treatment time and opportunity of patients. Therefore, there is a great need to adopt precision treatment for various situations of tumors. With the development of biological technologies, tumors have a continuous genotype distribution at the molecular level such as genes and proteins, and changes in the expression and activity of genes and proteins related to tumors have been continuously discovered one after another. The changes in the expression and activity of genes and proteins related to tumors play an important role in the occurrence of malignant tumors. The discovery and application of biomarkers provide precise guidance for the application of related drugs, enable precision treatment of tumors, thereby achieving targeted dosing, significantly improving the treatment effect, and reducing the dosage and toxic side effects of drugs.

[0003] Therefore, developing drugs that can precisely treat tumors has become an urgent task in this technical field.

Summary of the Invention

Problems to be Solved by the Invention

[0004] The present invention aims to provide a compound having an excellent precision treatment effect on tumors with low expression, non-expression, low activity or inactivity of mitochondrial membrane permeability transition pores, tumors with low expression, non-expression, low activity or inactivity of peptidylprolyl isomerase F, tumors with low expression or non-expression of the NNMT gene, tumors with high expression of DNA methyltransferase, tumors with high expression of UHRF1, tumors with high methylation of nucleotide sites of the NNMT gene, and / or tumors with high methylation of DNA CpG sites in the NNMT gene region.

Means for Solving the Problems

[0005] The first aspect of the present invention provides a compound of formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof;

[0006]

Chemical formula

[0007] I wherein R 1 , R 2 , R 3 and R 4 each independently represents a substituted or unsubstituted C3-C16 cycloalkyl group, a substituted or unsubstituted 3- to 16-membered heterocycloalkyl group, a substituted or unsubstituted C6-C16 aryl group, a substituted or unsubstituted 5- to 16-membered heteroaryl group, or a substituted or unsubstituted 5- to 16-membered heteroaryl group-substituted or unsubstituted C1-C8 alkyl group.

[0008] In another preferred example, any of the above-mentioned "substitutions" means that one or more (preferably one, two, three, four, five, six, seven or eight) hydrogen atoms on the atomic group are each independently substituted by a substituent.

[0009] In another preferred example, R 1 , R 2 , R 3 and R 4each independently represents a substituted or unsubstituted C3-C14 cycloalkyl group, a substituted or unsubstituted 3-14 membered heterocycloalkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted 5-14 membered heteroaryl group, or a substituted or unsubstituted 5-14 membered heteroaryl group-substituted or unsubstituted C1-C8 alkyl group-.

[0010] In another preferred example, R 1 R 2 R 3 and R 4 each independently represents a substituted or unsubstituted C3-C12 cycloalkyl group, a substituted or unsubstituted 3-12 membered heterocycloalkyl group, a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, or a substituted or unsubstituted 5-12 membered heteroaryl group-substituted or unsubstituted C1-C6 alkyl group-.

[0011] In another preferred example, R 1 R 2 R 3 and R 4 each independently represents a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocycloalkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, or a substituted or unsubstituted 5-10 membered heteroaryl group-substituted or unsubstituted C1-C4 alkyl group-.

[0012] In another preferred example, R 1 R 2 R 3 and R 4is, independently of each other, a substituted or unsubstituted 3-membered heterocycloalkyl group, a substituted or unsubstituted 4-membered heterocycloalkyl group, a substituted or unsubstituted 5-membered heterocycloalkyl group, a substituted or unsubstituted 6-membered heterocycloalkyl group, a substituted or unsubstituted 7-membered heterocycloalkyl group, a substituted or unsubstituted 8-membered heterocycloalkyl group, a substituted or unsubstituted 9-membered heterocycloalkyl group, a substituted or unsubstituted 10-membered heterocycloalkyl group, a substituted or unsubstituted 11-membered heterocycloalkyl group, a substituted or unsubstituted 12-membered heterocycloalkyl group, a substituted or unsubstituted 13-membered heterocycloalkyl group, a substituted or unsubstituted 14-membered heterocycloalkyl group, a substituted or unsubstituted 15-membered heterocycloalkyl group, a substituted or unsubstituted 16-membered heterocycloalkyl group, a substituted or unsubstituted C6 aryl group, a substituted or unsubstituted C7 aryl group, a substituted or unsubstituted C8 aryl group, a substituted or unsubstituted C9 aryl group, a substituted or unsubstituted C10 aryl group, a substituted or unsubstituted C11 aryl group, a substituted or unsubstituted C12 aryl group, a substituted or unsubstituted C13 aryl group, a substituted or unsubstituted C14 aryl group, a substituted or unsubstituted C15 aryl group, a substituted or unsubstituted C16 aryl group, a substituted or unsubstituted 5-membered heteroaryl group, a substituted or unsubstituted 6-membered heteroaryl group, a substituted or unsubstituted 7-membered heteroaryl group, a substituted or unsubstituted 8-membered heteroaryl group, a substituted or unsubstituted 9-membered heteroaryl group, a substituted or unsubstituted 10-membered heteroaryl group, a substituted or unsubstituted 11-membered heteroaryl group, a substituted or unsubstituted 12-membered heteroaryl group, a substituted or unsubstituted 13-membered heteroaryl group, a substituted or unsubstituted 14-membered heteroaryl group, a substituted or unsubstituted 15-membered heteroaryl group, a substituted or unsubstituted 16-membered heteroaryl group, or a substituted or unsubstituted 6-10 membered heteroaryl group-substituted or unsubstituted C1-C2 alkyl group-.

[0013] In another preferred example, R 1 、R 2 、R 3 and R 4are each independently a phenyl group, a methoxy group-phenyl group-, an indole group, an isoindole group, a methoxy group-indole group-, a methyl group-indole group-, a hydroxyl group-ethyl group-indole group-, a mercapto group-ethyl group-indole group-, a piperidyl group-ethyl group-indole group-, a morpholinyl group-ethyl group-indole group-, a halogenated ethyl group-indole group-, a pyrrolopyridine group, a methyl group-pyrrolopyridine group-, a benzimidazole group, a methyl group-benzimidazole group-, an indazole group, a methyl group-indazole group-, a pyridinyl group, a 3H-indole group, a 7H-pyrrolo[3,4-b]pyridine group, a 3H-pyrrolo[3,4-c]pyridine group, a 1H-pyrrolo[3,4-c]pyridine group, a 3H-pyrrolo[3,2-b]pyridine group, a 3H-pyrrolo[2,3-c]pyridine group, a 3H-indazole group, a 2H-indazole group, a 1H-pyrrolo[2,3-b]pyridine group, a monomethyl-substituted 3H-indazole group, a monomethyl-substituted 7H-pyrrolo[3,4-b]pyridine group, a monomethyl-substituted 3H-pyrrolo[3,4-c]pyridine group, a monomethyl-substituted 1H-pyrrolo[3,4-c]pyridine group, a monomethyl-substituted 3H-pyrrolo[3,2-b]pyridine group, a monomethyl-substituted 3H-pyrrolo[2,3-c]pyridine group, a monomethyl-substituted 3H-indazole group, a monomethyl-substituted 2H-indazole group, a monomethyl-substituted 1H-pyrrolo[2,3-b]pyridine group, a benzofuranyl group, a furanyl group, a benzothiazole group, a benzothiophene group, a thiazole group, a halogenated indole group-methyl group-, or a dihydropyran group.

[0014] In another preferred example, the chemical structural formula of the methoxy group-phenyl group- is as follows.

[0015]

Chem.

[0016] 。

[0017] methoxy group-phenyl group- In another preferred example, the indole group is a 1H-indole group or a 2H-indole group.

[0018] In another preferred example, the chemical structural formula of the methoxy group-indole group- is as follows.

[0019]

Chemical formula

[0020] Methoxy group-indole group- In another preferred example, the pyrrolopyridine group is a pyrrolo[2,3-c]pyridine group, a pyrrolo[2,3-b]pyridine group, a pyrrolo[3,2-b]pyridine group, a pyrrolo[3,2-c]pyridine group, a pyrrolo[3,4-b]pyridine group, a pyrrolo[3,4-c]pyridine group, a pyrrolo[3,2-b]pyridine group, or a pyrrolo[2,3-c]pyridine group.

[0021] In another preferred example, the pyrrolopyridine group is a 1H-pyrrolo[2,3-c]pyridine group, a 1H-pyrrolo[2,3-b]pyridine group, a 1H-pyrrolo[3,2-b]pyridine group, a 1H-pyrrolo[3,2-c]pyridine group, a 7H-pyrrolo[3,4-b]pyridine group, a 3H-pyrrolo[3,4-c]pyridine group, a 1H-pyrrolo[3,4-c]pyridine group, a 3H-pyrrolo[3,2-b]pyridine group, or a 3H-pyrrolo[2,3-c]pyridine group.

[0022] In another preferred example, the benzimidazole group is a benzimidazo[d]imidazole group.

[0023] In another preferred example, the benzimidazole group is a 1H-benzimidazo[d]imidazole group.

[0024] In another preferred example, the indazole group is a 1H-indazole group or a 3H-indazole group.

[0025] In another preferred example, the isoindazole group is a 1H-isoindazole group.

[0026] In another preferred example, the benzothiazole group is a benzothiazole group.

[0027] In another preferred example, the benzothiophene group is a benzothiophene group.

[0028] In another preferred example, the halogenated indole group-methyl group- is a 3-bromo-indole group-methyl group-.

[0029] In another preferred example, the halogenated indole group-methyl group- is a 3-bromo-1H-indole group-methyl group-.

[0030] In another preferred example, the dihydropyran group is a 3,6-dihydropyran group.

[0031] In another preferred example, the dihydropyran group is a 3,6-dihydro-2H-pyran group.

[0032] In another preferred example, R 1 , R 2 , R 3 and R 4 represent one, two, three, or four heteroaryl groups.

[0033] In another preferred example, R 1 , R 2 , R 3 and R 4 each independently have the following chemical structural formula;

[0034]

Chemical formula

[0035] , JPEG2025518287000006.jpg222146

[0036] , JPEG2025518287000007.jpg164166

[0037] R 5 , R 6 , R 7 , R 8 and R 9 each independently represents a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkyl group -O-, or a C1-C10 alkyl group -S-; R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkyl group -O-, a C1-C10 alkyl group -S-, or

[0038] [ka]

[0039] represents; R 17 , R 18 , R 19 , R 20 , R 21 and R 22 each independently represents a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkyl group -O-, or a C1-C10 alkyl group -S-; R 23 , R 24 , R 25 , R 26 , R 27 and R 28 each independently represents a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkyl group -O-, or a C1-C10 alkyl group -S-; R 29 , R 30 , R 31 , R 32 , R 33 and R 34Each independently represents a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkyl group -O-, or a C1-C10 alkyl group -S-; R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3-12 membered heterocycloalkyl group, or a halogen atom.

[0040] R 36 represents a hydrogen atom, or a halogen atom.

[0041] Z 1 represents a C1-C8 alkylidene group.

[0042] In another preferred example, R 1 R 2 R 3 and R 4 each independently have the following chemical structural formula.

[0043]

Chemical formula

[0044] , JPEG2025518287000010.jpg228154

[0045] , JPEG2025518287000011.jpg212153

[0046] , JPEG2025518287000012.jpg214158

[0047] , JPEG2025518287000013.jpg110152

[0048] In another preferred example, R 1 R 2 R 3 and R 4 each independently have the following chemical structural formula.

[0049] [Chemical]

[0050] 、 JPEG2025518287000015.jpg231153

[0051] 、 JPEG2025518287000016.jpg225161

[0052] 、 JPEG2025518287000017.jpg230133

[0053] 、

[0054] In another preferred example, R 5 、 R 6 、 R 7 、 R 8 and R 9 each independently represent a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkyl group -O-, or a C1-C10 alkyl group -S-.

[0055] In another preferred example, R 5 、 R 6 、 R 7 、 R 8 and R 9 each independently represent a hydrogen atom, a C1-C8 alkyl group, a C1-C8 alkyl group -O-, or a C1-C8 alkyl group -S-.

[0056] In another preferred example, R 5 、 R 6 、 R 7 、 R 8 and R 9 each independently represent a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkyl group -O-, or a C1-C6 alkyl group -S-.

[0057] In another preferred example, R 5 、 R 6 、 R 7 、 R8 and R 9 each independently represents a hydrogen atom, a C1-C4 alkyl group, a C1-C4 alkyl group - O -, or a C1-C4 alkyl group - S -.

[0058] In another preferred example, R 5 , R 6 , R 7 , R 8 and R 9 each independently represents a hydrogen atom, a methyl group, a methyl group - O -, or a methyl group - S -.

[0059] In another preferred example, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 each independently represents a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkyl group - O -, a C1-C10 alkyl group - S -, or

[0060]

Chemical formula

[0061] represents; R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3 - 12 membered heterocycloalkyl group, or a halogen atom.

[0062] Z 1 represents a C1-C8 alkylidene group.

[0063] In another preferred example, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 each independently represents a hydrogen atom, a C1-C8 alkyl group, a C1-C8 alkyl group - O -, a C1-C8 alkyl group - S -, or

[0064] [Chemistry]

[0065] represents; R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3- to 12-membered heterocycloalkyl group, or a halogen atom.

[0066] Z 1 represents a C1-C8 alkylidene group.

[0067] In another preferred example, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkyl group -O-, a C1-C6 alkyl group -S-, or

[0068] [Chemistry]

[0069] represents; R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3- to 12-membered heterocycloalkyl group, or a halogen atom. Z 1 represents a C1-C8 alkylidene group.

[0070] In another preferred example, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently a hydrogen atom, a C1-C4 alkyl group, a C1-C4 alkyl group -O-, a C1-C4 alkyl group -S-, or

[0071] [Chemistry]

[0072] represents; R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3- to 12-membered heterocycloalkyl group, or a halogen atom.

[0073] Z 1 represents a C1-C8 alkylidene group.

[0074] In another preferred example, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 each independently represents a hydrogen atom, a methyl group, a methyl group -O-, or a methyl group -S-, a hydroxyl group - ethyl group -, a mercapto group - ethyl group -, a piperidyl group - ethyl group -, a morpholinyl group - ethyl group -, or a halogenated ethyl group.

[0075] In another preferred example, the chemical structural formula of the hydroxyl group - ethyl group - is as follows.

[0076]

Chemical formula

[0077] hydroxyl group - ethyl group - In another preferred example, the chemical structural formula of the mercapto group - ethyl group - is as follows.

[0078]

Chemical formula

[0079] mercapto group - ethyl group - In another preferred example, the chemical structural formula of the piperidyl group - ethyl group - is as follows.

[0080] [Chemical]

[0081] Piperidyl group - ethyl group - In another preferred example, the chemical structural formula of the said morpholinyl group - ethyl group - is as follows.

[0082] [Chemical]

[0083] Morpholinyl group - ethyl group - In another preferred example, the said halogenated ethyl group is a fluorinated ethyl group.

[0084] In another preferred example, the chemical structural formula of the said halogenated ethyl group is as follows.

[0085] [Chemical]

[0086] Halogenated ethyl group In another preferred example, R 17 , R 18 , R 19 , R 20 , R 21 and R 22 each independently represents a hydrogen atom, a C1 - C10 alkyl group, a C1 - C10 alkyl group - O -, or a C1 - C10 alkyl group - S -. In another preferred example, R 17 , R 18 , R 19 , R 20 , R 21 and R 22 each independently represents a hydrogen atom, a C1 - C8 alkyl group, a C1 - C8 alkyl group - O -, or a C1 - C8 alkyl group - S -.

[0087] In another preferred example, R 17 , R 18 , R 19 , R20 and R 21 and R 22 each independently represents a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkyl group -O-, or a C1-C6 alkyl group -S-.

[0088] In another preferred example, R 17 and R 18 and R 19 and R 20 and R 21 and R 22 each independently represents a hydrogen atom, a C1-C4 alkyl group, a C1-C4 alkyl group -O-, or a C1-C4 alkyl group -S-.

[0089] In another preferred example, R 17 and R 18 and R 19 and R 20 and R 21 and R 22 each independently represents a hydrogen atom, or a methyl group.

[0090] In another preferred example, R 23 and R 24 and R 25 and R 26 and R 27 and R 28 each independently represents a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkyl group -O-, or a C1-C10 alkyl group -S-.

[0091] In another preferred example, R 23 and R 24 and R 25 and R 26 and R 27 and R 28 each independently represents a hydrogen atom, a C1-C8 alkyl group, a C1-C8 alkyl group -O-, or a C1-C8 alkyl group -S-.

[0092] In another preferred example, R 23 and R 24 and R 25 and R 26 and R 27 and R28 Each independently represents a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkyl group -O-, or a C1-C6 alkyl group -S-.

[0093] In another preferred example, R 23 , R 24 , R 25 , R 26 , R 27 and R 28 each independently represents a hydrogen atom, a C1-C4 alkyl group, a C1-C4 alkyl group -O-, or a C1-C4 alkyl group -S-.

[0094] In another preferred example, R 23 , R 24 , R 25 , R 26 , R 27 and R 28 each independently represents a hydrogen atom or a methyl group.

[0095] In another preferred example, R 29 , R 30 , R 31 , R 32 , R 33 and R 34 each independently represents a hydrogen atom, a C1-C10 alkyl group, a C1-C10 alkyl group -O-, or a C1-C10 alkyl group -S-.

[0096] In another preferred example, R 29 , R 30 , R 31 , R 32 , R 33 and R 34 each independently represents a hydrogen atom, a C1-C8 alkyl group, a C1-C8 alkyl group -O-, or a C1-C8 alkyl group -S-.

[0097] In another preferred example, R 29 , R 30 , R 31 , R 32 , R 33 and R 34Each independently represents a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkyl group -O-, or a C1-C6 alkyl group -S-.

[0098] In another preferred example, R 29 , R 30 , R 31 , R 32 , R 33 and R 34 Each independently represents a hydrogen atom, a C1-C4 alkyl group, a C1-C4 alkyl group -O-, or a C1-C4 alkyl group -S-.

[0099] In another preferred example, R 29 , R 30 , R 31 , R 32 , R 33 and R 34 Each independently represents a hydrogen atom, or a methyl group.

[0100] In another preferred example, any of the above-mentioned "substitutions" means that one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on the atomic group are each independently a C1-C12 alkyl group, a C3-C8 cycloalkyl group, a C1-C12 halogenated alkyl group, a C3-C8 halogenated cycloalkyl group, a C3-C8 cycloalkoxyl group, a C3-C8 cycloalkylthiol group, a C3-C8 halogenated cycloalkoxyl group, a C3-C8 halogenated cycloalkylthiol group, a halogen atom, a nitro group, -CN, a hydroxyl group, a mercapto group, an amino group, a C1-C4 carboxyl group, a C2-C8 ester group, a C2-C4 acylamino group, a C1-C12 alkyl group -O-, a C1-C12 alkyl group -S-, a C1-C12 halogenated alkoxyl group, a C1-C12 halogenated alkylthiol group, a C6-C12 aryl group, a 5-12 membered heteroaryl group, and

[0101]

Chemical formula

[0102] is substituted by a substituent selected from; R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3- to 12-membered heterocycloalkyl group, or a halogen atom; Z 1 represents a C1-C8 alkylidene group.

[0103] In another preferred example, any of the above-mentioned "substitutions" means that one or more (preferably one, two, three, four, five, six, seven or eight) hydrogen atoms on the atomic group are each independently a C1-C10 alkyl group, a C3-C8 cycloalkyl group, a C1-C10 halogenated alkyl group, a C3-C8 halogenated cycloalkyl group, a C3-C8 cycloalkoxyl group, a C3-C8 cycloalkylthiol group, a C3-C8 halogenated cycloalkoxyl group, a C3-C8 halogenated cycloalkylthiol group, a halogen atom, a nitro group, -CN, a hydroxyl group, a mercapto group, an amino group, a C1-C4 carboxyl group, a C2-C8 ester group, a C2-C4 acylamino group, a C1-C10 alkyl group -O-, a C1-C10 alkyl group -S-, a C1-C10 halogenated alkoxyl group, a C1-C10 halogenated alkylthiol group, a C6-C12 aryl group, a 5- to 12-membered heteroaryl group, and

[0104]

Chemical formula

[0105] is substituted by a substituent selected from; R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3- to 12-membered heterocycloalkyl group, or a halogen atom; Z 1 represents a C1-C8 alkylidene group.

[0106] In another preferred example, any of the above-mentioned "substitutions" means that one or more (preferably one, two, three, four, five, six, seven or eight) hydrogen atoms on the atomic group are each independently a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C1-C8 halogenated alkyl group, a C3-C8 halogenated cycloalkyl group, a C3-C8 cycloalkoxyl group, a C3-C8 cycloalkylthiol group, a C3-C8 halogenated cycloalkoxyl group, a C3-C8 halogenated cycloalkylthiol group, a halogen atom, a nitro group, -CN, a hydroxyl group, a mercapto group, an amino group, a C1-C4 carboxyl group, a C2-C8 ester group, a C2-C4 acylamino group, a C1-C8 alkyl group -O-, a C1-C8 alkyl group -S-, a C1-C8 halogenated alkoxyl group, a C1-C8 halogenated alkylthiol group, a C6-C10 aryl group, a 5-10 membered heteroaryl group, and

[0107] [Chemical formula]

[0108] is substituted by a substituent selected from; R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3-12 membered heterocycloalkyl group, or a halogen atom; Z 1 represents a C1-C8 alkylidene group.

[0109] In another preferred example, any of the above-mentioned "substitutions" means that one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on the atomic group are each independently a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 halogenated alkyl group, a C3-C8 halogenated cycloalkyl group, a C3-C8 cycloalkoxyl group, a C3-C8 cycloalkylthiol group, a C3-C8 halogenated cycloalkoxyl group, a C3-C8 halogenated cycloalkylthiol group, a halogen atom, a nitro group, -CN, a hydroxyl group, a mercapto group, an amino group, a C1-C4 carboxyl group, a C2-C6 ester group, a C2-C4 acylamino group, a C1-C6 alkyl group -O-, a C1-C6 alkyl group -S-, a C1-C6 halogenated alkoxyl group, a C1-C6 halogenated alkylthiol group, a C6-C10 aryl group, a 5-10 membered heteroaryl group, and

[0110] [Chemical formula]

[0111] is substituted by a substituent selected from; R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3-12 membered heterocycloalkyl group, or a halogen atom; Z 1 represents a C1-C8 alkylidene group.

[0112] In another preferred example, any of the above-mentioned "substitutions" means that one or more (preferably one, two, three, four, five, six, seven or eight) hydrogen atoms on the atomic group are each independently a C1-C4 alkyl group, a C3-C8 cycloalkyl group, a C1-C4 halogenated alkyl group, a C3-C8 halogenated cycloalkyl group, a C3-C8 cycloalkoxyl group, a C3-C8 cycloalkylthiol group, a C3-C8 halogenated cycloalkoxyl group, a C3-C8 halogenated cycloalkylthiol group, a halogen atom, a nitro group, -CN, a hydroxyl group, a mercapto group, an amino group, a C1-C4 carboxyl group, a C2-C6 ester group, a C2-C4 acylamino group, a C1-C4 alkyl group -O-, a C1-C4 alkyl group -S-, a C1-C4 halogenated alkoxyl group, a C1-C4 halogenated alkylthiol group, a C6-C10 aryl group, a 5-10 membered heteroaryl group, and

[0113] [Chemical formula]

[0114] is substituted by a substituent selected from; R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3-12 membered heterocycloalkyl group, or a halogen atom; Z 1 represents a C1-C8 alkylidene group.

[0115] In another preferred example, R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3-10 membered heterocycloalkyl group, or a halogen atom.

[0116] In another preferred example, R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3-8 membered heterocycloalkyl group, or a halogen atom.

[0117] In another preferred example, R 35represents a hydrogen atom, a hydroxyl group, a mercapto group, a 5- to 8-membered heterocycloalkyl group, or a halogen atom.

[0118] In another preferred example, R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a 5-membered heterocycloalkyl group, a 6-membered heterocycloalkyl group, a 7-membered heterocycloalkyl group, an 8-membered heterocycloalkyl group, a 9-membered heterocycloalkyl group, a 10-membered heterocycloalkyl group, an 11-membered heterocycloalkyl group, a 12-membered heterocycloalkyl group, or a halogen atom.

[0119] In another preferred example, R 35 represents a hydrogen atom, a hydroxyl group, a mercapto group, a piperidyl group, a morpholinyl group, or a halogen atom.

[0120] R 36 represents a hydrogen atom, or a halogen atom.

[0121] R 36 represents a hydrogen atom, or a bromine atom.

[0122] In another preferred example, the halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0123] In another preferred example, the halogenation refers to mono-halogenation, mono-halogenation or per-halogenation.

[0124] In another preferred example, the halogenation refers to fluorination, chlorination, bromination or iodination.

[0125] In another preferred example, Z 1 represents a C1-C6 alkylidene group.

[0126] In another preferred example, Z 1 represents a C1-C4 alkylidene group.

[0127] In another preferred example, Z 1 represents an ethylene group. In another preferred example, Z 1 is

[0128] [Chemical formula]

[0129] .

[0130] In another preferred example

[0131] [Chemical formula]

[0132] is specifically JPEG2025518287000034.jpg514

[0133] .

[0134] In another preferred example, on the heterocyclic rings of the heterocycloalkyl group and the heteroaryl group, there are, independently of each other, 1 to 4 (preferably 1, 2, 3 or 4) heteroatoms selected from N, O and S respectively.

[0135]

[0136] In another preferred example, on the heterocyclic ring of the heterocycloalkyl group, there are, independently of each other, 1 to 4 (preferably 1, 2, 3 or 4) heteroatoms selected from N, O and S respectively.

[0137] In another preferred example, the heterocycloalkyl group has 0, 1 or 2 C=C cyclic double bonds.

[0138] In another preferred example, the alkyl group is a methyl group.

[0139] In another preferred example, the chemical structural formula of the compound of formula I, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound, is as shown in the following formula I-1.

[0140]

Chemical formula

[0141] I-1 Among them, R 1 , R 2 , R 3 and R 4 are each independently as defined above; X - is an anionic base.

[0142] In another preferred example, X - is an anionic acid group.

[0143] In another preferred example, the pharmaceutically acceptable salts of the compound of formula I include salts formed by the compound of formula I with an acid.

[0144] In another preferred example, the acid includes one or more of hydrochloric acid, galactaric acid, D-glucuronic acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, 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, benzenemethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, aspartic acid and glutamic acid.

[0145] In another preferred example, the pharmaceutically acceptable salts of the compound of formula I include salts formed when the compound of formula I forms salts with hydrochloric acid, galactaric acid, D-glucuronic acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, 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, benzenemethanesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, aspartic acid, or glutamic acid.

[0146] In another preferred example, the base of the pharmaceutically acceptable salt of the compound of formula I includes bases formed when the acid loses one H + to form a salt.

[0147] In another preferred example, the base of the pharmaceutically acceptable salt of the compound of formula I includes bases formed when hydrochloric acid, galactaric acid, D-glucuronic acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, 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, benzenemethanesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, aspartic acid or glutamic acid loses one H + to form a salt.

[0148] In another preferred example, the base of the pharmaceutically acceptable salt of the compound of formula I is F - , Cl - , Br - , I - , HCOO - , CH 3 COO - ,

[0149]

Chemical Formula

[0150] , SO 4 2- , NO 3- or

[0151] [Chemical formula]

[0152] includes.

[0153] In another preferred example, X - represents a base formed by an acid losing one H + .

[0154] In another preferred example, X - represents a base formed by hydrochloric acid, galactaric acid, D-glucuronic acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, 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, benzenemethanesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, aspartic acid or glutamic acid losing one H + .

[0155] In another preferred example, X - is F - , Cl - , Br - , I - , HCOO - , CH 3 COO - ,

[0156] [Chemical formula]

[0157] , SO 4 2- , NO 3 - or

[0158] [Chemical formula]

[0159] represents.

[0160] In another preferred example, the chemical structural formula of the compound of formula I, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound is as follows.

[0161]

Chemical formula

[0162] In another preferred example, the content of (a) 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, or its deuterated compound relative to the total weight of the composition is 0.001 - 99.9 wt%.

[0163] In another preferred example, the composition is a pharmaceutical composition.

[0164] In another preferred example, the composition further comprises a pharmaceutically acceptable carrier.

[0165] In another preferred example, the dosage form of the composition is solid, liquid or semi-solid.

[0166] In another preferred example, the dosage type of the composition is an oral preparation, a topical preparation or an injectable preparation.

[0167] In another preferred example, the dosage type of the composition is a tablet, an injection, an infusion, an ointment, a gel, a solution, a pill or a coating agent.

[0168] A third aspect of the present invention provides the use of the compound of Formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, for manufacturing a composition or a preparation used for the prevention and / or treatment of tumors.

[0169] In another preferred example, the tumor is a human-derived tumor.

[0170] In another preferred example, the tumor is a human tumor.

[0171] In another preferred example, the tumor includes a tumor in which the mitochondrial membrane permeability transition pore is low-expressed, not expressed, low-activated or inactivated.

[0172] In another preferred example, the tumor includes a tumor in which peptidylprolyl isomerase F is low-expressed, not expressed, low-activated or inactivated.

[0173] In another preferred example, peptidylprolyl isomerase F has a protein number of UniProtKB / Swiss-Prot: P30405 and a gene number of NCBI Entrez Gene: 10105.

[0174] In another preferred example, the tumor in which the mitochondrial permeability transition pore is low-expressed or deactivated refers to a tumor in which the expression level or activity of the mitochondrial permeability transition pore in tumor cells is lower than that in the mitochondrial permeability transition pore in the same type of cells or normal cells.

[0175] In another preferred example, the tumor in which the mitochondrial permeability transition pore is low-expressed or deactivated refers to a tumor in which the ratio (H1 / H0) between the expression level or activity H1 of the mitochondrial permeability transition pore in a certain cell (for example, a tumor cell) and the expression level or activity H0 of the mitochondrial permeability transition pore in the same type of cells or normal cells is < 1.0, preferably ≤ 0.8, and more preferably ≤ 0.7, ≤ 0.6, ≤ 0.5, ≤ 0.4, ≤ 0.3, ≤ 0.2, ≤ 0.1, ≤ 0.05, ≤ 0.01, ≤ 0.005, ≤ 0.001, ≤ 0.0001, ≤ 0.00001, ≤ 0.000001 or ≤ 0.0000001.

[0176] In another preferred example, the certain cell refers to a tumor cell.

[0177] In another preferred example, the same type of cells includes cells of the same kind.

[0178] In another preferred example, the same type of cells includes the same type of tumor cells.

[0179] In another preferred example, the same type of cells includes the same type of tumor cells.

[0180] In another preferred example, the same type of cells refers to cells (the same type of tumor cells) in which the mitochondrial permeability transition pore is normally expressed, highly expressed, normally activated or highly activated.

[0181] In another preferred example, the same type of cells refers to cells of the same kind, in which the mitochondrial permeability transition pore is normally expressed, highly expressed, normally activated or highly activated.

[0182] In another preferred example, the normal cells refer to normal tissue cells (e.g., cells derived from tumor cells, tumor-adjacent cells, or carcinomatous bladder tissue cells) in which the mitochondrial membrane permeability transition pore is normally expressed or normally activated.

[0183] In another preferred example, H0 represents the expression level or activity of the mitochondrial membrane permeability transition pore in cells in which the mitochondrial membrane permeability transition pore is normally expressed, highly expressed, normally activated, or highly activated.

[0184] In another preferred example, the cells in which the mitochondrial membrane permeability transition pore is normally expressed, highly expressed, normally activated, or highly activated include cells that are insensitive to the compound of formula I, or its optical isomers or racemates, or its solvates, or its pharmaceutically acceptable salts, or its deuterated compounds.

[0185] In another preferred example, the tumor in which peptidylprolyl isomerase F is low-expressed or low-activated refers to a tumor in which the expression level or activity of peptidylprolyl isomerase F in tumor cells is lower than the expression level or activity of peptidylprolyl isomerase F in the same type of cells or normal cells.

[0186] In another preferred example, the tumor in which peptidylprolyl isomerase F is low-expressed or low-activated refers to a tumor in which the ratio (C1 / C0) between the expression level or activity C1 of peptidylprolyl isomerase F in a certain cell (e.g., tumor cells) and the expression level or activity C0 of peptidylprolyl isomerase F in the same type of cells or normal cells is < 1.0, preferably ≤ 0.8, more preferably ≤ 0.7, ≤ 0.6, ≤ 0.5, ≤ 0.4, ≤ 0.3, ≤ 0.2, ≤ 0.1, ≤ 0.05, ≤ 0.01, ≤ 0.005, ≤ 0.001, ≤ 0.0001, ≤ 0.00001, ≤ 0.000001, or ≤ 0.0000001.

[0187] In another preferred example, the certain cell refers to tumor cells.

[0188] In another preferred example, the same type of cells includes cells of the same kind.

[0189] In another preferred example, the homogeneous cells include homogeneous tumor cells.

[0190] In another preferred example, the homogeneous cells include tumor cells of the same type.

[0191] In another preferred example, the homogeneous cells refer to cells (homogeneous tumor cells) in which peptidylprolyl isomerase F is normally expressed, highly expressed, normally activated, or highly activated.

[0192] In another preferred example, the homogeneous cells refer to cells of the same type, in which peptidylprolyl isomerase F is normally expressed, highly expressed, normally activated, or highly activated.

[0193] In another preferred example, the normal cells refer to normal tissue cells (for example, cells derived from tumor cells, tumor-adjacent cells, or cancerated bladder tissue cells) in which peptidylprolyl isomerase F is normally expressed or normally activated.

[0194] In another preferred example, C0 represents the expression level or activity of peptidylprolyl isomerase F in cells in which peptidylprolyl isomerase F is normally expressed, highly expressed, normally activated, or highly activated.

[0195] In another preferred example, the cells in which peptidylprolyl isomerase F is normally expressed, highly expressed, normally activated, or highly activated include cells that are insensitive to the compound of formula I, or its optical isomers or racemates, or its solvates, or its pharmaceutically acceptable salts, or its deuterated compounds.

[0196] In another preferred example, the tumor with low expression, no expression, low activation, or inactivation of the mitochondrial membrane permeability transition pore can be achieved by administering an inhibitor of the mitochondrial membrane permeability transition pore.

[0197] In another preferred example, the inhibitor of the mitochondrial membrane permeability transition pore includes an inhibitor that can downregulate, underexpress, downactivate, or inactivate the mitochondrial membrane permeability transition pore of the tumor.

[0198] In another preferred example, the tumor that downregulates, underexpresses, downactivates, or inactivates peptidyl-prolyl isomerase F can be achieved by administering an inhibitor of peptidyl-prolyl isomerase F.

[0199] In another preferred example, the inhibitor of peptidyl-prolyl isomerase F includes an inhibitor that can downregulate, underexpress, downactivate, or inactivate peptidyl-prolyl isomerase F of the tumor.

[0200] In another preferred example, the inhibitor includes an inhibitor with specificity.

[0201] In another preferred example, the inhibitor is selected from small molecule compound inhibitors, protein inhibitors, gene inhibitors, or combinations thereof.

[0202] In another preferred example, the inhibitor of the mitochondrial membrane permeability transition pore is selected from Cyclosporin A, CyP-D protein inhibitor, peroxide scavenger, or combinations thereof.

[0203] In another preferred example, the inhibitor of peptidyl-prolyl isomerase F includes shRNA.

[0204] In another preferred example, the nucleotide sequence of shRNA is GTTCTTCATCTGCACCATAAA.

[0205] In another preferred example, the tumor includes a tumor in which the NNMT gene is downregulated or underexpressed.

[0206] In another preferred example, the tumor includes a tumor in which DNA methyltransferase is overexpressed.

[0207] In another preferred example, the DNA methyltransferase is selected from DNMT1, DNMT3a, DNMT3b or a combination thereof.

[0208] In another preferred example, the tumor includes a tumor in which DNMT1 is highly expressed.

[0209] In another preferred example, the tumor includes a tumor in which DNMT3a is highly expressed.

[0210] In another preferred example, the tumor includes a tumor in which DNMT3b is highly expressed.

[0211] In another preferred example, the tumor includes a tumor in which UHRF1 is highly expressed.

[0212] In another preferred example, the tumor includes a tumor in which the nucleotide site of the NNMT gene is highly methylated.

[0213] In another preferred example, the methylation of the nucleotide site of the NNMT gene refers to the methylation of the cytosine nucleotide site of the NNMT gene.

[0214] In another preferred example, the methylation of the nucleotide site of the NNMT gene refers to the methylation of the cytosine of the nucleotide of the NNMT gene.

[0215] In another preferred example, the methylation of the nucleotide site of the NNMT gene refers to the methylation of the 5th carbon atom on the cytosine of the nucleotide of the NNMT gene.

[0216] In another preferred example, the tumor includes a tumor in which the DNA CpG site in the NNMT gene region is highly methylated.

[0217] In another preferred example, the methylation of the DNA CpG site in the NNMT gene region refers to the methylation of the cytosine nucleotide site of the DNA CpG site in the NNMT gene region.

[0218] In another preferred example, the methylation of the NNMT gene region DNA CpG site refers to the methylation of cytosine of the nucleotide of the NNMT gene region DNA CpG site.

[0219] In another preferred example, the methylation of the NNMT gene region DNA CpG site refers to the methylation of the 5th carbon atom on cytosine of the nucleotide of the NNMT gene region DNA CpG site.

[0220] In another preferred example, the NNMT gene is a human-derived NNMT gene.

[0221] In another preferred example, the NNMT gene is a human NNMT gene.

[0222] In another preferred example, the tumor in which the NNMT gene is low-expressed or not expressed refers to a tumor in which the NNMT protein cannot be detected by an NNMT antibody in 1 μg of protein extracted from the tumor, more preferably a tumor in which the NNMT protein cannot be detected by an NNMT antibody in 5 μg of protein extracted from the tumor, more preferably a tumor in which the NNMT protein cannot be detected by an NNMT antibody in 10 μg of protein extracted from the tumor, more preferably a tumor in which the NNMT protein cannot be detected by an NNMT antibody in 100 μg of protein extracted from the tumor, more preferably a tumor in which the NNMT protein cannot be detected by an NNMT antibody in 1000 μg of protein extracted from the tumor.

[0223] In another preferred example, the tumor in which the NNMT gene is low-expressed or not expressed refers to a tumor in which the expression level of the NNMT gene in tumor cells is lower than the expression level of the NNMT gene in the same type of cells or normal cells.

[0224] In another preferred example, the tumor in which the NNMT gene is low-expressed or not expressed at all refers to a tumor in which the ratio (E1 / E0) between the expression level E1 of the NNMT gene in a certain cell (e.g., a tumor cell) and the expression level E0 of the NNMT gene in the same type of cell or normal cell is < 1.0, preferably ≦ 0.7, and more preferably ≦ 0.6, ≦ 0.5, ≦ 0.4, ≦ 0.3, ≦ 0.2, ≦ 0.1, ≦ 0.05, ≦ 0.01, ≦ 0.005, ≦ 0.001, ≦ 0.0001, ≦ 0.00001, ≦ 0.000001, or ≦ 0.0000001.

[0225] In another preferred example, the certain cell refers to a tumor cell.

[0226] In another preferred example, the same type of cell includes cells of the same kind.

[0227] In another preferred example, the same type of cell includes the same type of tumor cells.

[0228] In another preferred example, the same type of cell includes the same type of tumor cells.

[0229] In another preferred example, the same type of cell refers to a cell (the same type of tumor cell) in which the NNMT gene is normally expressed or highly expressed.

[0230] In another preferred example, the same type of cell refers to a cell of the same kind in which the NNMT gene is normally expressed or highly expressed.

[0231] In another preferred example, the normal cell refers to a normal tissue cell (e.g., a cell derived from a tumor cell, an adjacent cell to the tumor, or a carcinomatous bladder tissue cell).

[0232] In another preferred example, the normal cell refers to a normal tissue cell (e.g., a cell derived from a tumor cell, an adjacent cell to the tumor, or a carcinomatous bladder tissue cell) in which the NNMT gene is normally expressed.

[0233] In another preferred example, E0 is the expression level of the NNMT gene in a cell in which the NNMT gene is normally expressed or highly expressed.

[0234] In another preferred example, the cells in which the NNMT gene is normally expressed or highly expressed include cells that are insensitive to a compound of Formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.

[0235] In another preferred example, the tumor in which the DNA methyltransferase is highly expressed is a tumor in which the DNA methyltransferase can be detected with a DNA methyltransferase antibody in 20 μg of protein extracted from the tumor, more preferably a tumor in which the DNA methyltransferase can be detected with a DNA methyltransferase antibody in 5 μg of protein extracted from the tumor, more preferably a tumor in which the DNA methyltransferase can be detected with a DNA methyltransferase antibody in 1 μg of protein extracted from the tumor, more preferably a tumor in which the DNA methyltransferase can be detected with a DNA methyltransferase antibody in 0.2 μg of protein extracted from the tumor, more preferably a tumor in which the DNA methyltransferase can be detected with a DNA methyltransferase antibody in 0.05 μg of protein extracted from the tumor, more preferably a tumor in which the DNA methyltransferase can be detected with a DNA methyltransferase antibody in 0.01 μg of protein extracted from the tumor.

[0236] In another preferred example, the tumor in which the DNA methyltransferase is highly expressed refers to a tumor in which the expression level of the DNA methyltransferase in tumor cells is higher than the expression level of the DNA methyltransferase in the same type of cells or normal cells.

[0237] In another preferred example, the tumor in which the DNA methyltransferase is highly expressed refers to a tumor in which the ratio (A1 / A0) between the expression level A1 of the DNA methyltransferase in tumor cells and the expression level A0 of the DNA methyltransferase in the same type of cells or normal cells is >1.0, preferably ≧1.2 or ≧1.5, more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50, for example, 2 - 50.

[0238] In another preferred example, the homogeneous cells include cells of the same type.

[0239] In another preferred example, the homogeneous cells include homogeneous tumor cells.

[0240] In another preferred example, the homogeneous cells include tumor cells of the same type.

[0241] In another preferred example, the homogeneous cells refer to cells in which the DNA methylase is normally expressed or under-expressed (e.g., homogeneous tumor cells).

[0242] In another preferred example, the homogeneous cells refer to cells of the same type, in which the DNA methylase is normally expressed or under-expressed.

[0243] In another preferred example, the homogeneous cells refer to normal tissue cells (e.g., cells derived from tumor cells, adjacent tumor cells, or carcinomatous bladder tissue cells).

[0244] In another preferred example, the homogeneous cells refer to normal tissue cells in which the DNA methylase is normally expressed (e.g., cells derived from tumor cells, adjacent tumor cells, or carcinomatous bladder tissue cells).

[0245] In another preferred example, A0 is the expression level of the DNA methylase in cells in which the DNA methylase is normally expressed or under-expressed.

[0246] In another preferred example, the cells in which the DNA methylase is normally expressed or under-expressed include cells that are insensitive to the compound of formula I, or its optical isomers or racemates, or its solvates, or its pharmaceutically acceptable salts, or its deuterated compounds.

[0247] In another preferred example, the tumor with high expression of DNMT1 refers to a tumor in which the DNMT1 protein can be detected with a DNMT1 antibody in 20 μg of protein extracted from the tumor, more preferably a tumor in which the DNMT1 protein can be detected with a DNMT1 antibody in 5 μg of protein extracted from the tumor, even more preferably a tumor in which the DNMT1 protein can be detected with a DNMT1 antibody in 1 μg of protein extracted from the tumor, even more preferably a tumor in which the DNMT1 protein can be detected with a DNMT1 antibody in 0.2 μg of protein extracted from the tumor, even more preferably a tumor in which the DNMT1 protein can be detected with a DNMT1 antibody in 0.05 μg of protein extracted from the tumor, and even more preferably a tumor in which the DNMT1 protein can be detected with a DNMT1 antibody in 0.01 μg of protein extracted from the tumor.

[0248] In another preferred example, the tumor with high expression of DNMT1 refers to a tumor in which the expression level of DNMT1 in tumor cells is higher than that in the same type of cells or normal cells.

[0249] In another preferred example, the tumor with high expression of DNMT1 refers to a tumor in which the ratio (B1 / B0) between the expression level B1 of DNMT1 in tumor cells and the expression level B0 of DNMT1 in the same type of cells or normal cells is >1.0, preferably ≧1.2 or ≧1.5, and even more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50, for example, 2 - 50.

[0250] In another preferred example, the same type of cells includes cells of the same kind.

[0251] In another preferred example, the same type of cells includes the same type of tumor cells.

[0252] In another preferred example, the same type of cells includes the same type of tumor cells.

[0253] In another preferred example, the said homologous cells refer to cells in which DNMT1 is normally expressed or under-expressed (for example, homologous tumor cells).

[0254] In another preferred example, the said homologous cells refer to cells of the same type, yet in which DNMT1 is normally expressed or under-expressed.

[0255] In another preferred example, the said normal cells refer to normal tissue cells (for example, cells derived from tumor cells, tumor-adjacent cells or cancerated bladder tissue cells).

[0256] In another preferred example, the said normal cells refer to normal tissue cells in which DNMT1 is normally expressed (for example, cells derived from tumor cells, tumor-adjacent cells or cancerated bladder tissue cells).

[0257] In another preferred example, B0 is the expression level of DNMT1 in cells in which DNMT1 is normally expressed or under-expressed.

[0258] In another preferred example, the said cells in which DNMT1 is normally expressed or under-expressed include cells that are insensitive to the compound of formula I, or its optical isomers or racemates, or its solvates, or its pharmaceutically acceptable salts, or its deuterated compounds.

[0259] In another preferred example, the tumors in which DNMT3a is highly expressed refer to tumors in which the DNMT3a protein can be detected with a DNMT3a antibody in 20 μg of protein extracted from the tumor, more preferably tumors in which the DNMT3a protein can be detected with a DNMT3a antibody in 5 μg of protein extracted from the tumor, even more preferably tumors in which the DNMT3a protein can be detected with a DNMT3a antibody in 1 μg of protein extracted from the tumor, even more preferably tumors in which the DNMT3a protein can be detected with a DNMT3a antibody in 0.2 μg of protein extracted from the tumor, even more preferably tumors in which the DNMT3a protein can be detected with a DNMT3a antibody in 0.05 μg of protein extracted from the tumor, and even more preferably tumors in which the DNMT3a protein can be detected with a DNMT3a antibody in 0.01 μg of protein extracted from the tumor.

[0260] In another preferred example, the tumors in which DNMT3a is highly expressed refer to tumors in which the expression level of DNMT3a in tumor cells is higher than the expression level of DNMT3a in the same type of cells or normal cells.

[0261] In another preferred example, for the tumors in which DNMT3a is highly expressed, the ratio (P1 / P0) between the expression level P1 of DNMT3a in tumor cells and the expression level P0 of DNMT3a in the same type of cells or normal cells is > 1.0, preferably ≧ 1.2 or ≧ 1.5, and even more preferably ≧ 2, ≧ 3, ≧ 5, ≧ 8, ≧ 10, ≧ 15, ≧ 20, ≧ 30 or ≧ 50, for example, 2 - 50.

[0262] In another preferred example, the same type of cells includes cells of the same kind.

[0263] In another preferred example, the same type of cells includes the same type of tumor cells.

[0264] In another preferred example, the same type of cells includes the same type of tumor cells.

[0265] In another preferred example, the like cells refer to cells in which DNMT3a is normally expressed or is expressed at a low level (for example, like tumor cells).

[0266] In another preferred example, the like cells refer to cells of the same type, and yet cells in which DNMT3a is normally expressed or is expressed at a low level.

[0267] In another preferred example, the normal cells refer to normal tissue cells (for example, cells derived from tumor cells, tumor-adjacent cells, or carcinomatous bladder tissue cells).

[0268] In another preferred example, the normal cells refer to normal tissue cells in which DNMT3a is normally expressed (for example, cells derived from tumor cells, tumor-adjacent cells, or carcinomatous bladder tissue cells).

[0269] In another preferred example, P0 is the expression level of DNMT3a in cells in which DNMT3a is normally expressed or is expressed at a low level.

[0270] In another preferred example, the cells in which DNMT3a is normally expressed or is expressed at a low level include cells that are insensitive to the compound of formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.

[0271] In another preferred example, the tumor in which DNMT3b is highly expressed refers to a tumor in which the DNMT3b protein can be detected with a DNMT3b antibody in 20 μg of protein extracted from the tumor, more preferably a tumor in which the DNMT3b protein can be detected with a DNMT3b antibody in 5 μg of protein extracted from the tumor, even more preferably a tumor in which the DNMT3b protein can be detected with a DNMT3b antibody in 1 μg of protein extracted from the tumor, even more preferably a tumor in which the DNMT3b protein can be detected with a DNMT3b antibody in 0.2 μg of protein extracted from the tumor, even more preferably a tumor in which the DNMT3b protein can be detected with a DNMT3b antibody in 0.05 μg of protein extracted from the tumor, and even more preferably a tumor in which the DNMT3b protein can be detected with a DNMT3b antibody in 0.01 μg of protein extracted from the tumor.

[0272] In another preferred example, the tumor in which DNMT3b is highly expressed refers to a tumor in which the expression level of DNMT3b in tumor cells is higher than the expression level of DNMT3b in the same type of cells or normal cells.

[0273] In another preferred example, the tumor in which DNMT3b is highly expressed refers to a tumor in which the ratio (D1 / D0) between the expression level D1 of DNMT3b in tumor cells and the expression level D0 of DNMT3b in the same type of cells or normal cells is > 1.0, preferably ≧ 1.2 or ≧ 1.5, and even more preferably ≧ 2, ≧ 3, ≧ 5, ≧ 8, ≧ 10, ≧ 15, ≧ 20, ≧ 30 or ≧ 50, for example, 2 - 50.

[0274] In another preferred example, the same type of cells includes cells of the same kind.

[0275] In another preferred example, the same type of cells includes the same type of tumor cells.

[0276] In another preferred example, the same type of cells includes the same type of tumor cells.

[0277] In another preferred example, the said like cells refer to cells in which DNMT3b is normally expressed or under-expressed (like tumor cells).

[0278] In another preferred example, the said like cells refer to cells of the same type, yet cells in which DNMT3b is normally expressed or under-expressed.

[0279] In another preferred example, the said normal cells refer to normal tissue cells (for example, cells derived from tumor cells, tumor-adjacent cells or carcinomatous bladder tissue cells).

[0280] In another preferred example, the said normal cells refer to normal tissue cells in which DNMT3b is normally expressed (for example, cells derived from tumor cells, tumor-adjacent cells or carcinomatous bladder tissue cells).

[0281] In another preferred example, D0 is the expression level of DNMT3b in cells in which DNMT3b is normally expressed or under-expressed.

[0282] In another preferred example, the said cells in which DNMT3b is normally expressed or under-expressed include cells that are insensitive to the compound of formula I, or its optical isomers or racemates, or its solvates, or its pharmaceutically acceptable salts, or its deuterated compounds.

[0283] In another preferred example, the tumors in which the above-mentioned UHRF1 is highly expressed refer to tumors in which the UHRF1 protein can be detected with a UHRF1 antibody in 20 μg of protein extracted from the tumor, more preferably tumors in which the UHRF1 protein can be detected with a UHRF1 antibody in 5 μg of protein extracted from the tumor, even more preferably tumors in which the UHRF1 protein can be detected with a UHRF1 antibody in 1 μg of protein extracted from the tumor, even more preferably tumors in which the UHRF1 protein can be detected with a UHRF1 antibody in 0.2 μg of protein extracted from the tumor, even more preferably tumors in which the UHRF1 protein can be detected with a UHRF1 antibody in 0.05 μg of protein extracted from the tumor, and even more preferably tumors in which the UHRF1 protein can be detected with a UHRF1 antibody in 0.01 μg of protein extracted from the tumor.

[0284] In another preferred example, the above-mentioned tumors in which UHRF1 is highly expressed refer to tumors in which the expression level of UHRF1 in tumor cells is higher than the expression level of UHRF1 in the same type of cells or normal cells.

[0285] In another preferred example, the above-mentioned tumors in which UHRF1 is highly expressed refer to tumors in which the ratio (F1 / F0) between the expression level F1 of UHRF1 in tumor cells and the expression level F0 of UHRF1 in the same type of cells or normal cells is > 1.0, preferably ≧ 1.2 or ≧ 1.5, and even more preferably ≧ 2, ≧ 3, ≧ 5, ≧ 8, ≧ 10, ≧ 15, ≧ 20, ≧ 30 or ≧ 50, for example, 2 - 50.

[0286] In another preferred example, the above-mentioned same type of cells includes the same type of cells.

[0287] In another preferred example, the above-mentioned same type of cells includes the same type of tumor cells.

[0288] In another preferred example, the above-mentioned same type of cells includes the same type of tumor cells.

[0289] In another preferred example, the like cells refer to cells in which UHRF1 is normally expressed or low-expressed (like tumor cells).

[0290] In another preferred example, the like cells refer to cells of the same type, and yet in which UHRF1 is normally expressed or low-expressed.

[0291] In another preferred example, the normal cells refer to normal tissue cells (for example, cells derived from tumor cells, tumor-adjacent cells or carcinomatous bladder tissue cells).

[0292] In another preferred example, the normal cells refer to normal tissue cells in which UHRF1 is normally expressed (for example, cells derived from tumor cells, tumor-adjacent cells or carcinomatous bladder tissue cells).

[0293] In another preferred example, F0 is the expression level of UHRF1 in cells in which UHRF1 is normally expressed or low-expressed.

[0294] In another preferred example, the cells in which UHRF1 is normally expressed or low-expressed include cells that are insensitive to the compound of formula I, or its optical isomers or racemates, or its solvates, or its pharmaceutically acceptable salts, or its deuterated compounds.

[0295] In another preferred example, the tumor in which the nucleotide site of the NNMT gene is highly methylated refers to a tumor in which the methylation level of the nucleotide site of the NNMT gene in a certain cell (for example, a tumor cell) is higher than the methylation level of the nucleotide site of the NNMT gene in like cells or normal cells.

[0296] In another preferred example, the tumor in which the nucleotide site of the NNMT gene is hypermethylated refers to a tumor in which the ratio (L1 / L0) between the methylation level L1 of the nucleotide site of the NNMT gene in a certain cell (e.g., a tumor cell) and the methylation level L0 of the nucleotide site of the NNMT gene in cells of the same type or normal cells is >1.0, preferably ≧1.2 or ≧1.5, and more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50, for example, 2 - 50.

[0297] In another preferred example, the tumor in which the nucleotide site of the NNMT gene is hypermethylated refers to a tumor in which the methylation level of the nucleotide site of the NNMT gene in a certain cell (e.g., a tumor cell) is ≧1%, preferably ≧3%, ≧5%, ≧10%, ≧15% or ≧20%, and more preferably ≧25%, ≧30%, ≧40% or ≧50%.

[0298] In another preferred example, the certain cell refers to a tumor cell.

[0299] In another preferred example, the cells of the same type include cells of the same kind.

[0300] In another preferred example, the cells of the same type include tumor cells of the same type.

[0301] In another preferred example, the cells of the same type include tumor cells of the same kind.

[0302] In another preferred example, the cells of the same type refer to cells (tumor cells of the same type) in which the nucleotide site of the NNMT gene is normally methylated or hypomethylated.

[0303] In another preferred example, the cells of the same type refer to cells of the same kind, and the nucleotide site of the NNMT gene in these cells is normally methylated or hypomethylated.

[0304] In another preferred example, the normal cells refer to normal tissue cells (e.g., cells derived from tumor cells, tumor - adjacent cells or carcinomatous bladder tissue cells).

[0305] In another preferred example, the normal cells refer to normal tissue cells in which the nucleotide sites of the NNMT gene are normally methylated (for example, cells derived from tumor cells, adjacent tumor cells, or carcinomatous bladder tissue cells).

[0306] In another preferred example, L0 represents the methylation level of the nucleotide sites of the NNMT gene in cells in which the nucleotide sites of the NNMT gene are normally methylated or hypomethylated.

[0307] In another preferred example, the cells in which the nucleotide sites of the NNMT gene are normally methylated or hypomethylated include cells that are insensitive to the compound of formula I, or its optical isomers or racemates, or its solvates, or its pharmaceutically acceptable salts, or its deuterated compounds.

[0308] In another preferred example, the tumor in which the nucleotide sites of the NNMT gene are hypermethylated refers to a tumor in which the methylation level (M%) of the nucleotide sites of the NNMT gene in a certain cell (for example, a tumor cell) is ≧3% and ≦M1%, where M1 is any positive integer from 3 to 100.

[0309] In another preferred example, M1 is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95 or 100.

[0310] In another preferred example, the methylation level of the nucleotide sites of the NNMT gene refers to the ratio between the number of methylated nucleotides in the NNMT gene region and the number of all nucleotides in the NNMT gene region.

[0311] In another preferred example, the methylation level of the nucleotide sites of the NNMT gene includes the methylation level of the nucleotide sites in the NNMT gene promoter region.

[0312] In another preferred example, the nucleotide sequence of the NNMT gene promoter region is shown in SEQ ID NO:1.

[0313] In another preferred example, the methylation level of the nucleotide site of the NNMT gene includes the methylation level of the nucleotide site in the region from 1050 bp before the transcription start site of the NNMT gene to 499 bp after the transcription start site.

[0314] In another preferred example, the region from 1050 bp before the transcription start site of the NNMT gene to 499 bp after the transcription start site is positions 951 to 2500 of the nucleotide sequence shown in SEQ ID NO:1.

[0315] In another preferred example, the methylation level of the nucleotide site of the NNMT gene includes the methylation level of the nucleotide site in the region from 1050 bp before the transcription start site of the NNMT gene to 193 bp before the transcription start site.

[0316] In another preferred example, the region from 1050 bp before the transcription start site of the NNMT gene to 193 bp before the transcription start site is positions 951 to 1808 of the nucleotide sequence shown in SEQ ID NO:1.

[0317] In another preferred example, the methylation level of the nucleotide site of the NNMT gene includes the methylation level of the nucleotide site in the region from 840 bp before the transcription start site of the NNMT gene to 469 bp before the transcription start site.

[0318] In another preferred example, the region from 840 bp before the transcription start site of the NNMT gene to 469 bp before the transcription start site is positions 1161 to 1532 of the nucleotide sequence shown in SEQ ID NO:1.

[0319] In another preferred example, the methylation level of the nucleotide site of the NNMT gene includes the methylation level of the nucleotide site within the region between any two of positions 114165695, 114165730, 114165769, 114165804, 114165938, 114166050, and 114166066 on human chromosome 11 (including the nucleotide sites themselves of these two positions).

[0320] In another preferred example, the methylation level of the nucleotide site of the NNMT gene includes the methylation level of the nucleotide of the site selected from position 114165695 on human chromosome 11, position 114165730 on human chromosome 11, position 114165769 on human chromosome 11, position 114165804 on human chromosome 11, position 114165938 on human chromosome 11, position 114166050 on human chromosome 11, position 114166066 on human chromosome 11, or combinations thereof.

[0321] In another preferred example, the methylation level of the nucleotide site of the NNMT gene includes the methylation level of the nucleotide site within the region between any two of positions 1161, 1196, 1235, 1270, 1404, 1516, and 1532 of the site of the nucleotide sequence of SEQ ID NO:1 (including the nucleotide sites themselves of these two positions).

[0322] In another preferred example, the methylation level of the nucleotide site of the NNMT gene includes the methylation level of the nucleotide of the site selected from position 1161, position 1196, position 1235, position 1270, position 1404, position 1516, position 1532, or combinations thereof of the site of the nucleotide sequence of SEQ ID NO:1.

[0323] In another preferred example, the tumor in which the DNA CpG site in the NNMT gene region is hypermethylated refers to a tumor in which the methylation level of the DNA CpG site in the NNMT gene region of a certain cell (for example, a tumor cell) is higher than the methylation level of the DNA CpG site in the NNMT gene region in the same type of cell or normal cell.

[0324] In another preferred example, the tumor in which the DNA CpG site in the NNMT gene region is hypermethylated refers to a tumor in which the ratio (G1 / G0) between the methylation level G1 of the DNA CpG site in the NNMT gene region of a certain cell (e.g., a tumor cell) and the methylation level G0 of the DNA CpG site in the NNMT gene region of the same type of cell or normal cell is >1.0, preferably ≧1.2 or ≧1.5, and more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50, for example, 2 - 50.

[0325] In another preferred example, the tumor in which the DNA CpG site in the NNMT gene region is hypermethylated refers to a tumor in which the methylation level of the DNA CpG site in the NMT gene region of a certain cell (e.g., a tumor cell) is ≧1%, preferably ≧3%, ≧5%, ≧10%, ≧15% or ≧20%, and more preferably ≧25%, ≧30%, ≧40% or ≧50%.

[0326] In another preferred example, the certain cell refers to a tumor cell.

[0327] In another preferred example, the same type of cell includes cells of the same kind.

[0328] In another preferred example, the same type of cell includes tumor cells of the same type.

[0329] In another preferred example, the same type of cell includes tumor cells of the same kind.

[0330] In another preferred example, the same type of cell refers to a cell (e.g., a tumor cell of the same type) in which the DNA CpG site in the NNMT gene region is normally methylated or hypomethylated.

[0331] In another preferred example, the same type of cell refers to cells of the same kind, and the DNA CpG site in the NNMT gene region is normally methylated or hypomethylated.

[0332] In another preferred example, the normal cells refer to normal tissue cells (e.g., cells derived from tumor cells, tumor-adjacent cells, or cancerated bladder tissue cells).

[0333] In another preferred example, the normal cells refer to normal tissue cells (e.g., cells derived from tumor cells, tumor-adjacent cells, or cancerated bladder tissue cells) in which the DNA CpG sites in the NNMT gene region are normally methylated.

[0334] In another preferred example, G0 represents the methylation level of the DNA CpG sites in the NNMT gene region of cells in which the DNA CpG sites in the NNMT gene region are normally methylated or hypomethylated.

[0335] In another preferred example, the cells in which the DNA CpG sites in the NNMT gene region are normally methylated or hypomethylated include cells that are insensitive to the compound of formula I, or its optical isomers or racemates, or its solvates, or its pharmaceutically acceptable salts, or its deuterated compounds.

[0336] In another preferred example, the tumor in which the DNA CpG sites in the NNMT gene region are hypermethylated refers to a tumor in which the methylation level (M%) of the DNA CpG sites in the NNMT gene region of a certain cell (e.g., a tumor cell) is ≧3% and ≦M2%, where M2 is any positive integer from 3 to 100.

[0337] In another preferred example, M2 is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95, or 100.

[0338] In another preferred example, the methylation level of the DNA CpG sites in the NNMT gene region refers to the ratio between the number of methylated CpG nucleotides in the NNMT gene region and the number of all nucleotides in the NNMT gene region.

[0339] In another preferred example, the methylation level of the CpG site of the NNMT gene region DNA refers to the ratio between the number of CpG nucleotides methylated in the NNMT gene region and the number of all CpG nucleotides in the NNMT gene region.

[0340] In another preferred example, the methylation level of the CpG site of the NNMT gene region DNA refers to the ratio between the number of CpG sites methylated in the DNA of the NNMT gene region and the number of all CpG sites in the DNA of the NNMT gene region.

[0341] In another preferred example, the methylation level of the CpG site of the NNMT gene region DNA refers to the ratio between the number of CpG nucleotides methylated in the DNA of the NNMT gene region and the number of all CpG nucleotides in the DNA of the NNMT gene region.

[0342] In another preferred example, the methylation level of the CpG site of the NNMT gene region DNA includes the methylation level of the CpG site of the DNA in the NNMT gene promoter region.

[0343] In another preferred example, the nucleotide sequence of the NNMT gene promoter region is shown in SEQ ID NO:1.

[0344] In another preferred example, the methylation level of the CpG site of the NNMT gene region DNA includes the methylation level of the CpG site of the DNA in the region from 1050 bp before the transcription start site of the NNMT gene to 499 bp after the transcription start site.

[0345] In another preferred example, the region from 1050 bp before the transcription start site of the NNMT gene to 499 bp after the transcription start site is positions 951 to 2500 of the nucleotide sequence shown in SEQ ID NO:1.

[0346] In another preferred example, the methylation level of the DNA CpG sites in the NNMT gene region includes the methylation level of the DNA CpG sites in the region from 1050 bp upstream of the transcription start site of the NNMT gene to 193 bp upstream of the transcription start site.

[0347] In another preferred example, the region from 1050 bp upstream of the transcription start site of the NNMT gene to 193 bp upstream of the transcription start site is positions 951 to 1808 of the nucleotide sequence shown in SEQ ID NO:1.

[0348] In another preferred example, the methylation level of the DNA CpG sites in the NNMT gene region includes the methylation level of the DNA CpG sites in the region from 840 bp upstream of the transcription start site of the NNMT gene to 469 bp upstream of the transcription start site.

[0349] In another preferred example, the region from 840 bp upstream of the transcription start site of the NNMT gene to 469 bp upstream of the transcription start site is positions 1161 to 1532 of the nucleotide sequence shown in SEQ ID NO:1.

[0350] In another preferred example, the methylation level of the DNA CpG sites in the NNMT gene region includes the methylation level of the DNA CpG sites in the region between any two of positions 114165695, 114165730, 114165769, 114165804, 114165938, 114166050, and 114166066 on human chromosome 11 (including these two positions themselves).

[0351] In another preferred example, the methylation level of the DNA CpG sites in the NNMT gene region includes the methylation level of the sites selected from positions 114165695, 114165730, 114165769, 114165804, 114165938, 114166050, 114166066 on human chromosome 11 or combinations thereof.

[0352] In another preferred example, the methylation level of the DNA CpG site in the NNMT gene region includes the methylation level of the DNA CpG site within the region (including these two positions themselves) between any two of the 1161st, 1196th, 1235th, 1270th, 1404th, 1516th, and 1532nd positions of the site of the nucleotide sequence of SEQ ID NO:1.

[0353] In another preferred example, the methylation level of the DNA CpG site in the NNMT gene region includes the methylation level of the site selected from the 1161st, 1196th, 1235th, 1270th, 1404th, 1516th, 1532nd positions of the site of the SEQ ID NO:1 sequence or combinations thereof.

[0354] In another preferred example, the tumor in which the NNMT gene is low-expressed or not expressed can be achieved by administering an inhibitor of the NNMT gene.

[0355] In another preferred example, the tumor in which the DNA methyltransferase is highly expressed can be achieved by administering an enhancer of the DNA methyltransferase.

[0356] In another preferred example, the tumor in which DNMT1 is highly expressed can be achieved by administering an enhancer of DNMT1.

[0357] In another preferred example, the tumor in which DNMT3a is highly expressed can be achieved by administering an enhancer of DNMT3a.

[0358] In another preferred example, the tumor in which DNMT3b is highly expressed can be achieved by administering an enhancer of DNMT3b.

[0359] In another preferred example, the tumor in which UHRF1 is highly expressed can be achieved by administering an enhancer of UHRF1.

[0360] In another preferred example, the tumor in which the nucleotide site of the NNMT gene is hypermethylated can be achieved by administering an enhancer of the methylation of the nucleotide site of the NNMT gene.

[0361] In another preferred example, the tumor in which the DNA CpG site in the NNMT gene region is hypermethylated can be obtained by administering an agent that promotes methylation of the DNA CpG site in the NNMT gene region.

[0362] In another preferred example, the inhibitor includes an inhibitor having specificity.

[0363] In another preferred example, the promoter includes a promoter having specificity.

[0364] In another preferred example, the inhibitor of the NNMT gene includes an inhibitor that can downregulate or abolish the expression of the NNMT gene in the tumor.

[0365] In another preferred example, the promoter of the DNA methyltransferase includes a promoter that can upregulate the expression of the DNA methyltransferase in the tumor.

[0366] In another preferred example, the promoter of DNMT1 includes a promoter that can upregulate the expression of DNMT1 in the tumor.

[0367] In another preferred example, the promoter of DNMT3a includes a promoter that can upregulate the expression of DNMT3a in the tumor.

[0368] In another preferred example, the promoter of DNMT3b includes a promoter that can upregulate the expression of DNMT3b in the tumor.

[0369] In another preferred example, the promoter of UHRF1 includes a promoter that can upregulate the expression of UHRF1 in the tumor.

[0370] In another preferred example, the promoter for methylation of the nucleotide site of the NNMT gene includes a promoter that can hypermethylate the nucleotide site of the NNMT gene in the tumor.

[0371] In another preferred example, the promoter for methylation of the DNA CpG site in the NNMT gene region includes a promoter that can hypermethylate the DNA CpG site in the NNMT gene region of the tumor.

[0372] In another preferred example, the tumor is selected from lung cancer, brain tumor, or a combination thereof.

[0373] In another preferred example, the tumor includes lung cancer and / or brain tumor.

[0374] In another preferred example, the tumor includes an intracranial tumor.

[0375] In another preferred example, the tumor includes a malignant tumor.

[0376] In another preferred example, the brain tumor includes glioblastoma.

[0377] In another preferred example, the brain tumor includes supratentorial glioblastoma.

[0378] In another preferred example, the brain tumor includes medulloblastoma.

[0379] In another preferred example, the tumor cells of the brain tumor include Daoy cells.

[0380] In another preferred example, the lung cancer is selected from non-small cell lung cancer, small cell lung cancer, or a combination thereof.

[0381] In another preferred example, the cells of the lung cancer include NCI-H82 cells.

[0382] In another preferred example, the level includes protein level and / or mRNA level.

[0383] In another preferred example, the expression includes protein expression and / or mRNA expression.

[0384] In another preferred example, the composition or formulation is a pharmaceutical composition or pharmaceutical formulation.

[0385] In another preferred example, the composition or formulation further includes a pharmaceutically acceptable carrier.

[0386] In another preferred example, the form of the composition or formulation is solid, liquid or semi-solid.

[0387] In another preferred example, the type of the composition or formulation is an oral preparation, a topical preparation or an injectable preparation.

[0388] In another preferred example, the type of the composition or formulation is a tablet, an injection, an infusion, an ointment, a gel, a solution, a pill or a coating agent.

[0389] A fourth aspect of the present invention provides a marker for determining whether the compound of Formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof is suitable for tumor prevention and / or treatment in tumor patients. The marker has a mitochondrial membrane permeability transition pore, peptidylprolyl isomerase F, NNMT gene, DNA methyltransferase, UHRF1, methylation of nucleotide sites of the NNMT gene and / or methylation of DNA CpG sites in the NNMT gene region.

[0390] In another preferred example, the marker comprises the expression level or activity of the mitochondrial membrane permeability transition pore, the expression level or activity of peptidylprolyl isomerase F, the expression level of the NNMT gene, the expression level of DNA methyltransferase, the expression level of UHRF1, the methylation level of nucleotide sites of the NNMT gene and / or the methylation level of DNA CpG sites in the NNMT gene region.

[0391] In another preferred example, the above-mentioned content of the mitochondrial membrane permeability transition pore, peptidylprolyl isomerase F, NNMT gene, DNA methyltransferase, UHRF1, methylation of nucleotide sites of the NNMT gene and / or methylation of DNA CpG sites in the NNMT gene region includes the mitochondrial membrane permeability transition pore, peptidylprolyl isomerase F, NNMT gene, DNA methyltransferase, UHRF1, methylation of nucleotide sites of the NNMT gene and / or methylation of DNA CpG sites in the NNMT gene region in tumor cells.

[0392] In another preferred example, in the tumor cells of a tumor patient, the mitochondrial membrane permeability transition pore is low-expressed, not expressed, low-activated or inactivated, the peptidylprolyl isomerase F is low-expressed, not expressed, low-activated or inactivated, the NNMT gene is low-expressed or not expressed, the DNA methylase is high-expressed, UHRF1 is high-expressed, the nucleotide site of the NNMT gene is hypermethylated, and / or the DNA CpG site in the NNMT gene region is hypermethylated, then 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, or its deuterated compound, becomes suitable for tumor prevention and / or treatment for the tumor patient.

[0393] In another preferred example, in the tumor cells of a tumor patient, the mitochondrial membrane permeability transition pore is high-expressed or highly activated, the peptidylprolyl isomerase F is high-expressed or highly activated, the NNMT gene is high-expressed, the DNA methylase is low-expressed, UHRF1 is low-expressed, the nucleotide site of the NNMT gene is hypomethylated, and / or the DNA CpG site in the NNMT gene region is hypomethylated, then 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, or its deuterated compound, becomes unsuitable for tumor prevention and / or treatment for the tumor patient.

[0394] In another preferred example, the above content that 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, or its deuterated compound is suitable for tumor prevention and / or treatment for a tumor patient means that the tumor cells of the tumor patient are sensitive to 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, or its deuterated compound.

[0395] In another preferred example, the content that the compound of formula I according to the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound is not suitable for the prevention and / or treatment of tumors in tumor patients means that the tumor cells of the tumor patients are insensitive to the compound of formula I according to the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound.

[0396] In another preferred example, the tumor with high expression or high activation of the mitochondrial membrane permeability transition pore refers to a tumor in which the ratio (H1 / H0) between the expression level or activity H1 of the mitochondrial membrane permeability transition pore in a certain cell (for example, a tumor cell) and the expression level or activity H0 of the mitochondrial membrane permeability transition pore in the same type of cell or normal cell is >1.0, preferably ≧1.2 or ≧1.5, and more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50, for example, 2 - 50.

[0397] In another preferred example, the tumor with high expression or high activation of peptidylprolyl isomerase F refers to a tumor in which the ratio (C1 / C0) between the expression level or activity C1 of peptidylprolyl isomerase F in a certain cell (for example, a tumor cell) and the expression level or activity C0 of peptidylprolyl isomerase F in the same type of cell or normal cell is >1.0, preferably ≧1.2 or ≧1.5, and more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50, for example, 2 - 50.

[0398] In another preferred example, the tumor with high expression of the NNMT gene refers to a tumor in which the ratio (E1 / E0) between the expression level E1 of the NNMT gene in a certain cell (for example, a tumor cell) and the expression level E0 of the NNMT gene in the same type of cell or normal cell is >1.0, preferably ≧1.2 or ≧1.5, and more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50, for example, 2 - 50.

[0399] In another preferred example, the tumor with low expression of DNA methyltransferase refers to a tumor in which the ratio (A1 / A0) between the expression level A1 of DNA methyltransferase in tumor cells and the expression level A0 of DNA methyltransferase in the same type of cells or normal cells is < 1.0, preferably ≦ 0.7, more preferably ≦ 0.6, ≦ 0.5, ≦ 0.4, ≦ 0.3, ≦ 0.2, ≦ 0.1, ≦ 0.05, ≦ 0.01, ≦ 0.005, ≦ 0.001, ≦ 0.0001, ≦ 0.00001, ≦ 0.000001 or ≦ 0.0000001.

[0400] In another preferred example, the tumor with low expression of UHRF1 refers to a tumor in which the ratio (F1 / F0) between the expression level F1 of UHRF1 in tumor cells and the expression level F0 of UHRF1 in the same type of cells or normal cells is < 1.0, preferably ≦ 0.7, more preferably ≦ 0.6, ≦ 0.5, ≦ 0.4, ≦ 0.3, ≦ 0.2, ≦ 0.1, ≦ 0.05, ≦ 0.01, ≦ 0.005, ≦ 0.001, ≦ 0.0001, ≦ 0.00001, ≦ 0.000001 or ≦ 0.0000001.

[0401] In another preferred example, the tumor with low methylation at the nucleotide site of the NNMT gene refers to a tumor in which the ratio (L1 / L0) between the methylation level L1 at the nucleotide site of the NNMT gene in a certain cell (e.g., tumor cells) and the methylation level L0 at the nucleotide site of the NNMT gene in the same type of cells or normal cells is < 1.0, preferably ≦ 0.7, more preferably ≦ 0.6, ≦ 0.5, ≦ 0.4, ≦ 0.3, ≦ 0.2, ≦ 0.1, ≦ 0.05, ≦ 0.01, ≦ 0.005, ≦ 0.001, ≦ 0.0001, ≦ 0.00001, ≦ 0.000001 or ≦ 0.0000001.

[0402] In another preferred example, the tumor with hypomethylation of the DNA CpG site in the NNMT gene region refers to a tumor in which the ratio (G1 / G0) between the methylation level G1 of the DNA CpG site in the NMT gene region of a certain cell (for example, a tumor cell) and the methylation level G0 of the DNA CpG site in the NMT gene region in the same cell or a normal cell is < 1.0, preferably ≦ 0.7, more preferably ≦ 0.6, ≦ 0.5, ≦ 0.4, ≦ 0.3, ≦ 0.2, ≦ 0.1, ≦ 0.05, ≦ 0.01, ≦ 0.005, ≦ 0.001, ≦ 0.0001, ≦ 0.00001, ≦ 0.000001 or ≦ 0.0000001.

[0403] The fifth aspect of the present invention provides a detection reagent kit. The detection reagent kit (i) comprises a detection reagent used for detecting the expression level or activity of the mitochondrial membrane permeability transition pore, the expression level or activity of peptidylprolyl isomerase F, the expression level of the NNMT gene, the expression level of DNA methyltransferase, the expression level of UHRF1, the methylation level of the nucleotide site of the NNMT gene, and / or the methylation level of the DNA CpG site in the NNMT gene region.

[0404] In another preferred example, the detection sample of the detection reagent kit contains tumor cells.

[0405] In another preferred example, the level includes the protein level and / or the mRNA level.

[0406] In another preferred example, the expression includes the expression of mRNA and / or protein.

[0407] The sixth aspect of the present invention provides the use of the detection reagent kit described in the fifth aspect of the present invention for manufacturing an adjoint diagnostic kit. The adjoint diagnostic kit is used to determine whether 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, or its deuterated compound is suitable for the prevention and / or treatment of tumors in tumor patients.

[0408] In another preferred example, the accompanying detection reagent kit further comprises an instruction manual or a label.

[0409] In another preferred example, the instruction manual or the label includes In tumor cells of a tumor patient, when there is low expression, no expression, low activation or inactivation of the mitochondrial membrane permeability transition pore, low expression, no expression, low activation or inactivation of peptidylprolyl isomerase F, low expression or no expression of the NNMT gene, high expression of DNA methyltransferase, high expression of UHRF1, high methylation of nucleotide sites of the NNMT gene, and / or high methylation of DNA CpG sites in the NNMT gene region, 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, or its deuterated compound becomes suitable for tumor prevention and / or treatment for the tumor patient. The content described above is described.

[0410] In another preferred example, the instruction manual or the label includes In tumor cells of a tumor patient, when there is high expression or high activation of the mitochondrial membrane permeability transition pore, high expression or high activation of peptidylprolyl isomerase F, high expression of the NNMT gene, low expression of DNA methyltransferase, low expression of UHRF1, low methylation of nucleotide sites of the NNMT gene, and / or low methylation of DNA CpG sites in the NNMT gene region, 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, or its deuterated compound becomes unsuitable for tumor prevention and / or treatment for the tumor patient. The content described above is described.

[0411] In another preferred example, the above content that 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, or its deuterated compound becomes suitable for tumor prevention and / or treatment for a tumor patient has the meaning described in the fourth aspect of the present invention.

[0412] In another preferred example, the content that the compound of formula I according to the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound becomes unsuitable for tumor prevention and / or treatment in tumor patients has the meaning described in the fourth aspect of the present invention.

[0413] The seventh aspect of the present invention provides a medical kit.

[0414] The medical kit includes (i) a detection reagent used to detect the expression level or activity of the mitochondrial membrane permeability transition pore, the expression level or activity of peptidylprolyl isomerase F, the expression level of the NNMT gene, the expression level of DNA methyltransferase, the expression level of UHRF1, the methylation level of the nucleotide site of the NNMT gene, and / or the methylation level of the DNA CpG site of the NNMT gene region, and (ii) the compound of formula I according to the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound.

[0415] In another preferred example, the detection sample contains a tumor.

[0416] In another preferred example, the medical kit further includes an instruction manual or a label.

[0417] In another preferred example, the instruction manual or the label includes In the tumor cells of a tumor patient, when the mitochondrial membrane permeability transition pore is low-expressed, not expressed, hypo-activated or inactivated, peptidylprolyl isomerase F is low-expressed, not expressed, hypo-activated or inactivated, the NNMT gene is low-expressed or not expressed, the DNA methylase is high-expressed, UHRF1 is high-expressed, the nucleotide site of the NNMT gene is hypermethylated, and / or the DNA CpG site in the NNMT gene region is hypermethylated, the compound of formula I described in the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound becomes suitable for tumor prevention and / or treatment for the tumor patient.

[0418] In another preferred example, the instruction manual or label In the tumor cells of a tumor patient, when the mitochondrial membrane permeability transition pore is high-expressed or hyper-activated, peptidylprolyl isomerase F is high-expressed or hyper-activated, the NNMT gene is high-expressed, the DNA methylase is low-expressed, UHRF1 is low-expressed, the nucleotide site of the NNMT gene is hypomethylated, and / or the DNA CpG site in the NNMT gene region is hypomethylated, the compound of formula I described in the first aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound becomes unsuitable for tumor prevention and / or treatment for the tumor patient.

[0419] The eighth aspect of the present invention provides a method for preventing and / or treating a tumor, which includes administering 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, or its deuterated compound to a treatment subject to achieve tumor prevention and / or treatment.

[0420] In another preferred example, the tumor is the tumor described in the third aspect of the present invention.

[0421] In another preferred example, the subject to be treated is a human or a non-human mammal (e.g., rodents, rabbits, monkeys, livestock, dogs, cats).

[0422] In another preferred example, the method first causes the tumor of the subject to be treated to have low expression, no expression, low activation or inactivation of the mitochondrial membrane permeability transition pore, low expression, no expression, low activation or inactivation of peptidylprolyl isomerase F, low expression or no expression of the NNMT gene, high expression of a DNA methylase, high expression of UHRF1, high methylation of the nucleotide site of the NNMT gene, and / or high methylation of the DNA CpG site of the NNMT gene region, and then involves administering the compound of formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof for prevention and / or treatment.

[0423] In another preferred example, the method first causes the tumor of the subject to be treated to have low expression, no expression, low activation or inactivation of the mitochondrial membrane permeability transition pore, low expression, no expression, low activation or inactivation of peptidylprolyl isomerase F, low expression or no expression of the NNMT gene, high expression of a DNA methylase, high expression of UHRF1, high methylation of the nucleotide site of the NNMT gene, and / or high methylation of the DNA CpG site of the NNMT gene region by administering an inhibitor of the mitochondrial membrane permeability transition pore, an inhibitor of peptidylprolyl isomerase F, an inhibitor of the NNMT gene, an accelerator of a DNA methylase, an accelerator of UHRF1, an accelerator of methylation of the nucleotide site of the NNMT gene, and / or an accelerator of methylation of the DNA CpG site of the NNMT gene region to the subject to be treated, and then involves administering the compound of formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof for prevention and / or treatment.

[0424] In another preferred example, the above content, i.e., an inhibitor of the mitochondrial membrane permeability transition pore, an inhibitor of peptidylprolyl isomerase F, an inhibitor of the NNMT gene, an accelerator of DNA methyltransferase, an accelerator of UHRF1, an accelerator of methylation of the nucleotide site of the NNMT gene, and / or an accelerator of methylation of the DNA CpG site of the NNMT gene region, has the meaning described in the third aspect of the present invention.

[0425] The ninth aspect of the present invention provides an apparatus or a system.

[0426] The apparatus or system includes (i) a detection module used to detect the expression level or activity of the mitochondrial membrane permeability transition pore, the expression level or activity of peptidylprolyl isomerase F, the expression level of the NNMT gene, the expression level of DNA methyltransferase, the expression level of UHRF1, the methylation level of the nucleotide site of the NNMT gene, and / or the methylation level of the DNA CpG site of the NNMT gene region; and (ii) an output module.

[0427] The output module When in the tumor cells of a tumor patient, the mitochondrial membrane permeability transition pore shows low expression, no expression, low activation or inactivation, peptidylprolyl isomerase F shows low expression, no expression, low activation or inactivation, the NNMT gene shows low expression or no expression, DNA methyltransferase shows high expression, UHRF1 shows high expression, the nucleotide site of the NNMT gene shows high methylation, and / or the DNA CpG site of the NNMT gene region shows high methylation, 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, or its deuterated compound is suitable for tumor prevention and / or treatment for the tumor patient, and / or In the tumor cells of a tumor patient, when there is high expression or high activation of the mitochondrial membrane permeability transition pore, high expression or high activation of peptidylprolyl isomerase F, high expression of the NNMT gene, low expression of DNA methyltransferase, low expression of UHRF1, low methylation of the nucleotide site of the NNMT gene, and / or low methylation of the DNA CpG site in the NNMT gene region, information is output indicating that 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, or its deuterated compound is not suitable for tumor prevention and / or treatment for the tumor patient.

[0428] In another preferred example, the detection sample contains a tumor.

[0429] In another preferred example, the device comprises a gene detector or a protein detector.

[0430] In another preferred example, the device or system further comprises a sample supply module.

[0431] In another preferred example, the sample supply module is used to supply a tumor cell extract.

[0432] In another preferred example, the device or system further comprises a data processing module.

[0433] In another preferred example, the data processing module processes the expression level or activity of the mitochondrial membrane permeability transition pore, the expression level or activity of peptidylprolyl isomerase F, the expression level of the NNMT gene, the expression level of DNA methyltransferase, the expression level of UHRF1, the methylation level of the nucleotide site of the NNMT gene, and / or the methylation level of the DNA CpG site in the NNMT gene region to obtain their numerical ranges.

[0434] The tenth aspect of the present invention provides the use of an inhibitor of the mitochondrial membrane permeability transition pore, an inhibitor of peptidyl-prolyl isomerase F, an inhibitor of the NNMT gene, an accelerator of DNA methyltransferase, an accelerator of UHRF1, an accelerator of methylation of the nucleotide site of the NNMT gene, and / or an accelerator of methylation of the DNA CpG site of the NNMT gene region for producing a composition or preparation used for enhancing the antitumor effect of an antitumor drug.

[0435] In another preferred example, the inhibitor of the mitochondrial membrane permeability transition pore includes an inhibitor that can downregulate, inactivate, or reduce the activity of the mitochondrial membrane permeability transition pore in tumors.

[0436] In another preferred example, the inhibitor of peptidyl-prolyl isomerase F includes an inhibitor that can downregulate, inactivate, or reduce the activity of peptidyl-prolyl isomerase F in tumors.

[0437] In another preferred example, the inhibitor of the NNMT gene includes an inhibitor that can downregulate or inactivate the NNMT gene in tumors.

[0438] In another preferred example, the DNA methyltransferase is selected from DNMT1, DNMT3a, DNMT3b, or a combination thereof.

[0439] In another preferred example, the accelerator of DNA methyltransferase includes an accelerator that can upregulate the DNA methyltransferase in tumors.

[0440] In another preferred example, the accelerator of DNA methyltransferase includes an accelerator of DNMT1.

[0441] In another preferred example, the accelerator of DNMT1 includes an accelerator that can upregulate DNMT1 in tumors.

[0442] In another preferred example, the accelerator of DNA methyltransferase includes an accelerator of DNMT3a.

[0443] In another preferred example, the promoter of DNMT3a includes a promoter that can highly express tumor DNMT3a.

[0444] In another preferred example, the promoter of the DNA methyltransferase includes a promoter of DNMT3b.

[0445] In another preferred example, the promoter of DNMT3b includes a promoter that can highly express tumor DNMT3b.

[0446] In another preferred example, the promoter of UHRF1 includes a promoter that can highly express tumor UHRF1.

[0447] In another preferred example, the promoter for methylation of the nucleotide site of the NNMT gene includes a promoter that can highly methylate the nucleotide site of the tumor NNMT gene.

[0448] In another preferred example, the promoter for methylation of the DNA CpG site in the NNMT gene region includes a promoter that can highly methylate the DNA CpG site in the tumor NNMT gene region.

[0449] In another preferred example, the inhibitor includes an inhibitor with specificity.

[0450] In another preferred example, the promoter includes a promoter with specificity.

[0451] In another preferred example, the anti-tumor drug includes 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, or its deuterated compound.

[0452] In another preferred example, the tumor is the tumor described in the third aspect of the present invention.

[0453] In another preferred example, the inhibitor of the mitochondrial membrane permeability transition pore is selected from Cyclosporin A, CyP-D protein inhibitor, peroxide scavenger or a combination thereof.

[0454] In another preferred example, the inhibitor of peptidylprolyl isomerase F includes shRNA.

[0455] In another preferred example, the nucleotide sequence of shRNA is GTTCTTCATCTGCACCATAAA.

[0456] In another preferred example, the composition or formulation is a pharmaceutical composition or pharmaceutical formulation.

[0457] In another preferred example, the composition or formulation further includes a pharmaceutically acceptable carrier.

[0458] In another preferred example, the form of the composition or formulation is solid, liquid or semi-solid.

[0459] In another preferred example, the type of the composition or formulation is an oral preparation, a topical preparation or an injectable preparation.

[0460] In another preferred example, the type of the composition or formulation is a tablet, an injection, an infusion, an ointment, a gel, a solution, a pill or a coating agent.

[0461] The eleventh aspect of the present invention provides a combination of active ingredients including the following components.

[0462] (1) A first active ingredient including an antitumor drug, and (2) A second active ingredient including an inhibitor of the mitochondrial membrane permeability transition pore, an inhibitor of peptidylprolyl isomerase F, an inhibitor of the NNMT gene, an accelerator of DNA methyltransferase, an accelerator of UHRF1, an accelerator of methylation of the nucleotide site of the NNMT gene and / or an accelerator of methylation of the DNA CpG site of the NNMT gene region.

[0463] In another preferred example, the antitumor drug includes the compound of Formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.

[0464] In another preferred example, the above-mentioned content of an inhibitor of the mitochondrial membrane permeability transition pore, an inhibitor of peptidylprolyl isomerase F, an inhibitor of the NNMT gene, an accelerator of DNA methyltransferase, an accelerator of UHRF1, an accelerator of methylation of the nucleotide site of the NNMT gene and / or an accelerator of methylation of the DNA CpG site of the NNMT gene region has the meaning described in the tenth aspect of the present invention.

[0465] In another preferred example, the molar ratio between the first active ingredient and the second active ingredient is 0.01 - 600:1, preferably 0.05 - 500:1, and even more preferably 0.1 - 400:1, 0.2 - 200:1, 0.5 - 100:1, 0.5 - 80:1 or 1 - 50:1.

[0466] In another preferred example, the combination of the above-mentioned active ingredients contains at least one independent active ingredient.

[0467] In another preferred example, in the combination of the above-mentioned active ingredients, the first active ingredient and the second active ingredient are independent of each other.

[0468] The twelfth aspect of the present invention provides a composition containing the following components.

[0469] (1) A first active ingredient containing an antitumor drug, and (2) A second active ingredient containing an inhibitor of the mitochondrial membrane permeability transition pore, an inhibitor of peptidylprolyl isomerase F, an inhibitor of the NNMT gene, an accelerator of DNA methyltransferase, an accelerator of UHRF1, an accelerator of methylation of the nucleotide site of the NNMT gene and / or an accelerator of methylation of the DNA CpG site of the NNMT gene region.

[0470] In another preferred example, the antitumor drug contains 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, or its deuterated compound.

[0471] In another preferred example, the above content, namely, an inhibitor of the mitochondrial membrane permeability transition pore, an inhibitor of peptidylprolyl isomerase F, an inhibitor of the NNMT gene, an enhancer of DNA methyltransferase, an enhancer of UHRF1, an enhancer of methylation of nucleotide sites of the NNMT gene and / or an enhancer of methylation of DNA CpG sites in the NNMT gene region, has the meaning described in the tenth aspect of the present invention.

[0472] In another preferred example, the composition is a pharmaceutical composition.

[0473] In another preferred example, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0474] In another preferred example, the form of the composition or formulation is solid, liquid or semi-solid.

[0475] In another preferred example, the type of the composition or formulation is an oral preparation, a topical preparation or an injectable preparation.

[0476] In another preferred example, the type of the composition or formulation is a tablet, an injection, an infusion, an ointment, a gel, a solution, a pill or a coating agent.

[0477] In another preferred example, the content of the first active ingredient relative to the total weight of the active ingredients of the composition is 0.01 - 99.99 wt%, preferably 0.1 - 99.9 wt%, more preferably 1 - 99 wt%, 10 - 99 wt% or 20 - 99 wt%.

[0478] In another preferred example, the content of the second active ingredient relative to the total weight of the active ingredients of the composition is 0.01 - 99.99 wt%, preferably 0.1 - 99.9 wt%, more preferably 1 - 99 wt%, 10 - 99 wt% or 20 - 99 wt%.

[0479] The thirteenth aspect of the present invention provides a medical kit comprising the following preparations.

[0480] (A) A first formulation having a first active ingredient containing an anti-tumor drug, and (B) A second formulation having a second active ingredient containing an inhibitor of the mitochondrial membrane permeability transition pore, an inhibitor of peptidylprolyl isomerase F, an inhibitor of the NNMT gene, an accelerator of DNA methyltransferase, an accelerator of UHRF1, an accelerator of methylation of the nucleotide site of the NNMT gene, and / or an accelerator of methylation of the DNA CpG site of the NNMT gene region.

[0481] In another preferred example, the anti-tumor drug includes the compound of Formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.

[0482] In another preferred example, the content of the inhibitor of the mitochondrial membrane permeability transition pore, the inhibitor of peptidylprolyl isomerase F, the inhibitor of the NNMT gene, the accelerator of DNA methyltransferase, the accelerator of UHRF1, the accelerator of methylation of the nucleotide site of the NNMT gene, and / or the accelerator of methylation of the DNA CpG site of the NNMT gene region has the meaning described in the tenth aspect of the present invention.

[0483] In another preferred example, the medical kit further includes an instruction manual.

[0484] In another preferred example, the first formulation and the second formulation are independent of each other.

[0485] In another preferred example, the first formulation and the second formulation are combined.

[0486] In another preferred example, the instruction manual describes the content of using the first formulation and the second formulation in combination so as to enhance the anti-tumor activity of the anti-tumor drug.

[0487] In another preferred example, the combined use method is to first administer the second formulation having the second active ingredient, and then administer the first formulation having the first active ingredient.

[0488] The 14th aspect of the present invention provides a method for suppressing tumor cells. The method includes contacting the tumor cells with the compound of Formula I described in the 1st aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound to suppress the tumor cells.

[0489] In another preferred example, the method is performed in vitro or is an in vitro method.

[0490] In another preferred example, the method for suppressing tumor cells is a non-therapeutic and non-diagnostic method in vitro.

[0491] In another preferred example, the contact is performed in vitro culture.

[0492] In another preferred example, the tumor is the tumor described in the 3rd aspect of the present invention.

[0493] In another preferred example, the method is First, make the tumor cells have low expression, non-expression, low activation or inactivation of the mitochondrial membrane permeability transition pore, low expression, non-expression, low activation or inactivation of peptidylprolyl isomerase F, low expression or non-expression of the NNMT gene, high expression of DNA methyltransferase, high expression of UHRF1, high methylation of the nucleotide site of the NNMT gene, and / or high methylation of the DNA CpG site in the NNMT gene region, and then contact the tumor cells with the compound of Formula I described in the 1st aspect of the present invention, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound to suppress the tumor cells.

[0494] In another preferred example, the method is First, a mitochondrial membrane permeability transition pore inhibitor, a peptidylprolyl isomerase F inhibitor, an NNMT gene inhibitor, a DNA methyltransferase promoter, a UHRF1 promoter, a promoter for methylation of nucleotide sites of the NNMT gene, and / or a promoter for methylation of DNA CpG sites in the NNMT gene region are given to the tumor cells so that the tumor cells become low-expressing, non-expressing, hypo-activated or inactivated in the mitochondrial membrane permeability transition pore, become low-expressing, non-expressing, hypo-activated or inactivated in peptidylprolyl isomerase F, become low-expressing or non-expressing in the NNMT gene, become high-expressing in the DNA methyltransferase, become high-expressing in UHRF1, become hypermethylated in the nucleotide sites of the NNMT gene, and / or become hypermethylated in the DNA CpG sites in the NNMT gene region. Next, the tumor cells are contacted with the compound of Formula I described in the first aspect of the present invention, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof to suppress the tumor cells.

[0495] In another preferred example, the mitochondrial membrane permeability transition pore inhibitor, the peptidylprolyl isomerase F inhibitor, the NNMT gene inhibitor, the DNA methyltransferase promoter, the UHRF1 promoter, the promoter for methylation of nucleotide sites of the NNMT gene, and / or the promoter for methylation of DNA CpG sites in the NNMT gene region have the meaning described in the tenth aspect of the present invention.

[0496] The fifteenth aspect of the present invention provides the use of the medical kit described in the seventh aspect of the present invention for manufacturing a drug kit for preventing and / or treating tumors.

[0497] In another preferred example, the drug kit further comprises an instruction manual or a label.

[0498] In another preferred example, the instruction manual or label includes In the tumor cells of a tumor patient, when the mitochondrial membrane permeability transition pore is low-expressed, not expressed, hypo-activated or inactivated, when peptidylprolyl isomerase F is low-expressed, not expressed, hypo-activated or inactivated, when the NNMT gene is low-expressed or not expressed, when the DNA methylase is high-expressed, when UHRF1 is high-expressed, when the nucleotide site of the NNMT gene is hyper-methylated, and / or when the DNA CpG site in the NNMT gene region is hyper-methylated, 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, or its deuterated compound becomes suitable for preventing and / or treating tumors in the tumor patient.

[0499] In another preferred example, the instruction manual or label states that In the tumor cells of a tumor patient, when the mitochondrial membrane permeability transition pore is high-expressed or hyper-activated, when peptidylprolyl isomerase F is high-expressed or hyper-activated, when the NNMT gene is high-expressed, when the DNA methylase is low-expressed, when UHRF1 is low-expressed, when the nucleotide site of the NNMT gene is hypo-methylated, and / or when the DNA CpG site in the NNMT gene region is hypo-methylated, 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, or its deuterated compound becomes unsuitable for preventing and / or treating tumors in the tumor patient.

[0500] Within the scope of the present invention, the above technical features of the present invention may be combined with the following specific technical features respectively to form new or preferred technical solutions. Since the size of the full text is limited, it will not be repeated here.

Brief Description of the Drawings

[0501]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

[0502] As a result of long-term and in-depth research, the present inventors unexpectedly found for the first time a compound having an excellent precision treatment effect on tumor cells with low expression, non-expression, low activation or inactivation of the mitochondrial membrane permeability transition pore, tumor cells with low expression, non-expression, low activation or inactivation of peptidylprolyl isomerase F, tumor cells with low expression or non-expression of the NNMT gene, tumor cells with high expression of DNA methyltransferase, tumor cells with high expression of UHRF1, tumor cells with high methylation of nucleotide sites of the NNMT gene, and / or tumor cells with high methylation of DNA CpG sites in the NNMT gene region. Based on this, the present inventors have completed the present invention.

[0503] TERMS Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art.

[0504] As used in this specification, the terms "comprising," "including," and "having" may be used interchangeably and have not only a closed definition but also semi-closed and open definitions. In other words, the above terms have the meaning of "consisting of..." and "essentially consisting of...".

[0505] As used in this specification, the terms "cancer" and "tumor" may be used interchangeably.

[0506] As used in this specification, the term "a certain cell" refers to a cell (e.g., a single tumor cell) or a cell group containing a plurality of similar cells (e.g., a certain tumor tissue).

[0507] As used herein, "the compound of the present invention is suitable for a tumor patient" means, for example, that the tumor of the tumor patient is sensitive to the compound of the present invention.

[0508] As used herein, "the compound of the present invention is not suitable for a tumor patient" means, for example, that the tumor of the tumor patient is insensitive to the compound of the present invention.

[0509] As used herein, "there is hypermethylation of a DNA CpG site", "hypermethylation of a DNA CpG site occurs", and "a DNA CpG site is hypermethylated" may be used interchangeably with each other.

[0510] As used herein, "there is hypomethylation of a DNA CpG site", "hypomethylation of a DNA CpG site occurs", and "a DNA CpG site is hypomethylated" may be used interchangeably with each other.

[0511] As used herein, "methylation of a DNA CpG site", "methylation of a CpG nucleotide", and "methylation of CpG" may be used interchangeably with each other.

[0512] As used herein, the terms "IC50" and "IC 50 " may be used interchangeably with each other, represent the half-inhibitory concentration (50% inhibiting concentration), that is, the concentration of an inhibitor when a 50% inhibitory effect is achieved.

[0513] As used herein, the term "P / S" refers to adding Penicillin and Streptomycin to the relevant medium.

[0514] As used herein, "becomes low expression, unexpressed, low activation or inactivation of the mitochondrial membrane permeability transition pore, becomes low expression, unexpressed, low activation or inactivation of peptidyl-prolyl isomerase F, becomes low expression or unexpressed of the NNMT gene, becomes high expression of DNA methyltransferase, becomes high expression of UHRF1, becomes high methylation of the nucleotide site of the NNMT gene, and / or becomes high methylation of the DNA CpG site of the NNMT gene region" refers to one or more of the cases where the mitochondrial membrane permeability transition pore becomes low expression, unexpressed, low activation or inactivation, the case where peptidyl-prolyl isomerase F becomes low expression, unexpressed, low activation or inactivation, the case where the NNMT gene becomes low expression or unexpressed, the case where DNA methyltransferase becomes high expression, the case where UHRF1 becomes high expression, the case where the nucleotide site of the NNMT gene becomes high methylation, and the case where the DNA CpG site of the NNMT gene region becomes high methylation.

[0515] As used herein, the term "mitochondrial membrane permeability transition pore" is abbreviated as mPTP (mitochondria permeability transition pore).

[0516] As used herein, the term "peptidyl-prolyl isomerase F" is abbreviated as PPIF (Peptidyl-prolyl cis-trans isomerase F).

[0517] As used herein, the English name of the term "NNMT" is Nicotinamide N-Methyltransferase.

[0518] As used herein, the term "bp" refers to base pair and means base pair.

[0519] As used herein, the term "SST" refers to the transcription start site.

[0520] As used herein, the term "Chr11" refers to human chromosome 11 as defined according to the human genome version GCF_000001405.25 (GRCh37.p13).

[0521] As used herein, the term "human chromosome 11" refers to human chromosome 11 as defined according to the human genome version GCF_000001405.25 (GRCh37.p13).

[0522] As used herein, the terms "before the transcription start site" and "after the transcription start site" do not include the transcription start site itself.

[0523] As used herein, "position 114165695 of human chromosome 11" refers to the nucleotide at position 114165695 of human chromosome 11. The same can be inferred therefrom.

[0524] As used herein, the term "S-adenosylmethionine" is abbreviated as SAM (S-adenosyl methionine).

[0525] As used herein, gene expression includes protein expression of the gene and / or mRNA expression of the gene, etc.

[0526] As used herein, the English name for DNA methylation is DNA methylation.

[0527] As used herein, the term "DNMT3a" refers to DNA methyltransferase 3a, which may be used interchangeably with "DNMT3A".

[0528] As used herein, the term "DNMT3b" refers to DNA methyltransferase 3b, which may be used interchangeably with "DNMT3B".

[0529] As used herein, the term "DNMT1" refers to DNA methyltransferase 1.

[0530] As used herein, the term "UHRF1" refers to ubiquitin-like protein 1 containing PHD and ring finger domains.

[0531] As used herein, "deuteration" refers to the replacement of one or more hydrogen atoms in a compound or atomic group by deuterium atoms. Deuteration can be monodeuteration, dideuteration, multiple deuterations, or total deuteration.

[0532] As used herein, the term "solvate" refers to a specific ratio of complex formed by a compound coordinating with solvent molecules.

[0533] As used herein, the term "MS-ESI" refers to electrospray ionization mass spectrometry.

[0534] As used herein, " 1 H NMR" refers to proton nuclear magnetic resonance spectrum.

[0535] One of ordinary skill in the art should understand that a chemically stable compound can be produced by selecting substituents and substitution forms on the compounds of the present invention, and the compounds can be synthesized by the methods described below and the existing techniques in the art. It should be understood that if substituted by one or more substituents, these substituents can be located on the same carbon or different carbons as long as a stable structure is generated.

[0536] As used herein, the terms "substituted" or "substituent" mean that a hydrogen atom on an atomic group is substituted with a non-hydrogen atom group, which must satisfy their valences and result in a chemically stable compound, i.e., a compound in which conversions such as cyclization or elimination do not occur spontaneously. As used herein, "deuteration" means that a deuterium atom substitutes for one or more hydrogen atoms in a compound or atomic group. Deuteration can be mono-deuteration, di-deuteration, multi-deuteration, or full deuteration.

[0537] As used herein, "R" 1 ", "R1" and "R" 1 " have the same meaning and may be used interchangeably, and have the same meaning as other analogous definitions.

[0538] As used herein,

[0539]

Chemical formula

[0540] represents the bonding site of an atomic group.

[0541] As used herein, the term "alkyl group" refers to a straight-chain (i.e., unbranched), or branched saturated hydrocarbon group containing only carbon and hydrogen atoms, or an atomic group combining a straight chain and a branched chain. An alkyl group limited by the number of carbon atoms in front (for example, C1-C6 alkyl group) refers to an alkyl group having that number (for example, 1 to 6) of carbon atoms. For example, a C1-C4 alkyl group refers to an alkyl group containing 1 to 4 carbon atoms. Representative examples of these alkyl groups include, but are not limited to, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, or analogous atomic groups.

[0542] As used herein, the term "alkylidene group" refers to a group formed by removing one hydrogen atom from an alkyl group. The alkyl group is as defined above. An alkylidene group that is limited by the number of carbon atoms before it (for example, a C1-C6 alkylidene group) refers to an alkylidene group having that number (for example, 1 to 6) of carbon atoms. For example, a C1-C4 alkylidene group refers to an alkylidene group containing 1 to 4 carbon atoms. Representative examples of these alkylidene groups include, but are not limited to, a methylidene group, an ethylidene group, a propylidene group, an isopropylidene group, a butylidene group, an isobutylidene group, an s-butylidene group, a t-butylidene group, or analogous groups.

[0543] As used herein, the term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0544] As used herein, the term "halogenation" refers to substitution with a halogen atom.

[0545] As used herein, the term "halogenated alkyl group" refers to a group formed by substituting one or more (preferably 1, 2, 3, or 4) hydrogen atoms of an alkyl group with a halogen atom. The alkyl group and halogen atom are as defined above. A halogenated alkyl group that is limited by the number of carbon atoms before it (for example, a C1-C8 halogenated alkyl group) refers to a halogenated alkyl group having that number (for example, 1 to 8) of carbon atoms. For example, a C1-C6 halogenated alkyl group refers to a halogenated alkyl group containing 1 to 6 carbon atoms. Representative examples of these halogenated alkyl groups include, but are not limited to, -CF 3 , -CHF 2 , an isopropyl monofluoride group, a butyl difluoride group, or analogous groups.

[0546] As used herein, the term "cycloalkyl group" refers to a saturated or partially saturated monocyclic, bicyclic or polycyclic (fused, bridged or spiro) cyclic atomic group. When a cycloalkyl group is limited by the number of carbon atoms in front (for example, C3-C12), it refers to a cycloalkyl group having that number (for example, 3 to 12) of carbon atoms on the ring. For example, the term "C3-C8 cycloalkyl group" refers to a saturated or partially saturated monocycloalkyl group or dicycloalkyl group having 3 to 8 carbon atoms on the ring, including a cyclopropyl group, a cyclobutyl group, a cycloamyl group, a cycloheptyl group or similar atomic groups. A "spirocycloalkyl group" refers to a bicyclic or polycyclic atomic group that shares one carbon atom (referred to as a spiro atom) between monocyclic rings. Such atomic groups may contain one or more double bonds, but there is no complete conjugated π electron system in any of the rings. A "fused cycloalkyl group" refers to a bicyclic or polycyclic atomic group in which each ring in the system shares and is adjacent to a pair of carbon atoms of the other rings in the system. Here, one or more rings may contain one or more double bonds, but there is no complete conjugated π electron system in any of the rings. A "bridged cycloalkyl group" refers to a polycyclic atomic group of all carbon atoms that shares two carbon atoms that are not directly connected between any two rings. Such atomic groups may contain one or more double bonds, but there is no complete conjugated π electron system in any of the rings. Representative examples of these cycloalkyl groups are as follows.

[0547]

Chemical formula

[0548] As used herein, the term "halogenated cycloalkyl group" refers to a group formed by substituting one or more (preferably one, two, three, or four) hydrogen atoms of a cycloalkyl group with halogen atoms. The cycloalkyl group and halogen atoms are as defined above. Those limited by the number of carbon atoms before the cycloalkyl group (for example, C3-C8 halogenated cycloalkyl group) refer to those in which the cycloalkyl group has that number (for example, 3 to 8) of carbon atoms on the ring. For example, a C3-C8 halogenated cycloalkyl group refers to a halogenated cycloalkyl group containing 3 to 8 carbon atoms on the ring. Representative examples of these halogenated cycloalkyl groups include, but are not limited to, a cyclopropyl monofluoride group, a cyclobutyl monochloride group, a cycloamyl monofluoride group, a cycloheptyl difluoride group or analogous groups.

[0549] As used herein, the term "alkoxyl group" refers to an R-O- group, where R refers to an alkyl group. The alkyl group is as defined above. Those limited by the number of carbon atoms before the alkoxyl group (for example, C1-C8 alkoxyl group) refer to those in which the alkyl group in the alkoxyl group has that number (for example, 1 to 8) of carbon atoms. Representative examples of these alkoxyl groups include, but are not limited to, a methoxy group, an ethoxyl group, an N-propoxy group, an isopropoxy group, a t-butoxy group or analogous groups.

[0550] As used herein, the term "alkylthiol group" refers to an R-S- group, where R refers to an alkyl group. The alkyl group is as defined above. Those limited by the number of carbon atoms before the alkylthiol group (for example, C1-C8 alkoxyl group) refer to those in which the alkyl group in the alkylthiol group has that number (for example, 1 to 8) of carbon atoms. Representative examples of these alkylthiol groups include, but are not limited to, a methylthio group, an ethylthio group, an N-propylthio group, an isopropylthio group, a t-butylthiol group or analogous groups.

[0551] As used herein, the term "halogenated alkoxyl group" refers to a halogenated alkyl group -O-. The halogenated alkyl group is as defined above. When the halogenated alkyl group is limited by the number of carbon atoms before it, for example, a C1-C6 halogenated alkoxyl group refers to a halogenated alkyl group -O- having 1 to 6 carbon atoms. Representative examples of these halogenated alkoxyl groups include, but are not limited to, a monofluoromethoxy group, a mono-fluoroethoxyl group, a difluorobutoxy group or similar atomic groups.

[0552] As used herein, the term "halogenated alkylthiol group" refers to a halogenated alkyl group -S-. The halogenated alkyl group is as defined above. When the halogenated alkylthiol group is limited by the number of carbon atoms before it, for example, a C1-C6 halogenated alkylthiol group refers to a halogenated alkyl group -S- having 1 to 6 carbon atoms. Representative examples of these halogenated alkylthiol groups include, but are not limited to, a monofluoromethylthio group, a mono-fluoroethylthio group, a difluorobutylthiol group or similar atomic groups.

[0553] As used herein, the term "cycloalkoxyl group" refers to an R-O- atomic group, where R refers to a cycloalkyl group. The cycloalkyl group is as defined above. When the cycloalkoxyl group is limited by the number of carbon atoms before it (for example, a C3-C8 cycloalkoxyl group), it refers to a cycloalkoxyl group in which the cycloalkyl group has that number (for example, 3 to 8) of carbon atoms. Representative examples of these cycloalkoxyl groups include, but are not limited to, a cyclopropoxy group, a cyclobutoxy group or similar atomic groups.

[0554] As used herein, the term "cycloalkylthiol group" refers to an R-S- moiety, where R refers to a cycloalkyl group. The cycloalkyl group is as defined above. When a cycloalkylthiol group is limited by the number of carbon atoms in front (for example, C3-C8 cycloalkoxyl group), it refers to a cycloalkylthiol group in which the cycloalkyl group in the cycloalkylthiol group has that number (for example, 3 to 8) of carbon atoms. Representative examples of these cycloalkylthiol groups include, but are not limited to, cyclopropylthio group, cyclobutylthiol group or analogous moieties.

[0555] As used herein, the term "halogenated cycloalkoxyl group" refers to a moiety formed by substitution of one or more (preferably one, two, three or four) hydrogen atoms of a cycloalkoxyl group with halogen atoms. The cycloalkoxyl group and the halogen atom are as defined above. When a halogenated cycloalkoxyl group is limited by the number of carbon atoms in front (for example, C3-C8 halogenated cycloalkoxyl group), it refers to a halogenated cycloalkoxyl group having that number (for example, 3 to 8) of ring carbon atoms, for example, a C3-C8 halogenated cycloalkoxyl group refers to a halogenated cycloalkoxyl group containing 3 to 8 ring carbon atoms. Representative examples of these halogenated cycloalkoxyl groups include, but are not limited to, monofluorocyclopropyl group -O-, monochlorocyclobutyl group -O-, monofluorocyclopentyl group -O-, difluorocycloheptyl group -O- or analogous moieties.

[0556] As used herein, the term "halogenated cycloalkylthiol group" refers to a group formed by substituting one or more (preferably one, two, three or four) hydrogen atoms of a cycloalkylthiol group with halogen atoms. The cycloalkylthiol group and the halogen atom are as defined above. When the halogenated cycloalkylthiol group is limited by the number of carbon atoms in front (for example, C3-C8 halogenated cycloalkoxyl group), it refers to the halogenated cycloalkylthiol group having that number (for example, 3 to 8) of carbon atoms on the ring. For example, the C3-C8 halogenated cycloalkylthiol group refers to a halogenated cycloalkylthiol group containing 3 to 8 carbon atoms on the ring. Representative examples of these halogenated cycloalkylthiol groups include, but are not limited to, cyclopropyl group-S-monofluoride, cyclobutyl group-S-monochloride, cycloamyl group-S-monofluoride, cycloheptyl group-S-difluoride or similar groups.

[0557] As used herein, the term "heterocycloalkyl group" refers to a completely saturated or partially unsaturated cyclic atomic group (including, but not limited to, series such as 3- to 7-membered monocycles, 7- to 11-membered bicyclic rings, 8- to 16-membered tricyclic rings, etc.), where at least one heteroatom is present in a ring having at least one carbon atom. The point of attachment of the atomic group is located on the ring having the heteroatom. The number of members limiting the heterocycloalkyl group in front refers to the number of ring atoms of the heterocycloalkyl group. For example, a 3- to 16-membered heterocycloalkyl group refers to a heterocycloalkyl group having 3 to 16 ring atoms. Each heterocycle having a heteroatom may have one or more (e.g., 1, 2, 3, or 4) heteroatoms, and those heteroatoms are each independently selected from a nitrogen atom, an oxygen atom, or a sulfur atom, where the nitrogen atom or sulfur atom may be oxidized, and the nitrogen atom may also be quaternized. Representative examples of these monocyclic heterocycloalkyl groups include, but are not limited to, azetidinyl group, oxetane group, tetrahydrofuranyl group, piperidine group, piperazine group, etc. Polycyclic heterocycloalkyl groups include spiro ring, fused ring, and bridged ring heterocyclic groups. Related spiro ring, fused ring, and bridged ring heterocycloalkyl groups may optionally be linked to other atomic groups by a single bond or further fused to other cycloalkyl rings and heterocycloalkyl rings through any two or more atoms on the ring.

[0558] As used herein, the term "aryl group" refers to a monocyclic or fused polycyclic (rings sharing an adjacent pair of carbon atoms) atomic group of all carbon atoms having a conjugated π electron system, which is an atomic group of an aromatic cyclic hydrocarbon compound. What is limited by the number of carbon atoms in front of the aryl group (e.g., C6-C12 aryl group) refers to the aryl group having the corresponding number (e.g., 6 to 12) of ring carbon atoms. Representative examples of these aryl groups include phenyl group, naphthoyl group, etc.

[0559] As used herein, the term "heteroaryl group" refers to an atomic group of an aromatic heterocyclic system having one or more (preferably one, two, three or four) heteroatoms, wherein at least one heteroatom is present in a ring having at least one carbon atom. The atomic group may be monocyclic (monocyclic) or a fused or covalently bonded polycyclic (bicyclic, tricyclic or polycyclic), and in addition, each heterocyclic ring containing a heteroatom may have one or more (e.g., one, two, three or four) heteroatoms independently selected from oxygen atoms, sulfur atoms and nitrogen atoms. The number of members limiting the heteroaryl group in front refers to the number of ring atoms of the heteroaryl group. For example, a 5-12 member heteroaryl group refers to a heteroaryl group having 5 to 12 ring atoms. Representative examples of these heteroaryl groups include, but are not limited to, pyrrole group, pyrazole group, imidazole group, thiazole, furan group, pyridine group, pyrimidine group, etc.

[0560] As used herein, the term "carboxyl group" refers to the atomic group of -COOH or the atomic group of -alkyl group-COOH, wherein the alkyl group is as defined above. For example, "C 2 -C 4 carboxyl group" refers to the atomic group of -C 1 -C 3 alkyl group-COOH. Representative examples of these carboxyl groups include, but are not limited to, -COOH, -CH 2 COOH or similar atomic groups.

[0561] As used herein, the term "ester group" refers to the atomic group of R-C(O)-O- or the atomic group of -C(O)-O-R, wherein the alkyl group (R) is as defined above. For example, "C 2 -C 4 ester group" refers to the atomic group of -C 1 -C 3 alkyl group-C(O)-O- or the atomic group of -C(O)-O-C 1 -C 3 alkyl group. Representative examples of these ester groups include CH 3 C(O)O-, C2 H 5 C(O)O-, (CH 3 ) 2 CHC(O)O-, -C(O)OCH 3 , -C(O)OC 2 H 5 and includes, but is not limited to, similar atomic groups.

[0562] As used herein, the term "acylamino group" refers to an atomic group of R-C(O)-N- or -C(O)-N-R, where the alkyl group (R) is as defined above. For example, "C 2 -C 4 acylamino group" refers to an atomic group of -C 1 -C 3 alkyl group -C(O)-N- or -C(O)-N-C 1 -C 3 alkyl group. Representative examples of these acylamino groups are CH 3 C(O)-N-, C 2 H 5 C(O)-N-, (CH 3 ) 2 CHC(O)-N-, -C(O)-N-CH 3 , -C(O)-N-C 2 H 5 and includes, but is not limited to, similar atomic groups.

[0563] As used herein, the carbonyl group

[0564]

Chemical formula

[0565] refers to.

[0566] As used herein, the "amino group" represents -NH 2 either alone or as part of another substituent.

[0567] As used herein, the "nitro group" represents -NO 2 either alone or as part of another substituent.

[0568] As used herein, "cyano group" represents -CN alone or as part of another substituent.

[0569] As used herein, "hydroxyl group" represents -OH alone or as part of another substituent.

[0570] As used herein, "mercapto group" represents -SH alone or as part of another substituent.

[0571] In this specification, all substituents, unless explicitly stated as "substituted", are meant to be unsubstituted. The term "substitution" refers to a substituent replacing one or more hydrogen atoms on an atomic group. The said substituent is the substituent described above or the substituent appearing in each example. Preferably, the said "substitution" means that one or more (preferably one, two, three, four, five, six, seven or eight) hydrogen atoms on a ring or atomic group are replaced by a C1-C12 alkyl group, a C3-C8 cycloalkyl group, a C1-C12 halogenated alkyl group, a C3-C8 halogenated cycloalkyl group, a C3-C8 cycloalkoxyl group, a C3-C8 cycloalkylthiol group, a C3-C8 halogenated cycloalkoxyl group, a C3-C8 halogenated cycloalkylthiol group, a halogen atom, a nitro group, -CN, a hydroxyl group, a mercapto group, an amino group, a C1-C4 carboxyl group, a C2-C8 ester group, a C2-C4 acylamino group, a C1-C12 alkyl group -O-, a C1-C12 alkyl group -S-, a C1-C12 halogenated alkoxyl group, a C1-C12 halogenated alkylthiol group, a C6-C12 aryl group, a 5-12 membered heteroaryl group, and

[0572]

Chemical formula

[0573] is meant to be substituted by a substituent selected from. R 35represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3- to 12-membered heterocycloalkyl group, or a halogen atom; Z 1 represents a C1-C8 alkylidene group. Unless otherwise specified, an optionally substituted atomic group may have a substituent selected from a specific group at any substitutable site of the atomic group, and the substituents may be the same or different at each site.

[0574] In the present invention, "prevention" refers to a method of preventing the onset of a disease and / or its accompanying symptoms, or protecting a subject from getting the disease. As used herein, "prevention" also refers to delaying the onset of a disease and / or its accompanying symptoms and reducing the risk of the subject getting the disease.

[0575] "Treatment" as described in the present invention means delaying and terminating the progression of a disease or eliminating the disease, but does not require 100% suppression, elimination, and reversal. In some embodiments, the compounds of the present invention reduce, suppress, and / or reverse related diseases (e.g., tumors) and their complications by at least about 10%, 30%, 50%, 80%, or 100% compared to the levels observed in the absence of the compounds of the present invention.

[0576] Compound As used herein, "the compound of the present invention", "the said compound of the present invention", "the compound of formula I of the present invention", or "the compound of formula I" may be used interchangeably and refers to a compound having the chemical structural formula of formula I, or its optical isomers or racemates, or its solvates, or its pharmaceutically acceptable salts, or its deuterated compounds.

[0577] The chemical structural formula of the compound of formula I of the present invention is as follows.

[0578]

Chemical formula

[0579] I Specifically, the compound of formula I, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound, is as described in the first aspect of the present invention.

[0580] Typically, the compound of formula I of the present invention is a specific compound (including their salts or the free state without salt ions or bases) prepared according to the examples of the present invention.

[0581] The compound of formula I of the present invention may be prepared by organic synthesis methods known in the art.

[0582] The present invention may convert the compound of formula I into their pharmaceutically acceptable salts by conventional methods. For example, adding a solution of the corresponding acid to the solution of the above compound and removing the solvent after all salification, the corresponding salts of the compounds of the present invention can be obtained.

[0583] Preferably, the compound of the present invention is prepared in the examples of the present invention.

[0584] Mitochondrial permeability transition pore In the present invention, the English name of the term "mitochondrial permeability transition pore" is mitochondria permeability transition pore, which is abbreviated as mPTP.

[0585] For tumors with low expression, non-expression, low activity or inactivity of the mitochondrial permeability transition pore, the excellent precision treatment effect provided by the compound of the present invention means that tumors with low expression, non-expression, low activity or inactivity of the mitochondrial permeability transition pore are sensitive to the compound of the present invention, etc.

[0586] Peptidyl-prolyl cis-trans isomerase F In the present invention, the English name of the term "Peptidyl-prolyl cis-trans isomerase F" is Peptidyl-prolyl cis-trans isomerase F, which is abbreviated as PPIF.

[0587] For tumors with low expression, no expression, low activity or inactivity of peptidylprolyl isomerase F, the excellent precision treatment effect provided by the compound of the present invention means that tumors with low expression, no expression, low activity or inactivity of peptidylprolyl isomerase F are sensitive to the compound of the present invention, etc.

[0588] NNMT gene In the present invention, the English name of NNMT is Nicotinamide N-Methyltransferase. If the database is different, the identification number of the NNMT gene is also different. For example, HGNC:7861; Entrez Gene:4837; Ensembl:ENSG00000166741; OMIM:600008; UniProtKB:P40261.

[0589] According to the human genome version GCF_000001405.25(GRCh37.p13), the NNMT gene region is located at bp 114,128,528 to bp 114,184,258 on human chromosome 11, and is a DNA sequence with a full length of 55,731 bp. This region includes the NNMT gene promoter region, the NNMT gene exon region and the NNMT gene intron region, and the NNMT gene transcription start site is at bp 114,166,535.

[0590] The NNMT gene promoter region is the nucleotide sequence from bp 114,164,535 to bp 114,167,034 on human chromosome 11, that is, the sequence from 2000 bp before (the bracketed part) the transcription start site of the NNMT gene to the transcription start site itself and 499 bp after (the bracketed part). The NNMT gene promoter region has a full length of 2500 bp, and its nucleotide sequence is shown in SEQ ID NO:1 below.

[0591] SEQ ID NO: 1:

[0592] In the present invention, the sites of the nucleotide sequence of SEQ ID NO:1 corresponding to positions 114165695, 114165730, 114165769, 114165804, 114165938, 114166050, and 114166066 on human chromosome 11 are shown in Table 1, respectively.

[0593] [Table 1] DNA methylation DNA methylation is a form of chemical modification of DNA that changes gene expression without altering the DNA sequence.

[0594] Typically, DNA methylation is the methylation of DNA CpG sites. CpG dinucleotides are very unevenly distributed in the human genome, and in some segments of the genome, CpG is maintained at a higher than normal probability. The regions enriched in CpG sites (also called CpG islands), which are mainly located in the promoter and exon regions of genes, are some regions that concentrate CpG dinucleotides, and more than 60% of the promoters of genes are contained in CpG islands. Here, CpG is an abbreviation for cytosine (C)-phosphate (p)-guanine (G).

[0595] Tumor In the present invention, "tumor", "cancer", "carcinoma", and "neoplasm" may be used interchangeably.

[0596] In a preferred example of the present invention, the "tumor" described in the present invention includes tumors with low expression, unexpression, low activity, or inactivity of the mitochondrial membrane permeability transition pore. As a representative example, the tumors with low expression, unexpression, low activity, or inactivity of the mitochondrial membrane permeability transition pore described in the present invention are as described in the third aspect of the present invention.

[0597] In a preferred example of the present invention, the "tumor" described in the present invention includes tumors with low expression, no expression, low activity or inactivity of peptidylprolyl isomerase F. As a representative example, the tumors with low expression, no expression, low activity or inactivity of peptidylprolyl isomerase F described in the present invention are as described in the third aspect of the present invention.

[0598] In a preferred example of the present invention, the "tumor" described in the present invention includes tumors with low expression or no expression of the NNMT gene. As a representative example, the tumors with low expression or no expression of the NNMT gene described in the present invention are as described in the third aspect of the present invention.

[0599] In a preferred example of the present invention, the "tumor" described in the present invention includes tumors with high expression of DNA methyltransferase. As a representative example, the tumors with high expression of DNA methyltransferase described in the present invention are as described in the third aspect of the present invention.

[0600] The DNA methyltransferase described in the present invention includes, but is not limited to, DNMT1, DNMT3a, DNMT3b or combinations thereof. Preferably, the DNA methyltransferase described in the present invention includes DNMT1.

[0601] In a preferred example of the present invention, the "tumor" described in the present invention includes tumors with high expression of DNMT1. As a representative example, the tumors with high expression of DNMT1 described in the present invention are as described in the third aspect of the present invention.

[0602] In a preferred example of the present invention, the "tumor" described in the present invention includes tumors with high expression of DNMT3a. As a representative example, the tumors with high expression of DNMT3a described in the present invention are as described in the third aspect of the present invention.

[0603] In a preferred example of the present invention, the "tumor" described in the present invention includes tumors with high expression of DNMT3b. As a representative example, the tumors with high expression of DNMT3b described in the present invention are as described in the third aspect of the present invention.

[0604] In a preferred example of the present invention, the "tumor" described in the present invention includes tumors with high expression of UHRF1 (ubiquitin-like with PHD and RING finger domains 1). As a representative example, the tumors with high expression of UHRF1 described in the present invention are as described in the third aspect of the present invention.

[0605] In a preferred example of the present invention, the "tumor" described in the present invention includes tumors with high methylation of nucleotide sites of the NNMT gene. As a representative example, the tumors with high methylation of nucleotide sites of the NNMT gene described in the present invention are as described in the third aspect of the present invention.

[0606] In a preferred example of the present invention, the "tumor" described in the present invention includes tumors with high methylation of DNA CpG sites in the NNMT gene region. As a representative example, the tumors with high methylation of DNA CpG sites in the NNMT gene region described in the present invention are as described in the third aspect of the present invention.

[0607] More specifically, the "tumor" described in the present invention is as described in the third aspect of the present invention.

[0608] In the present invention, Table 2 below shows representative tumor types corresponding to various tumor cell lines.

[0609]

Table 2

[0610] Use The compounds of the present invention have a significantly excellent precision therapeutic effect on tumors with low expression, non-expression, low activity or inactivity of the mitochondrial membrane permeability transition pore, tumors with low expression, non-expression, low activity or inactivity of peptidylprolyl isomerase F, tumors with low expression or non-expression of the NNMT gene, tumors with high expression of DNA methylase, tumors with high expression of UHRF1, tumors with high methylation of nucleotide sites of the NNMT gene and / or tumors with high methylation of DNA CpG sites in the NNMT gene region, that is, tumors with low expression, non-expression, low activity or inactivity of the mitochondrial membrane permeability transition pore, tumors with low expression, non-expression, low activity or inactivity of peptidylprolyl isomerase F, tumors with low expression or non-expression of the NNMT gene, tumors with high expression of DNA methylase, tumors with high expression of UHRF1, tumors with high methylation of nucleotide sites of the NNMT gene and / or tumors with high methylation of DNA CpG sites in the NNMT gene region are sensitive to the compounds of the present invention.

[0611] The present invention further provides a method for preventing and / or treating tumors, which aims to administer the compounds of the present invention to a subject to be treated.

[0612] The compounds of the present invention have a significantly excellent precision treatment effect on tumors with low expression, unexpression, low activity or inactivity of mitochondrial membrane permeability transition pores, tumors with low expression, unexpression, low activity or inactivity of peptidylprolyl isomerase F, tumors with low expression or unexpression of the NNMT gene, tumors with high expression of DNA methyltransferase, tumors with high expression of UHRF1, tumors with high methylation of nucleotide sites of the NNMT gene and / or tumors with high methylation of DNA CpG sites in the NNMT gene region. In the process of tumor prevention and / or treatment, first, inhibitors of mitochondrial membrane permeability transition pores, inhibitors of peptidylprolyl isomerase F, inhibitors of the NNMT gene, promoters of DNA methyltransferase, promoters of UHRF1, promoters of methylation of nucleotide sites of the NNMT gene and / or promoters of methylation of DNA CpG sites in the NNMT gene region are administered to the treatment target so that the tumor to be treated becomes low expression, unexpression, low activation or inactivation of mitochondrial membrane permeability transition pores, low expression, unexpression, low activation or inactivation of peptidylprolyl isomerase F, low expression or unexpression of the NNMT gene, high expression of DNA methyltransferase, high expression of UHRF1, high methylation of nucleotide sites of the NNMT gene, and / or high methylation of DNA CpG sites in the NNMT gene region. Then, the above-mentioned compounds of the present invention are administered to prevent and / or treat tumors. Therefore, a compound that can significantly enhance the anti-tumor effect by combining inhibitors of mitochondrial membrane permeability transition pores, inhibitors of peptidylprolyl isomerase F, inhibitors of the NNMT gene, promoters of DNA methyltransferase, promoters of UHRF1, promoters of methylation of nucleotide sites of the NNMT gene and / or promoters of methylation of DNA CpG sites in the NNMT gene region has been developed. By being able to be used in combination with inhibitors of mitochondrial membrane permeability transition pores, inhibitors of peptidylprolyl isomerase F, inhibitors of the NNMT gene, promoters of DNA methyltransferase, promoters of UHRF1, promoters of methylation of nucleotide sites of the NNMT gene and / or promoters of methylation of DNA CpG sites in the NNMT gene region, the treatment effect of the compounds of the present invention on tumors is significantly enhanced.

[0613] In another preferred example, the subject to be treated is a human or a non-human mammal (e.g., rodents, rabbits, monkeys, domestic animals, dogs, cats).

[0614] In the present invention, a method of reducing the expression, non-expressing, reducing the activation or inactivating the mitochondrial membrane permeability transition pore in tumors, reducing the expression, non-expressing, reducing the activation or inactivating peptidylprolyl isomerase F, reducing the expression or non-expressing the NNMT gene, increasing the expression of DNA methyltransferase, increasing the expression of UHRF1, hypermethylating the nucleotide site of the NNMT gene, and / or hypermethylating the DNA CpG site of the NNMT gene region is not particularly limited. For example, the expression and activity of the mitochondrial membrane permeability transition pore and / or peptidylprolyl isomerase F can be specifically suppressed through means such as gene knockout and gene suppression (e.g., introducing shRNA).

[0615] In another preferred example, the inhibitor of peptidylprolyl isomerase F contains shRNA.

[0616] In another preferred example, the nucleotide sequence of shRNA is GTTCTTCATCTGCACCATAAA.

[0617] Marker The present invention further provides a marker for determining whether the compound of the present invention is suitable for the prevention and / or treatment of tumors in tumor patients. The marker has the mitochondrial membrane permeability transition pore, peptidylprolyl isomerase F, NNMT gene, DNA methyltransferase, UHRF1, methylation of the nucleotide site of the NNMT gene, and / or methylation of the DNA CpG site of the NNMT gene region.

[0618] In one embodiment, the expression level or activity of the mitochondrial membrane permeability transition pore, the expression level or activity of peptidylprolyl isomerase F, the expression level of the NNMT gene, the expression level of DNA methyltransferase, the expression level of UHRF1, the methylation level of the nucleotide site of the NNMT gene, and / or the methylation level of the DNA CpG site of the NNMT gene region function as markers for determining whether the compound of the present invention is suitable for the prevention and / or treatment of tumors in tumor patients. The method is as follows: In the tumor cells of a tumor patient, when the mitochondrial membrane permeability transition pore shows low expression, no expression, low activation or inactivation, peptidylprolyl isomerase F shows low expression, no expression, low activation or inactivation, the NNMT gene shows low expression or no expression, DNA methyltransferase shows high expression, UHRF1 shows high expression, the nucleotide site of the NNMT gene shows high methylation, and / or the DNA CpG site of the NNMT gene region shows high methylation, 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, or its deuterated compound is suitable for the prevention and / or treatment of tumors in the tumor patient, and / or In the tumor cells of a tumor patient, when the mitochondrial membrane permeability transition pore shows high expression or high activation, peptidylprolyl isomerase F shows high expression or high activation, the NNMT gene shows high expression, DNA methyltransferase shows low expression, UHRF1 shows low expression, the nucleotide site of the NNMT gene shows low methylation, and / or the DNA CpG site of the NNMT gene region shows low methylation, 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, or its deuterated compound becomes not suitable for the prevention and / or treatment of tumors in the tumor patient, including but not limited to this.

[0619] Specifically, the marker described in the present invention is as described in the fourth aspect of the present invention.

[0620] Composition Preferably, the composition or formulation described in the present invention is a pharmaceutical composition or pharmaceutical formulation, and the composition or formulation described in the present invention may contain a pharmaceutically acceptable carrier.

[0621] As used herein, "pharmaceutically acceptable carrier" refers to one or more compatible solids, semi-solids, liquids, and gel fillers that are suitable for human or animal use and must have sufficient purity and low enough toxicity. "Compatibility" means that when each component in the composition or formulation is mixed with the active ingredient and they are combined, the medicinal effect will not be significantly reduced.

[0622] In the present invention, the pharmaceutically acceptable carrier is not particularly limited and should be understood to be selected from materials commonly used in the art, prepared by conventional methods, or purchased from the market. Some representative examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (such as stearic acid and magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), buffering agents, chelating agents, thickening agents, pH adjusters, penetration enhancers, coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, bacteriostatic agents, heat-free raw water, etc.

[0623] In a preferred example of the present invention, the form of the composition or formulation is solid, liquid or semi-solid.

[0624] In a preferred example of the present invention, the type of the composition or formulation is an oral preparation, a topical preparation or an injectable preparation.

[0625] As representative examples thereof, the type of the composition or formulation is tablets, injections, infusions, ointments, gels, solutions, pills or coatings.

[0626] The pharmaceutical preparation should be consistent with the dosing method. The drugs of the present invention are also used together with other synergistic therapeutic drugs (before use, during use, or after use). When using a drug composition or preparation, a safe and effective amount of the drug is administered to the treatment subject (for example, a human or non-human mammal). The above-mentioned safe and effective amount is usually at least about 10 μg / kg of body weight, and in most cases, less than about 8 mg / kg of body weight, preferably about 10 μg / kg of body weight to about 1 mg / kg of body weight. Of course, the specific dosage needs to consider conditions such as the dosing route and the health status of the patient, and these conditions are taken into account by a skilled physician.

[0627] The present invention mainly has the following excellent technical effects.

[0628] The present invention has unexpectedly found for the first time a compound having a significantly superior precision treatment effect on tumors with low expression, non-expression, low activity or inactivity of the mitochondrial membrane permeability transition pore, tumors with low expression, non-expression, low activity or inactivity of peptidylprolyl isomerase F, tumors with low expression or non-expression of the NNMT gene, tumors with high expression of DNA methyltransferase, tumors with high expression of UHRF1, tumors with high methylation of nucleotide sites of the NNMT gene and / or tumors with high methylation of DNA CpG sites in the NNMT gene region. Tumors with low expression, non-expression, low activity or inactivity of the mitochondrial membrane permeability transition pore, tumors with low expression, non-expression, low activity or inactivity of peptidylprolyl isomerase F, tumors with low expression or non-expression of the NNMT gene, tumors with high expression of DNA methyltransferase, tumors with high expression of UHRF1, tumors with high methylation of nucleotide sites of the NNMT gene and / or tumors with high methylation of DNA CpG sites in the NNMT gene region have high sensitivity to the drug of the compound of the present invention, that is, the above-mentioned compound of the present invention has a significantly superior treatment effect on tumors with low expression, non-expression, low activity or inactivity of the mitochondrial membrane permeability transition pore, tumors with low expression, non-expression, low activity or inactivity of peptidylprolyl isomerase F, tumors with low expression or non-expression of the NNMT gene, tumors with high expression of DNA methyltransferase, tumors with high expression of UHRF1, tumors with high methylation of nucleotide sites of the NNMT gene and / or tumors with high methylation of DNA CpG sites in the NNMT gene region. Therefore, the above-mentioned compound of the present invention performs precision treatment on tumors with low expression, non-expression, low activity or inactivity of the mitochondrial membrane permeability transition pore, tumors with low expression, non-expression, low activity or inactivity of peptidylprolyl isomerase F, tumors with low expression or non-expression of the NNMT gene, tumors with high expression of DNA methyltransferase, tumors with high expression of UHRF1, tumors with high methylation of nucleotide sites of the NNMT gene and / or tumors with high methylation of DNA CpG sites in the NNMT gene region, improves the treatment effect, and may avoid administering the compound of the present invention to tumor patients who are not sensitive to it.Therefore, the compounds of the present invention, which have a significantly better precision treatment effect on tumors with low expression, non-expression, low activity or inactivity of the mitochondrial permeability transition pore, tumors with low expression, non-expression, low activity or inactivity of peptidyl-prolyl isomerase F, tumors with low expression or non-expression of the NNMT gene, tumors with high expression of DNA methyltransferase, tumors with high expression of UHRF1, tumors with high methylation of nucleotide sites of the NNMT gene and / or tumors with high methylation of DNA CpG sites in the NNMT gene region, have advantages such as better preventive and therapeutic effects on tumors, low drug dosage and small side effects. In addition to improving the precision preventive and therapeutic effects of the compounds of the present invention on tumors, the side effects are reduced and the compliance of patients taking the medicine is improved.

[0629] Next, we will further explain the present invention in combination with specific examples. The following specific embodiments are based on this technical solution, and detailed embodiments and specific operation procedures are listed. However, it should be understood that the protection scope of the present invention is not limited to these embodiments.

[0630] The English name of the term "mitochondria permeability transition pore" is mitochondria permeability transition pore, and it is abbreviated as mPTP.

[0631] The English name of the term "Peptidyl-prolyl cis-trans isomerase F" is Peptidyl-prolyl cis-trans isomerase F, and it is abbreviated as PPIF.

[0632] DNMT3a refers to DNA methyltransferase 3a, and its English name is DNA methyltransferase 3a, NCBI entrez gene: 1788; Uniprotkb / Swiss-port: Q9Y6K1.

[0633] DNMT3b refers to DNA methyltransferase 3b, whose English name is NDNA methyltransferase 3b, CBI entrez gene: 1789; Uniprotkb / Swiss-port: Q9UBC3.

[0634] DNMT1 refers to DNA methyltransferase 1, whose English name is DNA methyltransferase 1, NCBI entrez gene: 1786; Uniprotkb / Swiss-port: P26358.

[0635] UHRF1 refers to ubiquitin-like protein 1 containing PHD and ring finger domains, whose English name is NCBI entrez gene: 29128; Uniprotkb / Swiss-port: Q96T88.

[0636] The English name of the NNMT gene is Nicotinamide N-Methyltransferase.

[0637] Example 1 Synthesis of Compound AB35419 The chemical structural formula of Compound AB35419 is as follows.

[0638]

Chemical formula

[0639] Compound AB35419 The synthesis route of Compound AB35419 is as follows.

[0640] Step (1):

[0641]

Chemical formula

[0642] In a sealed tube, compound 1 (700 mg, 3.46 mmol, 1 eq) was dissolved in dimethyl sulfoxide (10 mL), and compound 2 (678 mg, 3.46 mmol, 1 eq), triethylamine (419 mg, 4.15 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (194 mg, 0.35 mmol, 0.1 eq), and palladium acetate (39 mg, 0.17 mmol, 0.05 eq) were added. Then, the reaction was carried out at 100 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with dichloromethane, and the organic phase was washed 3 times with water, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 3 was obtained from the crude product through flash chromatography (DCM / MeOH = 100 / 1 - 50 / 1).

[0643] MS-ESI: Calculated value [M+H] + : 318.10, Measured value [M+H] + : 318.25.

[0644] Step (2):

[0645]

Chemical formula

[0646] In a sealed tube, compound 3 (700 mg, 2.2 mmol, 1 eq) was dissolved in methylbenzene (10 mL), and triphenylphosphine (1.1 g, 4.4 mmol, 2 eq) and trichlorosilane (5.9 g, 44 mmol, 20 eq) were added. Then, the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, rapid cooling was carried out using methanol (20 mL), the pH of the reaction solution was adjusted to neutral using 2N NaOH, the solvent was concentrated, diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 4 was obtained from the crude product through flash chromatography (PE / EA = 100 / 1 - 25 / 1). MS-ESI: Calculated value [M+H] +: 302.11, Measured value [M+H] + : 302.05

[0647] Step (3):

[0648]

Chem.

[0649] In a sealed tube, compound 4 (243 mg, 0.81 mmol, 1 eq) was dissolved in DMSO (2 mL), compound 2 (158 mg, 0.81 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (7 mg, 0.081 mmol, 0.01 eq) were added. Then, the reaction was carried out at 130 °C for 5 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid. Compound AB35419 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35419: MS-ESI: Calculated value [M] + : 417.15, Measured value [M+H] + : 417.15 1 H NMR (400 MHz, CDCl3) δ 12.68 (s, 2H), 8.86 (s, 1H), 8.01 (d, J = 4.0 Hz, 2H), 7.76 - 7.72 (m, 2H), 7.61 - 7.53 (m, 8H), 7.19 (s, 2H), 7.06 - 7.01 (m, 4H), 5.53 (d, J = 4.0 Hz, 2H). Example 2 Synthesis of Compound AB35431 The chemical structural formula of compound AB35431 is as follows.

[0650]

Chem.

[0651] Compound AB35431 The synthetic route of Compound AB35431 is as follows.

[0652]

Chem.

[0653] In a sealed tube, Compound 1 (200 mg, 1.02 mmol, 1 eq) was dissolved in dimethylbenzene (2 mL), triphenylphosphine (268 mg, 1.02 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (10 mg, 0.0102 mmol, 0.01 eq) were added, and then the reaction was carried out at 110 °C for 3 hours under the protection of nitrogen gas. After cooling, the solvent was concentrated, and Compound AB35431 was obtained from the solid through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35431 MS-ESI: Calculated value [M] + 378.14, Measured value [M+H] + : 378.30. 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.23 (d, J = 12.0 Hz, 1H), 7.83 - 7.60 (m, 17H), 6.98 - 6.93 (m, 1H), 6.58 (s, 1H). Example 3 Synthesis of Compound AB35437 The chemical structural formula of Compound AB35437 is as follows.

[0654]

Chem.

[0655] Compound AB35437 The synthetic route of Compound AB35437 is as follows.

[0656] Step (1):

[0657]

Chem.

[0658] In a sealed tube, compound 1 (500 mg, 2.47 mmol, 1 eq) was dissolved in dimethyl sulfoxide (5 mL), and compound 2 (581 mg, 2.96 mmol, 1.2 eq), triethylamine (300 mg, 2.96 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (137 mg, 0.24 mmol, 0.1 eq) and palladium acetate (28 mg, 0.12 mmol, 0.05 eq) were added. Then, the reaction was carried out at 100 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with dichloromethane, and the organic phase was washed 3 times with water, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 3 was obtained from the crude product through flash chromatography (DCM / MeOH = 100 / 1 - 50 / 1). MS-ESI: Calculated value [M+H] + 318.10, Measured value [M+H] + : 318.25

[0659] Step (2):

[0660]

Chem.

[0661] In a sealed tube, compound 3 (700 mg, 2.2 mmol, 1 eq) was dissolved in methylbenzene (10 mL), triphenylphosphine (1.1 g, 4.4 mmol, 2 eq) and trichlorosilane (5.9 g, 44 mmol, 20 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, rapid cooling was carried out using methanol (20 mL), the pH of the reaction solution was adjusted to neutral using 2N NaOH, the solvent was concentrated, diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 4 was obtained from the crude product through flash chromatography (PE / EA = 100 / 1 - 25 / 1). MS-ESI: Calculated value [M] + 302.11, Measured value [M + H] + : 302.05.

[0662] Step (3):

[0663]

Chemical Structure

[0664] In a sealed tube, compound 4 (100 mg, 0.33 mmol, 1 eq) was dissolved in DMSO (2 mL), compound 2 (65 mg, 0.33 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.0066 mmol, 0.02 eq) were added, and then the reaction was carried out at 110 °C for 5 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound AB35437 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35437: MS-ESI: Calculated value [M] + 417.15, Measured value [M] + : 417.30. 11H NMR (400 MHz, CDCl3) δ 12.25 (s, 1H), 11.99 (s, 1H), 8.49 (s, 1H), 7.95 - 7.88 (m, 4H), 7.81 - 7.71 (m, 10H), 7.65 - 7.61 (m, 2H), 7.35 - 7.23 (m, 2H), 6.67 - 6.65 (m, 2H). Example 4 Synthesis of Compound AB35449 The chemical structural formula of Compound AB35449 is as follows.

[0665]

Chemical Structure

[0666] Compound AB35449 The synthetic route of Compound AB35449 is as follows.

[0667] Step:

[0668]

Chemical Structure

[0669] In a sealed tube, Compound 1 (200 mg, 1.02 mmol, 1 eq) was dissolved in anhydrous dimethyl sulfoxide (2 mL), triphenylphosphine (267 mg, 1.02 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (9 mg, 0.0102 mmol, 0.01 eq) were added, and then the reaction was carried out at 110 °C for 5 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB35449 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35449: MS-ESI: Calculated value [M] + 378.14, Measured value [M + H] + : 378.30. 1 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.46 (s, 1H), 8.18 (d, J = 4.0 Hz, 1H), 7.92 - 7.88 (m, 3H), 7.74 - 7.64 (m, 12H), 7.38 (d, J = 4.0 Hz, 1H), 7.30 (s, 1H), 6.85 - 6.84 (m, 1H), 6.72 (s, 1H). Example 5 Synthesis of Compound AB35450 The chemical structural formula of Compound AB35450 is as follows.

[0670] [Chemical formula]

[0671] Compound AB35450 The synthetic route of Compound AB35450 is as follows.

[0672] [Chemical formula]

[0673] In a sealed tube, Compound 1 (300 mg, 1.5 mmol, 1 eq) was dissolved in anhydrous dimethyl sulfoxide (2 mL), triphenylphosphine (400 mg, 1.5 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (15 mg, 0.015 mmol, 0.01 eq) were added, and then the reaction was carried out at 110 °C for 5 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB35450 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35450: MS-ESI: Calculated value [M] + 378.14, Measured value [M + H] +: 378.15. 1 H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 8.55 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.95 - 7.91 (m, 3H), 7.77 - 7.70 (m, 12H), 7.57 (d, J = 4.0 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.07 - 7.01 (m, 1H), 5.51 (s, 1H). Example 6 Synthesis of Compound AB35451 The chemical structural formula of Compound AB35451 is as follows.

[0674] [Chemical formula]

[0675] Compound AB35451 The synthetic route of Compound AB35451 is as follows.

[0676] Step (1):

[0677] [Chemical formula]

[0678] In a sealed tube, compound 1 (1.5 g, 7.42 mmol, 1 eq) was dissolved in dimethyl sulfoxide (30 mL), and compound 2 (1.6 g, 8.16 mmol, 1.1 eq), triethylamine (899 mg, 8.90 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (410 mg, 0.74 mmol, 0.1 eq), and palladium acetate (83 mg, 0.37 mmol, 0.05 eq) were added. Then, the reaction was carried out at 100 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with dichloromethane, and the organic phase was washed 3 times with water, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 3 was obtained from the crude product through flash chromatography (DCM / MeOH = 100 / 1 - 50 / 1). MS-ESI: Calculated value [M+H] + 318.10, Measured value [M+H] + : 318.25。

[0679] Step (2):

[0680]

Chemical formula

[0681] In a sealed tube, compound 3 (1.3 g, 4.09 mmol, 1 eq) was dissolved in methylbenzene (40 mL), and triphenylphosphine (2.1 g, 8.18 mmol, 2 eq) and trichlorosilane (11.1 g, 81.8 mmol, 20 eq) were added. Then, the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, rapid cooling was carried out using methanol (50 mL), the pH of the reaction solution was adjusted to neutral using 2N NaOH, the solvent was concentrated, diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 4 was obtained from the crude product through flash chromatography (PE / EA = 100 / 1 - 25 / 1). MS-ESI: Calculated value [M+H] + 302.11, Measured value [M+H]+ : 302.05

[0682] Step (3):

[0683]

Chem.

[0684] In a sealed tube, compound 4 (200 mg, 0.66 mmol, 1 eq) was dissolved in dimethylbenzene (3 mL), compound 2 (143 mg, 0.73 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol, 0.02 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound AB35451 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35451: MS-ESI: Calculated value [M] + : 417.15, Measured value [M] + : 417.10. 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 2H), 8.52 (s, 1H), 7.93 - 7.72 (m, 14H), 7.64 (s, 2H), 7.36 - 7.31 (m, 2H), 6.66 (s, 2H). Example 7 Synthesis of compound AB35452 The chemical structural formula of compound AB35452 is as follows.

[0685]

Chem.

[0686] Compound AB35452 The synthetic route of compound AB35452 is as follows.

[0687] Step (1):

[0688]

Chem.

[0689] In a sealed tube, compound 1 (2 g, 9.9 mmol, 1 eq) was dissolved in dimethyl sulfoxide (30 mL), and compound 2 (2.33 g, 11.87 mmol, 1.2 eq), triethylamine (1.2 g, 11.87 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (550 mg, 0.99 mmol, 0.1 eq) and palladium acetate (111 mg, 0.495 mmol, 0.05 eq) were added. Then, the reaction was carried out at 100 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with dichloromethane, and the organic phase was washed 3 times with water, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 3 was obtained from the crude product through flash chromatography (DCM / MeOH = 100 / 1 - 50 / 1). MS-ESI: Calculated value [M+H] + 318.10, Measured value [M+H] + : 318.05

[0690] Step (2):

[0691]

Chem.

[0692] In a sealed tube, compound 3 (2 g, 6.3 mmol, 1 eq) was dissolved in methylbenzene (200 mL), triphenylphosphine (3.3 g, 12.6 mmol, 2 eq) and trichlorosilane (12.8 ml, 126 mmol, 20 eq) were added, and then the reaction was carried out at 100 °C for 16 hours under the protection of nitrogen gas. After cooling, rapid cooling was carried out using methanol (20 mL), the pH of the reaction solution was adjusted to neutral using 2N NaOH, the solid was filtered off, the solvent was concentrated, diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 4 was obtained from the crude product through flash chromatography (PE / EA = 100 / 1 to 25 / 1). MS-ESI: calculated value [M+H] + 301.11, measured value [M+H] + : 302.10

[0693] Step (3):

[0694]

Chemical Structure

[0695] In a sealed tube, compound 4 (200 mg, 0.66 mmol, 1 eq) was dissolved in DMSO (2 mL), compound 5 (156 mg, 0.79 mmol, 1.2 eq) and tris(dibenzylideneacetone)dipalladium (60 mg, 0.066 mmol, 0.1 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound AB35452 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35452: MS-ESI: calculated value [M] + 418.15, measured value [M] + : 418.10 11H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.22 (d, J = 4.0 Hz, 1H), 8.57 (s, 1H), 8.08 - 8.02 (m, 2H), 7.93 - 7.89 (m, 2H), 7.78 - 7.73 (m, 9H), 7.54 (d, J = 4.0 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.22 - 7.16 (m, 1H), 5.60 - 5.56 (m, 2H). Example 8 Synthesis of Compound AB35461 The chemical structural formula of Compound AB35461 is as follows.

[0696] [Chemical Structure Diagram]

[0697] Compound AB35461 The synthetic route of Compound AB35461 is as follows.

[0698] [Chemical Structure Diagram]

[0699] In a sealed tube, Compound 1 (200 mg, 0.76 mmol, 1 eq) was dissolved in dimethylbenzene (2 mL), Compound 2 (165 mg, 0.84 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol, 0.05 eq) were added, and then the reaction was carried out at 130 °C for 4 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB35461 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35461: MS-ESI: Calculated value [M] + 379.14, Measured value [M] +: 379.20. 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.45 (s, 1H), 7.97 - 7.90 (m, 4H), 7.81 - 7.71 (m, 14H), 7.41 - 7.35 (m, 1H). Example 9 Synthesis of Compound AB35462 The chemical structural formula of Compound AB35462 is as follows.

[0700]

Chemical Structure

[0701] Compound AB35462 The synthetic route of Compound AB35462 is as follows.

[0702] Step (1):

[0703]

Chemical Structure

[0704] In a sealed tube, Compound 1 (560 mg, 2.77 mmol, 1 eq) was dissolved in dimethyl sulfoxide (10 mL), and Compound 2 (652 mg, 3.32 mmol, 1.2 eq), triethylamine (335 mg, 3.32 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (155 mg, 0.28 mmol, 0.1 eq), and palladium acetate (31 mg, 0.14 mmol, 0.05 eq) were added. Then, the reaction was carried out at 100 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with dichloromethane, and the organic phase was washed 3 times with water, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and a white solid Compound 3 (340 mg, yield: 38.7%) was obtained from the crude product through flash chromatography (DCM / MeOH = 100 / 1 - 50 / 1). MS-ESI: Calculated value [M+H] + 318.10, Measured value [M+H] + : 318.05。

[0705] Step (2):

[0706]

Chem.

[0707] In a sealed tube, compound 3 (340 mg, 1.07 mmol, 1 eq) was dissolved in methylbenzene (10 mL), triphenylphosphine (561 mg, 2.14 mmol, 2 eq) and trichlorosilane (2.9 g, 21.4 mmol, 20 eq) were added, then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, rapid cooling was carried out using methanol (50 mL), the pH of the reaction solution was adjusted to neutral using 2N NaOH, the solid was filtered off, the solvent was concentrated, diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 4 (300 mg) was obtained from the crude product through flash chromatography (PE / EA = 100 / 1 - 25 / 1). MS-ESI: Calculated value [M+H] + 302.11, Measured value [M+H] + : 302.05。

[0708] Step (3):

[0709]

Chem.

[0710] In the tube sealing step, compound 4 (200 mg, 0.66 mmol, 1 eq) was dissolved in dimethylbenzene (1 mL), compound 2 (156 mg, 0.79 mmol, 1.2 eq) and tris(dibenzylideneacetone)dipalladium (64 mg, 0.07 mmol, 0.1 eq) were added, and then the reaction was carried out at 130 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound AB35462 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35462: MS-ESI: Calculated value [M] + 417.15, Measured value [M] + : 417.10 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.41 (s, 1H), 8.17 (d, J = 8.0 Hz, 2H), 7.87 - 7.85 (m, 2H), 7.75 - 7.62 (m, 9H), 7.3 - 7.25 (m, 4H), 7.06 - 7.03 (m, 2H), 6.71 (s, 2H). Example 10 Synthesis of Compound AB35470 The chemical structural formula of compound AB35470 is as follows.

[0711]

Chemical formula

[0712] Compound AB35470 The synthesis route of compound AB35470 is as follows.

[0713]

Chemical formula

[0714] In the tube sealing step, compound 1 (200 mg, 0.76 mmol, 1 eq) was dissolved in dimethyl sulfoxide (2 mL), compound 2 (166 mg, 0.84 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol, 0.05 eq) were added, and then the reaction was carried out at 130 °C for 4 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound AB35470 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35470: MS-ESI: Calculated value [M] + 379.14, Measured value [M] + : 379.10. 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.32 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 4.0 Hz, 1H), 7.79 - 7.77 (m, 3H), 7.76 - 7.77 (m, 12H), 7.57 - 7.52 (m, 1H). Example 11 Synthesis of compound AB35471 The chemical structural formula of compound AB35471 is as follows.

[0715]

Chemical formula

[0716] Compound AB35471 The synthetic route of compound AB35471 is as follows.

[0717] Step (1):

[0718]

Chemical formula

[0719] In a sealed tube, compound 1 (2 g, 9.9 mmol, 1 eq) was dissolved in dimethyl sulfoxide (30 mL), and compound 2 (2.33 g, 11.87 mmol, 1.2 eq), triethylamine (1.2 g, 11.87 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (550 mg, 0.99 mmol, 0.1 eq) and palladium acetate (111 mg, 0.495 mmol, 0.05 eq) were added. Then, the reaction was carried out at 100 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with dichloromethane, and the organic phase was washed 3 times with water, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid. Compound 3 as a white solid was obtained from the crude product through flash chromatography (DCM / MeOH = 100 / 1 - 50 / 1). MS-ESI: Calculated value [M+H] + 318.10, Measured value [M+H] + : 318.05.

[0720] Step (2):

[0721]

Chemical formula

[0722] In a sealed tube, compound 3 (2 g, 6.3 mmol, 1 eq) was dissolved in methylbenzene (200 mL), and triphenylphosphine (3.3 g, 12.6 mmol, 2 eq) and trichlorosilane (12.8 ml, 126 mmol, 20 eq) were added. Then, the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, rapid cooling was carried out using methanol (50 mL), the pH of the reaction solution was adjusted to neutral using 2N NaOH, the solid was filtered off, the solvent was concentrated, diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid. Compound 4 was obtained from the crude product through flash chromatography (PE / EA = 100 / 1 - 25 / 1). MS-ESI: Calculated value [M+H] + 302.11, Measured value [M+H] + : 302.10

[0723] Step (3):

[0724]

Chem.

[0725] In a sealed tube, compound 4 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethylbenzene (1 mL), compound 2 (78 mg, 0.39 mmol, 1.2 eq) and tris(dibenzylideneacetone)dipalladium (30 mg, 0.033 mmol, 0.1 eq) were added, and then the reaction was carried out at 130 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound AB35471 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35471: MS-ESI: Calculated value [M] + 418.15, Measured value [M+H] + : 418.10 1 H NMR (400 MHz, DMSO-d6) δ 8.54 - 8.51 (m, 2H), 8.01 (d, J = 4.0 Hz, 1H), 7.90 - 7.80 (m, 2H), 7.75 - 7.68 (m, 10H), 7.52 (s, 1H), 7.40 - 7.38 (m, 1H), 7.19 - 7.14 (m, 2H), 5.56 (s, 1H), 5.47 (s, 1H). Example 12 Synthesis of compound AB35472 The chemical structural formula of compound AB35472 is as follows.

[0726]

Chem.

[0727] Compound AB35472 The synthetic route of Compound AB35472 is as follows.

[0728]

Chemical Structure

[0729] In a sealed tube, Compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (1 mL), Compound 2 (63 mg, 0.40 mmol, 1.2 eq) and tris(dibenzylideneacetone)dipalladium (27 mg, 0.03 mmol, 0.1 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB35472 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35472: MS-ESI: Calculated value [M] + 379.14, Measured value [M] + : 379.10. 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 9.05 (s, 1H), 8.86 (d, J = 4.0 Hz, 1H), 8.47 (s, 1H), 8.20 - 8.18 (m, 1H), 7.91 - 7.85 (m, 3H), 7.80 - 7.77 (m, 11H), 7.28 - 7.23 (m, 1H), 6.67 (s, 1H). Example 13 Synthesis of Compound AB35473 The chemical structural formula of Compound AB35473 is as follows.

[0730]

Chemical Structure

[0731] Compound AB35473 The synthetic route of Compound AB35473 is as follows.

[0732]

Chemical formula

[0733] In a sealed tube, Compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (1 mL), Compound 2 (63 mg, 0.40 mmol, 1.2 eq) and tris(dibenzylideneacetone)dipalladium (30 mg, 0.033 mmol, 0.1 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB35473 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35473: MS-ESI: Calculated value [M] + 379.14, Measured value [M] + : 379.30. 1 H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 9.03 (s, 1H), 8.86 (d, J = 4.0 Hz, 1H), 8.53 (s, 1H), 8.19 - 8.16 (m, 1H), 7.85 - 7.78 (m, 13H), 7.63 (s, 1H), 7.36 - 7.31 (m, 1H), 6.64 (s, 1H). Example 14 Synthesis of Compound AB35474 The chemical structural formula of Compound AB35474 is as follows.

[0734]

Chemical formula

[0735] Compound AB35474 The synthetic route of Compound AB35474 is as follows.

[0736]

Chem.

[0737] In a sealed tube, Compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (2 mL), Compound 2 (63 mg, 0.40 mmol, 1.2 eq) and tris(dibenzylideneacetone)dipalladium (30 mg, 0.033 mmol, 0.1 eq) were added, and then the reaction was carried out at 130 °C for 4 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB35474 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35474: MS-ESI: Calculated value [M] + 379.14, Measured value [M] + : 379.10. 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.98 - 8.96 (m, 2H), 8.50 (s, 1H), 7.94 - 7.72 (m, 14H), 7.64 (s, 1H), 7.35 - 7.30 (m, 1H), 6.65 (s, 1H). Example 15 Synthesis of Compound AB35477 The chemical structural formula of Compound AB35477 is as follows.

[0738]

Chem.

[0739] Compound AB35477 The synthetic route of Compound AB35477 is as follows.

[0740] Step (1):

[0741]

Chemical formula

[0742] In a sealed tube, dissolve Compound 1 (2 g, 9.89 mmol, 1 eq) in dimethyl sulfoxide (50 mL), add Compound 2 (2.3 g, 11.87 mmol, 1.2 eq), triethylamine (1.2 g, 11.87 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (549 mg, 0.99 mmol, 0.1 eq), and palladium acetate (110 mg, 0.49 mmol, 0.05 eq). Then, carry out the reaction at 100 °C for 16 hours under the protection of nitrogen gas. After cooling, dilute the reaction solution with dichloromethane, wash the organic phase 3 times with water, dry it over anhydrous sodium sulfate, filter and centrifuge to remove the liquid, and obtain Compound 3 as a white solid from the crude product through flash chromatography (DCM / MeOH = 100 / 1 to 50 / 1).

[0743] Step (2):

[0744]

Chemical formula

[0745] In a sealed tube, compound 3 (2 g, 6.28 mmol, 1 eq) was dissolved in methylbenzene (50 mL), triphenylphosphine (3.3 g, 12.56 mmol, 2 eq) and trichlorosilane (17.0 g, 125.6 mmol, 20 eq) were added, and then the reaction was carried out at 100 °C for 16 hours under the protection of nitrogen gas. After cooling, rapid cooling was carried out using methanol (50 mL), the pH of the reaction solution was adjusted to neutral using 2N NaOH, the solid was filtered off, the solvent was concentrated, diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 4 was obtained from the crude product through flash chromatography (PE / EA = 100 / 1 - 25 / 1).

[0746] Step (3):

[0747]

Chemical formula

[0748] In a sealed tube, compound 4 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethylbenzene (2 mL), compound 2 (65 mg, 0.33 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (30 mg, 0.066 mmol, 0.1 eq) were added, and then the reaction was carried out at 120 °C for 5 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound AB35477 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35477: MS-ESI: Calculated value [M] + 419.14, Measured value [M + H] + : 419.15. 11H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 2H), 8.49 (s, 3H), 8.06 (d, J = 8.0 Hz, 2H), 7.92 - 7.88 (m, 2H), 7.83 - 7.73 (m, 10H), 5.62 (s, 2H). Example 16 Synthesis of Compound AB35479 The chemical structural formula of Compound AB35479 is as follows.

[0749] [Chemical Structure Diagram]

[0750] Compound AB35479 The synthetic route of Compound AB35479 is as follows.

[0751] [Chemical Structure Diagram]

[0752] In a sealed tube, Compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (1 mL), Compound 2 (63 mg, 0.40 mmol, 1.2 eq) and tris(dibenzylideneacetone)dipalladium (20 mg, 0.033 mmol, 0.1 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB35479 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35479: MS-ESI: Calculated value [M] + 379.14, Measured value [M + H] + : 379.10. 11H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.99 - 8.97 (m, 2H), 8.47 (s, 1H), 7.95 - 7.93 (m, 3H), 7.79 - 7.73 (m, 12H), 7.27 - 7.22 (m, 1H), 6.68 (s, 1H). Example 17 Synthesis of Compound AB35480 The chemical structural formula of Compound AB35480 is as follows.

[0753] [Chemical formula]

[0754] Compound AB35480 The synthetic route of Compound AB35480 is as follows.

[0755] Step (1):

[0756] [Chemical formula]

[0757] Dissolve Compound 1 (5 g, 24.73 mmol, 1 eq) in dimethyl sulfoxide (50 mL), add Compound 2 (5.8 g, 29.67 mmol, 1.2 eq), triethylamine (3.0 g, 29.67 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (1.3 g, 2.47 mmol, 0.1 eq) and palladium acetate (276 mg, 1.23 mmol, 0.05 eq), then carry out the reaction at 100 °C for 16 hours through the protection of nitrogen gas. After cooling, dilute the reaction solution with dichloromethane, wash the organic phase 3 times with water, dry it over anhydrous sodium sulfate, filter and centrifuge to remove the liquid, and obtain Compound 3 as a white solid from the crude product through flash chromatography (DCM / MeOH = 100 / 1 - 50 / 1).

[0758] Step (2):

[0759]

Chem.

[0760] In a sealed tube, compound 3 (8.0 g, 25.13 mmol, 1 eq) was dissolved in methylbenzene (100 mL), triphenylphosphine (13.2 g, 50.26 mmol, 2 eq) and trichlorosilane (68 g, 502.6 mmol, 20 eq) were added, and then the reaction was carried out at 110 °C for 16 h under the protection of nitrogen gas. After cooling, rapid cooling was carried out using methanol (200 mL), the pH of the reaction solution was adjusted to neutral using 2N NaOH, the solid was filtered off, the solvent was concentrated, diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 4 was obtained from the crude product through flash chromatography (PE / EA = 100 / 1 - 25 / 1).

[0761] Step (3):

[0762]

Chem.

[0763] In a sealed tube, compound 4 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethylbenzene (2 mL), compound 2 (65 mg, 0.33 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (30 mg, 0.033 mmol, 0.1 eq) were added, and then the reaction was carried out at 120 °C for 5 h under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound AB35480 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35480: MS-ESI: Calculated value [M] +419.14, Measured value [M+H] + : 419.10 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.23 (d, J = 4.0 Hz, 2H), 7.93 - 7.91 (m, 2H), 7.8 - 7.74 (m, 9H), 7.63 - 7.61 (m, 2H), 7.41 - 7.35 (m, 2H), 7.07 (s, 2H). Example 18 Synthesis of Compound AB35481 The chemical structural formula of Compound AB35481 is as follows

[0764]

Chemical Structure

[0765] Compound AB35481 The synthetic route of Compound AB35481 is as follows

[0766]

Chemical Structure

[0767] In a sealed tube, Compound 1 (100 mg, 0.38 mmol, 1 eq) was dissolved in dimethyl sulfoxide (1 mL), Compound 2 (89 mg, 0.45 mmol, 1.2 eq) and tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol, 0.1 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB35481 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35481: MS-ESI: Calculated value [M] + 379.14, Measured value [M+H] + : 379.15 1 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.94 - 8.92 (m, 3H), 7.76 - 7.66 (m, 12H), 7.63 - 7.61 (m, 1H), 7.24 - 7.20 (m, 1H), 7.02 (s, 1H). Example 19 Synthesis of Compound AB35482 The chemical structural formula of Compound AB35482 is as follows.

[0768] [Chemical formula]

[0769] Compound AB35482 The synthetic route of Compound AB35482 is as follows.

[0770] [Chemical formula]

[0771] In a sealed tube, Compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (1 mL), Compound 2 (78 mg, 0.40 mmol, 1.2 eq) and tris(dibenzylideneacetone)dipalladium (30 mg, 0.033 mmol, 0.1 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB35482 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35482: MS-ESI: Calculated value [M] + 418.15, Measured value [M + H] + : 418.25. 11H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.51 (s, 1H), 8.20 - 8.00 (m, 2H), 7.95 - 7.91 (m, 2H), 7.74 - 7.64 (m, 10H), 7.51 (s, 1H), 7.41 - 7.37 (m, 2H), 7.19 - 7.14 (m, 1H), 7.00 (s, 1H), 5.56 (s, 1H). Example 20 Synthesis of Compound AB35495 The chemical structural formula of Compound AB35495 is as follows.

[0772] [Chemical Structure Diagram]

[0773] Compound AB35495 The synthesis route of Compound AB35495 is as follows.

[0774] [Chemical Structure Diagram]

[0775] In a sealed tube, Compound 1 (200 mg, 0.57 mmol, 1 eq) was dissolved in dimethyl sulfoxide (2 mL), Compound 2 (134 mg, 0.68 mmol, 1.2 eq) and tris(dibenzylideneacetone)dipalladium (52 mg, 0.057 mmol, 0.1 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB35495 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35495: MS-ESI: Calculated value [M] + 468.17, Measured value [MH] + : 468.40. 1 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.81 - 7.77 (m, 2H), 7.55 - 7.53 (m, 7H), 7.30 - 7.22 (m, 7H), 6.62 (s, 1H), 3.87 (s, 9H). Example 21 Synthesis of Compound AB35503 The chemical structural formula of Compound AB35503 is as follows.

[0776]

Chemical Structure

[0777] Compound AB35503 The synthetic route of Compound AB35503 is as follows.

[0778]

Chemical Structure

[0779] In a sealed tube, Compound 1 (200 mg, 0.57 mmol, 1 eq) was dissolved in dimethyl sulfoxide (2 mL), Compound 2 (134 mg, 0.68 mmol, 1.2 eq) and tris(dibenzylideneacetone)dipalladium (52 mg, 0.057 mmol, 0.1 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB35503 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35503: MS-ESI: Calculated value [M] + 468.17, Measured value [M + H] + : 468.20. 11H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.49 (s, 1H), 7.91 - 7.89 (m, 1H), 7.62 - 7.50 (m, 8H), 7.30 - 7.25 (m, 6H), 7.16 - 7.13 (m, 1H), 6.64 (s, 1H), 3.87 (s, 9H). Example 22 Synthesis of Compound AB35507 The chemical structural formula of Compound AB35507 is as follows.

[0780]

Chemical Structure

[0781] Compound AB35507 The synthetic route of Compound AB35507 is as follows.

[0782] Step (1):

[0783]

Chemical Structure

[0784] Dissolve Compound 1 (3.5 g, 17.31 mmol, 1 eq) in dimethyl sulfoxide (50 mL), add Compound 2 (3.3 g, 20.77 mmol, 1.2 eq), triethylamine (2.1 g, 20.77 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (959 mg, 1.73 mmol, 0.1 eq) and palladium acetate (194 mg, 0.86 mmol, 0.05 eq), and then carry out the reaction at 100 °C overnight under the protection of nitrogen gas. After the reaction is completed, dilute the reaction solution with dichloromethane, wash the organic phase twice with water, dry it over anhydrous sodium sulfate, filter and centrifuge to remove the liquid, and obtain Compound 3 from the crude product through flash chromatography (DCM / MeOH = 100 / 1 - 50 / 1).

[0785] Step (2):

[0786]

Chem.

[0787] In a sealed tube, compound 3 (2 g, 7.16 mmol, 1 eq) was dissolved in methylbenzene (200 mL), triphenylphosphine (3.7 g, 14.32 mmol, 2 eq) and trichlorosilane (19.4 ml, 143.2 mmol, 20 eq) were added, and then the reaction was carried out at 110 °C for 16 h under the protection of nitrogen gas. After cooling, rapid cooling was carried out using methanol (50 mL), the pH of the reaction solution was adjusted to neutral using 2N NaOH, the solid was filtered off, the solvent was concentrated, diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 4 was obtained from the crude product through flash chromatography (PE / EA = 100 / 1 to 25 / 1).

[0788] Step (3):

[0789]

Chem.

[0790] In a sealed tube, compound 4 (100 mg, 0.38 mmol, 1 eq) was dissolved in dimethylbenzene (2 mL), compound 5 (89 mg, 0.45 mmol, 1.2 eq) and tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol, 0.1 eq) were added, and then the reaction was carried out at 120 °C for 5 h under the protection of nitrogen gas. After the reaction was completed, the reaction solution was diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound AB35507 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35507: MS-ESI: Calculated value [M]+ 379.14, measured value [M+H] + : 379.10 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 4.0 Hz, 1H), 8.47 (s, 1H), 8.15 - 8.13 (m, 1H), 7.83 - 7.71 (m, 15H), 7.29 - 7.24 (m, 1H), 6.66 (s, 1H). Example 23 Compound 24 Compound 24 is synthesized by the conventional synthesis method. The chemical structural formula of Compound 24 is as follows.

[0791]

Chemical formula

[0792] Compound 24 Example 24 Compound 33 Compound 33 is synthesized by the conventional synthesis method. The chemical structural formula of Compound 33 is as follows.

[0793]

Chemical formula

[0794] Compound 33 Example 25 Compound 35 Compound 35 is synthesized by the conventional synthesis method. The chemical structural formula of Compound 35 is as follows.

[0795]

Chemical formula

[0796] Compound 35 Example 26 Compound 36 Compound 36 is synthesized by the conventional synthesis method. The chemical structural formula of Compound 36 is as follows.

[0797]

Chem.

[0798] Compound 36 Example 27 Compound 42 Compound 42 is synthesized by the conventional synthesis method. The chemical structural formula of Compound 42 is as follows.

[0799]

Chem.

[0800] Compound 42 Example 28 Compound 43 Compound 43 is synthesized by the conventional synthesis method. The chemical structural formula of Compound 43 is as follows.

[0801]

Chem.

[0802] Compound 43 Example 29 Compound 46 Compound 46 is synthesized by the conventional synthesis method. The chemical structural formula of Compound 46 is as follows.

[0803]

Chem.

[0804] Compound 46 Example 30 Compound 47 Compound 47 is synthesized by the conventional synthesis method. The chemical structural formula of Compound 47 is as follows.

[0805]

Chem.

[0806] Compound 47 Example 31 Compound 48 Synthesize Compound 48 by the conventional synthesis method. The chemical structural formula of Compound 48 is as follows.

[0807]

Chemical Structure

[0808] Compound 48 Example 32 Compound 49 Synthesize Compound 49 by the conventional synthesis method. The chemical structural formula of Compound 49 is as follows.

[0809]

Chemical Structure

[0810] Compound 49 Example 33 Compound 50 Synthesize Compound 50 by the conventional synthesis method. The chemical structural formula of Compound 50 is as follows.

[0811]

Chemical Structure

[0812] Compound 50 Example 34 Compound 51 Synthesize Compound 51 by the conventional synthesis method. The chemical structural formula of Compound 51 is as follows.

[0813]

Chemical Structure

[0814] Compound 51 Example 35 Compound 52 Compound 52 is synthesized by a conventional synthesis method. The chemical structural formula of Compound 52 is as follows.

[0815] [Chemical formula]

[0816] Compound 52 Example 36 Compound 53 Compound 53 is synthesized by a conventional synthesis method. The chemical structural formula of Compound 53 is as follows.

[0817] [Chemical formula]

[0818] Compound 53 Example 37 Compound 54 Compound 54 is synthesized by a conventional synthesis method. The chemical structural formula of Compound 54 is as follows.

[0819] [Chemical formula]

[0820] Compound 54 Example 38 Compound 55 Compound 55 is synthesized by a conventional synthesis method. The chemical structural formula of Compound 55 is as follows.

[0821] [Chemical formula]

[0822] Compound 55 Example 39 Compound 56 Compound 56 is synthesized by a conventional synthesis method. The chemical structural formula of Compound 56 is as follows.

[0823] [Chemical]

[0824] Compound 56 Example 40 Compound 57 Compound 57 is synthesized by a conventional synthesis method. The chemical structural formula of Compound 57 is as follows.

[0825] [Chemical]

[0826] Compound 57 Example 41 Compound 59 Compound 59 is synthesized by a conventional synthesis method. The chemical structural formula of Compound 59 is as follows.

[0827] [Chemical]

[0828] Compound 59 Example 42 Compound 60 Compound 60 is synthesized by a conventional synthesis method. The chemical structural formula of Compound 60 is as follows.

[0829] [Chemical]

[0830] Compound 60 Example 43 Compound 61 Compound 61 is synthesized by a conventional synthesis method. The chemical structural formula of Compound 61 is as follows.

[0831] [Chemical]

[0832] Compound 61 Example 44 Compound 62 Synthesize Compound 62 by the conventional synthesis method. The chemical structural formula of Compound 62 is as follows.

[0833]

Chemical formula

[0834] Compound 62 Example 45 Compound 63 Synthesize Compound 63 by the conventional synthesis method. The chemical structural formula of Compound 63 is as follows.

[0835]

Chemical formula

[0836] Compound 63 Example 46 Compound 64 Synthesize Compound 64 by the conventional synthesis method. The chemical structural formula of Compound 64 is as follows.

[0837]

Chemical formula

[0838] Compound 64 Example 47 Compound 65 Synthesize Compound 65 by the conventional synthesis method. The chemical structural formula of Compound 65 is as follows.

[0839]

Chemical formula

[0840] Compound 65 Example 48 Compound 66 Synthesize compound 66 by the conventional synthesis method. The chemical structural formula of compound 66 is as follows.

[0841]

Chem.

[0842] Compound 66 Example 49 Compound 67 Synthesize compound 67 by the conventional synthesis method. The chemical structural formula of compound 67 is as follows.

[0843]

Chem.

[0844] Compound 67 Example 50 Compound 68 Synthesize compound 68 by the conventional synthesis method. The chemical structural formula of compound 68 is as follows.

[0845]

Chem.

[0846] Compound 68 Example 51 Compound 69 Synthesize compound 69 by the conventional synthesis method. The chemical structural formula of compound 69 is as follows.

[0847]

Chem.

[0848] Compound 69 Example 52 Compound 73 Synthesize compound 73 by the conventional synthesis method. The chemical structural formula of compound 73 is as follows.

[0849]

Chem.

[0850] Compound 73 Example 53 Compound 74 Synthesize Compound 74 by the conventional synthesis method. The chemical structural formula of Compound 74 is as follows.

[0851]

Chem.

[0852] Compound 74 Example 54 Compound 76 Synthesize Compound 76 by the conventional synthesis method. The chemical structural formula of Compound 76 is as follows.

[0853]

Chem.

[0854] Compound 76 Example 55 Compound 80 Synthesize Compound 80 by the conventional synthesis method. The chemical structural formula of Compound 80 is as follows.

[0855]

Chem.

[0856] Compound 80 Example 56 Compound 83 Synthesize Compound 83 by the conventional synthesis method. The chemical structural formula of Compound 83 is as follows.

[0857]

Chem.

[0858] Compound 83 Example 57 Compound 84 Compound 84 is synthesized by a conventional synthesis method. The chemical structural formula of Compound 84 is as follows.

[0859]

Chemical formula

[0860] Compound 84 Example 58 Compound 85 Compound 85 is synthesized by a conventional synthesis method. The chemical structural formula of Compound 85 is as follows.

[0861]

Chemical formula

[0862] Compound 85 Example 59 Compound 87 Compound 87 is synthesized by a conventional synthesis method. The chemical structural formula of Compound 87 is as follows.

[0863]

Chemical formula

[0864] Compound 87 Example 60 Compound AB35527 The chemical structural formula of Compound AB35527 is as follows.

[0865]

Chemical formula

[0866] Compound AB35527 The synthesis route of Compound AB35527 is as follows.

[0867] [Chemical formula]

[0868] In a sealed tube, Compound 1 (200 mg, 0.57 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (111 mg, 0.57 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (52 mg, 0.057 mmol, 0.1 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35527 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). Compound AB35527: MS-ESI: Calculated value [M] + 468.17, Measured value [M] + : 468.20. 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.52 - 7.50 (m, 7H), 7.26 - 7.24 (m, 1H), 7.02 - 6.95 (m, 6H), 7.05 - 7.00 (m, 1H), 5.53 (s, 1H), 3.85 (s, 9H). Example 61 Compound AB35529 The chemical structural formula of Compound AB35529 is as follows.

[0869] [Chemical formula]

[0870] Compound AB35529 The synthetic route of Compound AB35529 is as follows.

[0871] [Chemical formula]

[0872] In the tube sealing process, compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35529 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35529: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.15 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.59 (s, 1H), 8.34 (s, 1H), 8.15 (d, J = 12 Hz, 1H), 7.98 - 7.73 (m, 14H), 7.65 (d, J = 4 Hz, 1H), 7.58 - 7.55 (m, 1H), 7.38 - 7.32 (m, 1H), 6.67 (d, J = 4 Hz, 1H). Example 62 Compound AB35537 The chemical structural formula of compound AB35537 is as follows.

[0873]

Chemical formula

[0874] Compound AB35537 The synthetic route of compound AB35537 is as follows.

[0875] [Chemical formula]

[0876] In a sealed tube, compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35537 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35537: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.15 1 H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.53 (s, 1H), 8.37 - 8.27 (m, 2H), 8.79 - 7.80 (m, 3H), 7.77 - 7.73 (m, 11H), 7.62 (s, 1H), 7.34 - 7.32 (m, 1H), 6.67 - 6.64 (m, 2H). Example 63 Compound AB35538 The chemical structural formula of compound AB35538 is as follows.

[0877] [Chemical formula]

[0878] Compound AB35538 The synthetic route of compound AB35538 is as follows.

[0879] [Chemical formula]

[0880] In the tube sealing step, compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35538 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35538: MS-ESI: Calculated value [M] + 418.15, measured value [M + H] + : 418.15 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.16 - 8.13 (m, 1H), 7.92 - 7.87 (m, 4H), 7.83 - 7.75 (m, 10H), 7.63 (d, J = 4.0 Hz, 1H), 7.37 - 7.32 (m, 2H). Example 64 Compound AB35539 The chemical structural formula of compound AB35539 is as follows.

[0881]

Chemical formula

[0882] Compound AB35539 The synthetic route of compound AB35539 is as follows.

[0883]

Chemical formula

[0884] In the tube sealing, compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours through the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35539 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35539: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.10 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.55 (s, 1H), 8.47 (m, 1H), 7.99 - 7.96 (m, 1H), 7.91 - 7.74 (m, 14H), 7.65 - 7.64 (d, J = 4.0 Hz, 1H), 7.46 - 7.33 (m, 2H), 6.67 (d, J = 4.0 Hz, 1H),. Example 65 Compound AB35548 The chemical structural formula of compound AB35548 is as follows.

[0885]

Chemical formula

[0886] Compound AB35548 The synthetic route of compound AB35548 is as follows.

[0887]

Chemical formula

[0888] In the tube sealing step, compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35548 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35548: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.15. 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.57 (s, 1H), 8.50 (s, 1H), 8.02 - 7.67 (m, 15H), 7.67 (d, J = 4.0 Hz, 1H), 7.49 - 7.36 (m, 2H), 7.70 (d, J = 4.0 Hz, 1H). Example 66 Compound AB35549 The chemical structural formula of compound AB35549 is as follows.

[0889]

Chemical formula

[0890] Compound AB35549 The synthetic route of compound AB35549 is as follows.

[0891]

Chemical formula

[0892] In the tube sealing step, compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35549 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35549: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.10 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.54 - 8.50 (m, 3H), 8.12 - 8.08 (m, 2H), 7.94 - 7.91 (m, 3H), 7.82 - 7.79 (m, 10H), 7.66 (d, J = 4.0 Hz, 1H), 7.41 - 7.36 (m, 1H), 6.82 (d, J = 4.0 Hz, 1H), 6.68 (d, J = 4.0 Hz, 1H). Example 67 Compound AB35563 The chemical structural formula of compound AB35563 is as follows.

[0893]

Chemical formula

[0894] Compound AB35563 The synthetic route of compound AB35563 is as follows.

[0895]

Chemical formula

[0896] In the tube sealing process, compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and after filtration, the filtrate was centrifuged to remove the liquid. Compound AB35563 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35563: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.10. 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.37 - 8.31 (m, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.94 - 7.91 (m, 2H), 7.79 - 7.75 (m, 10H), 7.56 (d, J = 4.0 Hz, 1H), 7.44 - 7.41 (m, 1H), 7.11 - 7.05 (m, 1H), 6.68 (d, J = 4.0 Hz, 1H), 5.56 (d, J = 4.0 Hz, 1H). Example 68 Compound AB35564 The chemical structural formula of compound AB35564 is as follows.

[0897]

Chemical Structure

[0898] Compound AB35564 The synthetic route of compound AB35564 is as follows.

[0899]

Chem.

[0900] In a sealed tube, compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (69 mg, 0.33 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35564 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35564: MS-ESI: Calculated value [M] + 431.17, Measured value [M] + : 431.15. 1 H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.57 (s, 1H), 8.09 - 8.01 (m, 2H), 7.91 - 7.87 (m, 2H), 7.74 - 7.68 (m, 8H), 7.51 - 7.44 (m, 3H), 7.41 - 7.36 (m, 1H), 7.25 - 7.14 (m, 2H), 5.54 (m, 2H), 3.89 (m, 3H). Example 69 Compound AB35569 The chemical structural formula of compound AB35569 is as follows.

[0901]

Chem.

[0902] Compound AB35569 The synthetic route of compound AB35569 is as follows.

[0903] [Chemical formula]

[0904] Dissolve compound 1 (100 mg, 0.33 mmol, 1 eq) in dimethyl sulfoxide (3 mL) in a sealed tube, add compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq), and then carry out the reaction at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, dilute the reaction solution with water, extract the organic phase with dichloromethane, collect the organic phase, dry it over anhydrous sodium sulfate, centrifuge the filtrate after filtration, and obtain compound AB35569 from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35569: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.05. 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.47 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.92 - 7.84 (m, 4H), 7.77 - 7.72 (m, 8H), 7.55 (d, J = 4.0 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.10 - 7.04 (m, 1H), 5.54 (d, J = 4.0 Hz, 1H). Example 70 Compound AB35570 The chemical structural formula of compound AB35570 is as follows.

[0905] [Chemical formula]

[0906] Compound AB35570 The synthetic route of Compound AB35570 is as follows.

[0907]

Chemical Structure

[0908] In a sealed tube, Compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35570 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35570: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.10. 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.46 (d, J = 4.0 Hz, 1H), 8.14 - 8.06 (m, 3H), 7.96 - 7.91 (m, 2H), 7.79 - 7.77 (m, 9H), 7.55 (s, 1H), 7.43 - 7.40 (m, 1H), 7.11 - 7.05 (m, 1H), 6.79 (s, 1H), 5.57 (s, 1H). Example 71 Compound AB35571 The chemical structural formula of Compound AB35571 is as follows.

[0909]

Chemical Structure

[0910] Compound AB35571 The synthetic route of Compound AB35571 is as follows.

[0911]

Chem.

[0912] In a sealed tube, Compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (88 mg, 0.42 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (7 mg, 0.008 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35571 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35571: MS-ESI: Calculated value [M] + 392.16, Measured value [M] + : 392.10. 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.96 - 7.93 (m, 3H), 7.89 - 7.86 (m, 2H), 7.82 - 7.71 (m, 12H), 7.66 (d, J = 4.0 Hz, 1H), 7.43 - 7.37 (m, 1H), 6.70 (d, J = 4.0 Hz, 1H), 3.91 (s, 3H). Example 72 Compound AB35572 The chemical structural formula of Compound AB35572 is as follows.

[0913]

Chem.

[0914] Compound AB35572 The synthetic route of Compound AB35572 is as follows.

[0915]

Chem.

[0916] In a sealed tube, Compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35572 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35572: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.10. 1 H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.54 (s, 1H), 8.25 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.85 - 7.81 (m, 2H), 7.74 - 7.66 (m, 9H), 7.48 (d, J = 4.0 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.12 - 7.03 (m, 2H), 5.49 (d, J = 4.0 Hz, 1H). Example 73 Compound AB35573 The chemical structural formula of Compound AB35573 is as follows.

[0917] [Chemical formula]

[0918] Compound AB35573 The synthetic route of Compound AB35573 is as follows.

[0919] [Chemical formula]

[0920] In a sealed tube, Compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (88 mg, 0.42 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (7 mg, 0.008 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35573 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35573: MS-ESI: Calculated value [M] + 392.16, Measured value [M] + : 392.10. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.96 - 7.92 (m, 3H), 7.78 - 7.70 (m, 12H), 7.57 - 7.49 (m, 2H), 7.12 - 7.06 (m, 1H), 5.52 (d, J = 4.0 Hz, 1H), 3.92 (s, 3H). Example 74 Compound AB35574 The chemical structural formula of Compound AB35574 is as follows.

[0921] [Chemical formula]

[0922] Compound AB35574 The synthetic route of Compound AB35574 is as follows.

[0923] [Chemical formula]

[0924] In a sealed tube, Compound 1 (100 mg, 0.32 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (70 mg, 0.35 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.006 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35574 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35574: MS-ESI: Calculated value [M] + 446.18, Measured value [M] + : 446.05. 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.23 - 8.19 (m, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.93 - 7.90 (m, 2H), 7.76 - 7.71 (m, 8H), 7.64 (s, 1H), 7.56 - 7.46 (m, 3H), 7.42 - 7.36 (m, 1H), 7.27 - 7.21 (m, 1H), 5.60 (d, J = 4.0 Hz, 1H), 4.05 (s, 3H), 3.90 (s, 3H). Example 75 Compound AB35576 The chemical structural formula of compound AB35576 is as follows.

[0925] [Chem.]

[0926] Compound AB35576 The synthetic route of compound AB35576 is as follows.

[0927] Step (1):

[0928] [Chem.]

[0929] Dissolve compound 1 (500 mg, 2.55 mmol, 1 eq) in tetrahydrofuran (10 mL) in a sealed tube, add sodium hydride (153 mg, 3.82 mmol, 1.5 eq, concentration in mineral oil is 60%) at 0 °C, and carry out the reaction for 0.5 h. Dissolve compound 2 (771 mg, 2.81 mmol, 1.1 eq) in tetrahydrofuran (5 mL), add the above reaction solution at 0 °C, and carry out the reaction for 1 h. Quench the reaction solution with a saturated aqueous ammonium chloride solution, and extract the organic phase with ethyl acetate. Dry the organic phase over anhydrous sodium sulfate, filter and centrifuge to remove the liquid, and obtain compound 3 from the crude product through flash chromatography (DCM / MeOH = 20:1).

[0930] Step (2):

[0931] [Chem.]

[0932] In the tube sealing process, compound 3 (100 mg, 0.32 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), triphenylphosphine (84 mg, 0.32 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (7 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35576 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35576: MS-ESI: Calculated value [M] + 491.22, Measured value [M] + : 491.20. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.96 - 7.93 (m, 4H), 7.77 - 7.71 (m, 14H), 7.40 - 7.36 (m, 1H), 6.70 (d, J = 4.0 Hz, 1H), 4.43 - 4.40 (m, 2H), 3.54 - 3.51 (m, 4H), 2.70 - 2.67 (m, 2H), 2.45 - 2.43 (m, 4H). Example 76 Compound AB35577 The chemical structural formula of compound AB35577 is as follows.

[0933]

Chem.

[0934] Compound AB35577 The synthetic route of compound AB35577 is as follows.

[0935]

Chem.

[0936] In the tube sealing step, compound 1 (100 mg, 0.32 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (62 mg, 0.32 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.006 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35577 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35577: MS-ESI: Calculated value [M] + 432.16, Measured value [M] + : 432.15 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.21 - 8.11 (m, 2H), 7.95 - 7.91 (m, 2H), 7.77 - 7.65 (m, 8H), 7.69 - 7.65 (m, 1H), 7.53 - 7.48 (m, 2H), 7.44 - 7.38 (m, 1H), 7.25 - 7.20 (m, 1H), 7.03 (m, 1H), 5.58 (d, J = 4.0 Hz, 1H), 3.90 (s, 3H). Example 77 Compound AB35578 The chemical structural formula of compound AB35578 is as follows.

[0937]

Chemical Structure

[0938] Compound AB35578 The synthetic route of compound AB35578 is as follows.

[0939] Step (1):

[0940] [Chem.]

[0941] In a sealed tube, compound 1 (500 mg, 2.55 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (153 mg, 3.82 mmol, 1.5 eq, with a concentration of 60% in mineral oil) was added at 0 °C, and the reaction was carried out for 0.5 h. MeI (771 mg, 2.81 mmol, 1.1 eq) was dissolved in N,N-dimethylformamide (5 mL), and the above reaction solution was added at 0 °C, and the reaction was carried out for 1 h. The reaction solution was quenched with a saturated aqueous ammonium chloride solution, and the organic phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 2 was obtained from the crude product via flash chromatography (DCM / MeOH = 20:1).

[0942] Step (2):

[0943] [Chem.]

[0944] In a sealed tube, compound 2 (100 mg, 0.47 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL). Compound 3 (149 mg, 0.47 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (9 mg, 0.009 mmol, 0.02 eq) were added. Then, the reaction was carried out at 120 °C for 16 h under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35578 was obtained from the crude product via reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35578: MS-ESI: Calculated value [M] +446.18, Measured value [M] + : 446.95 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.23 - 8.11 (m, 2H), 7.94 - 7.90 (m, 2H), 7.76 - 7.71 (m, 8H), 7.66 (s, 1H), 7.55 - 7.47 (m, 3H), 7.42 - 7.36 (m, 1H), 7.27 - 7.21 (m, 1H), 5.60 (d, J = 4.0 Hz, 1H), 4.05 (s, 3H), 3.90 (s, 3H). Example 78 Compound AB35579 The chemical structural formula of Compound AB35579 is as follows.

[0945]

Chemical Structure

[0946] Compound AB35579 The synthetic route of Compound AB35579 is as follows.

[0947] Step (1):

[0948]

Chemical Structure

[0949] In a sealed tube, compound 1 (500 mg, 2.55 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (153 mg, 3.83 mmol, 1.5 eq, with a concentration of 60% in mineral oil) was added at 0 °C, and the reaction was carried out for 0.5 h. Compound 2 (516 mg, 2.81 mmol, 1.1 eq) was dissolved in N,N-dimethylformamide (5 mL), and the above reaction solution was added at 0 °C, and the reaction was carried out for 1 h. The reaction solution was quenched with a saturated aqueous ammonium chloride solution, and the organic phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 3 was obtained from the crude product through flash chromatography (DCM / MeOH = 20:1).

[0950] Step (2):

[0951]

Chemical formula

[0952] In a sealed tube, compound 3 (100 mg, 0.32 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL). Triphenylphosphine (84 mg, 0.32 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (7 mg, 0.007 mmol, 0.02 eq) were added. Then, the reaction was carried out at 120 °C for 16 h under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35579 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35579: MS-ESI: Calculated value [M] + 489.25, Measured value [M] + : 489.20. 11H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.95 - 7.91 (m, 3H), 7.78 - 7.69 (m, 12H), 6.62 (d, J = 4.0 Hz, 1H), 7.49 - 7.46 (m, 1H), 7.10 - 7.04 (m, 1H), 5.53 (d, J = 4.0 Hz, 1H), 4.40 - 4.37 (m, 2H), 2.66 - 2.62 (m, 2H), 2.37 - 2.34 (m, 4H), 1.45 - 1.32 (m, 6H). Example 79 Compound AB35580 The chemical structural formula of Compound AB35580 is as follows.

[0953]

Chem.

[0954] The synthetic route of Compound AB35580 is as follows.

[0955]

Chem.

[0956] In a sealed tube, Compound 1 (100 mg, 0.32 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35580 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35580: MS-ESI: Calculated value [M]+ 418.15, measured value [M] + : 418.10. 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 12.0 Hz, 1H), 8.05 (d, J = 4.0 Hz, 1H), 7.97 - 7.90 (m, 3H), 7.77 - 7.72 (m, 9H), 7.56 - 7.54 (m, 2H), 7.44 - 7.40 (m, 1H), 7.10 - 7.04 (m, 1H), 5.54 (d, J = 4.0 Hz, 1H). Example 80 Compound AB35581 The chemical structural formula of compound AB35581 is as follows.

[0957]

Chemical formula

[0958] Compound AB35581 The synthetic route of compound AB35581 is as follows.

[0959]

Chemical formula

[0960] In a sealed tube, compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35581 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35581: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.10. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.35 (s, 1H), 8.17 - 8.15 (m, 1H), 8.06 (d, J = 4.0 Hz, 1H), 7.93 - 7.89 (m, 3H), 7.79 - 7.76 (m, 8H), 7.56 (d, J = 4.0 Hz, 1H), 7.43 - 7.41 (m, 1H), 7.38 - 7.33 (m, 1H), 7.13 - 7.07 (m, 1H), 5.56 (d, J = 4.0 Hz, 1H). Example 81 Compound AB35584 The chemical structural formula of Compound AB35584 is as follows.

[0961]

Chemical Structure Diagram

[0962] Compound AB35584 The synthetic route of Compound AB35584 is as follows.

[0963]

Chemical Structure Diagram

[0964] In the tube sealing step, compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35584 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35584: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.10 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.12 - 8.08 (m, 1H), 8.04 - 8.02 (m, 2H), 7.91 - 7.88 (m, 2H), 7.82 - 7.74 (m, 8H), 7.53 (d, J = 4.0 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.09 - 7.03 (m, 1H), 6.84 (d, J = 4.0 Hz, 1H), 5.56 (d, J = 4.0 Hz, 1H). Example 82 Compound AB35585 The chemical structural formula of compound AB35585 is as follows.

[0965]

Chemical Structure

[0966] Compound AB35585 The synthetic route of compound AB35585 is as follows.

[0967] Step (1):

[0968] [Chemical formula]

[0969] In a sealed tube, compound 1 (500 mg, 2.55 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (153 mg, 3.83 mmol, 1.5 eq, with a concentration of 60% in mineral oil) was added at 0 °C, and the reaction was carried out for 0.5 h. Compound 2 (523 mg, 2.81 mmol, 1.1 eq) was dissolved in N,N-dimethylformamide (5 mL), and the above reaction solution was added at 0 °C, and the reaction was carried out for 1 h. The reaction solution was quenched with a saturated aqueous ammonium chloride solution, and the organic phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 3 was obtained from the crude product through flash chromatography (DCM / MeOH = 20:1).

[0970] Step (2):

[0971] [Chemical formula]

[0972] In a sealed tube, compound 3 (140 mg, 0.45 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL). Triphenylphosphine (119 mg, 0.45 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (8 mg, 0.009 mmol, 0.02 eq) were added. Then, the reaction was carried out at 120 °C for 16 h under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35585 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35585: MS-ESI: Calculated value [M] + 491.22, Measured value [M] +: 489.20. 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.95 - 7.92 (m, 3H), 7.79 - 7.70 (m, 12H), 7.64 (d, J = 4.0 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.11 - 7.05 (m, 1H), 5.54 (d, J = 4.0 Hz, 1H), 4.43 - 4.40 (m, 2H), 3.47 (s, 4H), 2.71 - 2.68 (m, 2H), 2.41 - 2.38 (m, 4H). Example 83 Compound AB35588 The chemical structural formula of Compound AB35588 is as follows.

[0973]

Chemical formula

[0974] Compound AB35588 The synthetic route of Compound AB35588 is as follows.

[0975]

Chemical formula

[0976] In a sealed tube, Compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added. Then, the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35588 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35588: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.05. 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.55 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.90 - 7.87 (m, 3H), 7.81 - 7.70 (m, 8H), 7.52 (d, J = 4.0 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.10 - 7.05 (m, 1H), 6.73 (d, J = 4.0 Hz, 1H), 5.57 (d, J = 4.0 Hz, 1H). Example 84 Compound AB35589 The chemical structural formula of Compound AB35589 is as follows.

[0977]

Chemical formula

[0978] Compound AB35589 The synthetic route of Compound AB35589 is as follows.

[0979]

Chemical formula

[0980] In the tube sealing step, Compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35589 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35589: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.00。 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.29 - 8.26 (m, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.93 - 7.89 (m, 3H), 7.83 - 7.73 (m, 8H), 7.53 (d, J = 4.0 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.12 - 7.06 (m, 1H), 6.72 (d, J = 4.0 Hz, 1H), 5.57 (d, J = 4.0 Hz, 1H). Example 85 Compound AB35596 The chemical structural formula of Compound AB35596 is as follows.

[0981]

Chemical Structure

[0982] Compound AB35596 The synthetic route of Compound AB35596 is as follows.

[0983]

Chemical Structure

[0984] In the tube sealing, compound 1 (100 mg, 0.28 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (60 mg, 0.31 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (5 mg, 0.006 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35596 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35596: MS-ESI: Calculated value [M] + 477.17, Measured value [M] + : 477.55. 1 H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 2H), 8.54 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.61 - 7.56 (m, 4H), 7.50 (d, J = 4.0 Hz, 2H), 7.39 - 7.35 (m, 2H), 7.28 - 7.25 (m, 4H), 7.18 - 7.12 (m, 2H), 5.57 (d, J = 4.0 Hz, 2H), 3.87 (s, 6H). Example 86 Compound AB35597 The chemical structural formula of compound AB35597 is as follows.

[0985]

Chemical formula

[0986] Compound AB35597 The synthetic route of compound AB35597 is as follows.

[0987] [Chemical formula]

[0988] In a sealed tube, compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB35597 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB35597: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.10 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.50 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.89 - 7.85 (m, 4H), 7.78 - 7.71 (m, 10H), 7.60 (d, J = 4.0 Hz, 1H), 7.37 - 7.32 (m, 1H), 6.73 (d, J = 4.0 Hz, 1H), 6.63 (d, J = 4.0 Hz, 1H). Example 87 Compound AB36405 The chemical structural formula of compound AB36405 is as follows.

[0989] [Chemical formula]

[0990] Compound AB36405 The synthetic route of compound AB36405 is as follows.

[0991] [Chem.]

[0992] In a sealed tube, compound 1 (100 mg, 0.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (71 mg, 0.36 mmol, 1.1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB36405 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36405: MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.15. 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 9.27 (s, 1H), 8.49 (s, 1H), 7.90 - 7.87 (m, 3H), 7.79 - 7.72 (m, 12H), 7.61 (d, J = 4.0 Hz, 1H), 7.39 - 7.34 (m, 1H), 6.83 (d, J = 4.0 Hz, 1H), 6.64 (d, J = 4.0 Hz, 1H). Example 88 Compound AB36407 The chemical structural formula of compound AB36407 is as follows.

[0993] [Chem.]

[0994] Compound AB36407 The synthetic route of compound AB36407 is as follows.

[0995]

Chem.

[0996] In a sealed tube, compound 1 (500 mg, 1.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), compound 2 (281 mg, 1.33 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (24 mg, 0.027 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB36407 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36407: MS-ESI: Calculated value [M] + 506.20, Measured value [M] + : 506.35. 1 H NMR (400 MHz, DMSO-d6) δ 8.60 - 8.57 (m, 1H), 8.42 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 4.0 Hz, 1H), 7.65 - 7.59 (m, 4H), 7.53 (d, J = 4.0 Hz, 1H), 7.49 - 7.45 (m, 1H), 7.30 - 7.27 (m, 4H), 7.20 - 7.17 (m, 2H), 5.60 - 5.53 (m, 2H), 3.90 (s, 6H), 3.88 (s, 6H). Example 89 Compound AB36420 The chemical structural formula of compound AB36420 is as follows.

[0997]

Chem.

[0998] Compound AB36420 The synthetic route of Compound AB36420 is as follows.

[0999]

Chem.

[1000] In a sealed tube, Compound 1 (200 mg, 0.53 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (112 mg, 0.53 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.01 mmol, 0.02 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB36420 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36420: MS-ESI: Calculated value [M] + 505.20, Measured value [M] + : 505.10. 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 12.0 Hz, 1H), 8.05 (d, J = 4.0 Hz, 1H), 7.97 - 7.90 (m, 3H), 7.77 - 7.72 (m, 9H), 7.56 - 7.54 (m, 2H), 7.44 - 7.40 (m, 1H), 7.10 - 7.04 (m, 1H), 5.54 (d, J = 4.0 Hz, 1H). Example 90 Compound AB36438 The chemical structural formula of Compound AB36438 is as follows.

[1001] [Chemistry]

[1002] Compound AB36438 The synthetic route of Compound AB36438 is as follows.

[1003] [Chemistry]

[1004] In a sealed tube, Compound 1 (200 mg, 0.53 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (112 mg, 0.53 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.01 mmol, 0.02 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB36438 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36438: MS-ESI: Calculated value [M] + 506.20, Measured value [M] + : 506.65. 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.73 - 7.70 (m, 1H), 7.64 - 7.59 (m, 4H), 7.53 (d, J = 4.0 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.30 - 7.27 (m, 4H), 7.22 - 7.16 (m, 1H), 7.00 (s, 1H), 5.60 (d, J = 4.0 Hz, 1H), 4.13 (s, 3H), 3.90 (s, 3H), 3.88 (s, 6H). Example 91 Compound AB36439 The chemical structural formula of Compound AB36439 is as follows.

[1005]

Chem.

[1006] Compound AB36439 The synthetic route of Compound AB36439 is as follows.

[1007] Step (1):

[1008]

Chem.

[1009] Dissolve Compound 1 (2 g, 9.47 mmol, 1 eq) in dimethyl sulfoxide (20 mL) in a sealed tube, add Compound 2 (2.5 g, 9.47 mmol, 1 eq), triethylamine (1.1 g, 11.36 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (527 mg, 0.95 mmol, 0.1 eq) and palladium acetate (106 mg, 0.47 mmol, 0.05 eq), then carry out the reaction at 100 °C for 16 hours through nitrogen gas protection. After cooling, dilute the reaction solution with dichloromethane, wash the organic phase 3 times with water, dry it over anhydrous sodium sulfate, filter and centrifuge to remove the liquid, and obtain Compound 3 from the crude product through flash chromatography (DCM / MeOH = 100 / 1 - 50 / 1).

[1010] Step (2):

[1011]

Chem.

[1012] In a sealed tube, compound 3 (3 g, 7.64 mmol, 1 eq) was dissolved in methylbenzene (50 mL), triethylamine (1.5 g, 15.28 mmol, 2 eq) and trichlorosilane (10.3 g, 76.4 mmol, 10 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, rapid cooling was carried out using methanol (20 mL), and the pH of the reaction solution was adjusted to neutral using 2N NaOH. The solvent was concentrated, diluted with water, and then the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 4 was obtained from the crude product through flash chromatography (PE / EA = 100 / 1 - 25 / 1).

[1013] Step (3):

[1014]

Chemical formula

[1015] In a sealed tube, compound 4 (200 mg, 0.53 mmol, 1 eq) was dissolved in dimethylbenzene (2 mL), compound 5 (112 mg, 0.53 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (48 mg, 0.053 mmol, 0.01 eq) were added, and then the reaction was carried out at 130 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted and collected with dichloromethane, dried over anhydrous sodium sulfate, and after filtration, the filtrate was centrifuged to remove the liquid, and compound AB36439 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36439: MS-ESI: Calculated value [M] + 507.19, Measured value [M + H] + : 507.20. 11H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.31 (d, J = 12.0 Hz, 2H), 7.73 - 7.63 (m, 6H), 7.44 - 7.38 (m, 2H), 7.31 - 7.28 (m, 4H), 7.10 (s, 2H), 4.14 (s, 6H), 3.89 (s, 6H). Example 92 Compound AB36444 The chemical structural formula of Compound AB36444 is as follows.

[1016]

Chemical Structure

[1017] Compound AB36444 The synthetic route of Compound AB36444 is as follows.

[1018]

Chemical Structure

[1019] In a sealed tube, Compound 1 (200 mg, 0.53 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (112 mg, 0.53 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.01 mmol, 0.02 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB36444 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36444: MS-ESI: Calculated value [M] + 506.20, Measured value [M] + : 506.30. 11H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.19 - 8.07 (m, 2H), 7.64 - 7.53 (m, 5H), 7.49 - 7.44 (m, 3H), 7.33 - 7.32 (m, 1H), 7.29 - 7.27 (m, 4H), 7.22 - 7.17 (m, 1H), 5.62 (d, J = 4.0 Hz, 1H), 4.07 (s, 3H), 3.89 (s, 3H), 3.88 (s, 6H). Example 93 Compound AB36445 The chemical structural formula of Compound AB36445 is as follows.

[1020] [Chemical Structure Diagram]

[1021] Compound AB36445 The synthetic route of Compound AB36445 is as follows.

[1022] [Chemical Reaction Diagram]

[1023] In a sealed tube, Compound 1 (200 mg, 0.53 mmol, 1 eq) was dissolved in dimethyl sulfoxide (2 mL), Compound 2 (112 mg, 0.53 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (48 mg, 0.053 mmol, 0.01 eq) were added. Then, the reaction was carried out at 130 °C for 16 hours under nitrogen gas protection. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB36445 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36445: MS-ESI: Calculated value [M] + 507.19, Measured value [M]+ : 507.25. 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.31 - 8.28 (m, 1H), 8.22 - 8.19 (m, 1H), 7.73 (s, 2H), 7.68 - 7.63 (m, 4H), 7.57 - 7.52 (m, 1H), 7.42 - 7.35 (m, 2H), 7.31 - 7.28 (m, 4H), 7.11 (s, 1H), 4.14 (s, 3H), 4.07 (s, 3H), 3.88 (s, 6H). Example 94 Compound AB36448 The chemical structural formula of Compound AB36448 is as follows.

[1024]

Chemical Structure

[1025] Compound AB36448 The synthetic route of Compound AB36448 is as follows.

[1026] Step (1):

[1027]

Chemical Structure

[1028] In a sealed tube, compound 1 (3 g, 11.44 mmol, 1 eq) was dissolved in dimethyl sulfoxide (30 mL), and compound 2 (2.4 g, 11.44 mmol, 1 eq), triethylamine (1.4 g, 13.73 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (632 mg, 1.14 mmol, 0.1 eq), and palladium acetate (128 mg, 0.57 mmol, 0.05 eq) were added. Then, the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with dichloromethane, and the organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 3 was obtained from the crude product through flash chromatography (DCM / MeOH = 100 / 1 to 50 / 1).

[1029] Step (2):

[1030]

Chemical formula

[1031] In a sealed tube, compound 3 (3.7 g, 9.43 mmol, 1 eq) was dissolved in methylbenzene (50 mL), and triethylamine (1.9 g, 18.86 mmol, 2 eq) and trichlorosilane (12.8 g, 94.3 mmol, 10 eq) were added. Then, the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, rapid cooling was carried out using methanol (50 mL), and the pH of the reaction solution was adjusted to neutral using 2N NaOH. The solvent was concentrated, diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 4 was obtained from the crude product through flash chromatography (PE / EA = 100 / 1 to 25 / 1).

[1032] Step (3):

[1033]

Chemical formula

[1034] In the tube sealing step, compound 4 (200 mg, 0.53 mmol, 1 eq) was dissolved in dimethylbenzene (2 mL), compound 2 (112 mg, 0.53 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (48 mg, 0.053 mmol, 0.01 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted and collected with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB36448 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36448: MS-ESI: Calculated value [M] + 507.19, Measured value [M + H] + : 507.20. 1 HNMR (400 MHz, DMSO-d6) δ 8.61 - 8.59 (m, 1H), 8.39 (s, 1H), 8.23 - 8.20 (m, 1H), 7.77 - 7.75 (m, 2H), 7.68 - 7.63 (m, 4H), 7.57 - 7.53 (m, 1H), 7.40 - 7.34 (m, 1H), 7.31 - 7.28 (m, 4H), 7.24 - 7.19 (m, 1H), 5.61 (d, J = 4.0 Hz, 1H), 4.07 (s, 3H), 3.90 (s, 3H), 3.89 (s, 6H). Example 95 Compound AB36449 The chemical structural formula of compound AB36449 is as follows.

[1035]

Chemical Structure

[1036] Compound AB36449 The synthetic route of compound AB36449 is as follows.

[1037] [Chem.]

[1038] In a sealed tube, Compound 1 (200 mg, 0.53 mmol, 1 eq) was dissolved in dimethyl sulfoxide (2 mL), Compound 2 (112 mg, 0.53 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (48 mg, 0.053 mmol, 0.01 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB36449 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36449: MS-ESI: Calculated value [M] + 507.19, Measured value [M] + : 507.20. 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.19 - 8.07 (m, 2H), 7.64 - 7.53 (m, 5H), 7.49 - 7.44 (m, 3H), 7.33 - 7.32 (m, 1H), 7.29 - 7.27 (m, 4H), 7.22 - 7.17 (m, 1H), 5.62 (d, J = 4.0 Hz, 1H), 4.07 (s, 3H), 3.89 (s, 3H), 3.88 (s, 6H). Example 96 Compound AB36452 The chemical structural formula of Compound AB36452 is as follows.

[1039] [Chem.]

[1040] Compound AB36452 The synthetic route of compound AB36452 is as follows.

[1041] [Chemical formula]

[1042] In a sealed tube, compound 1 (200 mg, 0.55 mmol, 1 eq) was dissolved in dimethyl sulfoxide (2 mL), compound 2 (108 mg, 0.55 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (5 mg, 0.0055 mmol, 0.01 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB36452 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36452: MS-ESI: Calculated value [M] + 478.17, Measured value [M] + : 478.35. 1 H NMR (400 MHz, CDCl 3 ) δ 12.68 (s, 1H), 8.54 (s, 1H), 8.11 - 8.00 (m, 3H), 7.70 - 7.65 (m, 4H), 7.51 (d, J = 4.0 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.29 - 7.27 (m, 4H), 7.06 - 7.01 (m, 1H), 6.79 (d, J = 4.0 Hz, 1H), 5.57 (d, J = 4.0 Hz, 1H), 3.87 (s, 6H). Example 97 Compound AB36453 The chemical structural formula of compound AB36453 is as follows.

[1043] [Chemical formula]

[1044] Compound AB36453 The synthetic route of Compound AB36453 is as follows.

[1045]

Chemical formula

[1046] In a sealed tube, Compound 1 (200 mg, 0.55 mmol, 1 eq) was dissolved in dimethyl sulfoxide (2 mL), Compound 2 (108 mg, 0.55 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (5 mg, 0.0055 mmol, 0.01 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB36453 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36453: MS-ESI: Calculated value [M] + 478.17, Measured value [M] + : 478.30. 1 H NMR (400 MHz, CDCl 3 ) δ 12.73 (s, 1H), 9.24 (s, 1H), 8.60 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 4.0 Hz, 1H), 7.70 - 7.65 (m, 4H), 7.51 (d, J = 4.0 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.28 - 7.25 (m, 4H), 7.08 - 7.02 (m, 1H), 6.69 (d, J = 4.0 Hz, 1H), 5.59 (d, J = 4.0 Hz, 1H), 3.87 (s, 6H). Example 98 Compound AB36459 The chemical structural formula of Compound AB36459 is as follows.

[1047]

Chem.

[1048] Compound AB36459 The synthetic route of Compound AB36459 is as follows.

[1049] Step (1):

[1050]

Chem.

[1051] Dissolve Compound 1 (2 g, 6.47 mmol, 1 eq) in dimethyl sulfoxide (30 mL) in a sealed tube, add Compound 2 (1.7 g, 6.47 mmol, 1 eq), triethylamine (784 mg, 7.76 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocene (355 mg, 0.64 mmol, 0.1 eq), and palladium acetate (74 mg, 0.32 mmol, 0.05 eq), then carry out the reaction at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, dilute the reaction solution with dichloromethane, wash the organic phase 3 times with water, dry it over anhydrous sodium sulfate, filter and centrifuge to remove the liquid, and obtain Compound 3 from the crude product through flash chromatography (DCM / MeOH = 100 / 1 - 50 / 1).

[1052] Step (2):

[1053]

Chem.

[1054] In a sealed tube, compound 3 (1.8 g, 3.67 mmol, 1 eq) was dissolved in methylbenzene (30 mL), triethylamine (741 mg, 7.34 mmol, 2 eq) and trichlorosilane (5.0 g, 36.7 mmol, 10 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, rapid quenching was carried out using methanol (50 mL), the pH of the reaction solution was adjusted to neutral using 2N NaOH, the solvent was concentrated, diluted with water, and then the organic phase was extracted using dichloromethane, dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and compound 4 was obtained from the crude product through flash chromatography (PE / EA = 100 / 1 - 25 / 1).

[1055] Step (3):

[1056]

Chemical formula

[1057] In a sealed tube, compound 4 (200 mg, 0.42 mmol, 1 eq) was dissolved in dimethylbenzene (2 mL), compound 5 (83 mg, 0.42 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (4 mg, 0.0042 mmol, 0.01 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted and collected using dichloromethane, dried over anhydrous sodium sulfate, and after filtration, the filtrate was centrifuged to remove the liquid, and compound AB36459 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36459: MS-ESI: Calculated value [M] + 591.25, Measured value [M + H] + : 519.35。 11H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 8.42 (s, 1H), 8.15 - 8.07 (m, 2H), 8.01 (d, J = 4.0 Hz, 1H), 7.70 - 7.65 (m, 4H), 7.58 (d, J = 4.0 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.38 - 7.35 (m, 1H), 7.30 - 7.27 (m, 4H), 7.09 - 7.04 (m, 1H), 6.80 (d, J = 4.0 Hz, 1H), 5.58 (d, J = 4.0 Hz, 1H), 4.41 - 4.38 (m, 2H), 3.88 (s, 6H), 3.55 (s, 4H), 2.70 - 2.67 (m, 2H), 2.41 (d, J = 4.0 Hz, 4H). Example 99 Compound AB36471 The chemical structural formula of Compound AB36471 is as follows.

[1058] [Chemical formula]

[1059] Compound AB36471 The synthetic route of Compound AB36471 is as follows.

[1060] [Chemical formula]

[1061] In the tube sealing step, compound 1 (100 mg, 0.26 mmol, 1 eq) was dissolved in dimethyl sulfoxide (2 mL), compound 2 (56 mg, 0.26 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (16 mg, 0.026 mmol, 0.1 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was centrifuged to remove the liquid. Compound AB36471 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). Compound AB36471: MS-ESI: Calculated value [M] + 507.19, Measured value [M] + : 507.20. 1 H NMR (400 MHz, CDCl 3 ) δ 8.49 (s, 1H), 8.32 (d, J = 8.0 Hz, 2H), 7.75 - 7.64 (m, 6H), 7.45 - 7.39 (m, 2H), 7.30 (d, J = 4.0 Hz, 4H), 7.11 (s, 2H), 4.15 (s, 6H), 3.89 (s, 6H). Example 100 Compound AB35591 The chemical structural formula of compound AB35591 is as follows.

[1062]

Chemical Structure

[1063] Compound AB35591 The synthetic route of compound AB35591 is as follows.

[1064] Step (1):

[1065]

Chemical Structure

[1066] In a sealed tube, Compound 1 (700 mg, 3.57 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (214 mg, 5.36 mmol, 1.5 eq, with a concentration of 60% in mineral oil) was added at 0 °C, and the reaction was carried out for 0.5 h. Compound 2 (1.1 g, 3.93 mmol, 1.1 eq) was dissolved in N,N-dimethylformamide (5 mL), and the above reaction solution was added at 0 °C, and the reaction was carried out for 1 h. The reaction solution was quenched with a saturated aqueous ammonium chloride solution, and the organic phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound 3 was obtained from the crude product via flash chromatography (DCM / MeOH = 20:1).

[1067] Step (2):

[1068]

Chemical Structure

[1069] In a sealed tube, Compound 3 (200 mg, 0.65 mmol, 1 eq) was dissolved in dimethyl sulfoxide (5 mL). Triphenylphosphine (170 mg, 0.65 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol, 0.02 eq) were added. Then, the reaction was carried out at 120 °C for 16 h under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB35591 was obtained from the crude product via reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). MS-ESI: Calculated value [M] + 489.25, Measured value [M] + : 489.30。 11H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.07 - 7.80 (m, 21H), 7.51 - 7.46 (m, 1H), 6.80 (d, J = 4.0 Hz, 1H), 4.51 - 4.48 (m, 2H), 2.76 - 2.73 (m, 2H), 2.61 (s, 1H), 1.55 - 1.46 (m, 6H). Example 101 Compound AB36458 The chemical structural formula of Compound AB36458 is as follows.

[1070]

Chem.

[1071] Compound AB36458 The synthetic route of Compound AB36458 is as follows.

[1072]

Chem.

[1073] In a sealed tube, Compound 1 (200 mg, 0.53 mmol, 1 eq) was dissolved in dimethyl sulfoxide (3 mL), Compound 2 (112 mg, 0.53 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (6 mg, 0.01 mmol, 0.02 eq) were added, and then the reaction was carried out at 110 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB36458 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). MS-ESI: Calculated value [M] + 506.20, Measured value [M] + : 506.30. 11H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.43 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 4.0 Hz, 1H), 7.69 - 7.64 (m, 4H), 7.50 - 7.44 (m, 2H), 7.29 - 7.26 (m, 4H), 7.12 - 7.06 (m, 1H), 6.73 (d, J = 4.0 Hz, 1H), 5.58 (d, J = 4.0 Hz, 1H), 4.03 (s, 3H), 3.91 (s, 3H), 3.88 (s, 6H). Example 102 Compound AB36498 The chemical structural formula of Compound AB36498 is as follows.

[1074]

Chem.

[1075] Compound AB36498 The synthetic route of Compound AB36498 is as follows.

[1076]

Chem.

[1077] In a sealed tube, Compound 1 (150 mg, 0.41 mmol, 1 eq) was dissolved in dimethyl sulfoxide (2 mL), Compound 2 (82 mg, 0.41 mmol, 1 eq) and tris(dibenzylideneacetone)dipalladium (37 mg, 0.041 mmol, 0.1 eq) were added, and then the reaction was carried out at 120 °C for 16 hours under the protection of nitrogen gas. After cooling, the reaction solution was diluted with water, and then the organic phase was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound AB36498 was obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.01% formic acid). MS-ESI: Calculated value [M] + 478.17, Measured value [M] + : 478.25. 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.16 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.63 - 7.52 (m, 5H), 7.53 (d, J = 4.0 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.30 - 7.27 (m, 4H), 7.18 - 7.12 (m, 1H), 7.03 (s, 1H), 5.60 (s, 1H), 3.88 (s, 6H). Example 103 Compound AB36504 The chemical structural formula of Compound AB36504 is as follows.

[1078]

Chemical Structure

[1079] Compound AB36504 The synthetic route of Compound AB36504 is as follows.

[1080]

Chemical Structure

[1081] Dissolve Compound 1 (200 mg, 0.76 mmol, 1.0 eq) and Compound 2 (150 mg, 0.76 mmol, 1.0 eq) in dimethyl sulfoxide (3 mL), add tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol, 0.05 eq), and carry out the reaction at 120 °C for 16 hours. Dilute the reaction solution with water, then extract the organic phase with dichloromethane, collect the organic phase, dry and filter it over anhydrous sodium sulfate, centrifuge the filtrate to remove the liquid, and obtain Compound AB36504 from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). MS-ESI: Calculated value [M] + 379.14, Measured value [M] + : 379.25 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.92 - 7.88 (m, 3H), 7.74 - 7.69 (m, 13H), 7.59 - 7.55 (m, 1H), 7.17 - 7.11 (m, 1H).

[1082] Example 104 Compound AB36511 The chemical structural formula of Compound AB36511 is as follows.

[1083]

Chemical Structure

[1084] Compound AB36511 The synthetic route of Compound AB36511 is as follows.

[1085]

Chemical Structure

[1086] Compound 1 (200 mg, 0.76 mmol, 1.0 eq) and Compound 2 (150 mg, 0.76 mmol, 1.0 eq) are dissolved in dimethyl sulfoxide (3 mL), tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol, 0.05 eq) is added, and the reaction is carried out at 120 °C for 16 hours. The reaction solution is diluted with water, and then the organic phase is extracted with dichloromethane. The organic phase is collected, dried over anhydrous sodium sulfate, filtered, the filtrate is centrifuged to remove the liquid, and Compound AB36511 is obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). MS-ESI: Calculated value [M] + 379.14, Measured value [M] +: 379.15. 1 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.44 (s, 1H), 8.41 - 8.39 (m, 1H), 7.92 - 7.89 (m, 3H), 7.76 - 7.70 (m, 12H), 7.37 - 7.32 (m, 1H), 7.27 - 7.23 (m, 1H).

[1087] Example 105 Compound AB36513 The chemical structural formula of Compound AB36513 is as follows.

[1088]

Chemical formula

[1089] Compound AB36513 The synthetic route of Compound AB36513 is as follows.

[1090]

Chemical formula

[1091] Compound 1 (200 mg, 0.66 mmol, 1.0 eq) and Compound 2 (123 mg, 0.66 mmol, 1.0 eq) are dissolved in dimethyl sulfoxide (3 mL), tris(dibenzylideneacetone)dipalladium (30 mg, 0.033 mmol, 0.05 eq) is added, and the reaction is carried out at 120 °C for 16 hours. The reaction solution is diluted with water, then the organic phase is extracted with dichloromethane, the organic phase is collected, dried over anhydrous sodium sulfate and filtered, the filtrate is centrifuged to remove the liquid, and Compound AB36513 is obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 408.20. 11H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.51 (s, 1H), 8.06 - 8.01 (m, 1H), 7.93 - 7.89 (m, 2H), 7.79 - 7.50 (m, 11H), 7.44 - 7.31 (m, 3H), 7.20 - 7.00 (m, 1H), 5.53 (s, 1H), 3.89 (s, 3H).

[1092] Example 106 Compound AB36514 The chemical structural formula of Compound AB36514 is as follows.

[1093] [Chemical formula]

[1094] Compound AB36514 The synthetic route of Compound AB36514 is as follows.

[1095] [Chemical formula]

[1096] Compound 1 (200 mg, 0.66 mmol, 1.0 eq) and Compound 2 (130 mg, 0.66 mmol, 1.0 eq) are dissolved in dimethyl sulfoxide (3 mL), tris(dibenzylideneacetone)dipalladium (30 mg, 0.033 mmol, 0.05 eq) is added, and the reaction is carried out at 120 °C for 16 hours. The reaction solution is diluted with water, and then the organic phase is extracted with dichloromethane. The organic phase is collected, dried over anhydrous sodium sulfate, filtered, the filtrate is centrifuged to remove the liquid, and Compound AB36514 is obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). MS-ESI: Calculated value [M] + 418.15, Measured value [M] + : 418.10. 11H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.88 - 7.85 (m, 2H), 7.76 - 7.67 (m, 8H), 7.50 (d, J = 4.0 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.15 - 7.10 (m, 1H), 5.53 (d, J = 4.0 Hz, 1H).

[1097] Example 107 Compound AB36516 The chemical structural formula of Compound AB36516 is as follows.

[1098]

Chem.

[1099] Compound AB36516 The synthetic route of Compound AB36516 is as follows.

[1100]

Chem.

[1101] Compound 1 (300 mg, 0.83 mmol, 1.0 eq) and Compound 2 (164 mg, 0.83 mmol, 1.0 eq) are dissolved in dimethyl sulfoxide (5 mL), tris(dibenzylideneacetone)dipalladium (38 mg, 0.041 mmol, 0.05 eq) is added, and the reaction is carried out at 120 °C for 16 hours. The reaction solution is diluted with water, and then the organic phase is extracted with dichloromethane. The organic phase is collected, dried over anhydrous sodium sulfate, filtered, the filtrate is centrifuged to remove the liquid, and Compound AB36516 is obtained from the crude product through reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). MS-ESI: Calculated value [M] + 479.16, Measured value [M]+ : 479.30. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.19 - 8.17 (m, 2H), 7.66 - 7.61 (m, 6H), 7.37 - 7.31 (m, 2H), 7.29 - 7.26 (m, 4H), 7.08 (s, 2H), 3.86 (s, 6H).

[1102] Example 108 Compound AB36518 The chemical structural formula of Compound AB36518 is as follows.

[1103]

Chemical Structure

[1104] Compound AB36518 The synthetic route of Compound AB36518 is as follows.

[1105] Step (1):

[1106]

Chemical Structure

[1107] In a sealed tube, Compound 1 (1.0 g, 5.07 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (406 mg, 10.14 mmol, 2.0 eq, 60% concentration in mineral oil) was added at 0 °C, the reaction was carried out for 0.5 h, then methyl iodide (863 mg, 6.08 mmol, 1.2 eq) was added, and the reaction was carried out at room temperature for 1 h. The reaction solution was quenched with saturated aqueous ammonium chloride, and the organic phase was extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and centrifuged to remove the liquid, and Compound 2 was obtained from the crude product through normal-phase column chromatography (petroleum ether / ethyl acetate = 0% - 10%).

[1108] Step (2):

[1109] [Chem.]

[1110] Compound 2 (133 mg, 0.63 mmol, 1.0 eq) and Compound 3 (200 mg, 0.63 mmol, 1.0 eq) are dissolved in dimethyl sulfoxide (5 mL), tris(dibenzylideneacetone)dipalladium (29 mg, 0.032 mmol, 0.05 eq) is added, and the reaction is carried out at 120 °C for 16 hours. The reaction solution is diluted with water, then the organic phase is extracted with dichloromethane, the organic phase is collected, dried and filtered over anhydrous sodium sulfate, the filtrate is centrifuged to remove the liquid, and Compound AB36518 is obtained from the crude product via reverse-phase column chromatography (acetonitrile / water + 0.1% formic acid). MS-ESI: Calculated value [M] + 446.18, Measured value [M] + : 446.15. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 - 8.23 (m, 1H), 8.05 (d, J = 4.0 Hz, 1H), 7.91 - 7.86 (m, 4H), 7.79 - 7.75 (m, 8H), 7.65 (d, J = 4.0 Hz, 1H), 7.52 - 7.42 (m, 2H), 6.86 (d, J = 4.0 Hz, 1H), 6.68 (d, J = 4.0 Hz, 1H), 3.93 (s, 3H), 3.91 (s, 3H).

[1111] Example 109 Compound AB36521 The chemical structural formula of Compound AB36521 is as follows.

[1112] [Chem.]

[1113] Compound AB36521 The synthetic route of compound AB36521 is as follows.

[1114]

Chemical formula

[1115] Compound 1 (200 mg, 0.76 mmol, 1.0 eq) and compound 2 (150 mg, 0.76 mmol, 1.0 eq) are dissolved in dimethyl sulfoxide (5 mL), tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol, 0.05 eq) is added, and the reaction is carried out at 120 °C for 16 hours. The reaction solution is diluted with water, and then the organic phase is extracted with dichl...

Claims

1. A compound of formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof. 【Chemical 1】 (R １ , R ２ , R ３ and R ４ each independently represents a substituted or unsubstituted C3-C16 cycloalkyl group, a substituted or unsubstituted 3- to 16-membered heterocycloalkyl group, a substituted or unsubstituted C6-C16 aryl group, a substituted or unsubstituted 5- to 16-membered heteroaryl group, or a substituted or unsubstituted 5- to 16-membered heteroaryl group-substituted or unsubstituted C1-C8 alkyl group; On the heterocyclic rings of the heterocycloalkyl group and the heteroaryl group, there are, independently of each other, one to four (preferably one, two, three or four) heteroatoms selected from N, O and S; Any of the above-mentioned "substitutions" means that one or more (preferably one, two, three, four, five, six, seven or eight) hydrogen atoms on the atomic group are, independently of each other, a C1-C12 alkyl group, a C3-C8 cycloalkyl group, a C1-C12 halogenated alkyl group, a C3-C8 halogenated cycloalkyl group, a C3-C8 cycloalkoxyl group, a C3-C8 cycloalkylthiol group, a C3-C8 halogenated cycloalkoxyl group, a C3-C8 halogenated cycloalkylthiol group, a halogen atom, a nitro group, -CN, a hydroxyl group, a mercapto group, an amino group, a C1-C4 carboxyl group, a C2-C8 ester group, a C2-C4 acylamino group, a C1-C12 alkyl group -O-, a C1-C12 alkyl group -S-, a C1-C12 halogenated alkoxyl group, a C1-C12 halogenated alkylthiol group, a C6-C12 aryl group, a 5-12 membered heteroaryl group, and 【Chemical 2】 It is meant to be substituted by a substituent selected from; R ３５ represents a hydrogen atom, a hydroxyl group, a mercapto group, a 3- to 12-membered heterocycloalkyl group, or a halogen atom; Z １ represents a C1-C8 alkylidene group.)

2. A compound of formula I according to claim 1, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, characterized by having the following chemical structural formula. 【Chemical 3】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】

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

4. The tumor includes a tumor in which the mitochondrial membrane permeability transition pore is low-expressed or not expressed or low-activated or inactivated; The tumor includes a tumor in which peptidylprolyl isomerase F is low-expressed or not expressed or low-activated or inactivated; The tumor includes a tumor in which the NNMT gene is low-expressed or not expressed; The tumor includes a tumor in which DNA methyltransferase is highly expressed; The tumor includes a tumor in which DNMT1 is highly expressed; The tumor includes tumors with high expression of DNMT3a; The tumor includes tumors with high expression of DNMT3b; The tumor includes tumors with high expression of UHRF1; The tumor includes tumors with hypermethylation of the nucleotide site of the NNMT gene; and / or The tumor includes tumors with hypermethylation of the DNA CpG site in the NNMT gene region, The use according to claim 3, characterized in that. **Claim 5** The tumor with low expression or low activation of the mitochondrial membrane permeability transition pore refers to a tumor in which the ratio (H1 / H0) between the expression level or activity H1 of the mitochondrial membrane permeability transition pore in tumor cells and the expression level or activity H0 of the mitochondrial membrane permeability transition pore in the same type of cells or normal cells is < 1.0, preferably ≤ 0.8, more preferably ≤ 0.7, ≤ 0.6, ≤ 0.5, ≤ 0.4, ≤ 0.3, ≤ 0.2, ≤ 0.1, ≤ 0.05, ≤ 0.01, ≤ 0.005, ≤ 0.001, ≤ 0.0001, ≤ 0.00001, ≤ 0.000001 or ≤ 0.0000001; The tumor with low expression or low activation of peptidylprolyl isomerase F refers to a tumor in which the ratio (C1 / C0) between the expression level or activity C1 of peptidylprolyl isomerase F in tumor cells and the expression level or activity C0 of peptidylprolyl isomerase F in the same type of cells or normal cells is < 1.0, preferably ≤ 0.8, more preferably ≤ 0.7, ≤ 0.6, ≤ 0.5, ≤ 0.4, ≤ 0.3, ≤ 0.2, ≤ 0.1, ≤ 0.05, ≤ 0.01, ≤ 0.005, ≤ 0.001, ≤ 0.0001, ≤ 0.00001, ≤ 0.000001 or ≤ 0.0000001; The tumor with low expression or no expression of the NNMT gene refers to a tumor in which the ratio (E1 / E0) between the expression level E1 of the NNMT gene in tumor cells and the expression level E0 of the NNMT gene in the same type of cells or normal cells is < 1.0, preferably ≤ 0.7, more preferably ≤ 0.6, ≤ 0.5, ≤ 0.4, ≤ 0.3, ≤ 0.2, ≤ 0.1, ≤ 0.05, ≤ 0.01, ≤ 0.005, ≤ 0.001, ≤ 0.0001, ≤ 0.00001, ≤ 0.000001 or ≤ 0.0000001; The tumor with high expression of DNA methyltransferase refers to a tumor in which the ratio (A1 / A0) between the expression level A1 of DNA methyltransferase in tumor cells and the expression level A0 of DNA methyltransferase in the same type of cells or normal cells is >1.0, preferably ≧1.2 or ≧1.5, and more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50, for example, 2 - 50; The tumor with high expression of DNMT1 refers to a tumor in which the ratio (B1 / B0) between the expression level B1 of DNMT1 in tumor cells and the expression level B0 of DNMT1 in the same type of cells or normal cells is >1.0, preferably ≧1.2 or ≧1.5, and more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50, for example, 2 - 50; The tumor with high expression of DNMT3a refers to a tumor in which the ratio (P1 / P0) between the expression level P1 of DNMT3a in tumor cells and the expression level P0 of DNMT3a in the same type of cells or normal cells is >1.0, preferably ≧1.2 or ≧1.5, and more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50, for example, 2 - 50; The tumor with high expression of DNMT3b refers to a tumor in which the ratio (D1 / D0) between the expression level D1 of DNMT3b in tumor cells and the expression level D0 of DNMT3b in the same type of cells or normal cells is >1.0, preferably ≧1.2 or ≧1.5, and more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50, for example, 2 - 50; The tumor with high expression of UHRF1 refers to a tumor in which the ratio (F1 / F0) between the expression level F1 of UHRF1 in tumor cells and the expression level F0 of UHRF1 in the same type of cells or normal cells is >1.0, preferably ≧1.2 or ≧1.5, and more preferably ≧2, ≧3, ≧5, ≧8, ≧10, ≧15, ≧20, ≧30 or ≧50, for example, 2 - 50; The tumor in which the nucleotide site of the NNMT gene is hypermethylated refers to a tumor in which the ratio (L1 / L0) between the methylation level L1 of the nucleotide site of the NNMT gene in tumor cells and the methylation level L0 of the nucleotide site of the NNMT gene in the same type of cells or normal cells is > 1.0, preferably ≧ 1.2 or ≧ 1.5, more preferably ≧ 2, ≧ 3, ≧ 5, ≧ 8, ≧ 10, ≧ 15, ≧ 20, ≧ 30 or ≧ 50, for example, 2 - 50; and / or The tumor in which the DNA CpG site in the NNMT gene region is hypermethylated refers to a tumor in which the ratio (G1 / G0) between the methylation level G1 of the DNA CpG site in the NNMT gene region in tumor cells and the methylation level G0 of the DNA CpG site in the NNMT gene region in the same type of cells or normal cells is > 1.0, preferably ≧ 1.2 or ≧ 1.5, more preferably ≧ 2, ≧ 3, ≧ 5, ≧ 8, ≧ 10, ≧ 15, ≧ 20, ≧ 30 or ≧ 50, for example, 2 - 50. The use according to claim 4, characterized in that.

6. The same type of cells are The same type of tumor cells in which the mitochondrial membrane permeability transition pore is normally expressed, highly expressed, normally activated or highly activated; The same type of tumor cells in which peptidylprolyl isomerase F is normally expressed, highly expressed, normally activated or highly activated; The same type of tumor cells in which the NNMT gene is normally expressed or highly expressed; The same type of tumor cells in which the DNA methylase is normally expressed or lowly expressed; The same type of tumor cells in which DNMT1 is normally expressed or lowly expressed; The same type of tumor cells in which DNMT3a is normally expressed or lowly expressed; The same type of tumor cells in which DNMT3b is normally expressed or lowly expressed; The same type of tumor cells in which UHRF1 is normally expressed or lowly expressed; The same type of tumor cells in which the nucleotide site of the NNMT gene is normally methylated or hypomethylated, and / or The use according to claim 5, characterized in that it includes the same type of tumor cells in which the DNA CpG site in the NNMT gene region is normally methylated or hypomethylated. The use according to claim 5, characterized in that.

7. The use according to claim 3, characterized in that the tumor is selected from lung cancer, brain tumor or a combination thereof.

8. A marker used to determine whether the compound of formula I according to claim 1, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound is suitable for the prevention and / or treatment of tumors in tumor patients, having the mitochondrial membrane permeability transition pore, peptidylprolyl isomerase F, NNMT gene, DNA methyltransferase, UHRF1, methylation of nucleotide sites of the NNMT gene and / or methylation of DNA CpG sites in the NNMT gene region, characterized by this.

9. Used for manufacturing an in vitro diagnostic kit for determining whether the compound of formula I according to claim 1, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound is suitable for the prevention and / or treatment of tumors in tumor patients, (i) Use of a detection kit comprising a detection reagent used to detect the expression level or activity of the mitochondrial membrane permeability transition pore, the expression level or activity of peptidylprolyl isomerase F, the expression level of the NNMT gene, the expression level of DNA methyltransferase, the expression level of UHRF1, the methylation level of nucleotide sites of the NNMT gene and / or the methylation level of DNA CpG sites in the NNMT gene region, wherein the in vitro diagnostic kit In tumor cells of tumor patients, when there is low expression, no expression, low activation or inactivation of the mitochondrial membrane permeability transition pore, low expression, no expression, low activation or inactivation of peptidylprolyl isomerase F, low expression or no expression of the NNMT gene, high expression of DNA methyltransferase, high expression of UHRF1, high methylation of nucleotide sites of the NNMT gene, and / or high methylation of DNA CpG sites in the NNMT gene region, the compound of formula I according to claim 1, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound becomes suitable for the prevention and / or treatment of tumors in the said tumor patients; and / or In tumor cells of a tumor patient, when there is high expression or high activation of the mitochondrial membrane permeability transition pore, high expression or high activation of peptidylprolyl isomerase F, high expression of the NNMT gene, low expression of DNA methyltransferase, low expression of UHRF1, low methylation of the nucleotide site of the NNMT gene, and / or low methylation of the DNA CpG site in the NNMT gene region, the compound of formula I according to claim 1, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound becomes not suitable for the prevention and / or treatment of tumors in the tumor patient. The instruction manual or label further describes this content. Use of a detection reagent kit, characterized in that.

10. (i) A detection reagent used to detect the expression level or activity of the mitochondrial membrane permeability transition pore, the expression level or activity of peptidylprolyl isomerase F, the expression level of the NNMT gene, the expression level of DNA methyltransferase, the expression level of UHRF1, the methylation level of the nucleotide site of the NNMT gene, and / or the methylation level of the DNA CpG site in the NNMT gene region. (ii) Comprising the compound of formula I according to claim 1, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound. A medical kit, characterized in that.

11. It is used to manufacture a composition or preparation used to enhance the anti-tumor effect of an anti-tumor drug. The anti-tumor drug contains the compound of formula I according to claim 1, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound. Use of an inhibitor of the mitochondrial membrane permeability transition pore, an inhibitor of peptidylprolyl isomerase F, an inhibitor of the NNMT gene, an enhancer of DNA methyltransferase, an enhancer of UHRF1, an enhancer of methylation of the nucleotide site of the NNMT gene, and / or an enhancer of methylation of the DNA CpG site in the NNMT gene region, characterized in that.

12. (1) A first active ingredient having an anti-tumor drug containing the compound of formula I according to claim 1, or its optical isomer or racemate, or its solvate, or its pharmaceutically acceptable salt, or its deuterated compound. (2) A second active ingredient comprising an inhibitor of the mitochondrial membrane permeability transition pore, an inhibitor of peptidylprolyl isomerase F, an inhibitor of the NNMT gene, an enhancer of DNA methyltransferase (for example, DNMT1, DNMT3a and / or DNMT3b), an enhancer of UHRF1, an enhancer of methylation of the nucleotide site of the NNMT gene and / or an enhancer of methylation of the DNA CpG site of the NNMT gene region. A composition characterized by the above.

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