Heterocyclic compound, and preparation method therefor and use thereof

Abstract

The present invention relates to the field of pharmaceutical biology, and in particular to a heterocyclic compound, and a preparation method therefor and a use thereof. Specifically, the present invention relates to a compound of formula (I'), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotopic marker, metabolite or prodrug thereof, or a pharmaceutical composition, preparation method and use thereof. The compound can be used as a drug for treating diseases related to abnormal proliferation of cells.

Description

Heterocyclic compounds, their preparation methods and uses

[0001] This application is based on and claims priority to CN application number 202411582314.7 filed on November 7, 2024, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention relates to the pharmaceutical field, specifically to a pyrrolobenzodiazepine with antitumor activity. Class of compounds, their preparation methods, and uses. Background Technology

[0003] Compounds with tumor cell-killing effects are often used to treat tumors. In recent years, antibody-drug conjugates (ADCs) have become a hot research topic in the pharmaceutical field due to their ability to target and kill tumor cells. ADCs typically consist of a monoclonal antibody, a bioactive molecule primarily composed of a tumor-killing cytotoxic agent, and a linker. The bioactive molecule is covalently coupled to the antibody via the linker; the antibody recognizes specific targets on the surface of tumor cells, guiding the ADC to the tumor microenvironment and the surface of cancer cells, and allowing the ADC to enter cancer cells through endocytosis; then, the bioactive molecule is released within the cancer cells, and through inhibiting microtubule proteins or damaging cancer cell DNA, it kills cancer cells while minimizing damage to normal tissue cells.

[0004] Pyrrolobenzodiazepine This compound is a sequence-selective DNA minor groove binder and a member of the anthraxmycin family of antibiotics. Scientists have discovered that by linking two pyrrolobenzodiazepines via an alkylene chain... Units connected together can make pyrrolobenzodiazepine The dimer forms highly lethal interchain crosslinks or alkylation with DNA. Furthermore, this pyrrolobenzodiazepine... The activity of the dimer can reach pmol / L in various tumor cell lines.

[0005] However, currently, pyrrolobenzodiazepines are used... There are still many problems with using PBD-like compounds as antibody-drug conjugates as payloads. Therefore, there is still a need in the field to develop PBD-like drugs with ideal safety and efficacy so that they can be used in antibody-drug conjugates. Summary of the Invention

[0006] The present invention aims to provide a class of novel heterocyclic compounds that exhibit good tumor cell proliferation inhibition ability. The compounds have good anti-tumor activity and ideal efficacy and safety, and can be used to treat diseases such as colon cancer and breast cancer.

[0007] compound

[0008] On the one hand, this application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein the compound has the structure shown in formula (I'):

[0009] in,

[0010] R 1 and R 2 Each is independently selected from hydrogen, -CN, halogen, and -OR. a -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected by one or more of H, deuterium (D), -CN, halogen, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups;

[0011] R a Selected from H, C 1-6 Alkyl and C 3-6 cycloalkyl;

[0012] R 4 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-10 membered heterocyclic group, C6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamine, hydroxyl, hydroxyalkyl, amino, aminoalkyl, substituted or unsubstituted heterocyclic groups (e.g., 3-10 membered heterocyclic groups, 3-8 membered heterocyclic groups, or 3-6 membered heterocyclic groups), substituted or unsubstituted C 6-10 Substituents of aryl, substituted or unsubstituted 5-10 membered heteroaryl and hydroxyalkyl-amide groups;

[0013] Carbon-carbon single bond or carbon-carbon double bond

[0014] when Carbon-carbon double bond R 5 It does not exist, R 6 For hydrogen, R 3 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups may optionally be independently bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamine, hydroxyl, hydroxyalkyl, amino, aminoalkyl, substituted or unsubstituted heterocyclic groups (e.g., 3-10 membered heterocyclic groups, 3-8 membered heterocyclic groups, or 3-6 membered heterocyclic groups), substituted or unsubstituted C 6-10 Substituents of aryl, substituted or unsubstituted 5-10 membered heteroaryl and hydroxyalkyl-amide groups;

[0015] when Carbon-carbon single bond R 5 For hydrogen, R 3 With R 6 The atoms attached to it are connected to form substituted or unsubstituted C atoms. 3-6 cycloalkyl, or R 6 For hydrogen, R 3 With R 5 The atoms attached to it are connected to form substituted or unsubstituted C atoms. 3-6 cycloalkyl;

[0016] t is selected from 1-10.

[0017] In some implementations, when t is 5, R 1 and R 2 Each is independently a methyl group. Carbon-carbon double bond R 5 It does not exist, R 6 When it is hydrogen, R 3 and R 4 Not at the same time

[0018] In some implementation schemes, R 3 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups may optionally be independently bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 alkylamine group, hydroxyl group, -C 1-6 Alkyl -OH, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 alkyl group 2, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 heteroaryl groups and OH-C 1-6 Substituents of alkyl-NH-C(=O)- are used.

[0019] In some implementation schemes, R 3 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl, said C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-6-membered heteroaryl groups may optionally be independently reacted by one or more elements selected from halogens, C1-6 Alkyl, C 1- 6-alkoxy, C 1-6 alkylamine group, hydroxyl group, -C 1-6 Alkyl -OH, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 alkyl group 2, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl groups and OH-C 1-6 Substituents of alkyl-NH-C(=O)- are used.

[0020] In some implementation schemes, It is a carbon-carbon double bond, R 5 It does not exist, R 6 For hydrogen, R 3 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1- 6-alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1-6 Alkyl)2, C 1-6 Alkylamine, hydroxyalkyl, hydroxyalkyl-amide, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-10-membered heteroaryl substituents are replaced by the 3-8-membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally separated by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups.

[0021] In some implementation schemes, It is a carbon-carbon double bond, R 5 It does not exist, R 6 For hydrogen, R 3 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 6-10Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 6- 10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1-6 Alkyl) 2, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-10-membered heteroaryl substituents are replaced by the 3-8-membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally separated by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-6 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups.

[0022] In some implementation schemes, It is a carbon-carbon double bond, R 5 It does not exist, R 6 For hydrogen, R 3 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 6- 10 The aryl and 5-10 heteroaryl groups may optionally be separated by one or more groups selected from C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, amino, -N(C) 1-6 Alkyl) 2, 3-6 membered heterocyclic groups, C 6-10 The aryl and 5-10-membered heteroaryl substituents, the 3-6-membered heterocyclic groups and C 6-10 Aryl group is optionally surrounded by one or more compounds selected from C 1-6 Substituents of alkyl and amino groups.

[0023] In some implementation schemes, It is a carbon-carbon double bond, R 5 It does not exist, R 6 For hydrogen, R 3 Selected from methyl, phenyl, Cyclopropyl, pyridyl, thiophene, furanyl,

[0024] In some implementation schemes, For carbon-carbon single bonds, R 5 For hydrogen, R 3 With R 6 The atoms attached to it are linked to form cyclopropyl, cyclobutyl, or cyclopentyl groups. In some embodiments, For carbon-carbon single bonds, R 5 For hydrogen, R 3 With R 6 The atoms connected to it form a cyclopropyl group.

[0025] In some implementation schemes, For carbon-carbon single bonds, R 6 For hydrogen, R 3 With R 5 The atoms attached to it are linked to form cyclopropyl, cyclobutyl, or cyclopentyl groups. In some embodiments, For carbon-carbon single bonds, R 6 For hydrogen, R 3 With R 5 The atoms connected to it form a cyclopropyl group.

[0026] In some implementation schemes, R 4 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-10 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 alkylamine group, hydroxyl group, -C 1-6 Alkyl -OH, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl group 2, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 heteroaryl groups and OH-C 1-6 Substituents of alkyl-NH-C(=O)- are used.

[0027] In some implementation schemes, R 4 Selected from C1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl, said C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-6 heteroaryl groups may optionally be replaced by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, -C 1-6 Alkyl -OH, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 alkyl group 2, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl groups and OH-C 1-6 Substituents of alkyl-NH-C(=O)- are used.

[0028] In some implementation schemes, R 4 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl, said C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-6 heteroaryl groups may optionally be replaced by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, -C 1-6 Alkyl -OH, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 alkyl group 2, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl groups and OH-C 1-6 Substituents of alkyl-NH-C(=O)- are used.

[0029] In some implementation schemes, R 4 Selected from C 1-6 Alkyl, C 3-6cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1- 6-alkyl)2, C 1-6 Alkylamine, hydroxyalkyl, hydroxyalkyl-amide, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-10-membered heteroaryl substituents are replaced by the 3-8-membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally separated by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups.

[0030] In some implementation schemes, R 4 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1- 6-alkyl) 2, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-10-membered heteroaryl substituents are replaced by the 3-8-membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally separated by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-6 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups.

[0031] In some implementation schemes, R 4 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-6 membered heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups may optionally be separated by one or more groups selected from C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, amino, -N(C) 1-6 Alkyl) 2, 3-6 membered heterocyclic groups, C 6-10 The aryl and 5-10-membered heteroaryl substituents, the 3-6-membered heterocyclic groups and C 6-10 Aryl group is optionally surrounded by one or more compounds selected from C 1-6 Substituents of alkyl and amino groups.

[0032] In some implementation schemes, R 4 Selected from methyl, phenyl, Cyclopropyl, pyridyl, thiophene, furanyl,

[0033] In some implementation schemes, R 4 Selected from

[0034] In some implementation schemes, R 3 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl, said C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-6-membered heteroaryl groups may optionally be independently reacted by one or more elements selected from halogens, C 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 alkylamine group, hydroxyl group, -C 1-6 Alkyl -OH, amino, -NH-C 1-6 Alkyl, -N(C) 1-6alkyl group 2, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl groups and OH-C 1-6 Substituents of alkyl-NH-C(=O)- groups; or,

[0035] R 3 With R 6 The atoms attached to it are connected to form substituted or unsubstituted C atoms. 3-6 cycloalkyl, or R 6 For hydrogen, R 3 With R 5 The atoms attached to it are connected to form substituted or unsubstituted C atoms. 3-6 cycloalkyl;

[0036] R 4 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl, said C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered heterocyclic group, C 6-10 The aryl and 5-6 heteroaryl groups may optionally be replaced by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, -C 1-6 Alkyl -OH, amino, -NH-C 1-6 Alkyl, -N(C) 1-6 alkyl group 2, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl groups and OH-C 1-6 Substituents of alkyl-NH-C(=O)- are used.

[0037] In some implementation schemes, R 3 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl and 5-6 membered heteroaryl, said C 1-6 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl and 5-6 heteroaryl groups may optionally be independently separated by one or more groups selected from C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, -N(C)1-6 2. Alkyl group, substituted or unsubstituted 3-6 membered heterocyclic group; or, R 3 With R 6 The atoms attached to it are connected to form substituted or unsubstituted C atoms. 3-6 cycloalkyl, or R 6 For hydrogen, R 3 With R 5 The atoms attached to it are connected to form substituted or unsubstituted C atoms. 3-6 cycloalkyl;

[0038] R 4 Selected from C 6-10 Aryl, the C 6-10 The aryl group may optionally be replaced by one or more amino groups.

[0039] In some implementation schemes, R 3 Selected from methyl, phenyl, Cyclopropyl, pyridyl, thiophene, furanyl, Or, R 3 With R 6 And the atoms connected to it form a cyclopropyl group, or, R 6 For hydrogen, R 3 With R 5 The atoms connected to it form a cyclopropyl group;

[0040] R 4 Selected from phenyl, wherein the phenyl group is substituted with an amino group.

[0041] In some implementation schemes, R 1 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl; the alkyl and cycloalkyl groups may optionally be substituted with one or more deuterium (D);

[0042] R 3 Selected from methyl, phenyl, cyclopropyl, pyridyl, thiophenyl, furanyl, The phenyl, It may optionally be substituted by one or more substituents selected from methyl, methoxy, ethoxy, propoxy, hydroxy, amino, -N(CH3)2, methylpiperazinyl, morpholinyl.

[0043] In some implementation schemes, R 1 It is methyl;

[0044] R 3 Selected from methyl, phenyl, Cyclopropyl, pyridyl, thiophene, furanyl, Or, R 3 With R6 And the atoms connected to it form a cyclopropyl group, or, R 6 For hydrogen, R 3 With R 5 The atoms connected to it form a cyclopropyl group.

[0045] In some implementation schemes, R 2 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl; the alkyl and cycloalkyl groups may optionally be substituted with one or more deuterium (D);

[0046] R 3 Selected from methyl, phenyl, cyclopropyl, pyridyl, thiophenyl, furanyl, The phenyl, Optionally, it may be substituted with one or more substituents selected from methyl, methoxy, ethoxy, propoxy, hydroxy, amino, -N(CH3)2, methylpiperazinyl, morpholinyl; or, R 3 With R 6 And the atoms connected to it form a cyclopropyl group, or, R 6 For hydrogen, R 3 With R 5 The atoms connected to it form a cyclopropyl group.

[0047] In some implementation schemes, R 2 Selected from cyclopropyl and deuterated methyl;

[0048] R 3 Selected from methyl, phenyl, Cyclopropyl, pyridyl, thiophene, furanyl, Or, R 3 With R 6 And the atoms connected to it form a cyclopropyl group, or, R 6 For hydrogen, R 3 With R 5 The atoms connected to it form a cyclopropyl group.

[0049] In some embodiments, the compound has the structure shown in formula (I):

[0050] in,

[0051] R 1 and R 2 Each is independently selected from hydrogen, -CN, halogen, and -OR. a -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected by one or more of H, deuterium (D), -CN, halogen, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups;

[0052] R a Selected from H, C 1-6 Alkyl and C 3-6 cycloalkyl;

[0053] R 3 and R 4 Each is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-10 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substituents of alkylamine, hydroxyl, hydroxyalkyl, amino, aminoalkyl, substituted or unsubstituted heterocyclic groups, substituted or unsubstituted 5-10 membered heteroaryl and hydroxyalkyl-amide groups;

[0054] t is selected from 1-10.

[0055] In some implementations, t is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0056] In some implementations, t is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9.

[0057] In some implementations, t is selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0058] In some implementations, t is selected from 1, 2, 3, 4, 5, 6, and 7.

[0059] In some implementations, t is selected from 1, 2, 3, 4, 5, and 6.

[0060] In some implementations, t is selected from 3, 4, 5, and 6.

[0061] In some implementations, t is selected from 3, 4, and 5.

[0062] In some implementations, t is selected from 3 and 5.

[0063] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from one or more of deuterium (D), -CN, halogen, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups.

[0064] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, hydroxyl, and C. 1-6 Alkyl and C 3-6 Cycloalkyl; the alkyl group and cycloalkyl group may optionally be selected from one or more of deuterium (D), -CN, halogen, -OH, -NH2, C 1-6 Alkyl, C 1- 6-alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups.

[0065] In some implementation schemes, R 1 and R 2 Each of the following is independently selected from methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, and cyclopentyl, wherein the methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, and cyclopentyl groups are optionally selected by one or more of deuterium (D), -CN, halogen, -OH, -NH2, and C. 1-6 Alkyl, C1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups.

[0066] In some implementation schemes, R 1 and R 2 Each is independently selected from C 1-6 Alkyl and C 3-6 Cycloalkyl; the alkyl and cycloalkyl groups may optionally be substituted with one or more deuterium (D).

[0067] In some implementation schemes, R 1 and R 2 Each is independently selected from methyl, deuterated methyl, ethyl, and cyclopropyl.

[0068] In some implementation schemes, R 1 and R 2 Each is independently selected from methyl, deuterated methyl, and cyclopropyl.

[0069] In some implementation schemes, R 1 and R 2 Each is independently selected from methyl and cyclopropyl.

[0070] In some implementation schemes, R 1 and R 2 Each is independently a methyl group.

[0071] In some implementation schemes, R 3 and R 4 Each is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1-6 Alkyl)2, C 1-6 The substituents are alkylamine, hydroxyalkyl, hydroxyalkyl-amide, 3-8 membered heterocyclic, and 5-10 membered heteroaryl, wherein the 3-8 membered heterocyclic and 5-10 membered heteroaryl groups are optionally replaced by halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups.

[0072] In some implementation schemes, R 3 and R 4 Each is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic groups (e.g., 3-6 membered heterocyclic groups), C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic groups (e.g., 3-6 membered heterocyclic groups), C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1-6 The alkyl group is replaced by substituents of 2, 3-8 membered heterocyclic groups and 5-10 membered heteroaryl groups, wherein the 3-8 membered heterocyclic groups and 5-10 membered heteroaryl groups are optionally replaced by halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-6 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups.

[0073] In some implementation schemes, R 3 and R 4 Each is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1-6 The alkyl group is replaced by substituents of 2, 3-8 membered heterocyclic groups and 5-10 membered heteroaryl groups, wherein the 3-8 membered heterocyclic groups and 5-10 membered heteroaryl groups are optionally replaced by halogens, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-6 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups.

[0074] In some implementation schemes, R 3 and R 4 Each is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 The aryl and 5-10 heteroaryl groups may optionally be separated by one or more groups selected from C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, amino, -N(C) 1-6 The substituents are alkyl groups, 2-3-6-membered heterocyclic groups, and 5-10-membered heteroaryl groups, wherein the 3-6-membered heterocyclic groups are optionally replaced by C. 1-6 Alkyl groups are substituted.

[0075] In some implementation schemes, R 3 and R 4 Each is independently selected from methyl, phenyl, cyclopropyl, pyridyl, thiophenyl, furanyl, The methyl, phenyl, cyclopropyl, pyridyl, thiophene, furanyl, Optionally selected by one or more of C 1-4 Alkyl, C 1-4 The substituents are alkoxy, hydroxy, amino, -N(CH3)2, and 3-6 membered heterocyclic groups (e.g., 3-6 membered nitrogen-containing heterocyclic groups), wherein the 3-6 membered heterocyclic group is optionally replaced by C. 1-4 Alkyl groups are substituted.

[0076] In some implementation schemes, R 3 and R 4 Each is independently selected from methyl, phenyl, cyclopropyl, pyridyl, thiophenyl, furanyl, The methyl, phenyl, cyclopropyl, pyridyl, thiophene, furanyl, Optionally selected by one or more of C 1-4 Alkyl, C 1-4 The substituents are alkoxy, hydroxy, amino, -N(CH3)2, morpholino, and piperazine, wherein the morpholino and piperazine groups are optionally replaced by C. 1-4 Alkyl groups are substituted.

[0077] In some implementation schemes, R 3and R 4 Each is independently selected from methyl, phenyl, cyclopropyl, pyridyl, thiophenyl, furanyl, The phenyl and Optionally selected by one or more of C 1-4 Alkyl, C 1-4 The substituents are alkoxy, hydroxy, amino, -N(CH3)2, morpholino, and piperazine, wherein the morpholino and piperazine groups are optionally replaced by C. 1-4 Alkyl groups are substituted.

[0078] In some implementation schemes, R 3 and R 4 Each is independently selected from methyl, phenyl, cyclopropyl, pyridyl, thiophenyl, furanyl, The phenyl, It may optionally be substituted by one or more substituents selected from methyl, methoxy, ethoxy, propoxy, hydroxy, amino, -N(CH3)2, methylpiperazinyl, morpholinyl.

[0079] In some implementation schemes, R 3 and R 4 Each is independently selected from methyl, phenyl, Cyclopropyl, pyridyl, thiophene, furanyl,

[0080] In some implementation schemes, R 3 and R 4 Each is independently selected from methyl, phenyl, Cyclopropyl, pyridyl, thiophene, furanyl,

[0081] In some implementation schemes, R 3 Selected from methyl, phenyl, Cyclopropyl, pyridyl, thiophene, furanyl,

[0082] In some implementation schemes, R 4 Selected from phenyl, wherein the phenyl group is substituted with an amino group.

[0083] In some implementation schemes, R 1 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl; the alkyl and cycloalkyl groups may optionally be substituted with one or more deuterium (D);

[0084] R 4Selected from methyl, phenyl, cyclopropyl, pyridyl, thiophenyl, furanyl, The phenyl, It may optionally be substituted by one or more substituents selected from methyl, methoxy, ethoxy, propoxy, hydroxy, amino, -N(CH3)2, methylpiperazinyl, morpholinyl.

[0085] In some implementation schemes, R 1 Selected from C 1-4 Alkyl; R 4 Selected from phenyl groups, which may optionally be substituted with one or more amino groups.

[0086] In some implementation schemes, R 1 Selected from methyl; R 4 Selected from

[0087] In some implementation schemes, R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl; the alkyl and cycloalkyl groups may optionally be substituted with one or more deuterium (D);

[0088] R 4 Selected from methyl, phenyl, cyclopropyl, pyridyl, thiophenyl, furanyl, The methyl, phenyl, cyclopropyl, pyridyl, thiophene, furanyl, Optionally selected by one or more of C 1-4 Alkyl, C 1-4 The substituents are alkoxy, hydroxy, amino, -N(CH3)2, and 3-6 membered heterocyclic groups (e.g., 3-6 membered nitrogen-containing heterocyclic groups), wherein the 3-6 membered heterocyclic group is optionally replaced by C. 1-4 Alkyl groups are substituted.

[0089] In some implementation schemes, R 2 Selected from cyclopropyl and deuterated methyl;

[0090] R 4 Selected from phenyl groups, which may optionally be substituted with one or more amino groups.

[0091] In some implementation schemes, R 2 Selected from cyclopropyl and deuterated methyl;

[0092] R 4 Selected from

[0093] In some implementation schemes, R a Selected from H, C 1-4 Alkyl and C 3-6 cycloalkyl, preferably, R aIt is selected from H, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0094] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from one or more of deuterium (D), -CN, halogen, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups;

[0095] R 3 and R 4 Each is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1- 6-alkyl)2, C 1-6 The substituents are alkylamine, hydroxyalkyl, hydroxyalkyl-amide, 3-8 membered heterocyclic, and 5-10 membered heteroaryl, wherein the 3-8 membered heterocyclic and 5-10 membered heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups;

[0096] The t is selected from 1, 2, 3, 4, 5, 6, 7 and 8.

[0097] In some implementation schemes, R 1 and R 2 Each is independently selected from hydrogen, hydroxyl, and C. 1-6 Alkyl and C 3-6 Cycloalkyl; the alkyl group and cycloalkyl group may optionally be selected from one or more of deuterium (D), -CN, halogen, -OH, -NH2, C 1-6 Alkyl, C 1- 6-alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups;

[0098] R 3 and R 4 Each is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic groups (e.g., 3-6 membered heterocyclic groups), C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic groups (e.g., 3-6 membered heterocyclic groups), C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1-6 The substituents are alkyl groups, 2-3-8-membered heterocyclic groups, and 5-10-membered heteroaryl groups, wherein the 3-8-membered heterocyclic groups and 5-10-membered heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-6 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups;

[0099] The t is selected from 1, 2, 3, 4, 5, and 6.

[0100] In some implementation schemes, R 1 and R 2 Each of the following is independently selected from methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, and cyclopentyl, wherein the methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, and cyclopentyl groups are optionally selected by one or more of deuterium (D), -CN, halogen, -OH, -NH2, and C. 1-6 Alkyl, C 1-6Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups;

[0101] R 3 and R 4 Each is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1-6 The substituents are alkyl groups, 2-3-8-membered heterocyclic groups, and 5-10-membered heteroaryl groups, wherein the 3-8-membered heterocyclic groups and 5-10-membered heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-6 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups;

[0102] The t mentioned is selected from 3, 4, 5, and 6.

[0103] In some implementation schemes, R 1 and R 2 Each is independently selected from methyl, deuterated methyl, ethyl, and cyclopropyl;

[0104] R 3 and R 4 Each is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl and 5-10 heteroaryl, the C 1- 6-alkyl, C 3-6 cycloalkyl, C 6-10 The aryl and 5-10 heteroaryl groups may optionally be separated by one or more groups selected from C 1-4 Alkyl, C 1- 4. Alkoxy, hydroxy, amino, -N(C) 1-6The substituents are alkyl groups, 2-3-6-membered heterocyclic groups, and 5-10-membered heteroaryl groups, wherein the 3-6-membered heterocyclic groups are optionally replaced by C. 1-6 Alkyl groups are substituted;

[0105] The t mentioned is selected from 3, 4, and 5.

[0106] In some implementation schemes, R 1 and R 2 Each is independently selected from methyl and cyclopropyl;

[0107] R 3 and R 4 Each is independently selected from methyl, phenyl, cyclopropyl, pyridyl, thiophenyl, furanyl, The methyl, phenyl, cyclopropyl, pyridyl, thiophene, furanyl, Optionally selected by one or more of C 1-4 Alkyl, C 1-4 The substituents are alkoxy, hydroxy, amino, -N(CH3)2, and 3-6 membered heterocyclic groups (e.g., 3-6 membered nitrogen-containing heterocyclic groups), wherein the 3-6 membered heterocyclic group is optionally replaced by C. 1-4 Alkyl groups are substituted;

[0108] The t mentioned is selected from 3, 4, and 5.

[0109] In some implementation schemes, R 1 and R 2 Each is independently selected from methyl and cyclopropyl;

[0110] R 3 and R 4 Each is independently selected from methyl, phenyl, cyclopropyl, pyridyl, thiophenyl, furanyl, The methyl, phenyl, cyclopropyl, pyridyl, thiophene, furanyl, Optionally selected by one or more of C 1-4 Alkyl, C 1-4 The substituents are alkoxy, hydroxy, amino, -N(CH3)2, morpholino, and piperazine, wherein the morpholino and piperazine groups are optionally replaced by C. 1-4 Alkyl groups are substituted;

[0111] The t mentioned is selected from 3, 4, and 5.

[0112] In some implementation schemes, R 1 and R 2 Each is independently selected from methyl and cyclopropyl;

[0113] R3 and R 4 Each is independently selected from methyl, phenyl, cyclopropyl, pyridyl, thiophenyl, furanyl, The phenyl and Optionally selected by one or more of C 1-4 Alkyl, C 1-4 The substituents are alkoxy, hydroxy, amino, -N(CH3)2, morpholino, and piperazine, wherein the morpholino and piperazine groups are optionally replaced by C. 1-4 Alkyl groups are substituted;

[0114] The t mentioned is selected from 3, 4, and 5.

[0115] In some implementation schemes, R 1 and R 2 Each is independently selected from methyl and cyclopropyl;

[0116] R 3 and R 4 Each is independently selected from methyl, phenyl, cyclopropyl, pyridyl, thiophenyl, furanyl, The phenyl, It may optionally be substituted by one or more substituents selected from methyl, methoxy, ethoxy, propoxy, hydroxy, amino, -N(CH3)2, methylpiperazinyl, morpholinyl;

[0117] The t mentioned is selected from 3, 4, and 5.

[0118] In some implementation schemes, R 1 and R 2 Each is independently selected from methyl and cyclopropyl;

[0119] R 3 and R 4 Each is independently selected from methyl, phenyl, Cyclopropyl, pyridyl, thiophene, furanyl,

[0120] The t mentioned is selected from 3, 4, and 5.

[0121] In some implementation schemes, R 1 and R 2 Each is independently selected from methyl and cyclopropyl;

[0122] R 3 Selected from methyl, phenyl, Cyclopropyl, pyridyl, thiophene, furanyl,

[0123] R 4 Selected from phenyl groups, wherein the phenyl group is substituted with an amino group;

[0124] The t mentioned is selected from 3, 4, and 5.

[0125] On the other hand, this application provides the following compounds or their pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites, or prodrugs, wherein the compounds have the following structures:

[0126] All technical features disclosed in this specification, except for mutually exclusive features, can be combined in any way. This invention covers compounds obtained by arbitrary combinations of various embodiments, wherein the compounds of this invention can be optionally substituted with suitable substituents at suitable substitution positions.

[0127] definition

[0128] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0129] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0130] As used herein, an asterisk (*) in a compound structural formula indicates that the labeled carbon atom is a chiral carbon atom, and the invention includes a pair of enantiomers formed from that chiral carbon atom. If a compound contains two different chiral carbon atoms, the invention includes four optical isomers formed from that chiral carbon atom.

[0131] As used in this article, This indicates the location where a structural segment connects to other parts of the molecule.

[0132] The term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 12, for example, 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6"Alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl), which is optionally substituted by one or more (such as 1, 2, or 3) suitable substituents.

[0133] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is defined as described above. For example, the term "C" in this invention... 1-6 "Hydroxyalkyl" refers to hydroxyalkyl groups having 1-6 carbon atoms. Common hydroxyalkyl groups include (but are not limited to) -CH2OH, -CH2CH2OH, -CH2CH(OH)2, and -(CH2)3OH.

[0134] The term "amine alkyl" refers to an alkyl group substituted with one or more amino groups, wherein the alkyl group is defined as described above. For example, the term "C" in this invention... 1-6 "Aminoalkyl" refers to an aminoalkyl group having 1-6 carbon atoms. Common aminoalkyl groups include (but are not limited to) -CH2-NH2, -CH2CH2-NH2, -CH2CH(NH2)2, and -(CH2)3-NH2.

[0135] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond, including, for example, "C..." 2-6 "alkenyl", "C" 2-4 Examples of these include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexadienyl, etc.

[0136] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond. This includes, for example, "C..." 2-6 "Alkyne", "C" 4- Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1,3-butyrynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1,3-pentyrynyl, 1,4-pentyrynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,4-hexadiynyl, etc.

[0137] The term "cycloalkyl" refers to a saturated or partially saturated cyclic hydrocarbon group, including but not limited to monocycloalkyl and bicycloalkyl (such as spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl). The term "C" 3-6"Cycloalkyl" refers to a cycloalkyl group having 3 to 6 cyclic carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., which may optionally be substituted by one or more (such as 1, 2 or 3) suitable substituents, such as methyl-substituted cyclopropyl, cyclobutyl, cyclopentyl, etc. wait.

[0138] The term "heterocyclic group" or "heterocycle" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic cyclic structure whose ring atoms consist of carbon atoms and at least one (e.g., 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocyclic group can be connected to the rest of the molecule through any one ring atom, provided that valence requirements are met. The heterocyclic groups used in this invention are preferably 3-10 membered, 3-8 membered, or 3-6 membered heterocyclic groups. The term "3-6 membered heterocyclic group" as used in this invention refers to a heterocyclic group having 3 to 6 ring atoms, including 3-membered, 4-membered, 5-membered, and 6-membered heterocyclic groups, including nitrogen-containing heterocyclic groups and oxygen-containing heterocyclic groups, such as 4-6 membered heterocyclic groups, such as 4-6 membered nitrogen-containing heterocyclic groups, 4-6 membered oxygen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, and 5 membered oxygen-containing heterocyclic groups. Common heterocyclic groups include (but are not limited to) azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl. The heterocyclic groups in this invention may optionally be substituted with one or more of the substituents described herein. The heterocyclic groups in this invention may optionally be fused with one or more aromatic or non-aromatic rings.

[0139] The term "oxygen-containing heterocycle" refers to a heterocycle as described above that has one or more (e.g., 1, 2, or 3) ring atoms of oxygen atoms, such as 5-6 membered oxygen-containing heterocycles, five membered oxygen-containing heterocycles, and specific examples include, but are not limited to, ethylene oxide rings, tetrahydrofuran rings, furan rings, tetrahydropyran rings, pyran rings, 1,3-dioxolane rings, etc.

[0140] The "nitrogen-containing heterocycle" as described in this invention refers to the heterocycle described above, in which one or more (e.g., 1, 2 or 3) ring atoms are nitrogen atoms.

[0141] The term "halogenated alkyl" refers to an alkyl group substituted with one or more (such as 1, 2, or 3) identical or different halogen atoms, wherein the alkyl group is defined as described above. For example, the term "C" as used in this invention... 1-6"Halogenated alkyl" refers to an alkyl halogroup having 1 to 6 carbon atoms. Common alkyl halogroups include (but are not limited to) -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3, -CH2Cl, etc. The alkyl halogroups in this invention are optionally substituted by one or more substituents described in this invention.

[0142] The term "alkoxy" refers to a group having an "alkyl-O-" structure, where alkyl is defined as described above. For example, C 1-6 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkoxy or C 1-2 Alkoxy groups, etc. Common alkoxy groups include (but are not limited to) methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups in this invention are optionally substituted by one or more substituents described in this invention.

[0143] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, or 4) alkoxy groups, wherein the definitions of alkoxy and alkyl groups are as described above. For example, the term "C" as used in this invention... 1-6 "Alkoxyalkyl" refers to an alkyl group having 1-6 carbon atoms that is substituted with one or more (e.g., 1, 2, 3, or 4) alkoxy groups. Common alkoxyalkyl groups include (but are not limited to) CH3O-CH2-, C2H5-O-CH2-, C2H5-O-CH2CH2-, etc.

[0144] The term "halogenated" or "halogenated" is defined as including F, Cl, Br, or I.

[0145] The term "alkylamine" refers to an alkyl group substituted with NH2, as defined above, such as -C. 1-6 Alkyl-NH2, -C 1-4 Alkyl-NH2, etc.

[0146] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group, as defined above, such as -C 1-6 Alkyl -OH, -C 1- 4-alkyl-OH, etc.

[0147] The term "aminealkyl" refers to an amino group substituted with an alkyl group, as defined above, such as -NH-C. 1-6 Alkyl and -N(C) 1-6 Alkyl group 2, for example -NH-C 1-4 Alkyl and -N(C) 1-4 Alkyl)2.

[0148] The term "hydroxyalkyl-amide group" refers to an amide group substituted with a hydroxyalkyl group, wherein the hydroxyalkyl group is as defined above, for example, OH-C. 1-6 Alkyl-NH-C(=O)-, OH-C 1-4 Alkyl-NH-C(=O)- etc.

[0149] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more substituents from the list of substituents, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together by independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted by one or more substituents from the list of substituents, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted by independently selected optional substituents.

[0150] If a functional group or structural segment is described as “substituted or unsubstituted”, then the functional group or structural segment may be (1) unsubstituted or (2) substituted.

[0151] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0152] The term "substitution" refers to the replacement of one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms on a specified compound or structural segment by a substituent, provided that the substitution does not exceed the normal valence of the specified atom in the present case and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. For example, each substituent may independently consist of one or more of the following structures: -O-, -S-, -NR. 1 - Halogen, -CN, -OH, -NH2, -NO2, -CN, =O, C 1-6 (alkylene) group, C 1-6 Halogenated (alkylene) group, C1-6 alkoxy group, C 2-6 (imide)alkenyl, C 2-6 (Asyl) ynyl, C 3-8 (Hypo-cycloalkylene), 3-8 membered (hetero-cycloalkylene), C6- 10 (Anesthetic)aryl and 5-10 quinone (Anesthetic)heteroaryl, for example -OC 1-6 (alkylene)-OH, C 1-6 (alkylene)-OH, -OC 1-6 (alkylene)-NH2, -N(R3)-C 1-6 (alkylene) group, -N(R3)-C 1-6(alkylene)-OH, -NH-C 1-6 (Alkene)alkyl, 3-6 membered (heterocyclic)-OH, C 6-10 (A)aryl-OH, for example, wherein each of the substituents is independently selected from one or more of F, Cl, Br, methyl, ethyl, propyl, halogenated C. 1-6 Alkyl, Halogenated C 1-6 Alkoxy, -O-, -S-, CN, =O, methoxy, ethoxy, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, -OH, 3-6 membered nitrogen heterocyclic groups, phenyl, naphthyl, pyridyl, and phenolic groups, etc. If a substituent is described as being "independently selected" from a group of functional groups, then each substituent is chosen independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0153] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, six, seven, eight, nine, or ten.

[0154] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0155] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%).

[0156] Solid lines (—) and solid wedges may be used in this article. Or virtual wedge The carbon-carbon bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0157] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0158] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0159] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0160] Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts.

[0161] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts for the compounds of the present invention are known to those skilled in the art.

[0162] The term "ester" refers to esters derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves be esters.

[0163] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0164] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0165] This invention further includes, within its scope, prodrugs of the compounds of the invention. Typically, such prodrugs are functional group derivatives of the compounds that readily convert in vivo into the desired therapeutically active compound. Therefore, in these cases, the term "administration" for the treatment methods of the invention should include treating various diseases or conditions with one or more prodrug forms of the claimed compounds, but after administration to an individual, the prodrug form is converted in vivo into the aforementioned compound. For example, conventional methods for selecting and preparing suitable prodrug derivatives are described in "Design of Prodrug," ed. H. Bundgaard, Elsevier, 1985.

[0166] This invention further includes, within its scope, isotopic labels of the compounds of this invention, which are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in this invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H, deuterium (D), tritium (T); carbon isotopes (e.g., H, deuterium (D), tritium (T)); 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 37 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); and isotopes of sulfur (e.g. 35 S).

[0167] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in *Protective Groups in Organic Chemistry*, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. ​​G.W. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0168] Pharmaceutical Composition

[0169] In a third aspect, the present invention provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitride, isotope label, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0170] The term "pharmaceutical composition" refers to a composition that can be used as a medicine, comprising a pharmaceutically active ingredient (API) (or therapeutic agent) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceuticalally acceptable carrier" refers to an excipient administered co-administered with the therapeutic agent, and which, to the extent of reasonable medical judgment, is suitable for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0171] The above-described pharmaceutical compositions can act systemically and / or locally, which can be achieved through suitable dosage forms. These dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0172] The above-mentioned pharmaceutical composition may contain 0.01 mg to 1000 mg of at least one of the compounds of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof.

[0173] The present invention also provides a method for preparing the above-described pharmaceutical composition or its corresponding formulation, comprising combining at least one compound of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitride, isotope label, metabolite or prodrug with one or more pharmaceutically acceptable carriers.

[0174] Pillbox products

[0175] In a fourth aspect, the present invention provides a medicine box comprising:

[0176] a) at least one compound of the present invention as a first therapeutic agent, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof, or a pharmaceutical composition as a first pharmaceutical composition;

[0177] b) At least one other therapeutic agent optionally present as a second therapeutic agent, or a pharmaceutical composition comprising another therapeutic agent as a second pharmaceutical composition; and

[0178] c) Optional packaging and / or instructions.

[0179] The aforementioned kit may contain 0.01 mg to 1000 mg of at least one of the compounds of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof.

[0180] The present invention also provides a method for preparing the above-mentioned medicine box, which includes combining at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug or the above-mentioned pharmaceutical composition with at least one other therapeutic agent or a pharmaceutical composition containing other therapeutic agents, packaging and / or instructions.

[0181] Medical Use

[0182] The compound represented by formula (I') of this invention exhibits a strong inhibitory effect on abnormal cell proliferation.

[0183] The compound represented by formula (I) of this invention exhibits a strong inhibitory effect on abnormal cell proliferation.

[0184] This application provides the compounds described herein or their pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope-labeled substances, metabolites, and prodrugs, the pharmaceutical compositions described above, or the kits described above, for the treatment of diseases involving abnormal cell proliferation.

[0185] This application also provides the use of the compounds described herein or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope-labeled substances, metabolites, and prodrugs thereof, the pharmaceutical compositions described above, or the cassettes described above, in the preparation of medicaments for treating diseases involving abnormal cell proliferation.

[0186] In some implementations, the diseases involving abnormal cell proliferation include, but are not limited to, tumors, such as advanced solid tumors.

[0187] In some implementations, the disease involving abnormal cell proliferation is selected from tumors, such as advanced solid tumors.

[0188] This application also provides the use of the compounds described herein or their pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites, and prodrugs, or the pharmaceutical compositions described above in the present invention, in the preparation of formulations for inhibiting the proliferation of tumor cells.

[0189] In some embodiments, the formulation is for in vivo or in vitro administration. For example, the formulation may be administered to a subject to inhibit the proliferation of tumor cells in the subject; or, the formulation may be administered to in vitro cells (e.g., cell lines or cells derived from the subject) to inhibit the proliferation of tumor cells in vitro.

[0190] The tumors described in this invention include, but are not limited to, or are selected from: brain tumors, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, and sarcoma.

[0191] The present invention also provides the use of the compound of formula (I') for the preparation of antibody-drug conjugates.

[0192] The present invention also provides the use of the compound of formula (I) for the preparation of antibody-drug conjugates.

[0193] Treatment

[0194] In another aspect, the present invention provides a method for treating a disease involving abnormal cell proliferation, comprising the steps of administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, and prodrug or the pharmaceutical composition described above to an individual in need of it.

[0195] The term "effective dose" refers to a dose that is sufficient to induce a biological or medical response in cells, tissues, organs, or organisms (e.g., individuals) and to achieve the desired preventive and / or therapeutic effects.

[0196] The dosing regimen can be adjusted to provide the optimal required response. For example, it can be administered as a single dose, divided into doses over time, or the dose can be reduced or increased proportionally as needed. It is understood that, for any given individual, the specific dosing regimen should be adjusted as required and with the professional judgment of the person administering the composition or supervising the administration of the composition.

[0197] The dosage of the compounds of this invention will depend on individual circumstances, the severity of the disease or condition, the rate of administration, the disposal of the compound, and the prescribing physician's judgment. Generally, the effective dose is about 0.001-10000 mg / kg body weight / day. Where appropriate, the effective dose is about 0.01-1000 mg / kg body weight / day. The dosage and frequency of administration may vary depending on the half-life of the drug in the subject and may also vary depending on whether it is for prophylactic or therapeutic use. In prophylactic use, a relatively low dose is administered for a long period at relatively low frequency intervals; in therapeutic use, a relatively high dose may sometimes be administered at shorter intervals until the progression of the disease is slowed or stopped, preferably until the individual shows partial or complete improvement in the symptoms of the disease, after which prophylactic use may be adopted.

[0198] The term "treatment" refers to the reduction or elimination of a targeted disease or symptom. If a subject receives a therapeutic amount of a compound of the present invention or its pharmaceutically acceptable form, or a pharmaceutical composition of the present invention, and at least one indicator and symptom of the subject shows observable and / or detectable relief and / or improvement, the subject is considered to have been successfully "treated." It is understood that treatment includes not only complete cure but also the achievement of some biological or medically relevant outcome without achieving complete cure.

[0199] The term "administrate / administrating / administration" (or "drug administration") refers to the process of applying an active pharmaceutical ingredient (such as the compound of the present invention) or a pharmaceutical composition containing an active pharmaceutical ingredient (such as the pharmaceutical composition of the present invention) to an individual or its cells, tissues, organs, biological fluids, etc., so as to bring the active pharmaceutical ingredient or pharmaceutical composition into contact with the individual or its cells, tissues, organs, biological fluids, etc. Common methods of administration include (but are not limited to) oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, and vaginal administration.

[0200] The term “needs” refers to the judgment of a physician or other caregiver regarding an individual’s need for or potential benefit from preventive and / or treatment processes, which is based on various factors within the physician’s or other caregiver’s area of ​​expertise.

[0201] The term "individual" (or subject) refers to a human or non-human animal. Individuals in this invention include individuals suffering from diseases and / or conditions (patients) and healthy individuals. Non-human animals in this invention include all vertebrates, such as non-mammals, such as birds, amphibians, reptiles, etc., and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0202] Beneficial effects of the invention

[0203] The compounds of the present invention have good anti-tumor activity and can be used to treat diseases of abnormal cell proliferation, including but not limited to advanced solid tumors. Detailed Implementation

[0204] The following description of specific embodiments further illustrates this application, but it is not intended to limit the scope of the application. Those skilled in the art can make various modifications or improvements based on the teachings of this application without departing from its fundamental ideas and scope.

[0205] The abbreviations used in this invention have the following meanings:

[0206] The structures of the compounds described in the following examples were determined by nuclear magnetic resonance (NMR). 1 It can be determined by 1H NMR or mass spectrometry (MS).

[0207] Nuclear magnetic resonance (NMR) 1 The H NMR (H NMR) measurements were performed using a Bruker 400MHz NMR spectrometer; hexadeuterated dimethyl sulfoxide (DMSO-d6) was used; and tetramethylsilane (TMS) was used as the internal standard.

[0208] The abbreviations used in the nuclear magnetic resonance (NMR) spectra in the embodiments are shown below.

[0209] s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, DMSO-d6: dimethyl sulfoxide deuterated. δ values ​​are expressed in ppm.

[0210] The mass spectrometry (MS) measurements were performed using an Agilent (ESI) mass spectrometer, model Agilent 6120B.

[0211] Example 1 of intermediate preparation: Preparation of (S)-1-(4-benzyloxy)-5-methoxy-2-nitrobenzoyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydro-1H-pyrrole-3-yltrifluoromethanesulfonate (INT-1)

[0212] Step 1: Preparation of (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1-carboxylic acid benzyl ester (INT-1-2)

[0213] (2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidine-1-carboxylic acid benzyl ester (44 g, 175 mmol) and triethylamine (53.0 g, 525 mmol, 73.2 mL) were added to toluene (450 mL), followed by the addition of TBSCl (39.5 g, 262 mmol, 32.1 mL). The mixture was heated to 80 °C and stirred for 18 hours. Water (1000 mL) was added to the reaction mixture, and the mixture was extracted three times with dichloromethane (500 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. After purification by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 3 / 1), the product was concentrated again to obtain the title compound (50 g, 136.78 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 366.3 [M+H] +

[0214] Step 2: Preparation of (3R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-3-ol (INT-1-3)

[0215] (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1-carboxylic acid benzyl ester (50 g, 136 mmol) was dissolved in methanol (25 mL), and the Cbz protecting group was removed by a fluid-catalyzed reaction under 5% Pd / Al₂O₃ and 50 °C. The collected reaction solution was directly concentrated to give the title compound (31 g, 133.96 mmol), which was used directly in the next step without purification. Its structural characterization data are as follows:

[0216] ESI-MS (m / z): 232.2 [M+H] +

[0217] Step 3: Preparation of (4-(benzyloxy)-5-methoxy-2-nitrophenyl)((2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1-yl)methyl ketone (INT-1-4)

[0218] 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid (32.0 g, 105 mmol) was dissolved in a mixed solvent of dichloromethane (300 mL) and DMF (1.16 g, 15.8 mmol, 1.22 mL). The solution was cooled to 0 °C, and oxaloyl chloride (18.5 g, 146 mmol, 12.80 mL) was added. The solution was then allowed to recover naturally to 25 °C, and stirring was continued for 4 hours. The reaction solution was directly concentrated to obtain the crude product. (3R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-3-ol (26.1 g, 112 mmol) and triethylamine (31.1 g, 307 mmol, 42.8 mL) were added to dichloromethane (300 mL). The solution was cooled to 0 °C, and the crude product obtained in the previous step (33.0 g, 102 mmol) was added. The solution was then allowed to recover naturally to 25 °C, and stirring was continued for 2 hours. Water (600 mL) was added to the reaction system, and the mixture was extracted three times with dichloromethane (300 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. After purification by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1), the product was concentrated again to obtain the title compound (27.0 g, 52.2 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 517.2 [M+H] +

[0219] Step 4: Preparation of (S)-1-(4-benzyloxy)-5-methoxy-2-nitrobenzoyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-3-one (INT-1-5)

[0220] (4-(benzyloxy)-5-methoxy-2-nitrophenyl)((2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1-yl) methyl ketone (26.0 g, 50.3 mmol) and triethylamine (50.9 g, 503 mmol, 70.0 mL) were dissolved in a mixed solvent of dichloromethane (208 mL) and DMSO (260 mL), cooled to 0 °C, and pyridine sulfur trioxide (56.07 g, 352 mmol) was added. The mixture was then naturally heated to 25 °C and stirred for 2 hours. Dichloromethane (400 mL) was added to the reaction system, followed by quenching the reaction with a saturated ammonium chloride aqueous solution (500 mL). Then, water (500 mL), a saturated sodium bicarbonate aqueous solution (500 mL), and a saturated sodium thiosulfate aqueous solution (500 mL) were added sequentially. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was slurried with petroleum ether / ethyl acetate (10 / 1) at 25°C for 1 hour, filtered, and dried to obtain the title compound (22.0 g, 42.7 mmol), which was used directly in the next step without purification. Its structural characterization data are as follows: ESI-MS (m / z): 367.2 [M+H] +

[0221] Step 5: Preparation of (S)-1-(4-benzyloxy)-5-methoxy-2-nitrobenzoyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydro-1H-pyrrole-3-yltrifluoromethanesulfonate (INT-1)

[0222] (S)-1-(4-benzyloxy)-5-methoxy-2-nitrobenzoyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-3-one (21.0 g, 40.81 mmol) was dissolved in dichloromethane (400 mL) and cooled to -40 °C. 2,6-Dimethylpyridine (38.6 g, 360 mmol, 42.0 mL) was added, and stirring was continued for 15 minutes. Trifluoromethanesulfonic anhydride (34.5 g, 122 mmol, 20.2 mL) was slowly added dropwise to the above reaction solution over 2 hours, and stirring was continued at -40 °C for 1 hour. The reaction solution was allowed to return to 25 °C naturally, and saturated sodium bicarbonate aqueous solution (500 mL) was added. The mixture was extracted three times with dichloromethane (300 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. After purification by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 3 / 1), the compound was concentrated again to give the title compound (16.0 g, 23.01 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 647.3 [M+H] +

[0223] Example 2 of intermediate preparation: Preparation of (S)-8-(benzyloxy)-7-methoxy-5,11-dioxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-2-yltrifluoromethanesulfonate (INT-2)

[0224] Step 1: Preparation of (2S,4R)-1-(4-benzyloxy-5-methoxy-2-nitrobenzoyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (INT-2-2)

[0225] 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid (40.0 g, 131 mmol) was dissolved in dichloromethane (400 mL), and DMF (1.45 g, 19.7 mmol, 1.52 mL) was added. The mixture was then cooled to 0 °C, and oxaloyl chloride (18.4 g, 145 mmol, 12.7 mL) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature (25 °C) and stirred for 4 hours. The reaction solution was then concentrated to obtain crude 4-(benzyloxy)-5-methoxy-2-nitrobenzoyl chloride. (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride (24.8 g, 136 mmol) was dissolved in dichloromethane (400 mL), and DIPEA (48.2 g, 373 mmol, 64.9 mL) was added. The mixture was cooled to 0 °C. A dichloromethane solution (150 mL) of crude (benzyloxy)-5-methoxy-2-nitrobenzoyl chloride (40.0 g, 124 mmol) was slowly added dropwise to the above reaction solution. After the addition was complete, the mixture was allowed to return to room temperature (25 °C) and stirred for 1 hour. Water (1000 mL) was added to the reaction solution, and the mixture was extracted three times with dichloromethane (300 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain the crude title compound (50.0 g, 116 mmol), which was used directly in the next step without purification. Its structural characterization data are as follows: ESI-MS (m / z): 431.0 [M+H] +

[0226] Step 2: Preparation of (2R,11aS)-8-(benzyloxy)-2-hydroxy-7-methoxy-1,2,3,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H)-dione (INT-2-3)

[0227] Methyl (2S,4R)-1-(4-benzyloxy-5-methoxy-2-nitrobenzoyl)-4-hydroxypyrrolidine-2-carboxylic acid (40.0 g, 92.9 mmol) and NH4Cl (29.8 g, 557 mmol) were dissolved in a mixed solvent of ethanol (450 mL) and water (150 mL). Iron powder (31.1 g, 557 mmol) was added, and the mixture was heated to 80 °C and stirred for 3 hours. The reaction solution was filtered through diatomaceous earth and concentrated to obtain a crude product. The crude product was then slurried in petroleum ether (500 mL), filtered, and dried to obtain the crude title compound (43.0 g), which was used directly in the next step without purification. Its structural characterization data are as follows: ESI-MS (m / z): 369.1 [M+H] +

[0228] Step 3: Preparation of (S)-8-(benzyloxy)-7-methoxy-1,11a-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-2,5,11(3H,10H)-trione (INT-2-4)

[0229] (2R,11aS)-8-(benzyloxy)-2-hydroxy-7-methoxy-1,2,3,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H)-dione (10.0 g, 27.1 mmol) and TEA (27.4 g, 271 mmol, 37.7 mL) were added to dichloromethane (80.0 mL) and DMSO (100 mL). After cooling to 0 °C, pyridine sulfur trioxide (34.5 g, 217.17 mmol) was added, and the mixture was allowed to recover naturally to 25 °C and stirred for 3 hours. Dichloromethane (400 mL) was added to the reaction system. The mixture was washed with saturated ammonium chloride aqueous solution (500 mL), water (500 mL), saturated sodium bicarbonate aqueous solution (500 mL), and saturated sodium thiosulfate aqueous solution (500 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was slurried with petroleum ether / ethyl acetate (2 / 1) at 25 °C, filtered, and dried to obtain the title compound (7 g, 19.11 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 367.2 [M+H] +

[0230] Step 4: Preparation of (S)-8-(benzyloxy)-7-methoxy-5,11-dioxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-2-yltrifluoromethanesulfonate (INT-2)

[0231] (S)-8-(benzyloxy)-7-methoxy-1,11a-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-2,5,11(3H,10H)-trione (5.00 g, 13.6 mmol) was dissolved in dichloromethane (100 mL) and heated to 40 °C. Trifluoromethanesulfonic anhydride (38.5 g, 136 mmol, 22.5 mL) was added, and stirring continued for 30 minutes. Over 3 hours, 2,6-dimethylpyridine (9.20 g, 85.8 mmol, 10.0 mL) was slowly added dropwise to the above reaction solution. After the addition was complete, the temperature was lowered to -40 °C, and stirring continued for 4 hours. The reaction solution was heated to 0 °C, and the reaction was quenched by adding 10% citric acid aqueous solution. Then, water (800 mL) was added, and the mixture was extracted three times with dichloromethane (500 L x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. After purification by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1–3 / 1), the product was concentrated again to give the title compound (2.65 g, 5.21 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 499.2 [M+H] +

[0232] Example 3 of intermediate preparation: (S)-2-(4-(((allyloxy)carbonyl)amino)phenyl)-8-(3-bromopropoxy)-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (INT-3)

[0233] Step 1: Preparation of (S)-(4-(8-benzyloxy)-7-methoxy-5,11-dioxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-2-yl)phenyl)tert-butyl carbamate (INT-3-1)

[0234] (S)-8-(benzyloxy)-7-methoxy-5,11-dioxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-2-yltrifluoromethanesulfonate (1.5 g, 3.01 mmol) and 4-(tert-butoxycarbonyl)aminophenylboronic acid (1.43 g, 6.02 mmol), sodium carbonate (957.8 mg, 9.03 mmol) were dissolved in a mixture of toluene (50 mL), ethanol (5 mL), and water (5 mL). Tetra(triphenylphosphine)palladium (696.2 mg, 0.6 mmol) was added, and the mixture was heated at 80 °C for 5 hours under nitrogen purging twice and protection. The reaction solution was then added to ethyl acetate (150 mL) and water (200 mL) and stirred. The mixture was filtered, and the filtrate was allowed to stand and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. This crude product was then purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) and further concentrated to obtain the title compound (1.57 g, 2.9 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 542.3 [M+H] +

[0235] Step 2: Preparation of (S)-2-(4-aminophenyl)-8-(benzyloxy)-7-methoxy-1,11a-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H)-dione (INT-3-2)

[0236] (S)-(4-(8-benzyloxy)-7-methoxy-5,11-dioxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-2-yl)phenyl)tert-butyl carbamate (1.57 g, 2.9 mmol) was added to a single-necked flask, followed by 30 mL of ethyl acetate hydrochloride solution. The reaction was carried out at room temperature for 2 hours. The crude product of the title compound (1.19 g, 2.70 mmol) was concentrated under reduced pressure and used directly in the next step without purification. Its structural characterization data are as follows: ESI-MS (m / z): 442.2 [M+H]

[0237] Step 3: Preparation of (S)-2-(4-aminophenyl)-8-(benzyloxy)-7-methoxy-1,10,11,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-one (INT-3-3)

[0238] (S)-2-(4-aminophenyl)-8-(benzyloxy)-7-methoxy-1,11a-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H)-dione (650 mg, 1.47 mmol) was dissolved in dry tetrahydrofuran (45 mL), sodium borohydride (1.08 g, 29.4 mmol) was added, and trifluoroacetic acid (521.85 mg, 3.675 mmol) was slowly added dropwise, producing a large amount of gas. The mixture was slowly heated to 75 °C and refluxed for 16 hours. The reaction solution was cooled to room temperature, and the reaction was quenched dropwise with methanol. The solution was then concentrated under reduced pressure. After purification by silica gel column chromatography (dichloromethane / 20% methanol-dichloromethane = 0%–60%), the mixture was freeze-dried to obtain a mixture (390 mg, 0.91 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 428.1 [M+H] +

[0239] Step 4: Preparation of (S)-2-(4-(((allyloxy)carbonyl)amino)phenyl)-8-(benzyloxy)-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (INT-3-4)

[0240] (S)-2-(4-aminophenyl)-8-(benzyloxy)-7-methoxy-1,10,11,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-one (390 mg, 0.91 mmol) was dissolved in dichloromethane (5 mL), and DIPEA (353.5 mg, 2.74 mmol) and allyl chloroformate (220.2 mg, 1.83 mmol) were added. The mixture was stirred for 1 hour. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–60%) to give the title compound (360 mg, 0.61 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 596.2 [M+H] +

[0241] Step 5: Preparation of (S)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-8-hydroxy-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (INT-3-5)

[0242] (S)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-8-(benzyloxy)-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (360 mg, 0.61 mmol) was dissolved in dichloromethane (3 mL) and cooled to 0 °C. Then, methanesulfonic acid (1.2 mL) was added dropwise. The reaction mixture was kept at this temperature for 1 hour. Water (3 mL) was added to the reaction mixture, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane (10 mL x 3), and the combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude title compound (130 mg, 0.26 mmol), which was used directly in the next step without purification. Its structural characterization data are as follows: ESI-MS (m / z): 506.2 [M+H] +

[0243] Step Six: Preparation of (S)-2-(4-(((allyloxy)carbonyl)amino)phenyl)-8-(3-bromopropoxy)-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (INT-3)

[0244] (S)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-8-hydroxy-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (130 mg, 0.26 mmol) was dissolved in DMF (2 mL), followed by the addition of 1,3-dibromopropane (260 mg, 1.3 mmol) and potassium carbonate (53.9 mg, 0.39 mmol), and the reaction was stirred for 16 hours. The reaction was quenched with water, and the mixture was extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) yielded the title compound (125 mg, 0.2 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 626.2 [M+H] +

[0245] Example 4 of intermediate preparation: (S)-8-((5-bromopentyl)oxy)-7-methoxy-5-oxo-11,11a-dihydro-1H,3H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diazaphen-2,1'-cyclopropane]-10(5H)-carboxylic acid allyl ester (INT-4)

[0246] (S)-8-hydroxy-7-methoxy-5-oxo-11,11a-dihydro-1H,3H-spiro[benzo[e]pyrrolo[1,2-a][l,4]diaza-2,2'-cyclopropane]-10(5H)-carboxylic acid allyl ester (200 mg, 558.06 μmol) was dissolved in DMF (5 mL), and 1,5-dibromopentane (641.60 mg, 2.79 mmol) and potassium carbonate (115.69 mg, 837.08 μmol) were added. The mixture was heated to 40 °C and stirred overnight. Water and ethyl acetate were added and stirred. The mixture was allowed to stand and separated. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, washed three times with saturated brine, dried, and concentrated under reduced pressure. The solution was purified by silica gel column chromatography (eluent: 0-50% ethyl acetate / petroleum ether), and concentrated again under reduced pressure to give the title compound (160 mg, 315.32 μmol).

[0247] Its structural characterization data are as follows:

[0248] ESI-MS (m / z): 507.2 [M+H] +

[0249] Preparation Example 1: Preparation of (S)-2-(4-aminophenyl)-7-methoxy-8-((5-(((S)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)pentyl)oxy)-1,10,11,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-one (P-1)

[0250] Step 1: Preparation of (S)-2-(4-(((allyloxy)carbonyl)amino)phenyl)-8-((5-bromopentyl)oxy)-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (P-1-1)

[0251] (S)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-8-hydroxy-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (50 mg, 98.91 μmol) and 1,5-dibromopentane (113.72 mg, 494.54 μmol) were dissolved in DMF (1 mL), and potassium carbonate (20.50 mg, 148.36 μmol) was added. The reaction was carried out at 40 °C for 16 hours. The reaction was quenched with water, and the mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The crude product was used directly in the next step of the reaction (50 mg, 76.39 μmol). Its structural characterization data are as follows: ESI-MS (m / z): 654.2 [M+H] +

[0252] Step 2: Preparation of (S)-8-((5-(((S)-10-((allyloxy)carbonyl)-2-(4-(((allyloxy)carbonyl)amino)phenyl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazo-8-yl)oxy)pentyl)oxy)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazo-10(5H)-carboxylic acid allyl ester (P-1-2)

[0253] (S)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-8-((5-bromopentyl)oxy)-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (50 mg, 76.39 μmol) and (S)-8-hydroxy-7-methoxy-2-(4-methoxyphenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (40.01 mg, 91.67 μmol) were dissolved in DMF (1 mL), and potassium carbonate (15.84 mg, 114.58 μmol) was added. The mixture was reacted at 40 °C for 16 hours. The reaction was quenched with water, and the mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The crude product was used directly in the next reaction (61.73 mg, 61.11 μmol). Its structural characterization data are as follows: ESI-MS (m / z): 1011.4 [M+H] +

[0254] Step 3: Preparation of (S)-2-(4-aminophenyl)-7-methoxy-8-((5-(((S)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)pentyl)oxy)-1,10,11,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-one (P-1)

[0255] The (S)-8-((5-(((S)-10-((allyloxy)carbonyl)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)pentyl)oxy)-7-methoxy-2-(4-methoxyphenyl)-5-oxo- 11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (61.73 mg, 61.11 μmol) was dissolved in dry dichloromethane (1 mL). Tetra(triphenylphosphine)palladium (8.82 mg, 7.64 μmol) and tetrahydropyrrole (54.33 mg, 763.89 μmol) were added under nitrogen atmosphere and reacted for 30 min. The reaction was quenched with saturated ammonium chloride aqueous solution. The mixture was extracted three times with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by reversed-phase column chromatography (acetonitrile / 0.05% ammonium bicarbonate aqueous solution) and freeze-dried to give the title compound (3.5 mg, 4.57 μmol).

[0256] Its structural characterization data are as follows: ESI-MS (m / z): 758.3 [M+H] +

[0257] 1H NMR (400MHz, DMSO-d6) δ7.45(s,1H),7.39(s,1H),7.36(s,1H),7.29(d,J=2.0Hz,2H),7.26(s ,1H),7.11(d,J=8.4Hz,2H),6.90(d,J=8.8Hz,2H),6.57-6.47(m,4H),6.31(d,J=2.8Hz,2H), 5.19(s,2H),4.25-4.07(m,3H),3.94(t,J=6.0Hz,4H),3.75(s,3H),3.67(d,J=1.6Hz,6H),3. 58-3.48(m,2H),3.29-3.18(m,3H),2.80-2.69(m,2H),1.86-1.76(m,4H),1.62-1.53(m,2H).

[0258] Its preparation method is as follows:

[0259] Column: SunFire Prep C18 OBD 19mm×150mm×5.0μm;

[0260] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[0261] Preparation Example 2: Preparation of (S)-2-(4-aminophenyl)-7-methoxy-8-(3-(((S)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)propoxy)-1,10,11,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-one (P-2)

[0262] Step 1: Preparation of (S)-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrolo-1-yl)methyl ketone (P-2-1)

[0263] (S)-1-(4-benzyloxy)-5-methoxy-2-nitrobenzoyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydro-1H-pyrrole-3-yltrifluoromethanesulfonate (0.5 g, 773.15 μmol) and (4-methoxyphenyl)boronic acid (352.45 mg, 2.32 mmol) were dissolved in toluene (6 mL), ethanol (2 mL), and water (2 mL). Tetra(triphenylphosphine)palladium (44.65 mg, 38.66 μmol) and sodium carbonate (245.86 mg, 2.32 mmol) were added, and the mixture was then heated to 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated, and saturated brine (30 mL) was added. The mixture was then extracted twice with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–30%) and concentrated again to obtain the title compound (320 mg, 529.13 μmol). Its structural characterization data are as follows:

[0264] ESI-MS (m / z): 605.3 [M+H] +

[0265] Step 2: Preparation of (S)-(2-amino-4-(benzyloxy)-5-methoxyphenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrolo-1-yl)methyl ketone (P-2-2)

[0266] (S)-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrolo-1-yl)methyl ketone (320 mg, 529.13 μmol) was dissolved in methanol (30 mL), and zinc powder (34.4 mg, 5.3 mmol) and saturated ammonium chloride aqueous solution (5 mL) were added. After the reaction was completed within 30 minutes, the mixture was filtered and concentrated to obtain the crude title compound (292 mg, 508.87 mmol), which was used directly in the next step without purification. Its structural characterization data are as follows: ESI-MS (m / z): 575.3 [M+H] +

[0267] Step 3: Preparation of (S)-(5-(benzyloxy)-2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrole-1-carbonyl)-4-methoxyphenyl)carbamate (P-2-3)

[0268] (S)-(2-amino-4-(benzyloxy)-5-methoxyphenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrolo-1-yl)methyl ketone (292 mg, 508.65 mmol) was dissolved in DMF (3 mL), and DIPEA (197 mg, 1.52 mmol) and allyl chloroformate (183 mg, 1.52 mmol) were added. The mixture was stirred for 2 hours. The reaction was quenched with water, and the mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–30%) to give the title compound (320 mg, 486.32 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 659.3 [M+H] +

[0269] Step 4: Preparation of (S)-(5-benzyloxy)-2-(2-hydroxymethyl)-4-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrole-1-carbonyl)-4-methoxyphenyl)carbamate (P-2-4)

[0270] (S)-(5-(benzyloxy)-2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrole-1-carbonyl)-4-methoxyphenyl)carbamate (320 mg, 486.32 μmol) was dissolved in THF (5 mL), and a pyridine hydrogen fluoride complex (70%) (0.5 mL) was added. The mixture was stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) to give the title compound (224 mg, 411.32 μmol). Its structural characterization data are as follows: ESI-MS (m / z): 545.2 [M+H] +

[0271] Step 5: Preparation of (S)-8-(benzyloxy)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (P-2-5)

[0272] (S)-(5-benzyloxy)-2-(2-hydroxymethyl)-4-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrolo-1-carbonyl)-4-methoxyphenyl)carbamate (224 mg, 411.32 μmol) was dissolved in dry tetrahydrofuran (5 mL). Triphenylphosphine (323.65 mg, 1.23 mmol) was added under nitrogen, followed by slow dropwise addition of DIAD (415.86 mg, 2.06 mmol). After the addition was complete, the mixture was heated to 40 °C and reacted for 2 hours. The reaction was quenched with water, and the mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. Purification by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) yielded the title compound (120 mg, 227.89 μmol). Its structural characterization data are as follows: ESI-MS (m / z): 527.3 [M+H] +

[0273] Step Six: Preparation of (S)-8-hydroxy-7-methoxy-2-(4-methoxyphenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (P-2-6)

[0274] (S)-8-(benzyloxy)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (120 mg, 227.89 μmol) was dissolved in dichloromethane (3 mL), and methanesulfonic acid (1.5 mL) was added at 0 °C. The reaction was allowed to proceed for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The crude product was used directly in the next step of the reaction (90 mg, 205.95 μmol). Its structural characterization data are as follows: ESI-MS (m / z): 437.3 [M+H] +

[0275] Step 7: Preparation of (S)-8-(3-(((S)-10-((allyloxy)carbonyl)-2-(4-(((allyloxy)carbonyl)amino)phenyl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazo-8-yl)oxy)propoxy)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazo-10(5H)-carboxylic acid allyl ester (P-2-7)

[0276] (S)-8-hydroxy-7-methoxy-2-(4-methoxyphenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (25.08 mg, 57.46 μmol) and (S)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-8-(3-bromopropoxy)-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (30 mg, 47.89 μmol) were dissolved in DMF (1 mL), and potassium carbonate (9.93 mg, 71.83 μmol) was added. The mixture was reacted at 40 °C for 16 hours. The reaction was quenched with water, and the mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The crude product was used directly in the next reaction (40 mg, 40.71 μmol). Its structural characterization data are as follows: ESI-MS (m / z): 982.6 [M+H] +

[0277] Step 8: Preparation of (S)-2-(4-aminophenyl)-7-methoxy-8-(3-(((S)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)propoxy)-1,10,11,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-one (P-2)

[0278] The (S)-8-(3-(((S)-10-((allyloxy)carbonyl)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)propoxy)-7-methoxy-2-(4-methoxyphenyl)-5-oxo- 11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (40 mg, 40.71 μmol) was dissolved in dry dichloromethane (1 mL). Tetra(triphenylphosphine)palladium (5.53 mg, 4.79 μmol) and tetrahydropyrrole (34.06 mg, 478.90 μmol) were added under nitrogen atmosphere and reacted for 30 min. The reaction was quenched with saturated ammonium chloride aqueous solution. The mixture was extracted three times with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated brine, dried, and concentrated. The purified product was purified by reversed-phase column chromatography (acetonitrile / 0.05% ammonium bicarbonate aqueous solution) and freeze-dried to give the title compound (7.7 mg, 10.55 μmol).

[0279] Its structural characterization data are as follows:

[0280] ESI-MS (m / z): 730.3 [M+H] +

[0281] 1 H NMR (400MHz, DMSO-d6) δ7.45(s,1H),7.37(d,J=8.8Hz,2H),7.30(d,J=1.6Hz,2H),7.25 (s,1H),7.11(d,J=8.4Hz,2H),6.90(d,J=8.8Hz,2H),6.57-6.48(m,4H),6.34(d,J=2.4H z,2H),5.19(s,2H),4.22-4.11(m,3H),4.07((t,J=6.0Hz,4H)),3.75(s,3H),3.67(d,J= 1.0Hz,6H),3.56-3.50(m,3H),3.27-3.20(m,4H),2.79-2.71(m,2H),2.26-2.17(m,2H).

[0282] Its preparation method is as follows:

[0283] Column: SunFire Prep C18 OBD 19mm×150mm×5.0μm

[0284] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[0285] Preparation Example 3: Preparation of (S)-2-(4-aminophenyl)-7-methoxy-8-(3-(((S)-7-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)propoxy)-1,10,11,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-one (P-6)

[0286] Step 1: Preparation of (S)-(4-benzyloxy)-5-methoxy-2-nitrophenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo-1-yl)methyl ketone (P-6-1)

[0287] (S)-1-(4-benzyloxy)-5-methoxy-2-nitrobenzoyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydro-1H-pyrrole-3-yltrifluoromethanesulfonate (1.0 g, 1.55 mmol) and (4-(4-methylpiperazin-1-yl)phenyl)boronic acid (682.2 mg, 3.1 mmol) were dissolved in toluene (20 mL), ethanol (2 mL), and water (2 mL). Tetra(triphenylphosphine)palladium (358.3 mg, 31.1 μmol) and sodium carbonate (492.9 mg, 4.65 mmol) were added, and the mixture was then heated to 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated, saturated brine (60 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then purified by silica gel column chromatography (dichloromethane / methanol = 0%–15%) and concentrated again to obtain the title compound (678.1 mg, 1.01 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 673.3 [M+H] +

[0288] Step 2: Preparation of (S)-(2-amino-4-(benzyloxy)-5-methoxyphenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo-1-yl)methyl ketone (P-6-2)

[0289] (S)-(4-benzyloxy)-5-methoxy-2-nitrophenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo-1-yl) methyl ketone (678.1 mg, 1.01 mmol) was dissolved in methanol (30 mL), and zinc powder (1.3 g, 20.2 mmol) and saturated ammonium chloride aqueous solution (12 mL) were added. After the addition was complete, the reaction was allowed to proceed for 16 hours. The filtrate was filtered, and saturated brine (100 mL) was added. The mixture was then extracted three times with dichloromethane (60 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (584.5 mg, 0.91 mmol), which was used directly in the next step without purification. Its structural characterization data are as follows: ESI-MS (m / z): 643.2 [M+H] +

[0290] Step 3: Preparation of (S)-(5-benzyloxy)-2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-2,3-dihydro-1H-pyrrole-1-carbonyl)-4-methoxyphenyl)carbamate (P-6-3)

[0291] (S)-(2-amino-4-(benzyloxy)-5-methoxyphenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo-1-yl) methyl ketone (584.5 mg, 0.91 mmol) was dissolved in dichloromethane (5 mL), and DIPEA (352.2 mg, 2.73 mmol) and allyl chloroformate (219.3 mg, 1.82 mmol) were added. The mixture was stirred for 2 hours. The reaction was quenched with water, and the mixture was extracted three times with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by silica gel column chromatography (dichloromethane / methanol = 0%–20%) to give the title compound (595.4 mg, 0.82 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 727.3 [M+H]+

[0292] Step 4: Preparation of (S)-(5-benzyloxy)-2-(2-hydroxymethyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-2,3-dihydro-1H-pyrrole-1-carbonyl)-4-methoxyphenyl)carbamate (P-6-4)

[0293] (S)-(5-benzyloxy)-2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-2,3-dihydro-1H-pyrrole-1-carbonyl)-4-methoxyphenyl)carbamate (595.4 mg, 0.82 mmol) was dissolved in THF (7 mL), and a pyridine hydrogen fluoride complex (70%) (0.7 mL) was added. The mixture was stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate water, and the mixture was extracted three times with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by silica gel column chromatography (dichloromethane / methanol = 0%–20%) to give the title compound (245 mg, 0.40 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 613.2 [M+H] +

[0294] Step 5: Preparation of (S)-8-(benzyloxy)-7-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (P-6-5)

[0295] (S)-(5-benzyloxy)-2-(2-hydroxymethyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo-1-carbonyl)-4-methoxyphenyl)carbamate (185 mg, 0.30 mmol) was dissolved in dry tetrahydrofuran (6 mL). Triphenylphosphine (395.8 mg, 1.51 mmol) and molecular sieve (100 mg) were added under nitrogen, followed by slow dropwise addition of DIAD (366.1 mg, 1.81 mmol). After the addition was complete, the mixture was heated to 50 °C and reacted for 2 hours. The reaction was quenched with water, and the mixture was extracted three times with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by silica gel column chromatography (dichloromethane / methanol = 0%–10%) to give the title compound (86 mg, 0.15 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 595.2 [M+H] +

[0296] Step Six: Preparation of (S)-8-hydroxy-7-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (P-6-6)

[0297] (S)-8-(benzyloxy)-7-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (86 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL), and methanesulfonic acid (1.0 mL) was added at 0 °C. The reaction was allowed to proceed for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The crude product was used directly in the next step of the reaction (57 mg, 0.11 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 505.3 [M+H] +

[0298] Step 7: Preparation of (S)-8-(3-(((S)-10-((allyloxy)carbonyl)-2-(4-(((allyloxy)carbonyl)amino)phenyl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazo-8-yl)oxy)propoxy)-7-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazo-10(5H)-carboxylic acid allyl ester (P-6-7)

[0299] (S)-8-hydroxy-7-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (30.0 mg, 59.5 μmol) and (S)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-8-(3-bromopropoxy)-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (37.3 mg, 59.5 μmol) were dissolved in DMF (2 mL), and potassium carbonate (9.93 mg, 71.83 μmol) was added. The mixture was reacted at 40 °C for 16 hours. The reaction was quenched with water, and the mixture was extracted three times (30 mL x 3) with dichloromethane. The organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by reversed-phase column chromatography (acetonitrile / 0.05% formic acid aqueous solution) and then freeze-dried to give the title compound (12.0 mg, 11.4 μmol).

[0300] Its structural characterization data are as follows:

[0301] ESI-MS (m / z): 1050.3 [M+H] +

[0302] Its preparation method is as follows:

[0303] Column: SunFire Prep C18 OBD 19mm×150mm×5.0μm

[0304] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[0305] Step 8: Preparation of (S)-2-(4-aminophenyl)-7-methoxy-8-(3-(((S)-7-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)propoxy)-1,10,11,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-one (P-6)

[0306] The (S)-8-(3-(((S)-10-((allyloxy)carbonyl)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)propoxy)-7-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl) -5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (12.0 mg, 11.4 μmol) was dissolved in dry dichloromethane (1 mL). Tetra(triphenylphosphine)palladium (1.98 mg, 1.7 μmol) and tetrahydropyrrole (8.1 mg, 114.1 μmol) were added under nitrogen and reacted for 30 min. The reaction was quenched with saturated ammonium chloride aqueous solution. The mixture was extracted three times with dichloromethane (10 mL x 3), and the organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by reversed-phase column chromatography (acetonitrile / 0.05% formic acid aqueous solution) and freeze-dried to give the title compound (1.75 mg, 2.05 μmol). Its structural characterization data are as follows: ESI-MS (m / z): 799.1 [M+H] +

[0307] Its preparation method is as follows:

[0308] Column: SunFire Prep C18 OBD 19mm×150mm×5.0μm

[0309] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[0310] Preparation Example 4: Preparation of (S)-2-(4-aminophenyl)-8-(3-(((S)-2-cyclopropyl-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)propoxy)-7-methoxy-1,10,11,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-one (P-10)

[0311] Step 1: Preparation of (S)-(4-benzyloxy)-5-methoxy-2-nitrophenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-cyclopropyl-2,3-dihydro-1H-pyrrole-1-yl)methyl ketone (P-10-1)

[0312] (S)-1-(4-benzyloxy)-5-methoxy-2-nitrobenzoyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydro-1H-pyrrole-3-yltrifluoromethanesulfonate (1.0 g, 1.55 mmol) and cyclopropylboronic acid (275.3 mg, 3.1 mmol) were dissolved in tetrahydrofuran (15 mL) and water (5 mL), and Pd(dppf)Cl2 (226.3 mg, 0.31 mmol) and potassium carbonate (427.4 mg, 3.09 mmol) were added. The mixture was then heated to 75 °C and reacted for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated, saturated brine (60 mL) was added, and the mixture was extracted twice with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) and concentrated again to obtain the title compound (310.3 mg, 0.58 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 539.3 [M+H] +

[0313] Step 2: Preparation of (S)-(2-amino-4-(benzyloxy)-5-methoxyphenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-cyclopropyl-2,3-dihydro-1H-pyrrole-1-yl)methyl ketone (P-10-2)

[0314] (S)-(4-benzyloxy)-5-methoxy-2-nitrophenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-cyclopropyl-2,3-dihydro-1H-pyrrolo-1-yl)methyl ketone (310.3 mg, 0.58 mmol) was dissolved in methanol (10 mL), and zinc powder (371.2 mg, 5.8 mmol) and saturated ammonium chloride aqueous solution (3 mL) were added. After the addition was complete, the reaction was allowed to proceed for 20 minutes. The filtrate was filtered, and saturated brine (30 mL) was added. The filtrate was then extracted twice with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (290.6 mg, 0.57 mmol), which was used directly in the next step without purification. Its structural characterization data are as follows: ESI-MS (m / z): 508.2 [M+H] +

[0315] Step 3: Preparation of (S)-(5-benzyloxy)-2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-cyclopropyl-2,3-dihydro-1H-pyrrole-1-carbonyl)-4-methoxyphenyl)carbamate (P-10-3)

[0316] (S)-(2-amino-4-(benzyloxy)-5-methoxyphenyl)(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-cyclopropyl-2,3-dihydro-1H-pyrrolo-1-yl) methyl ketone (290.6 mg, 0.57 mmol) was dissolved in dichloromethane (3 mL), and DIPEA (221.4 mg, 1.72 mmol) and allyl chloroformate (137.3 mg, 1.14 mmol) were added. The mixture was stirred for 2 hours. The reaction was quenched with water, and the mixture was extracted twice with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to give the title compound (240.1 mg, 0.41 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 593.3 [M+H] +

[0317] Step 4: Preparation of (S)-(5-benzyloxy)-2-(4-cyclopropyl-2-(hydroxymethyl)-2,3-dihydro-1H-pyrrole-1-carbonyl)-4-methoxyphenyl)carbamate (P-10-4)

[0318] (S)-(5-benzyloxy)-2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-cyclopropyl-2,3-dihydro-1H-pyrrole-1-carbonyl)-4-methoxyphenyl)carbamate (240.1 mg, 0.41 mmol) was dissolved in THF (3 mL), and a pyridine hydrogen fluoride complex (70%) (0.3 mL) was added. The mixture was stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate water, and the mixture was extracted three times with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to give the title compound (130 mg, 0.27 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 479.2 [M+H] +

[0319] Step 5: Preparation of (S)-8-(benzyloxy)-2-cyclopropyl-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (P-10-5)

[0320] (S)-(5-benzyloxy)-2-(4-cyclopropyl-2-(hydroxymethyl)-2,3-dihydro-1H-pyrrole-1-carbonyl)-4-methoxyphenyl)carbamate (130 mg, 0.27 mmol) was dissolved in dry tetrahydrofuran (5 mL). Triphenylphosphine (222.1 mg, 0.81 mmol) was added under nitrogen, followed by slow dropwise addition of DIAD (285.1 mg, 1.41 mmol). After the addition was complete, the mixture was heated to 45 °C and reacted for 2 hours. The reaction was quenched with water, and the mixture was extracted three times with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) yielded the title compound (70 mg, 0.15 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 461.2 [M+H] +

[0321] Step Six: Preparation of (S)-2-cyclopropyl-8-hydroxy-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (P-10-6)

[0322] (S)-8-(benzyloxy)-2-cyclopropyl-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (70 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL), and methanesulfonic acid (1.0 mL) was added at 0 °C. The reaction was allowed to proceed for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The crude product was used directly in the next step of the reaction (50 mg, 0.13 mmol). Its structural characterization data are as follows: ESI-MS (m / z): 371.3 [M+H] +

[0323] Step 7: Preparation of (S)-8-(3-(((S)-10-((allyloxy)carbonyl)-2-(4-(((allyloxy)carbonyl)amino)phenyl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazo-8-yl)oxy)propoxy)-2-cyclopropyl-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazo-10(5H)-carboxylic acid allyl ester (P-10-7)

[0324] (S)-2-cyclopropyl-8-hydroxy-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (20.0 mg, 54.1 μmol) and (S)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-8-(3-bromopropoxy)-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (33.8 mg, 54.1 μmol) were dissolved in DMF (2 mL), and potassium carbonate (9.8 mg, 71.83 μmol) was added. The mixture was reacted at 40 °C for 16 hours. The reaction was quenched with water, and the organic phases were extracted three times with dichloromethane (20 mL x 3). The extracted phases were combined, washed with saturated brine, dried, and concentrated. The crude product was used directly in the next reaction (36 mg, 39.3 μmol). Its structural characterization data are as follows: ESI-MS (m / z): 916.3 [M+H]+

[0325] Step 8: Preparation of (S)-2-(4-aminophenyl)-8-(3-(((S)-2-cyclopropyl-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)propoxy)-7-methoxy-1,10,11,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-one (P-10)

[0326] (S)-8-(3-(((S)-10-((allyloxy)carbonyl)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazo-8-yl)oxy)propoxy)-2-cyclopropyl-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazo-10(5H)-carboxylic acid allyl ester (36 mg, 39.3 μmol) was dissolved in dry dichloromethane (2 mL), and tetra(triphenylphosphine)palladium (6.8 mg, 5.9 μmol) and tetrahydropyrrole (27.9 mg, 393.2 μmol) were added under nitrogen and reacted for 30 minutes. The reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted three times with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by reversed-phase column chromatography (acetonitrile / 0.05% formic acid aqueous solution) and then freeze-dried to give the title compound (4.82 mg, 6.99 μmol). Its structural characterization data are as follows: ESI-MS (m / z): 664.3 [M+H]+

[0327] 1 H NMR (400MHz, DMSO-d6) δ7.29 (s, 1H), 7.26-7.23 (m, 2H), 7.11 (d, J = 8.4Hz, 2H), 6.57-6.48 (m, 3H),6.44(d,J=6.4Hz,1H),6.32(d,J=9.0Hz,2H),5.19(s,2H),4.19-4.10(m,1H),4.09-4.04 (m,4H),4.02-3.94(m,1H),3.66(s,3H),3.65(s,3H),3.56-3.47(m,2H),3.26-3.19(m,2H),3 .17-3.09(m,1H),2.83-2.65(m,3H),2.26-2.15(m,3H),0.69-0.62(m,2H),0.55-0.45(m,2H).

[0328] Its preparation method is as follows:

[0329] Column: SunFire Prep C18 OBD 19mm×150mm×5.0μm

[0330] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[0331] Preparation Example 5: Preparation of (S)-2-(4-aminophenyl)-8-((5-(((S)-2-cyclopropyl-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)pentyl)oxy)-7-methoxy-1,10,11,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-one (P-9)

[0332] Step 1: Preparation of (S)-8-((5-(((S)-10-((allyloxy)carbonyl)-2-(4-(((allyloxy)carbonyl)amino)phenyl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazo-8-yl)oxy)pentyl)oxy)-2-cyclopropyl-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazo-10(5H)-carboxylic acid allyl ester (P-9-1)

[0333] (S)-2-cyclopropyl-8-hydroxy-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (12.2 mg, 0.03 mmol) and (S)-2-(4-(((allyloxy)carbonyl)amino)phenyl)-8-((5-bromopentyl)oxy)-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (22.1 mg, 0.03 mmol) were dissolved in DMF (2 mL), and potassium carbonate (7.0 mg, 50.7 μmol) was added. The mixture was reacted at 40 °C for 16 hours. The reaction was quenched with water, and the mixture was extracted twice with ethyl acetate (15 mL x 2). The organic phases were combined, washed with saturated brine, dried, and concentrated. The crude product was used directly in the next reaction (30.5 mg, 32.3 μmol).

[0334] Its structural characterization data are as follows:

[0335] ESI-MS (m / z): 944.3 [M+H] +

[0336] Step 2: Preparation of (S)-2-(4-aminophenyl)-8-((5-(((S)-2-cyclopropyl-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)pentyl)oxy)-7-methoxy-1,10,11,11a-tetrahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-one (P-9)

[0337] The (S)-8-((5-(((S)-10-((allyloxy)carbonyl)-2-(4-((((allyloxy)carbonyl)amino)phenyl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)pentyl)oxy)-2-cyclopropyl-7-methoxy-5-oxo -11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylic acid allyl ester (30.5 mg, 32.3 μmol) was dissolved in dry DCM (2 mL), and tetra(triphenylphosphine)palladium (5.5 mg, 4.7 μmol) and tetrahydropyrrole (22.6 mg, 317.8 μmol) were added under nitrogen and reacted for 30 min. The reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted three times with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. After purification by reversed-phase column chromatography (acetonitrile / 0.05% formic acid aqueous solution), the mixture was freeze-dried to give the title compound (6.35 mg, 8.73 μmol).

[0338] Its structural characterization data are as follows:

[0339] ESI-MS (m / z): 692.4 [M+H] +

[0340] 1 H NMR (400MHz, DMSO-d6) δ7.45 (s, 1H), 7.33 (d, J = 8.2Hz, 2H), 7.29 (s, 1H), 7.25 (s, 1H), 6.95-6. 82(m,2H),6.74(s,1H),6.31(s,1H),6.28(s,1H),4.24-4.13(m,1H),4.04-3.98(m,1H),3.97-3 .89(m,4H),3.66(s,3H),3.65(s,3H),3.31-3.20(m,4H),3.18-3.20(m,2H),2.84-2.65(m,2H), 2.26-2.18(m,1H),1.86-1.72(m,4H),1.61-1.48(m,3H),0.71-0.61(m,2H),0.54-0.47(m,2H).

[0341] Its preparation method is as follows:

[0342] Column: SunFire Prep C18 OBD 19mm×150mm×5.0μm

[0343] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% trifluoroacetic acid)

[0344] Preparation Example 6: Preparation of (S)-8-((5-(((S)-2-((E)-4-aminostyryl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)pentyl)oxy)-7-methoxy-1,10,11,11a-tetrahydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diazepine-2,1'-cyclopropane]-5-one (P-31)

[0345] Step 1: Preparation of (S,E)-(4-(4-aminostyryl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydro-1H-pyrrolo-1-yl)(4-(benzyloxy)-5-methoxy-2-nitrophenyl) ketone (P-31-1)

[0346] (S)-1-(4-benzyloxy)-5-methoxy-2-nitrobenzoyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydro-1H-pyrrole-3-yltrifluoromethanesulfonate (1.0 g, 1.55 mmol) and (E)-(4-aminostyryl)boronic acid (504.1 mg, 3.1 mmol) were dissolved in toluene (30 mL), ethanol (3 mL), and water (3 mL). Pd(PPh3)4 (357.4 mg, 0.31 mmol) and sodium carbonate (491.7 mg, 4.64 mmol) were added. The mixture was then purged with nitrogen and heated to 80 °C for 2 hours under protection. After the reaction was completed, the reaction solution was concentrated, saturated saline (100 mL) was added, and the mixture was extracted twice with ethyl acetate (80 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–80%) and concentrated again to obtain the title compound (579.3 mg, 0.95 mmol).

[0347] Its structural characterization data are as follows:

[0348] ESI-MS (m / z): 616.3 [M+H]+

[0349] Step 2: Preparation of (S,E)-(2-amino-4-(benzyloxy)-5-methoxyphenyl)(4-(4-aminostyryl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydro-1H-pyrrolo-1-yl)methyl ketone (P-31-2)

[0350] (S,E)-(4-(4-aminostyryl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydro-1H-pyrrolo-1-yl)(4-(benzyloxy)-5-methoxy-2-nitrophenyl) ketone (579.3 mg, 0.95 mmol) was dissolved in methanol (10 mL), and zinc powder (617.5 mg, 9.5 mmol) and saturated ammonium chloride aqueous solution (3 mL) were added. After the addition was complete, the reaction was allowed to proceed for 20 minutes. After the reaction was complete, the filtrate was filtered, and saturated brine (60 mL) was added. The filtrate was then extracted twice with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product (523.3 mg, 0.89 mmol), which was used directly in the next step without purification.

[0351] Its structural characterization data are as follows:

[0352] ESI-MS (m / z): 586.4 [M+H]+

[0353] Step 3: Preparation of allyl (S,E)-(2-(4-(4-((((allyloxy)carbonyl)amino)styryl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydro-1H-pyrrole-1-carbonyl)-5-(benzyloxy)-4-methoxyphenyl)carbamate (P-31-3)

[0354] (S,E)-(2-amino-4-(benzyloxy)-5-methoxyphenyl)(4-(4-aminostyryl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydro-1H-pyrrolo-1-yl) methyl ketone (523.3 mg, 0.89 mmol) was dissolved in DCM (6 mL), and DIPEA (574.1 mg, 4.5 mmol) and allyl chloroformate (321.7 mg, 2.67 mmol) were added. The mixture was stirred for 2 hours. The reaction was quenched with water, and the mixture was extracted twice with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to give the title compound (610.7 mg, 0.81 mmol).

[0355] Its structural characterization data are as follows:

[0356] ESI-MS (m / z): 754.2 [M+H]+

[0357] Step 4: Preparation of allyl (S,E)-(2-(4-(4-((((allyloxy)carbonyl)amino)styryl)-2-(hydroxymethyl)-2,3-dihydro-1H-pyrrole-1-carbonyl)-5-(benzyloxy)-4-methoxyphenyl)carbamate (P-31-4)

[0358] Allyl(S,E)-(2-(4-(4-((((allyloxy)carbonyl)amino)styryl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydro-1H-pyrrole-1-carbonyl)-5-(benzyloxy)-4-methoxyphenyl)carbamate (610.7 mg, 0.81 mmol) was dissolved in THF (5 mL), and a pyridine hydrogen fluoride complex (70%, 0.5 mL) was added. The mixture was stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–80%) to give the title compound (347.3 mg, 0.54 mmol).

[0359] Its structural characterization data are as follows:

[0360] ESI-MS (m / z): 640.3 [M+H]+

[0361] Step 5: Preparation of allyl(S,E)-2-(4-((((allyloxy)carbonyl)amino)styryl)-8-(benzyloxy)-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazaphen-10(5H)-carboxylic acid ester (P-31-5)

[0362] Allyl(S,E)-(2-(4-(4-((((allyloxy)carbonyl)amino)styryl)-2-(hydroxymethyl)-2,3-dihydro-1H-pyrrole-1-carbonyl)-5-(benzyloxy)-4-methoxyphenyl)carbamate (200 mg, 0.31 mmol) was dissolved in dry tetrahydrofuran (6 mL). Triphenylphosphine (246.1 mg, 0.94 mmol) was added under nitrogen, followed by slow dropwise addition of DIAD (316.1 mg, 1.56 mmol). After the addition was complete, the mixture was heated to 45 °C and reacted for 2 hours. The reaction was quenched with water, and the mixture was extracted three times with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%–50%) to give the title compound (120 mg, 0.19 mmol).

[0363] Its structural characterization data are as follows:

[0364] ESI-MS (m / z): 622.3 [M+H]+

[0365] Step Six: Preparation of (S,E)-2-(4-((((allyloxy)carbonyl)amino)styryl)-8-hydroxy-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazazo-10(5H)-carboxylic acid allyl ester (P-31-6)

[0366] Allyl(S,E)-2-(4-((((allyloxy)carbonyl)amino)styryl)-8-(benzyloxy)-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazaphen-10(5H)-carboxylic acid ester (115 mg, 0.18 mmol) was dissolved in DCM (3 mL), and methanesulfonic acid (1.0 mL) was added at 0 °C. The reaction was allowed to proceed for 1 hour. The reaction was quenched with saturated sodium bicarbonate aqueous solution, and the mixture was extracted three times with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The crude product was used directly in the next step of the reaction (45 mg, 0.08 mmol).

[0367] Its structural characterization data are as follows:

[0368] ESI-MS (m / z): 532.2 [M+H]+

[0369] Step 7: Preparation of allyl (S)-8-((5-(((S)-10-((allyloxy)carbonyl))-2-((E)-4-(((allyloxy)carbonyl)amino)styryl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazaphen-8-yl)oxy)pentyl)oxy)-7-methoxy-5-oxo-11,11a-dihydro-1H,3H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diazaphen-2,1'-cyclopropane]-10(5H)-carboxylic acid ester (P-31-7)

[0370] Allyl (S,E)-2-(4-((((allyloxy)carbonyl)amino)styryl)-8-hydroxy-7-methoxy-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazaphen-10(5H)-carboxylic acid (22.0 mg, 41.4 μmol) and (S)-8-((5-bromopentyl)oxy)-7-methoxy -5-oxo-11,11a-dihydro-1H,3H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diazaphen-2,1'-cyclopropane]-10(5H)-carboxylic acid allyl ester (INT-4) (22.1 mg, 43.5 μmol) was dissolved in DMF (2 mL), and potassium carbonate (8.6 mg, 62.1 μmol) was added. The reaction was carried out at 45 °C for 16 hours. The reaction was quenched with water, and the mixture was extracted three times with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The crude product was used directly in the next reaction (35 mg, 36.5 μmol).

[0371] Its structural characterization data are as follows:

[0372] ESI-MS (m / z): 958.2 [M+H]+

[0373] Step 8: Preparation of (S)-8-((5-(((S)-2-((E)-4-aminostyryl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-8-yl)oxy)pentyl)oxy)-7-methoxy-1,10,11,11a-tetrahydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diazepine-2,1'-cyclopropane]-5-one (P-31)

[0374] Allyl(S)-8-((5-(((S)-10-((allyloxy)carbonyl))-2-((E)-4-(((allyloxy)carbonyl)amino)styryl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazaphen-8-yl)oxy)pentyl)oxy)-7-methoxy-5-oxo-11, 11a-dihydro-1H,3H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diazaphen-2,1'-cyclopropane]-10(5H)-carboxylic acid ester (35 mg, 36.5 μmol) was dissolved in dry DCM (2 mL). Tetra(triphenylphosphine)palladium (6.8 mg, 5.9 μmol) and tetrahydropyrrole (26.1 mg, 380.2 μmol) were added under nitrogen atmosphere and reacted for 30 min. The reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted three times with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. After purification by preparative high-performance liquid chromatography, the mixture was freeze-dried to give the title compound (12.78 mg, 17.7 μmol).

[0375] Its structural characterization data are as follows:

[0376] ESI-MS (m / z): 707.4 [M+H]+

[0377] 1 H NMR (400MHz, DMSO-d6) δ7.39(d,J=8.4Hz,2H),7.32(s,1H),7.28(s,0H),7.18(s,1H),7.06( d,J=16.0Hz,1H),6.97(d,J=8.0Hz,1H),6.29(dd,J=23.2,12.4Hz,3H),3.97-3.90(m,5H),3 .86-3.80(m,,2H),3.66(s,3H),3.65(s,3H),3.56-3.47(m,3H),3.34(d,J=11.8Hz,1H),3.2 5-3.12(m,2H),2.04-1.95(m,1H),1.86-1.74(m,5H),1.60-1.50(m,2H),0.67-0.49(m,4H).

[0378] Its preparation method is as follows:

[0379] Column: SunFire Prep C18 OBD 19mm×150mm×5.0μm

[0380] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% trifluoroacetic acid)

[0381] Preparation Example 7: Preparation of (S)-8-((5-(((S)-2-(4-aminophenyl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diaza-8-yl)oxy)pentyl)oxy)-7-(methoxy-d3)-1,10,11,11a-tetrahydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-5-one (P-32)

[0382] Step 1: Preparation of methyl 4-bromo-5-fluoro-2-nitrobenzene (P-32-2)

[0383] 4-Bromo-5-fluoro-2-nitrobenzoic acid (5.9 g, 22.35 mmol) was dissolved in methanol (30 mL), thionyl chloride (30 mL) was added, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) and concentrated again to obtain the title compound (3.05 g, 10.97 mmol).

[0384] Step 2: Preparation of methyl 4-bromo-5-(methoxy-d3)-2-nitrobenzoate-d3 (P-32-3)

[0385] Methyl 4-bromo-5-fluoro-2-nitrobenzene (1.5 g, 5.4 mmol) was dissolved in DMF (6 mL), and deuterated methanol (388.5 mg, 10.8 mmol) and cesium carbonate (2.64 mg, 8.09 mmol) were added. After purging with nitrogen three times, the reaction was carried out at room temperature for 16 hours. The reaction solution was then added to ethyl acetate (20 mL) and water (30 mL), stirred, and allowed to stand before separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) and concentrated to obtain the title compound (1.08 g, 3.68 mmol).

[0386] Its structural characterization data are as follows:

[0387] 1 H NMR (400MHz, DMSO-d6): δ8.35(s,1H),7.51(s,1H).

[0388] Step 3: Preparation of methyl 5-(methoxy-d3)-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)benzoate-d3 (P-32-4)

[0389] Methyl 4-bromo-5-(methoxy-d3)-2-nitrobenzoate-d3 (1.08 g, 3.68 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboronane) (2.34 g, 9.21 mmol), bis(triphenylphosphine)-palladium dichloride (775.94 mg, 1.11 mmol), and potassium acetate (1.08 g, 11.05 mmol) were added to a single-necked flask, followed by 1,4-dioxane (15 mL). The mixture was purged with nitrogen three times, heated to 101 °C, and reacted for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated to obtain the crude product (1.1 g, 3.23 mmol), which was used directly in the next step without purification.

[0390] Step 4: Preparation of methyl 4-hydroxy-5-(methoxy-d3)-2-nitrobenzoate-d3 (P-32-5)

[0391] Methyl 5-(methoxy-d3)-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)benzoate-d3 (1.1 g, 3.23 mmol) was dissolved in tetrahydrofuran (30 mL), and glacial acetic acid (3.75 mL) was added at 0 °C. Hydrogen peroxide (7 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 3 hours. Saturated sodium sulfite solution (30 mL) was added to the reaction solution, and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure until no tetrahydrofuran residue was found. 30 mL of ethyl acetate was added for extraction. After separation, the organic phase was dried over anhydrous sodium sulfate and then filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–70%) and concentrated to obtain the title compound (680 mg, 2.95 mmol).

[0392] Its structural characterization data are as follows:

[0393] ESI-MS (m / z): 230.2 [MH] -

[0394] Step 5: Preparation of methyl 4-(benzyloxy)-5-(methoxy-d3)-2-nitrobenzoate-d3 (P-32-6)

[0395] Methyl 4-hydroxy-5-(methoxy-d3)-2-nitrobenzoate-d3 (680 mg, 2.95 mmol) was dissolved in DMF (5 mL), potassium carbonate (815.3 mg, 5.91 mmol) and benzyl bromide (1.01 g, 5.91 mmol) were added, and the mixture was reacted at room temperature for 15 hours. After adding 30 mL of water, 30 mL of ethyl acetate was added for extraction. After separation, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) and concentrated to obtain the title compound (688 mg, 2.15 mmol).

[0396] Step Six: Preparation of 4-(benzyloxy)-5-(methoxy-d3)-2-nitrobenzoic acid (P-32-7)

[0397] Methyl 4-(benzyloxy)-5-(methoxy-d3)-2-nitrobenzoate-d3 (688 mg, 2.15 mmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), and lithium hydroxide (103.1 mg, 4.3 mmol) was added. The mixture was reacted at room temperature for 3 hours. The pH of the system was adjusted to 5 with dilute hydrochloric acid, and a solid precipitated out. The solid was extracted with 30 mL of ethyl acetate, and after separation, the layers were washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered to obtain the title compound (400 mg, 1.31 mmol).

[0398] Step 7: Preparation of (S)-5-(4-(benzyloxy)-5-(methoxy-d3)-2-nitrobenzoyl)-5-azaspiro[2.4]heptane-6-carboxylic acid methyl ester (P-32-8)

[0399] 4-(benzyloxy)-5-(methoxy-d3)-2-nitrobenzoic acid (400 mg, 1.31 mmol) and methyl (S)-5-azaspiro[2.4]heptane-6-carboxylate (203 mg, 1.31 mmol) were dissolved in DMF (5 mL), and HATU (597.3 mg, 1.57 mmol) and DIPEA (507 mg, 3.93 mmol) were added. The mixture was reacted at room temperature for 15 hours. After adding 30 mL of water, 30 mL of ethyl acetate was added for extraction. After separation, the organic phase was dried over anhydrous sodium sulfate and then filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) and concentrated to obtain the title compound (570 mg, 1.29 mmol).

[0400] Its structural characterization data are as follows:

[0401] ESI-MS (m / z): 444.1 [M+H] +

[0402] Step 8: Preparation of (S)-8-(benzyloxy)-7-(methoxy-d3)-1,11a-dihydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-5,11(10H)-dione (P-32-9)

[0403] Methyl (S)-5-(4-(benzyloxy)-5-(methoxy-d3)-2-nitrobenzoyl)-5-azaspiro[2.4]heptane-6-carboxylate (570 mg, 1.29 mmol) was dissolved in methanol (30 mL), and 10% ammonium chloride aqueous solution (4 mL) and zinc powder (1.28 g, 19.51 mmol) were added. The mixture was heated to 40 °C and reacted for 1 hour, then heated to 80 °C and reacted overnight. The crude product was concentrated and dissolved in 35 mL of ethyl acetate. The mixture was washed three times with saturated brine. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reversed-phase column chromatography (acetonitrile / 1% formic acid aqueous solution = 0%–70%) and then lyophilized to obtain the title compound (306 mg, 0.8 mmol).

[0404] Its structural characterization data are as follows:

[0405] ESI-MS (m / z): 382.2 [M+H] +

[0406] Step Nine: Preparation of (S)-8-hydroxy-7-(methoxy-d3)-1,11a-dihydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-5,11(10H)-dione (P-32-10)

[0407] (S)-8-(benzyloxy)-7-(methoxy-d3)-1,11a-dihydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-5,11(10H)-dione (132 mg, 0.29 mmol) was dissolved in dichloromethane (1 mL) and cooled to 0 °C. Then, methanesulfonic acid (0.5 mL) was added dropwise. The reaction mixture was kept at this temperature for 1 hour. Water (3 mL) was added to the reaction mixture, and the pH was adjusted to 8 with a saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane (5 mL x 3), and the combined organic phases were washed with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude title compound (100 mg, 0.27 mmol), which was used directly in the next step without purification.

[0408] Its structural characterization data are as follows:

[0409] ESI-MS (m / z): 292.1 [M+H] +

[0410] Step 10: Preparation of tert-butyl carbamate (P-32-11)

[0411] (S)-(4-(8-((5-bromopentyl)oxy)-7-methoxy-5,11-dioxy-50,11,11-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diaza-2-yl)phenyl)carbamate tert-butyl ester (167 mg, 0.27 mmol) and (S)-8-hydroxy-7-(methoxy-d3)-1,11a-dihydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-5,11(10H)-dione (100 mg, 0.27 mmol) were dissolved in DMF (2 mL), potassium carbonate (60 mg, 0.54 mmol) was added, and the mixture was stirred for 16 hours. The reaction was quenched with water, and the mixture was extracted three times (10 mL x 3) with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and concentrated. Purification by silica gel column chromatography (MeOH / DCM = 0%–5%) yielded the title compound (120 mg, 0.136 mmol).

[0412] Its structural characterization data are as follows:

[0413] ESI-MS (m / z): 797.3 [M+H] +

[0414] Step 11: Preparation of (S)-2-(4-aminophenyl)-7-methoxy-8-((5-(((S)-7-(methoxy-d3)-5-oxo-5,10,11,11a-tetrahydro-1H,3H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-8-yl)oxy)pentyl)oxy)-1,11a-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diaza-5,11(10H)-dione (P-32-12)

[0415] 120 mg (0.136 mmol) of tert-butyl carbamate (4-((S)-7-methoxy-8-((5-((((S)-7-(methoxy-d3))-5-oxo-5,10,11,11a-tetrahydro-1H,3H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-8-yl)oxy)pentyl)oxy)-5,11-dioxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diaza-2-yl)phenyl)carbamate (3 mL) was dissolved in dichloromethane. Trifluoroacetic acid (0.6 mL) was added dropwise with stirring. After the addition was complete, stirring was continued for 1 hour. After concentration under reduced pressure, the compound was purified by reversed-phase column chromatography (acetonitrile / 1% formic acid aqueous solution = 0%–70%) and then lyophilized to obtain the title compound (35 mg, 0.05 mmol).

[0416] Its structural characterization data are as follows:

[0417] ESI-MS (m / z): 697.3 [M+H] +

[0418] Step Twelve: Preparation of (S)-8-((5-(((S)-2-(4-aminophenyl)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diaza-8-yl)oxy)pentyl)oxy)-7-(methoxy-d3)-1,10,11,11a-tetrahydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-5-one (P-32)

[0419] (S)-2-(4-aminophenyl)-7-methoxy-8-((5-(((S)-7-(methoxy-d3)-5-oxo-5,10,11,11a-tetrahydro-1H,3H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-8-yl)oxy)pentyl)oxy)-1,11a-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diaza-5,11(10H)-dione (35 mg, 0.05 mmol) was dissolved in dry tetrahydrofuran (5 mL), sodium borohydride (8.8 mg, 0.225 mmol) was added, and trifluoroacetic acid (20.9 mg, 0.18 mmol) was slowly added dropwise, producing a large amount of gas. After the gas dissipated, the temperature was slowly raised to 70 °C and refluxed for 16 hours. The reaction solution was cooled to room temperature, and the reaction was quenched dropwise with methanol. The solution was then concentrated under reduced pressure. After purification by preparative high-performance liquid chromatography, the solution was freeze-dried to obtain the title compound (2.9 mg, 0.004 mmol).

[0420] Its structural characterization data are as follows:

[0421] ESI-MS (m / z): 683.3 [M+H] +

[0422] 1 H NMR (400MHz, DMSO-d6): δ7.33(s,1H),7.30(s,1H),7.27(s,1H),7.13(d,J=8.4Hz,1H ),6.58-6.53(m,2H),6.34-6.26(m,2H),4.20-4.10(m,1H),4.0-3.92(m,4H),3.86-3 .80(m,2H),3.67(s,3H),3.56(s,3H),3.3-3.22(m,3H),3.20-3.12(m,2H),2.76-2.6 6(m,2H),2.02-1.94(m,1H),1.85-1.77(m,4H),1.63-1.52(m,2H),0.62-0.52(m,3H).

[0423] Its preparation method is as follows:

[0424] Column: SunFire Prep C18 OBD 19mm×150mm×5.0μm

[0425] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[0426] Preparation Example 8: Preparation of (S)-2-(4-aminophenyl)-8-((5-(((S)-7-cyclopropoxy-5-oxo-5,10,11,11a-tetrahydro-1H,3H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-8-yl)oxy)pentyl)oxy)-7-methoxy-1,11a-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diaza-5,11(10H)-dione (P-33)

[0427] Step 1: Preparation of methyl 4-bromo-5-cyclopropoxy-2-nitrobenzene (P-33-1)

[0428] Methyl 4-bromo-5-fluoro-2-nitrobenzoate (1.5 g, 5.4 mmol) was dissolved in DMF (6 mL), and cyclopropanol (635 mg, 10.97 mmol) and cesium carbonate (2.68 mg, 8.3 mmol) were added. After purging with nitrogen three times, the reaction was carried out at room temperature for 16 hours. The reaction solution was then added to ethyl acetate (30 mL) and water (30 mL) and stirred. The mixture was allowed to stand and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) and concentrated to obtain the title compound (750 mg, 2.37 mmol).

[0429] Its structural characterization data are as follows:

[0430] 1 H NMR (400MHz, DMSO-d6): δ8.41(s,1H),7.70(s,1H),4.21(tt,J=5.8,2.8Hz,1H),3.88(s,3H),0.92(m,2H),0.80(m,2H).

[0431] Step 2: Preparation of methyl 5-cyclopropoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)benzoate (P-33-2)

[0432] Methyl 4-bromo-5-cyclopropoxy-2-nitrobenzene (750 mg, 2.37 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboronane) (1.5 g, 5.93 mmol) were dissolved in 1,4-dioxane (15 mL). Palladium dichloride dichloride (499.6 mg, 0.71 mmol) and potassium acetate (700 mg, 7.12 mmol) were added. The mixture was heated to 100 °C for 16 hours under nitrogen purging and protection. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated to obtain a crude product (1.6 g, 4.41 mmol), which was used directly in the next step without purification.

[0433] Step 3: Preparation of methyl 5-cyclopropoxy-4-hydroxy-2-nitrobenzene (P-33-3)

[0434] Methyl 5-cyclopropoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)benzoate (1.6 g, 4.41 mmol) was dissolved in tetrahydrofuran (40 mL), and glacial acetic acid (5 mL) was added at 0 °C. Hydrogen peroxide (10 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours. Saturated sodium sulfite solution (50 mL) was added to the reaction solution and stirred for 1 hour. The solution was concentrated under reduced pressure until no tetrahydrofuran residue was found. The solution was extracted with 30 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–70%) and concentrated to obtain the title compound (1.05 g, 4.15 mmol).

[0435] Its structural characterization data are as follows:

[0436] ESI-MS (m / z): 253.2 [MH] -

[0437] Step 4: Preparation of methyl 4-(benzyloxy)-5-cyclopropoxy-2-nitrobenzene (P-33-4)

[0438] Methyl 5-cyclopropoxy-4-hydroxy-2-nitrobenzoate (1.05 g, 4.15 mmol) was dissolved in DMF (5 mL), potassium carbonate (1.2 g, 8.6 mmol) and benzyl bromide (1.49 g, 8.6 mmol) were added, and the mixture was reacted at room temperature for 15 hours. After adding 30 mL of water, 50 mL of ethyl acetate was added for extraction. After separation, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) and concentrated to obtain the title compound (1.09 g, 3.17 mmol).

[0439] Step 5: Preparation of 4-(benzyloxy)-5-cyclopropoxy-2-nitrobenzoic acid (P-33-5)

[0440] Methyl 4-(benzyloxy)-5-cyclopropoxy-2-nitrobenzoate (1.09 g, 3.17 mmol) was dissolved in tetrahydrofuran (8 mL) and water (2 mL). Lithium hydroxide (152.1 mg, 6.35 mmol) was added, and the mixture was reacted at room temperature for 3 hours. The pH of the system was adjusted to 5 with dilute hydrochloric acid, and a solid precipitated out. The solid was extracted with 60 mL of ethyl acetate, and after separation, the layers were washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The concentrate yielded the title compound (743 mg, 2.26 mmol), which was used directly in the next step without purification.

[0441] Step Six: Preparation of (S)-5-(4-(benzyloxy)-5-cyclopropoxy-2-nitrobenzoyl)-5-azaspiro[2.4]heptane-6-carboxylic acid methyl ester (P-33-6)

[0442] 4-(benzyloxy)-5-cyclopropoxy-2-nitrobenzoic acid (743 mg, 2.26 mmol) and methyl (S)-5-azaspiro[2.4]heptane-6-carboxylate (700 mg, 4.51 mmol) were dissolved in DMF (5 mL), and HATU (1.71 g, 4.51 mmol) and DIPEA (875 mg, 6.77 mmol) were added. The mixture was reacted at room temperature for 2 hours. After adding 30 mL of water, 50 mL of ethyl acetate was added for extraction. After separation, the organic phase was dried over anhydrous sodium sulfate and then filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) and concentrated to obtain the title compound (910 mg, 1.95 mmol).

[0443] Its structural characterization data are as follows:

[0444] ESI-MS (m / z): 467.1 [M+H] +

[0445] Step 7: Preparation of (S)-8-(benzyloxy)-7-cyclopropoxy-1,11a-dihydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-5,11(10H)-dione (P-33-7)

[0446] Methyl (S)-5-(4-(benzyloxy)-5-cyclopropoxy-2-nitrobenzoyl)-5-azaspiro[2.4]heptane-6-carboxylate (910 mg, 1.95 mmol) was dissolved in methanol (30 mL), and 10% ammonium chloride aqueous solution (6 mL) and zinc powder (1.28 g, 19.51 mmol) were added. The mixture was heated to 40 °C and reacted for 1 hour, then heated to 80 °C and reacted overnight. The crude product was concentrated and dissolved in 35 mL of ethyl acetate. The mixture was washed three times with saturated brine. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reversed-phase column chromatography (acetonitrile / 1% formic acid aqueous solution = 0%–70%) and then lyophilized to obtain the title compound (467 mg, 1.15 mmol).

[0447] Its structural characterization data are as follows:

[0448] ESI-MS (m / z): 405.2 [M+H] +

[0449] Step 8: Preparation of (S)-8-(benzyloxy)-7-cyclopropoxy-1,10,11,11a-tetrahydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-5-one (P-33-8)

[0450] (S)-8-(benzyloxy)-7-cyclopropoxy-1,11a-dihydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-5,11(10H)-dione (467 mg, 1.15 mmol) was dissolved in dry tetrahydrofuran (20 mL), sodium borohydride (128 mg, 3.46 mmol) was added, and trifluoroacetic acid (264 mg, 2.31 mmol) was slowly added dropwise, producing a large amount of gas. After the gas dissipated, the mixture was slowly heated to 70 °C and refluxed for 16 hours. The reaction solution was cooled to room temperature, and the reaction was quenched dropwise with methanol and concentrated under reduced pressure. After purification by reversed-phase column chromatography (acetonitrile / 1% formic acid aqueous solution = 0%–80%), the solution was freeze-dried to give the title compound (380 mg, 0.97 mmol).

[0451] Its structural characterization data are as follows:

[0452] ESI-MS (m / z): 363.3 [M+H] +

[0453] Step Nine: Preparation of (S)-7-cyclopropoxy-8-hydroxy-1,10,11,11a-tetrahydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-5-one (P-33-9)

[0454] (S)-8-(benzyloxy)-7-cyclopropoxy-1,10,11,11a-tetrahydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-5-one (380 mg, 0.97 mmol) was dissolved in dichloromethane (1.5 mL) and cooled to 0 °C. Then, methanesulfonic acid (0.6 mL) was added dropwise. The reaction mixture was kept at this temperature for 1 hour. Water (10 mL) was added to the reaction mixture, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted three times with dichloromethane (8 mL x 3), and the combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude title compound (118 mg, 0.31 mmol), which was used directly in the next step without purification.

[0455] Its structural characterization data are as follows:

[0456] ESI-MS (m / z): 301.1 [M+H] +

[0457] Step 10: Preparation of tert-butyl carbamate (P-33-10)

[0458] (S)-(4-(8-((5-bromopentyl)oxy)-7-methoxy-5,11-dioxy-50,11,11-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diaza-2-yl)phenyl)carbamate tert-butyl ester (141 mg, 0.23 mmol) and (S)-7-cyclopropoxy-8-hydroxy-1,10,11,11a-tetrahydro-3H,5H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-5-one (118 mg, 0.31 mmol) were dissolved in DMF (2 mL), potassium carbonate (49 mg, 0.47 mmol) was added, and the mixture was stirred for 16 hours. The reaction was quenched with water, and the mixture was extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. Purification by silica gel column chromatography (MeOH / DCM = 0%–5%) yielded the title compound (81 mg, 0.09 mmol).

[0459] Its structural characterization data are as follows:

[0460] ESI-MS (m / z): 806.3 [M+H] +

[0461] Step 11: Preparation of (S)-2-(4-aminophenyl)-8-((5-(((S)-7-cyclopropoxy-5-oxo-5,10,11,11a-tetrahydro-1H,3H-spiro[benzo[e]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-8-yl)oxy)pentyl)oxy)-7-methoxy-1,11a-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diaza-5,11(10H)-dione (P-33)

[0462] 81 mg (0.09 mmol) of tert-butyl carbamate (4-((S)-8-((5-((((S)-7-cyclopropoxy-5-oxo-5,10,11,11a-tetrahydro-1H,3H-spiro[benzo[e]]pyrrolo[1,2-a][1,4]diaza-2,1'-cyclopropane]-8-yl)oxy)pentyl)oxy)-7-methoxy-5-oxo-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diaza-2-yl)phenyl)carbamate was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.6 mL) was added dropwise with stirring. After the addition was complete, stirring was continued for 1 hour. After concentration under reduced pressure, the solution was purified by preparative high performance liquid chromatography and then freeze-dried to obtain the title compound (3.5 mg, 0.005 mmol).

[0463] Its structural characterization data are as follows:

[0464] ESI-MS (m / z): 706.3 [M+H]+

[0465] 1 H NMR (400MHz, DMSO-d6): δ7.58(s,1H),7.27(d,J=11.8Hz,2H),7.11(d,J=8.4Hz,2H),6.57-6. 51(m,2H),6.29(d,J=9.0Hz,2H),5.19(s,2H),4.18-4.07(m,1H),4.01-3.88(m,4H),3.86-3.8 0(m,1H),3.67(s,3H),3.57-3.51(m,4H),3.27-3.10(m,4H),2.73-2.65(m,1H),2.02-1.93(m, 1H),1.88-1.71(m,5H),1.61-1.48(m,2H),1.24(s,2H),0.88-0.75(m,1H),0.69-0.48(m,6H).

[0466] Its preparation method is as follows:

[0467] Column: SunFire Prep C18 OBD 19mm×150mm×5.0μm

[0468] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[0469] Other compounds in this application can be prepared by referring to the methods of intermediate preparation examples 1 to 3 and preparation examples 1 to 8.

[0470] Biological evaluation

[0471] Experimental Example 1. Inhibitory effect of the compound on the proliferation of HT29 cells

[0472] Cell plating: First, HT29 tumor cells were cultured in the appropriate culture medium, digested with trypsin, centrifuged, resuspended, and counted. The cell concentration was then adjusted to a suitable level for plating. The source of tumor cells is shown in Table 1.

[0473] Table 1. Tumor cell origin

[0474] The present invention involves co-incubating the test compound and tumor cells: cell suspension is added to each well of a 96-well plate, and after the cells adhere, the test compound diluted with culture medium is added to the wells and incubated.

[0475] In vitro cell viability assay: After incubation, Cell Counting-Lite was added to each well. TM 2.0 Reagent, mix thoroughly by shaking in the dark, and perform detection after a certain reaction time using an ELISA reader (manufacturer: BMG). The readings from cell-free culture wells are the background RLU, and the readings from wells containing cells but not the test compound are the cell control RLU. Cell inhibition rate = (1 - (Test compound RLU - Background RLU) / (Cell control RLU - Background RLU)) × 100%. Calculate the half-maximal inhibitory concentration (IC50) of the compound using a four-parameter model to fit the curve. 50 The test results are shown in Table 2.

[0476] Table 2. Inhibitory activity of compounds against HT29 cell proliferation

[0477] Test results show that the compounds of this invention have a good inhibitory effect on the proliferation of HT29 human colon cancer cells. For example, compounds P-1 and P-10 have an inhibitory activity IC50 of 100% against the proliferation of HT29 human colon cancer cells. 50 The value is between 1 and 50 nM.

[0478] Experimental Example 2. Inhibitory effect of the compound on the proliferation of HCC1954 cells

[0479] Cell plating: First, HCC1954 tumor cells were cultured in the appropriate culture medium, digested with trypsin, centrifuged, resuspended and counted, and the cell concentration was adjusted to a suitable level for plating. The source of tumor cells is shown in Table 3.

[0480] Table 3. Tumor cell origin

[0481] The present invention involves co-incubating the test compound and tumor cells: after the cells adhere, the culture medium in the cells is removed, and the diluted test compound is added to the wells of the plate for incubation.

[0482] In vitro cell viability assay: After incubation, add Cell Counting-Lite™ 2.0 reagent to each well, mix thoroughly by shaking in the dark, and allow to react for a certain period before detection. Read the values ​​using a microplate reader (manufacturer: BMG). Obtain the background RLU using the readings from cell-free culture wells, and obtain the solvent RLU using the readings from culture wells containing cells but without the compound. Cell inhibition rate = (1 - (analyte RLU - background RLU) / (solvent RLU - background RLU)) × 100%. Calculate the half-maximal inhibitory concentration (IC50) of the compound by fitting a curve using a four-parameter model. 50 RLU (relative light unit): The detection results are shown in Table 4.

[0483] Table 4. Inhibitory activity of compounds on the proliferation of HCC1954 cells

[0484] Test results show that the compound of the present invention has a good inhibitory effect on the proliferation of HCC1954 human breast cancer cells.

[0485] Although specific embodiments of the invention have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all the teachings disclosed, and all such changes are within the scope of protection of the invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein the compound has the structure shown in formula (I'): in, R 1 and R 2 Each is independently selected from hydrogen, -CN, halogen, and -OR. a -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected by one or more of H, deuterium (D), -CN, halogen, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups; R a Selected from H, C 1-6 Alkyl and C 3-6 cycloalkyl; R 4 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-10 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamine, hydroxyl, hydroxyalkyl, amino, aminoalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted C 6-10 Substituents of aryl, substituted or unsubstituted 5-10 membered heteroaryl and hydroxyalkyl-amide groups; Carbon-carbon single bond or carbon-carbon double bond when Carbon-carbon double bond R 5 R does not exist. 6 For hydrogen, R 3 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2- 6-olefin, C 2-6 Alkyne group, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups may optionally be independently bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamine, hydroxyl, hydroxyalkyl, amino, aminoalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted C 6-10 Substituents of aryl, substituted or unsubstituted 5-10 membered heteroaryl and hydroxyalkyl-amide groups; when Carbon-carbon single bond R 5 For hydrogen, R 3 With R 6 The atoms attached to it are connected to form substituted or unsubstituted C atoms. 3-6 cycloalkyl, or R 6 For hydrogen, R 3 With R 5 The atoms attached to it are connected to form substituted or unsubstituted C atoms. 3-6 cycloalkyl; t is selected from 1-10.

2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof. R 1 and R 2 Each is independently selected from hydrogen, hydroxyl, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected from one or more of deuterium (D), -CN, halogen, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups.

3. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof. R 1 and R 2 Each is independently selected from hydrogen, hydroxyl, and C. 1-6 Alkyl and C 3-6 Cycloalkyl; the alkyl group and cycloalkyl group may optionally be selected from one or more of deuterium (D), -CN, halogen, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, R 1 and R 2 Each is independently selected from hydrogen, hydroxyl, and C. 1-6 Alkyl and C 3-6 Cycloalkyl; the alkyl group and cycloalkyl group may optionally be selected from one or more of deuterium (D), -CN, halogen, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, R 1 and R 2 Each of the following is independently selected from methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, and cyclopentyl, wherein the methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, and cyclopentyl groups are optionally selected by one or more of deuterium (D), -CN, halogen, -OH, -NH2, and C. 1- 6-alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Substituents of aryl and 5-10 heteroaryl groups.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, R 1 and R 2 Each is independently selected from methyl, deuterated methyl, ethyl, and cyclopropyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, R 1 and R 2 Each is independently selected from methyl, deuterated methyl, and cyclopropyl.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, R 4 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1-6 Alkyl)2, C 1-6 Alkylamine, hydroxyalkyl, hydroxyalkyl-amide, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-10-membered heteroaryl substituents are replaced by the 3-8-membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally separated by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, R 4 Selected from C 1-6 Alkyl, C 3- 6-cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1-6 Alkyl) 2, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-10-membered heteroaryl substituents are replaced by the 3-8-membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally separated by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-6 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups.

10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, R 4 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-6 membered heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups may optionally be separated by one or more groups selected from C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, amino, -N(C) 1-6 Alkyl) 2, 3-6 membered heterocyclic groups, C 6-10 The aryl and 5-10-membered heteroaryl substituents, the 3-6-membered heterocyclic groups and C 6-10 Aryl group is optionally surrounded by one or more compounds selected from C 1-6 Substituents of alkyl and amino groups.

11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, R 4 Selected from methyl, phenyl, Cyclopropyl, pyridyl, thiophene, furanyl, 12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, It is a carbon-carbon double bond, R 5 It does not exist, R 6 For hydrogen, R 3 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, 3-8 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1-6 Alkyl)2, C 1-6 Alkylamine, hydroxyalkyl, hydroxyalkyl-amide, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-10-membered heteroaryl substituents are replaced by the 3-8-membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally separated by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, It is a carbon-carbon double bond, R 5 It does not exist, R 6 For hydrogen, R 3 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 6-10 The aryl group and the 5-10 heteroaryl group may optionally be bonded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, amino, -N(C) 1-6 Alkyl) 2, 3-8 membered heterocyclic groups, C 6-10 The aryl and 5-10-membered heteroaryl substituents are replaced by the 3-8-membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally separated by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, hydroxyl group, hydroxyl C 1-6 Alkyl, amino, aminoalkyl, 3-6 membered heterocyclic, 5-10 membered heteroaryl and hydroxy-C 1-6 Substituents of alkyl-amide groups.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, It is a carbon-carbon double bond, R 5 It does not exist, R 6 For hydrogen, R 3 Selected from C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 6-10 The aryl and 5-10 heteroaryl groups may optionally be separated by one or more groups selected from C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, amino, -N(C) 1-6 Alkyl) 2, 3-6 membered heterocyclic groups, C 6-10 The aryl and 5-10-membered heteroaryl substituents, the 3-6-membered heterocyclic groups and C 6-10 Aryl group is optionally surrounded by one or more compounds selected from C 1- It is substituted by 6-alkyl and amino substituents.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, It is a carbon-carbon double bond, R 5 It does not exist, R 6 For hydrogen, R 3 Selected from methyl, phenyl, Cyclopropyl, pyridyl, thiophene, furanyl, 16. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, For carbon-carbon single bonds, R 5 For hydrogen, R 3 With R 6 The atoms connected to it form cyclopropyl, cyclobutyl, or cyclopentyl groups.

17. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, For carbon-carbon single bonds, R 6 For hydrogen, R 3 With R 5 The atoms connected to it form cyclopropyl, cyclobutyl, or cyclopentyl groups.

18. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof, wherein t is selected from 1, 2, 3, 4, 5 and 6.

19. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein said compound has the following structure: P-1: P-2: P-3: P-4: P-5: P-6: P-7: P-8: P-9: P-10: P-11: P-12: P-13: P-14: P-15: P-16: P-17: P-18: P-19: P-20: P-21: P-22: P-23: P-24: P-25: P-26: P-27: P-28: P-29: P-30: P-31: P-32: P-33:

20. A pharmaceutical composition comprising a compound of any one of claims 1-19 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitride, isotope label, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

21. A medicine box, which contains: a) at least one compound of any one of claims 1-19 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug, or the pharmaceutical composition of claim 20, as a first therapeutic agent; b) At least one other therapeutic agent optionally present as a second therapeutic agent, or a pharmaceutical composition comprising another therapeutic agent as a second pharmaceutical composition; and c) Optional packaging and / or instructions.

22. The use of the compound of any one of claims 1-19 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug of claim 20, or the cassette of claim 21, in the preparation of a medicament for treating diseases of abnormal cell proliferation; Preferably, the disease is a tumor, such as an advanced solid tumor; Preferably, the tumor is selected from brain tumors, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, or sarcoma.

23. Use of the compound of any one of claims 1-19, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitride, isotope label, metabolite, or prodrug thereof, in the preparation of an antibody-drug conjugate.

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