Polycyclic compound, and preparation method therefor and use thereof

Abstract

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

Description

Polycyclic cyclic compounds, their preparation methods and uses

[0001] This application is based on and claims priority to CN application number 202411566322.2 filed on November 5, 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 polycyclic aromatic hydrocarbons, particularly anthracycline compounds, their preparation methods and uses, and compounds exhibiting antitumor activity. Background Technology

[0003] Antibody-drug conjugates (ADCs) typically consist of monoclonal antibodies, bioactive molecules, and linkers. The bioactive molecules are primarily cytotoxic agents that kill tumor cells. These bioactive molecules are covalently coupled to the antibodies via the linkers. The antibodies can recognize specific targets on the surface of tumor cells, thereby guiding the ADC to the tumor microenvironment and the surface of cancer cells. The ADC then enters the cancer cells through endocytosis. The bioactive molecules are then released within the cancer cells and kill them by inhibiting the microtubules of cancer cells or damaging their DNA, thereby minimizing damage to normal tissue cells.

[0004] Camptothecin compounds can act as bioactive molecules, and anthracyclines possess multiple antitumor mechanisms, functioning not only as DNA cross-linking agents and topoisomerase II inhibitors but also as bioactive molecules. Currently, doxorubicin, a widely used antitumor anthracycline compound, shows poor efficacy when used as an antibody-drug conjugate (ADC) toxin. In recent years, anthracyclines have been increasingly studied as ADC toxins, including PNU-159682 and PNU-EDA. However, there are still many problems with antibody-drug conjugates using highly active anthracyclines as payloads. Therefore, the field still needs to develop anthracyclines and their antibody-drug conjugates with ideal safety and efficacy. Summary of the Invention

[0005] The present invention aims to provide a class of novel anthracycline compounds that exhibit strong inhibitory effects on abnormal cell proliferation, good antitumor activity and ideal safety. Compared with compounds in the prior art, the compounds of the present invention are more easily metabolized and inactivated, and can be rapidly excreted or inactivated from the body, thereby reducing the toxic side effects on non-target tissues.

[0006] compound

[0007] 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'):

[0008] in,

[0009] X is selected from -O-, -S-, and -N(R3)-;

[0010] L is selected from single bonds and -C(R4)(R5)-;

[0011] R1 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cyano, HO-(CH2) n -O-(CH2) n -、H2N-(CH2) n -O-(CH2) n - HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n - aryl, benzyl, heteroaryl and heterocyclic groups, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2- 6. Acynyl, aryl, benzyl, heteroaryl, and heterocyclic groups may optionally be selected from one or more halogens, C 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 Substituents include alkylamine, hydroxyl, hydroxyalkyl, amino, and aminoalkyl groups;

[0012] R2 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, haloalkyl, amino, aminoalkyl, hydroxyalkyl, HO-(CH2) n -O-(CH2) n - and H2N-(CH2) n -O-(CH2) n -;

[0013] n is selected independently from 1-10;

[0014] R3 is selected from H and C. 1-6 Alkyl, haloalkyl, and hydroxyl;

[0015] R4 is selected from H and C. 1-6 Alkyl, haloalkyl, and hydroxyl;

[0016] R5 is selected from H and C. 1-6 Alkyl, haloalkyl, and hydroxyl; or,

[0017] When X is selected from -N(R3)-, R3 can also be linked with R1 and its attached atoms to form a ring;

[0018] The condition is that when R2 is methyl, X is NH, and L is -CH2-, R1 is not H2N-(CH2)2-.

[0019] In some embodiments, the compound has the structure shown in formula (I):

[0020] in,

[0021] X is selected from -O-, -S-, and -N(R3)-;

[0022] R1 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - aryl, benzyl, heteroaryl and heterocyclic groups, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 The alkynyl, aryl, benzyl, heteroaryl, and heterocyclic groups may optionally be selected from one or more halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substituents include alkylamine, hydroxyl, hydroxyalkyl, amino, and aminoalkyl groups;

[0023] R2 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, haloalkyl, amino, aminoalkyl, hydroxyalkyl, HO-(CH2) n -O-(CH2) n - and H2N-(CH2) n -O-(CH2) n -;

[0024] n is selected independently from 1-10;

[0025] R3 is selected from H and C. 1-6 Alkyl, haloalkyl, and hydroxyl; or,

[0026] When X is selected from -N(R3)-, R3 can also form a ring with R1 and the atoms attached to it.

[0027] In some implementations, R1 is selected from hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n - HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n -、C 6-10 Aryl, benzyl, 5-10 membered heteroaryl and 3-14 membered heterocyclic groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, benzyl, 5-10 membered heteroaryl, and 3-14 membered heterocyclic groups may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-NH2, -C 1- 6-alkyl-(OH) n ,amine group, -NH-C 1-6 Alkyl groups are substituted.

[0028] In some implementations, R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n -、C6-10 Aryl, benzyl, 5-10 membered heteroaryl and 3-14 membered heterocyclic groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, benzyl, 5-10 membered heteroaryl, and 3-14 membered heterocyclic groups may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-(OH) n ,amine group, -NH-C 1-6 Alkyl groups are substituted.

[0029] In some implementations, R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n -、C 6-10 Aryl, benzyl, 5-10 membered heteroaryl and 3-14 membered heterocyclic groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, benzyl, 5-10 membered heteroaryl, and 3-14 membered heterocyclic groups may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-(OH) n ,amine group, -NH-C 1-6 Alkyl groups are substituted.

[0030] In some embodiments, R1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2NH2-substituted cyclobutyl, -CH2NH2-substituted cyclohexyl, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n- HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n - Phenyl, benzyl, amino-substituted phenyl, hydroxy-substituted phenyl, amino-substituted benzyl, hydroxy-substituted benzyl, azacyclobutyl, pyrrolidinyl, piperidinyl, piperazineyl, and morpholinyl.

[0031] In some embodiments, R1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, and HO-(CH2). n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - Phenyl, benzyl, amino-substituted phenyl, hydroxy-substituted phenyl, amino-substituted benzyl and hydroxy-substituted benzyl.

[0032] In some implementations, R1 is selected from halogens, C 3-6 Cycloalkyl, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n - HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n -、C 6-10 Aryl, benzyl, and 4-7 membered heterocyclic groups, wherein the C 3-6 cycloalkyl, C 6-10 The aryl, benzyl, and 4-7 membered heterocyclic groups may optionally be replaced by one or more substituents selected from halogens, hydroxyl groups, -CH2NH2, -CH2OH, and amines.

[0033] In some embodiments, R1 is selected from fluorine, cyclohexyl, -CH2NH2-substituted cyclohexyl, and HO-(CH2). n -O-(CH2) n -、HO-(CH2) n - HS-(CH2) n - Phenyl, amino-substituted phenyl, azacyclobutyl and piperidinyl.

[0034] In some embodiments, R1 is selected from fluorine, -CH2NH2-substituted cyclohexyl, HOCH2CH2OCH2-, HOCH2CH2-, HOCH2-, HSCH2-, amino-substituted phenyl, azacyclobutyl, and piperidinyl.

[0035] In some implementations, R1 is selected from hydrogen, fluorine, methyl, and HO-(CH2). n - H2N-(CH2) n - Phenyl and amino-substituted phenyl groups.

[0036] In some implementation schemes, R1 is selected from fluorine, HO(CH2) n - H2N-(CH2) n - and amino-substituted phenyl groups.

[0037] In some embodiments, R1 is selected from fluorine, HOCH2-, H2NCH2-, and amino-substituted phenyl groups.

[0038] In some embodiments, R1 is selected from fluorine, HOCH2- and amino-substituted phenyl groups.

[0039] In some implementations, X is selected from -O-, -S-, and -NH-.

[0040] In some implementations, X is selected from -O- and -S-.

[0041] In some implementations, X is selected from -S- and -NH-.

[0042] In some implementations, X is -S-.

[0043] In some implementations, L is selected from single bond, -CH2-, -CH(CH3)- and -C(CH3)2-.

[0044] In some implementations, L is selected from -CH2- and -CH(CH3)-.

[0045] In some implementations, L stands for -CH2-.

[0046] In some implementations, R2 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, amino, HO-(CH2) n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - and H2N-(CH2) n -O-(CH2) n -

[0047] In some embodiments, R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, and HO-(CH2). n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n - and amino groups.

[0048] In some implementations, R2 is selected from hydrogen, methyl, ethyl, HO-(CH2). n - and H2N-(CH2) n -

[0049] In some implementations, R2 is selected from methyl, HO-(CH2) n - and H2N-(CH2) n -

[0050] In some embodiments, R2 is selected from methyl, HO-(CH2)2- and H2N-(CH2)2-.

[0051] In some implementations, R2 is methyl.

[0052] In some implementations, n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0053] In some implementations, n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9.

[0054] In some implementations, n is independently selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0055] In some implementations, n is independently selected from 1, 2, 3, 4, 5, 6, and 7.

[0056] In some implementations, n is independently selected from 1, 2, 3, 4, 5, and 6.

[0057] In some implementations, n is independently selected from 1, 2, 3, 4, and 5.

[0058] In some implementations, n is independently selected from 1, 2, 3, and 4.

[0059] In some implementations, n is independently selected from 1, 2, and 3.

[0060] In some implementations, n is independently selected from 1 and 2.

[0061] In some implementations, R3 is selected from H, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 can be linked with R1 and the atoms attached to it to form a heterocycle.

[0062] In some implementations, R3 is selected from H, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 may be connected to R1 and the atoms attached thereto to form nitrogen-containing heterocycles, such as 3-14 membered nitrogen-containing heterocycles, such as 3-8 membered nitrogen-containing heterocycles, such as 3-6 membered nitrogen-containing heterocycles, such as 3 membered nitrogen-containing heterocycles, 4 membered nitrogen-containing heterocycles, 5 membered nitrogen-containing heterocycles or 6 membered nitrogen-containing heterocycles.

[0063] In some implementations, R4 is selected from H, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups.

[0064] In some implementations, R4 is selected from H and C. 1-4 alkyl.

[0065] In some implementations, R4 is selected from H and methyl.

[0066] In some implementations, R5 is selected from H, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups.

[0067] In some implementations, R5 is selected from H and C. 1-4 alkyl.

[0068] In some implementations, R5 is selected from H and methyl.

[0069] In some implementations, X is selected from -O-, -S-, and -NH-;

[0070] L is selected from single bonds and -C(R4)(R5)-;

[0071] R1 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n - HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n- HS-(CH2) n -、C 6-10 Aryl, benzyl, 5-10 membered heteroaryl and 3-14 membered heterocyclic groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, benzyl, 5-10 membered heteroaryl, and 3-14 membered heterocyclic groups may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl -OH, amino, -NH-C 1-6 Substituents of alkyl groups;

[0072] R2 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, amino, HO-(CH2) n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - and H2N-(CH2) n -O-(CH2) n -;

[0073] R4 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups;

[0074] R5 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups;

[0075] n is independently selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0076] In some implementations, X is selected from -O-, -S-, and -NH-;

[0077] R1 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2)n -、C 6-10 Aryl, benzyl, 5-10 membered heteroaryl and 3-14 membered heterocyclic groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, benzyl, 5-10 membered heteroaryl, and 3-14 membered heterocyclic groups may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl -OH, amino, -NH-C 1-6 Substituents of alkyl groups;

[0078] R2 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, amino, HO-(CH2) n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - and H2N-(CH2) n -O-(CH2) n -;

[0079] R3 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 can be connected to R1 and the atoms attached thereto to form nitrogen-containing heterocycles, such as 3-14 member nitrogen-containing heterocycles;

[0080] n is independently selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0081] In some implementations, X is selected from -O-, -S-, and -NH-;

[0082] R1 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n -、C 6-10aryl, benzyl, 5-6 membered heteroaryl and 3-10 membered heterocyclic groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, benzyl, 5-6 membered heteroaryl, and 3-10 membered heterocyclic groups may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl -OH, amino, -NH-C 1-6 Substituents of alkyl groups;

[0083] R2 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, amino, HO-(CH2) n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - and H2N-(CH2) n -O-(CH2) n -;

[0084] R3 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 can be connected to R1 and the atoms attached thereto to form nitrogen-containing heterocycles, such as 3-14 member nitrogen-containing heterocycles;

[0085] n is independently selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0086] In some implementations, X is selected from -O-, -S-, and -NH-;

[0087] R1 is selected from hydrogen, halogens, and C. 1-4 Alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 Alkyne, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n -、C 6-10 Aryl, benzyl, 5-6 membered heteroaryl and 3-8 membered heterocyclic groups (e.g., 3-6 membered heterocyclic groups), wherein the C 1-4 Alkyl, C3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 6-10 Aryl, benzyl, 5-6 membered heteroaryl, and 3-8 membered heterocyclic groups (e.g., 3-6 membered heterocyclic groups) may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, -C 1-4 Alkyl-NH2, -C 1-4 Alkyl -OH, amino, -NH-C 1-4 Substituents of alkyl groups;

[0088] R2 is selected from hydrogen, C 1-4 Alkyl, C 3-6 cycloalkyl, halogenated C 1-4 Alkyl, amino, HO-(CH2) n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - and H2N-(CH2) n -O-(CH2) n -;

[0089] R3 is selected from H and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl and hydroxyl groups; or, R3 can be connected to R1 and the atoms attached thereto to form nitrogen-containing heterocycles, such as 3-10 membered nitrogen-containing heterocycles (e.g., 3-8 membered nitrogen-containing heterocycles or 3-6 membered nitrogen-containing heterocycles);

[0090] n is independently selected from 1, 2, 3, 4, 5, 6, 7, and 8.

[0091] In some implementations, X is selected from -O-, -S-, and -NH-;

[0092] R1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2NH2-substituted cyclobutyl, -CH2NH2-substituted cyclohexyl, and HO-(CH2). n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n - HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n- Phenyl, benzyl, amino-substituted phenyl, hydroxy-substituted phenyl, amino-substituted benzyl, hydroxy-substituted benzyl, azacyclobutyl, pyrrolidinyl, piperidinyl, piperazineyl, and morpholinyl;

[0093] R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, and HO-(CH2). n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -and amino groups;

[0094] R4 is selected from H, methyl, and ethyl;

[0095] R5 is selected from H, methyl, and ethyl;

[0096] n is independently selected from 1, 2, 3, 4, and 5.

[0097] In some implementations, X is selected from -O- and -S-;

[0098] R1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, and HO-(CH2). n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - Phenyl, benzyl, amino-substituted phenyl, hydroxy-substituted phenyl, amino-substituted benzyl and hydroxy-substituted benzyl;

[0099] R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, and HO-(CH2). n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -and amino groups;

[0100] R3 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6Alkyl and hydroxyl groups; or, R3 can be connected to R1 and the atoms attached thereto to form nitrogen-containing heterocycles, such as 3-8 membered nitrogen-containing heterocycles, such as 3-6 membered nitrogen-containing heterocycles, such as 3 membered nitrogen-containing heterocycles, 4 membered nitrogen-containing heterocycles, 5 membered nitrogen-containing heterocycles or 6 membered nitrogen-containing heterocycles;

[0101] n is independently selected from 1, 2, 3, 4, and 5.

[0102] In some implementations, X is selected from -S- and -NH-;

[0103] L is selected from -CH2- and -CH(CH3)-;

[0104] R1 is selected from hydrogen, fluorine, methyl, cyclohexyl, -CH2NH2-substituted cyclohexyl, and HO-(CH2). n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n - phenyl, amino-substituted phenyl, aziridine and piperidinyl;

[0105] R2 is selected from hydrogen, methyl, ethyl, or HO-(CH2). n - and H2N-(CH2) n -;

[0106] n is independently selected from 1, 2, and 3.

[0107] In some implementations, X is -S-;

[0108] R1 is selected from hydrogen, fluorine, methyl, and HO-(CH2). n - H2N-(CH2) n - Phenyl and amino-substituted phenyl groups;

[0109] R2 is selected from hydrogen, methyl, ethyl, or HO-(CH2). n - and H2N-(CH2) n -;

[0110] R3 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 can be connected to R1 and the atoms attached thereto to form 3-6 nitrogen-containing heterocycles, such as 3-membered nitrogen-containing heterocycles, 4-membered nitrogen-containing heterocycles, 5-membered nitrogen-containing heterocycles or 6-membered nitrogen-containing heterocycles;

[0111] n is independently selected from 1 and 2.

[0112] In some embodiments, the compound has one or more of the following characteristics:

[0113] (1) R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n - HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n -、C 6-10 Aryl, benzyl, 5-10 membered heteroaryl and 3-14 membered heterocyclic groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, benzyl, 5-10 membered heteroaryl, and 3-14 membered heterocyclic groups may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-(OH) n ,amine group, -NH-C 1-6 Substituents of alkyl groups;

[0114] (2) X is selected from -O- and -S-;

[0115] (3) R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, HO-(CH2). n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -and amino groups;

[0116] (4) n is independently selected from 1, 2, 3, 4, 5 and 6;

[0117] (5) R3 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6Alkyl and hydroxyl groups; or, R3 may be connected to R1 and the atoms attached thereto to form nitrogen-containing heterocycles, such as 3-14-membered nitrogen-containing heterocycles, such as 3-10-membered nitrogen-containing heterocycles, such as 3-8-membered nitrogen-containing heterocycles, such as 3-6-membered nitrogen-containing heterocycles, such as 3-membered nitrogen-containing heterocycles, 4-membered nitrogen-containing heterocycles, 5-membered nitrogen-containing heterocycles or 6-membered nitrogen-containing heterocycles;

[0118] (6) L is selected from single bonds and -C(R4)(R5)-;

[0119] (7) R4 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl; and / or,

[0120] (8) R5 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups.

[0121] In some embodiments, the compound has one or more of the following characteristics:

[0122] (1) R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n -、C 6-10 Aryl, benzyl, 5-10 membered heteroaryl and 3-14 membered heterocyclic groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, benzyl, 5-10 membered heteroaryl, and 3-14 membered heterocyclic groups may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1- 6-alkyl-NH2,-C 1-6 Alkyl-(OH) n ,amine group, -NH-C 1-6 Substituents of alkyl groups;

[0123] (2) X is selected from -O- and -S-;

[0124] (3) R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, HO-(CH2). n - H2N-(CH2)n -、HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -and amino groups;

[0125] (4) n is independently selected from 1, 2, 3, 4, 5, and 6; and / or,

[0126] (5) R3 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 may be connected to R1 and the atoms attached thereto to form nitrogen-containing heterocycles, such as 3-14-membered nitrogen-containing heterocycles, such as 3-10-membered nitrogen-containing heterocycles, such as 3-8-membered nitrogen-containing heterocycles, such as 3-6-membered nitrogen-containing heterocycles, such as 3-membered nitrogen-containing heterocycles, 4-membered nitrogen-containing heterocycles, 5-membered nitrogen-containing heterocycles or 6-membered nitrogen-containing heterocycles.

[0127] In some embodiments, the compound has one or more of the following characteristics:

[0128] (1) R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n -、C 6-10 Aryl, benzyl, 5-10 membered heteroaryl and 3-14 membered heterocyclic groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, benzyl, 5-10 membered heteroaryl, and 3-14 membered heterocyclic groups may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1- 6-alkyl-NH2,-C 1-6 Alkyl-(OH) n ,amine group, -NH-C 1-6 Substituents of alkyl groups;

[0129] (2) X is selected from -O- and -S-;

[0130] (3) R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, HO-(CH2). n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -and amino groups;

[0131] (4) n is independently selected from 1, 2, 3, 4, 5, and 6; and / or,

[0132] (5) R3 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 may be connected to R1 and the atoms attached thereto to form nitrogen-containing heterocycles, such as 3-14 membered nitrogen-containing heterocycles, such as 3-8 membered nitrogen-containing heterocycles, such as 3-6 membered nitrogen-containing heterocycles, such as 3 membered nitrogen-containing heterocycles, 4 membered nitrogen-containing heterocycles, 5 membered nitrogen-containing heterocycles or 6 membered nitrogen-containing heterocycles.

[0133] In some embodiments, the compound has one or more of the following characteristics:

[0134] (1) R1 is selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n -、C 6-10 Aryl, benzyl, 5-10 membered heteroaryl and 3-10 membered heterocyclic groups (e.g., 3-8 membered or 3-6 membered heterocyclic groups), wherein C 1-4 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl, benzyl, 5-10-membered heteroaryl, and 3-10-membered heterocyclic groups (e.g., 3-8-membered or 3-6-membered heterocyclic groups) may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-(OH) n ,amine group, -NH-C 1-6 Substituents of alkyl groups;

[0135] (2) X is selected from -O- and -S-;

[0136] (3) R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, HO-(CH2). n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -and amino groups;

[0137] (4) n is independently selected from 1, 2, 3, 4, 5, and 6; and / or,

[0138] (5) R3 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 may be connected to R1 and the atoms attached thereto to form nitrogen-containing heterocycles, such as 3-14-membered nitrogen-containing heterocycles, such as 3-10-membered nitrogen-containing heterocycles, such as 3-8-membered nitrogen-containing heterocycles, such as 3-6-membered nitrogen-containing heterocycles, such as 3-membered nitrogen-containing heterocycles, 4-membered nitrogen-containing heterocycles, 5-membered nitrogen-containing heterocycles or 6-membered nitrogen-containing heterocycles.

[0139] On the other 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 (II):

[0140] in,

[0141] Y is selected from the following structure:

[0142] In some implementations, Y is selected from the following structures:

[0143] In some implementations, Y is selected from the following structures:

[0144] On the other hand, the compound is selected from the following structures:

[0145] P-1:

[0146] P-2:

[0147] P-3:

[0148] P-4:

[0149] P-5:

[0150] P-6:

[0151] P-7:

[0152] P-8:

[0153] P-9:

[0154] P-10:

[0155] P-11:

[0156] P-12:

[0157] P-13:

[0158] P-14:

[0159] P-15:

[0160] 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.

[0161] definition

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] The term "cycloalkyl" refers to a 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.

[0170] 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 a carbon atom 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 via any one of its ring atoms, provided that valence requirements are met. Examples of heterocyclic groups in this invention include 3-14 membered heterocyclic groups, 3-12 membered heterocyclic groups, 3-8 membered heterocyclic groups, 3-6 membered heterocyclic groups, or 5-6 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 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 group in this invention may optionally be substituted with one or more substituents described in this invention. The heterocyclic group in this invention may optionally be fused with one or more aromatic or non-aromatic rings.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] The term "halogenated" or "halogenated" is defined as including F, Cl, Br, or I.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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 of the substituents may independently consist of one or more of the following structures: -O-, -S-, -N(R3)-, halogen, -CN, -OH, -NH2, -NO2, -CN, =O, C 1-6 (alkylene) group, C 1-6 Halogenated (alkylene) group, C 1-6 Alkoxy, C 2-6 (imide)alkenyl, C 2-6 (Asyl) ynyl, C 3-8 (Hypo-cycloalkylene), 3-8 membered (hetero-cycloalkylene), C 6-10 (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.

[0181] 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.

[0182] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0183] 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%).

[0184] Solid lines may be used in this article. solid wedge 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).

[0185] 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 isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) of more than one polymorph.

[0186] 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.

[0187] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts. 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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).

[0194] 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.

[0195] This application is by no means limited to the methods and materials described herein. In the event that one or more of the cited documents, patents and similar materials differ from or contradict this application (including but not limited to defined terms, application of terms, described techniques, etc.), the descriptions and accompanying compound structural formulas of this application shall prevail. In this application, if the chemical name and the chemical structural formula are inconsistent, the chemical structural formula shall prevail.

[0196] Composition or drug combination, pharmaceutical composition

[0197] In a third aspect, the present invention provides a composition or pharmaceutical combination comprising the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitride, isotope label, metabolite or prodrug thereof, optionally further comprising one or more active pharmaceutical ingredients.

[0198] The present invention provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

[0199] 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.

[0200] The term "pharmaceutically acceptable carrier" refers to an excipient that is administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] Pillbox products

[0205] In a fourth aspect, the present invention provides a medicine box comprising:

[0206] 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;

[0207] 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

[0208] c) Optional packaging and / or instructions.

[0209] The aforementioned kit products may contain 0.01 mg to 1000 mg of at least one compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof.

[0210] 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.

[0211] Medical Use

[0212] The compounds represented by formulas (I'), (I), and (II) of this invention exhibit strong inhibitory effects on abnormal cell proliferation.

[0213] The compound represented by formula (I) of this invention exhibits a strong inhibitory effect on abnormal cell proliferation.

[0214] 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 compositions or pharmaceutical combinations described above, or the pharmaceutical compositions described above, or the kit products described above, for the treatment of diseases involving abnormal cell proliferation.

[0215] This application also provides the use of the compounds described herein or their pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope-labeled substances, metabolites, and prodrugs, the compositions or pharmaceutical combinations described above, the pharmaceutical compositions described above, or the aforementioned cassettes in the preparation of a medicament for treating diseases of abnormal cell proliferation.

[0216] This application provides the compounds described herein or their pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope labels, metabolites, and prodrugs, the pharmaceutical compositions described above, or the kit products described above, for the treatment of diseases involving abnormal cell proliferation.

[0217] 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, the pharmaceutical compositions described above, or the cassettes described above in the preparation of a medicament for treating diseases of abnormal cell proliferation.

[0218] In some implementations, the diseases involving abnormal cell proliferation include, but are not limited to, tumors, such as advanced solid tumors.

[0219] In some implementations, the disease involving abnormal cell proliferation is selected from tumors, such as advanced solid tumors.

[0220] 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 compositions or pharmaceutical combinations described above, or the use of the pharmaceutical compositions described above in the preparation of formulations for inhibiting the proliferation of tumor cells.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] The present invention also provides the use of compounds of formula (I'), formula (I), and formula (II) for the preparation of antibody-drug conjugates.

[0225] The present invention also provides the use of the compound of formula (I) for the preparation of antibody-drug conjugates.

[0226] Treatment

[0227] 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, nitride, isotope label, metabolite, and prodrug, or the composition or pharmaceutical combination described above, or the pharmaceutical composition described above, to an individual in need of it.

[0228] The present invention provides a method for treating diseases 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.).

[0236] Beneficial effects of the invention

[0237] The compounds described in this 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

[0238] 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.

[0239] The abbreviations used in this invention have the following meanings:

[0240] 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).

[0241] 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.

[0242] The abbreviations used in the nuclear magnetic resonance (NMR) spectra in the embodiments are shown below.

[0243] 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.

[0244] The mass spectrometry (MS) measurements were performed using an Agilent (ESI) mass spectrometer, model Agilent 6120B.

[0245] Example 1: Preparation of (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzophenanthrene-2-thiocarboxylic acid fluoromethyl ester (P-4)

[0246] Step 1: Preparation of 2,5-dioxopyrrolidine-1-yl(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzophenanthrene-2-carboxylic acid ester (P-4-2)

[0247] 1-Hydroxypyrrolidine-2,5-dione (110.03 mg, 956.04 μmol) and (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzophenanthrene-2-carboxylic acid (200 mg, 318.68 μmol) were dissolved in dichloromethane (12 mL), and EDCI (183.27 mg, 956.04 μmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane, then washed twice with water, and the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product of the title compound (330 mg, 273.23 μmol).

[0248] Its structural characterization data are as follows:

[0249] MS m / z (ESI): 725.2 [M+H] +

[0250] Step 2: Preparation of (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarboxylic acid (P-4-3)

[0251] 2,5-dioxopyrrolidine-1-yl(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzophenanthrene-2-carboxylic acid ester (330 mg, 273.23 μmol) was dissolved in DMF (7 mL), and sodium hydrosulfide (30.64 mg, 546.46 μmol) in DMF (7 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was purified by preparative high performance liquid chromatography and then freeze-dried to obtain the title compound (50 mg, 77.68 μmol).

[0252] Its structural characterization data are as follows:

[0253] MS m / z (ESI): 644.2 [M+H] +

[0254] The preparation method for a high-performance liquid chromatograph is as follows:

[0255] Column: Waters Xbridge Prep C18 OBD (5μm*19mm*150mm)

[0256] Mobile phase A: Acetonitrile; Mobile phase B: Water (0.05% ammonium bicarbonate)

[0257] Step 3: Preparation of (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzophenanthrene-2-thiocyanate fluoromethyl ester (P-4)

[0258] DMF (2 mL) was added to crude (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarboxylic acid (25 mg, 38.84 μmol), followed by the addition of fluoroiodomethane (12.42 mg, 77.68 μmol) and DIPEA (16 mg, 123.80 μmol). The mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was extracted with water and ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography and then freeze-dried to obtain the title compound (8 mg, 11.48 μmol).

[0259] Its structural characterization data are as follows:

[0260] MS m / z (ESI): 676.2 [M+H] +

[0261] 1 H NMR(400MHz,DMSO-d6)δ13.99(s,1H),13.20(s,1H),7.93-7.88(m,2H),7.66-7.63(m,1H),6.21(s,1H),5.9 3(s,1H),5.81(s,1H),5.21(t,J=4.4Hz,1H),4.98-4.96(m,1H),4.59(d,J=2.0Hz,1H),4.27-4.23(m,2H),3. 98(s,3H),3.94-3.92(m,1H),3.69-3.63(m,1H),3.53-3.48(m,2H),3.40-3.36(m,1H),3.31(s,3H),3.11-2. 87(m,2H),2.70-2.60(m,2H),2.34-2.31(m,1H),2.18-2.13(m,1H),1.70-1.65(m,2H),1.23(d,J=6.4Hz,3H)

[0262] Its preparation method is as follows:

[0263] Column: Waters Xbridge Prep C18 OBD (5μm*19mm*150mm)

[0264] Mobile phase A: Acetonitrile; Mobile phase B: Water (0.05% ammonium bicarbonate)

[0265] Example 2: Preparation of S-(2-hydroxyethyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-2-thioester (P-1)

[0266] In a reaction mixture of (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarboxylic acid (50 mg, 77.68 μmol), DMF (2 mL), and excess sodium hydrosulfide (4.0 eq)), 2-iodoethanol (133.58 mg, 776.81 μmol) was added dropwise, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction mixture was purified by preparative high-performance liquid chromatography and then freeze-dried to obtain the title compound (20 mg, 26.90 μmol).

[0267] Its structural characterization data are as follows:

[0268] MS m / z (ESI): 688.2 [M+H] +

[0269] 1 H NMR(400MHz,DMSO-d6)δ14.00(s,1H),13.21(s,1H),7.93-7.88(m,2H),7.66-7.64(m,1H),5.91(s,1H) ),5.21(t,J=4.4Hz,1H),4.98-4.95(m,2H),4.59(d,J=2.0Hz,1H),4.26-4.22(m,2H),3.98(s,3H),3. 93-3.91(m,1H),3.68-3.64(m,1H),3.53-3.46(m,3H),3.40-3.36(m,2H),3.31(s,3H),3.05-2.86(m, 4H),2.70-2.60(m,2H),2.30-2.23(m,1H),2.17-2.12(m,1H),1.69-1.64(m,2H),1.23(d,J=6.4Hz,3H)

[0270] Its preparation method is as follows:

[0271] Column: Waters Xbridge Prep C18 OBD (5μm*19mm*150mm)

[0272] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[0273] Example 3: Preparation of S-(4-aminobenzyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-2-thioester (P-2)

[0274] Step 1: Preparation of (9H-fluorene-9-yl)methyl(4-(hydroxymethyl)phenyl)carbamate (P-2-1)

[0275] (4-Aminophenyl)methanol (2 g, 16.24 mmol) and (9H-fluorene-9-yl)methyl(2,5-dioxopyrrolidone-1-yl)carbonate (5.75 g, 17.05 mmol) were added to acetonitrile (60 mL) and water (60 mL), followed by sodium bicarbonate (2.73 g, 32.48 mmol). The reaction mixture was reacted at 25 °C for 2 hours. The reaction solution was then mixed with 60 mL of water, filtered, washed with water and eluted with acetonitrile, and the filter cake was collected and dried to give the title compound (5 g, 14.48 mmol).

[0276] Its structural characterization data are as follows:

[0277] MS m / z (ESI): 368.2 [M+Na] +

[0278] Step 2: Preparation of (9H-fluorene-9-yl)methyl(4-(mercaptomethyl)phenyl)carbamate (P-2-3)

[0279] (9H-fluorene-9-yl)methyl(4-(hydroxymethyl)phenyl)carbamate (50 mg, 144.76 μmol) was dissolved in toluene (10 mL), Lawson's reagent (70.26 mg, 173.72 μmol) was added, the mixture was purged with nitrogen, and the mixture was refluxed at 110 °C overnight. The reaction solution was directly purified by silica gel column chromatography (petroleum ether-ethyl acetate = 0-90%) and concentrated under reduced pressure to give the title compound (28 mg, 77.46 μmol).

[0280] Its structural characterization data are as follows:

[0281] MS m / z (ESI): 384.2 [M+Na] +

[0282] 1 H NMR(400MHz, DMSO-d6)δ9.68(s,1H),7.91(d,J=7.2Hz,2H),7.75(d,J=7.2Hz,2H),7.45-7.33(m,6H),7.23( d,J=8.0Hz,2H),4.48(d,J=6.4Hz,2H),4.31(t,J=5.6Hz,1H),3.67(d,J=7.6Hz,2H),2.77(t,J=7.6Hz,1H).

[0283] Step 3: Preparation of S-(4-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)benzyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-2-thioester (P-2-4)

[0284] (9H-fluorene-9-yl)methyl(4-(mercaptomethyl)phenyl)carbamate (28 mg, 77.46 μmol) and (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1, 4)Oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzophenanthrene-2-carboxylic acid (63.20 mg, 100.70 μmol) was dissolved in DMF (3 mL), PyBOP (80.62 mg, 154.93 μmol) was added, and DIPEA (30.04 mg, 232.39 μmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with water and ethyl acetate, washed with organic phase brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product of the title compound (75 mg, 77.24 μmol), which was used directly in the next reaction without purification.

[0285] Its structural characterization data are as follows:

[0286] MS m / z (ESI): 972.3 [M+H] +

[0287] Step 4: Preparation of S-(4-aminobenzyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-2-thioester (P-2)

[0288] Crude S-(4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)benzyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-2-thioester (70 mg, 72.09 μmol) was dissolved in DMF (3 mL), and diethylamine (26.36 mg, 360.44 μmol) was added dropwise. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was purified directly by preparative high performance liquid chromatography and then freeze-dried to obtain the title compound (10 mg, 12.42 μmol).

[0289] Its structural characterization data are as follows:

[0290] MS m / z (ESI): 749.2 [M+H] +

[0291] Its preparation method is as follows:

[0292] Column: Waters Xbridge Prep C18 OBD (5μm*19mm*150mm)

[0293] Mobile phase A: Acetonitrile; Mobile phase B: Water (0.05% ammonium bicarbonate)

[0294] Example 4: Preparation of S-(3-aminobenzyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzophenanthrene-2-thioester (P-3)

[0295] Step 1: Preparation of (9H-fluorene-9-yl)methyl(3-(hydroxymethyl)phenyl)carbamate (P-3-2)

[0296] (3-Aminophenyl)methanol (2 g, 16.24 mmol) and (9H-fluorene-9-yl)methyl(2,5-dioxopyrrolidone-1-yl)carbonate (5.75 g, 17.05 mmol) were added to acetonitrile (60 mL) and water (60 mL), followed by sodium bicarbonate (2.73 g, 32.48 mmol). The reaction was carried out at 25 °C for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was stirred, filtered, washed with water, and rinsed with acetonitrile. The filter cake was collected and dried to give the title compound (3.6 g, 10.42 mmol).

[0297] Its structural characterization data are as follows:

[0298] MS m / z (ESI): 363.1 [M+H2O] +

[0299] Step 2: Preparation of (9H-fluorene-9-yl)methyl(3-(bromomethyl)phenyl)carbamate (P-3-3)

[0300] (9H-fluorene-9-yl)methyl(3-(hydroxymethyl)phenyl)carbamate (500.00 mg, 1.45 mmol) was suspended in dichloromethane (25 mL), and N,N'-dimethylthiourea (60.32 mg, 579.05 μmol) was added, followed by the addition of NBS (386.48 mg, 2.17 mmol) in portions. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was filtered to remove insoluble matter. The filtrate was directly concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether-ethyl acetate = 0-50%) and concentrated again under reduced pressure to obtain the title compound (210 mg, 514.34 μmol).

[0301] Its structural characterization data are as follows:

[0302] MS m / z (ESI): 408.2 [M+H] +

[0303] Step 3: Preparation of (9H-fluorene-9-yl)methyl(3-((triphenylmethylthio)methyl)phenyl)carbamate (P-3-4)

[0304] DMF (2 mL) was added to (9H-fluorene-9-yl)methyl(3-(bromomethyl)phenyl)carbamate (50 mg, 122.46 μmol) and triphenylmethanethiol (67.70 mg, 244.93 μmol), followed by potassium iodide (2.03 mg, 12.25 μmol) and DIPEA (31.65 mg, 244.93 μmol). The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was extracted with water and ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 10:1) and concentrated under reduced pressure to give the title compound (120 mg, 49.69 μmol).

[0305] Step 4: Preparation of (9H-fluorene-9-yl)methyl(3-(mercaptomethyl)phenyl)carbamate (P-3-5)

[0306] Dichloromethane (1 mL) and trifluoroacetic acid (48.39 mg, 424.41 μmol) were added to (9H-fluorene-9-yl)methyl(3-((triphenylmethylthio)methyl)phenyl)carbamate (130 mg, 215.31 μmol), followed by the dropwise addition of triisopropylsilane (41.87 mg, 264.41 μmol). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was extracted with water and ethyl acetate, washed with anhydrous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of the title compound (120 mg, 199.19 μmol), which was used directly in the next reaction without purification.

[0307] Its structural characterization data are as follows:

[0308] MS m / z (ESI): 379.1 [M+H2O] +

[0309] Step 5: Preparation of S-(3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)benzyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-2-thioester (P-3-6)

[0310] (9H-fluorene-9-yl)methyl(3-(mercaptomethyl)phenyl)carbamate (130 mg, 215.79 μmol) and (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1, 4]Oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzophenanthrene-2-carboxylic acid (176.06 mg, 280.53 μmol) was dissolved in DMF (3 mL), PyBOP (224.59 mg, 431.59 μmol) was added, and DIPEA (83.67 mg, 647.38 μmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was extracted with water and ethyl acetate, washed with organic phase brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (dichloromethane-methanol = 0-10%), and concentrated again under reduced pressure to obtain the crude product of the title compound (50 mg, 21.11 μmol).

[0311] Its structural characterization data are as follows:

[0312] MS m / z (ESI): 971.3 [M+H] +

[0313] Step Six: Preparation of S-(3-aminobenzyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzophenanthrene-2-thioester (P-3)

[0314] Crude S-(3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)benzyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetraphenyl-2-thioester (50 mg, 51.49 μmol) was dissolved in DMF (2 mL), and diethylamine (18.83 mg, 257.46 μmol) was added dropwise. The mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was lyophilized to remove diethylamine, purified by preparative high performance liquid chromatography, and then freeze-dried to obtain the title compound (2.15 mg, 2.71 μmol).

[0315] Its structural characterization data are as follows:

[0316] MS m / z (ESI): 749.2 [M+H] +

[0317] Its preparation method is as follows:

[0318] Column: Waters Xbridge Prep C18 OBD (5μm*19mm*150mm)

[0319] Mobile phase A: Acetonitrile; Mobile phase B: Water (0.05% ammonium bicarbonate)

[0320] Example 5: Preparation of S-(2-(2-hydroxyethoxy)ethyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarbamate (P-7)

[0321] (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarboxylic acid (174 mg, 234.59 μmol) was dissolved in DMF (3 mL), and 2-(2-iodoethoxy)ethanol (50.27 mg, 469.18 μmol) and 2,6-dimethylpyridine (50.27 mg, 469.18 μmol) were added. The reaction mixture was stirred at 25 °C for 0.25 h. The reaction solution was purified by reversed-phase column chromatography to obtain a crude product, which was then purified twice by high-performance liquid chromatography and freeze-dried to obtain the title compound (29 mg, 37.65 μmol).

[0322] Its structural characterization data are as follows:

[0323] ESI-MS (m / z): 732.3 (M+H) +

[0324] 1 H NMR (400MHz, DMSO-d6) δ13.99(s,1H),13.19(s,1H),7.92-7.90(m,1H),7.88(s,1H),7.64(dd,J=2.0,7.2Hz,1H),5.93(s,1H) ,5.20(t,J=4.4Hz,1H),4.96-4.92(m,1H),4.65-4.62(m,1H),4.59(d,J=2Hz,1H),4.28-4.25(m,1H),4.23(d,J=2Hz,1H),3.9 8(s,3H),3.92(dd,J=1.6,6.4Hz,1H),3.69-3.63(m,1H),3.53-3.47(m,5H),3.44-3.41(m,2H),3.40-3.31(m,3H),3.04-2.97 (m,3H),2.88-2.84(m,1H),2.70-2.59(m,2H),2.33-2.27(m,1H),2.15-2.10(m,1H),1.69-1.64(m,2H),1.23(d,J=6.4Hz,3H).

[0325] The first purification method is as follows:

[0326] Column: Agilent Prep C18 OBD 19*150mm*5μm

[0327] Mobile phase A: Acetonitrile; Mobile phase B: Water (0.05% ammonium formate)

[0328] The second purification method is as follows:

[0329] Column: Agilent Prep C18 OBD 19*150mm*5μm

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

[0331] Example 6: Preparation of S-(3-hydroxypropyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarbamate (P-8)

[0332] To a DMF (3 mL) solution of (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarboxylic acid (35.53 mg, 55.20 μmol), 3-iodopropanol (20.53 mg, 110.40 μmol) was added, and the reaction was stirred at 25 °C for 0.25 h. The reaction solution was purified by reversed-phase column chromatography to obtain a crude product, which was then purified by high-performance liquid chromatography and freeze-dried to obtain the title compound (3.78 mg, 5.12 μmol).

[0333] Its structural characterization data are as follows:

[0334] ESI-MS (m / z): 702.2 (M+H) + .

[0335] 1H NMR (400MHz, DMSO-d6) δ14.03(s,1H),13.25(s,1H),7.93(d,J=4.4Hz,1H),7.68-7.66(m,1H),5.89(s,1H),5.21(t,J=4.4 Hz,1H),5.0-4.75(m,1H),4.59(d,J=2.0Hz,1H),4.85-4.65(m,1H),4.27-4.24(m,1H),4.23(d,J=2Hz,1H),4.00(s,3H),3 .94-3.92(m,1H),3.68-3.64(m,1H),3.54-3.48(m,1H),3.46-3.41(m,2H),3.40-3.20(m,2H),3.30(s,3H),3.06-2.90(m, 3H),2.85-2.79(m,2H),2.71-2.58(m,3H),2.35-2.26(m,2H),2.17-2.12(m,1H),1.70-1.60(m,4H),1.22(d,J=6.8Hz,3H).

[0336] The purification method is as follows:

[0337] Column: Agilent Prep C18 OBD 19*150mm*5μm

[0338] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[0339] Example 7: Preparation of S-(piperidin-4-ylmethyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarbamate (P-9)

[0340] Step 1: Preparation of 4-iodomethylpiperidine (P-9-2):

[0341] 4-(iodomethyl)piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.54 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added dropwise with stirring. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile-water and then freeze-dried to obtain the crude trifluoroacetate of the title compound (500 mg, 1.47 mmol).

[0342] Its structural characterization data are as follows:

[0343] MS m / z(ESI): 226.1 [M+H] +

[0344] Step 2: Preparation of S-(piperidin-4-ylmethyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarbamate (P-9):

[0345] (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarboxylic acid (36 mg, 55.93 μmol) and trifluoroacetate of 4-iodomethylpiperidine (42 mg, 123.86 μmol) were dissolved in DMF (2 mL), and DIPEA (14.46 mg, 111.86 μmol) was added dropwise with stirring. The reaction was stirred at room temperature for 1 hour. After adding 4-iodomethylpiperidine trifluoroacetate (42 mg, 123.86 μmol) and potassium carbonate (15.46 mg, 111.86 μmol), the reaction was continued at room temperature with stirring for 1 hour. After the reaction was complete, formic acid was added dropwise to the reaction solution, followed by purification by reversed-phase column chromatography (acetonitrile-0.05% formic acid aqueous solution = 0-90%), and then freeze-drying to obtain the crude product. Further purification by two preparative high-performance liquid chromatography (HPLC) cycles yielded the formate salt of the title compound (15.27 mg, 19.17 μmol).

[0346] Its structural characterization data are as follows:

[0347] MS m / z (ESI): 741.3 [M+H] +

[0348] 1H NMR(400MHz, DMSO-d6)δ8.39(s,1H),7.92-7.86(m,2H),7.67-7.61(m,1H),6.04-5.81(m,1H),5.20(t,J=4.8Hz,1H),4.98 -4.92(m,1H),4.60-4.57(d,J=2.0Hz,1H),4.27-4.19(m,2H),4.01-3.96(s,3H),3.95-3.89(m,1H),3.69-3.62(m,1H),3.5 5-3.46(m,1H),3.40-3.32(m,2H),3.32-3.28(s,3H),3.13-3.05(m,2H),3.05-2.99(m,1H),2.95-2.87(m,1H),2.80-2.74 (m,2H),2.69-2.58(m,4H),2.31-2.24(m,1H),2.18-2.09(m,1H),1.77-1.63(m,4H),1.63-1.54(m,1H),1.25-1.16(m,4H).

[0349] The preparation conditions for the first time are as follows:

[0350] Column: Waters Xbridge Prep C18 OBD (5μm*19mm*150mm)

[0351] Mobile phase A: Acetonitrile; Mobile phase B: Water (0.05% ammonium formate)

[0352] The preparation conditions for the second preparation are as follows:

[0353] Column: Waters Sunfire Prep C18 OBD (5μm*19mm*150mm)

[0354] Mobile phase A: Acetonitrile; Mobile phase B: Water (0.05% ammonium bicarbonate)

[0355] Example 8: Preparation of S-(azacyclobutane-3-ylmethyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzophenanthrene-2-thiocarbamate (P-10)

[0356] Step 1: Preparation of 3-(iodomethyl)azacyclobutane (P-10-2):

[0357] 0.5 g (1.68 mmol) of tert-butyl 3-(iodomethyl)azacyclobutane-1-carboxylate was dissolved in dichloromethane (3 mL), and TFA (3 mL) was added dropwise with stirring. The reaction was carried out at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile-water and freeze-dried to obtain the crude trifluoroacetate of the title compound (560 mg, 1.62 mmol).

[0358] Its structural characterization data are as follows:

[0359] MS m / z (ESI): 198.1 [M+H] +

[0360] Step 2: Preparation of S-(azacyclobutane-3-ylmethyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzophenanthrene-2-thiocarbamate (P-10):

[0361] (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarboxylic acid (64 mg, 99.43 μmol) and trifluoroacetate of 3-(iodomethyl)azacyclobutane (123.71 mg, 397.73 μmol) were dissolved in DMF (4 mL), and DIPEA (64 mg, 495.19 μmol) was added dropwise with stirring. The reaction was carried out at room temperature for 1.5 hours. After the reaction was completed, formic acid was added dropwise to the reaction solution, followed by purification by reversed-phase column chromatography (acetonitrile-0.05% formic acid aqueous solution = 0-90%), and then freeze-drying to obtain the crude product. The crude product was further purified by three preparative high-performance liquid chromatography cycles to obtain the trifluoroacetate of the title compound (3.34 mg, 3.64 μmol).

[0362] Its structural characterization data are as follows:

[0363] MS m / z (ESI): 713.2 [M+H] +

[0364] 1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),7.94-7.87(m,2H),7.67-7.60(m,1H),6.12-5.81(m,1H),5.23-5.13( m,1H),4.98-4.91(m,1H),4.60-4.57(m,1H),4.27-4.19(m,2H),3.98(s,3H),3.96-3.89(m,2H),3.83-3.7 6(m,1H),3.69-3.62(m,1H),3.54-3.47(m,3H),3.40-3.33(m,2H),3.30(s,3H),3.10-2.99(m,3H),2.93-2 .85(m,2H),2.72-2.58(m,3H),2.32-2.24(m,1H),2.18-2.08(m,1H),1.72-1.61(m,2H),1.28-1.11(m,4H).

[0365] The preparation conditions for the first time are as follows:

[0366] Column: Waters Xbridge Prep C18 OBD (5μm*19mm*150mm)

[0367] Mobile phase A: Acetonitrile; Mobile phase B: Water (0.05% ammonium formate)

[0368] The preparation conditions for the second preparation are as follows:

[0369] Column: Waters Sunfire Prep C18 OBD (5μm*19mm*150mm)

[0370] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[0371] The preparation conditions for the third preparation are as follows:

[0372] Column: Waters Sunfire Prep C18 OBD (5μm*19mm*150mm)

[0373] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% trifluoroacetic acid)

[0374] Example 9: Preparation of S-(((1R,4S)-4-(aminomethyl)cyclohexyl)methyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarbamate (P-11)

[0375] Step 1: Preparation of tert-butyl (((1R,4R)-4-(iodomethyl)cyclohexyl)methyl)carbamate (P-11-2):

[0376] tert-butyl(((1R,4R)-4-(hydroxymethyl)cyclohexyl)methyl)carbamate (1.00 g, 4.11 mmol) was dissolved in tetrahydrofuran (5 mL), and iodine (1.56 g, 6.16 mmol), triphenylphosphine (1.62 g, 6.16 mmol), and imidazole (419.66 mg, 6.16 mmol) were added with stirring. The reaction was continued for 2 hours. The reaction solution was concentrated under reduced pressure and the title compound (413.00 mg, 1.17 mmol) was prepared by high performance liquid chromatography.

[0377] Its structural characterization data are as follows:

[0378] ESI-MS(m / z):254.1(M-100+H)+.

[0379] The purification method is as follows:

[0380] Column: Agilent Prep C18 OBD 19*150mm*5μm

[0381] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[0382] Step 2: Preparation of ((1R,4R)-4-(iodomethyl)cyclohexyl)methylamine (P-11-3):

[0383] tert-butyl(((1R,4R)-4-(iodomethyl)cyclohexyl)methyl)carbamate (413.00 mg, 1.17 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added dropwise with stirring. The reaction was continued for 2 hours. The reaction solution was concentrated under reduced pressure and the title compound (195.00 mg, 770.38 μmol) was prepared by high performance liquid chromatography.

[0384] Its structural characterization data are as follows:

[0385] ESI-MS(m / z):254.1(M+H)+.

[0386] The purification method is as follows:

[0387] Column: Agilent Prep C18 OBD 19*150mm*5μm

[0388] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% trifluoroacetic acid)

[0389] Step 3: Preparation of S-(((1R,4S)-4-(aminomethyl)cyclohexyl)methyl)(2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarbamate (P-11)

[0390] (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarboxylic acid (71 mg, 110.31 μmol) was dissolved in DMF (3 mL), and ((1R,4R)-4-(iodomethyl)cyclohexyl)methylamine (121.50 mg, 330.92 μmol) and DIPEA (71.28 mg, 551.54 μmol) were added. The reaction mixture was stirred at 25 °C for 2 hours. The title compound (2.23 mg, 4.82 μmol) was prepared directly from the reaction solution by high performance liquid chromatography.

[0391] Its structural characterization data are as follows:

[0392] ESI-MS (m / z): 769.3 (M+H)+

[0393] 1H NMR (400MHz, CD3OD) δ8.53(s,2H),7.99(d,J=8.0Hz,1H),7.84(t,J=7.2Hz,1H),7.31(d,J=15.2Hz,1H),5.37(s,1H),5.11(s,1H),4. 68(s,1H),4.41(s,1H),4.29(d,J=6.8Hz,1H),4.08(d,J=6.8Hz,1H),4.04(s,3H),3.89-3.83(m,1H),3.57-3.50(m,1H),3.48-3.47(m ,1H),3.42(s,3H),3.14-3.10(m,1H),3.06-3.04(m,1H),2.89-2.84(m,1H),2.78(d,J=5.2Hz,3H),2.80-2.74(m,2H),2.45(d,J=14.8 Hz,1H),2.20-2.16(m,1H),1.93-1.87(m,2H),1.86-1.82(m,4H),1.58(s,1H),1.47(s,1H),1.34(d,J=6.4Hz,3H),1.15-1.00(m,6H).

[0394] The purification method is as follows:

[0395] Column: Agilent Prep C18 OBD 19*150mm*5μm

[0396] Mobile phase A: Acetonitrile; Mobile phase B: Water (0.05% FA)

[0397] Example 10: Preparation of (2S,4S)-2,5,12-trihydroxy-N-(1-mercaptopropane-2-yl)-7-methoxy-4-(((1S,3R,4aR,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-carboxamide (P-12)

[0398] Step 1: Preparation of 1-iodoprop-2-amine (P-12-2):

[0399] N-(2-iodo-1-methylethyl)carbamate tert-butyl ester (210 mg, 736.53 μmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added dropwise with stirring. The reaction was carried out at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of the title compound, which was directly used in the next reaction.

[0400] Its structural characterization data are as follows:

[0401] MS m / z (ESI): 186.1 [M+H] +

[0402] Step 2: Preparation of (2S,4S)-2,5,12-trihydroxy-N-(1-mercaptopropane-2-yl)-7-methoxy-4-(((1S,3R,4aR,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-carboxamide (P-12):

[0403] (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetrabenzo-2-thiocarboxylic acid (62 mg, 91.51 μmol) and trifluoroacetate of 1-iodopropyl-2-amine (33.86 mg, 183.02 μmol) were dissolved in DMF (2 mL), and DIPEA (59.13 mg, 457.54 μmol) was added dropwise with stirring. The reaction was continued for one hour. The reaction solution was directly purified by preparative high performance liquid chromatography and then freeze-dried to obtain the title compound (1.13 mg, 1.53 μmol).

[0404] Its structural characterization data are as follows:

[0405] MS m / z (ESI): 701.3 [M+H] +

[0406] 1H NMR (400MHz, DMSO-d6) δ7.93(d,J=4.5Hz,2H),7.70-7.65(m,1H),5.36(d,J=9.1Hz,1H),5.25(m,1H),5.01(m,1H ),4.59(d,J=2.0Hz,1H),4.23(d,J=2.1Hz,1H),4.16(s,1H),4.00(s,3H),3.65(d,J=8.6Hz,1H),3.53-3.50(m,1 H),3.31(s,3H),3.25(t,J=7.1Hz,1H),3.11-2.90(m,4H),2.65-2.57(m,2H),2.30-2.16(m,4H),2.00(dd,J=14. 5,6.9Hz,1H),1.73-1.65(m,2H),1.24-1.19(m,4H),1.15(dd,J=6.6,2.3Hz,3H).H),1.15(dd,J=6.6,2.3Hz,3H).

[0407] Its preparation method is as follows:

[0408] Column: Waters Sunfire Prep C18 OBD (5μm*19mm*150mm)

[0409] Mobile phase A: acetonitrile; Mobile phase B: water (0.05% formic acid)

[0410] Biological evaluation

[0411] Experimental Example 1. Inhibitory effect of the compound on the proliferation of HT29 cells

[0412] 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.

[0413] Table 1. Tumor cell origin

[0414] 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.

[0415] In vitro cell viability assay: After incubation, Cell Counting-Lite was added to each well. TM2.0 Reagent, mix thoroughly by shaking in the dark, and perform detection after an appropriate reaction time. Read the values ​​on a microplate reader (manufacturer: BMG). The readings of cell-free culture wells are the background RLU, and the readings of 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 Tables 2-1 and 2-2.

[0416] Table 2-1. Inhibitory activity of compounds on HT29 cell proliferation

[0417] Table 2-2. Inhibitory activity of compounds against HT29 cell proliferation

[0418] Test results show that the compound of the present invention has an inhibitory effect on the proliferation of HT29 human colon cancer cells.

[0419] Experimental Example 2. Inhibitory effect of the compound on the proliferation of NCI-N87 cells

[0420] Cell plating: First, NCI-N87 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.

[0421] Table 3. Tumor cell origin

[0422] The present invention involves co-incubation of 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 for 72 hours.

[0423] 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 an appropriate reaction time. Read the values ​​on a microplate reader (manufacturer: BMG). The readings of cell-free culture wells are the background RLU, and the readings of 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 Tables 4-1 and 4-2.

[0424] Table 4-1. Inhibitory activity of compounds on NCI-N87 cell proliferation

[0425] Table 4-2. Inhibitory activity of compounds against NCI-N87 cell proliferation

[0426] Test results show that the compound of the present invention has an inhibitory effect on the proliferation of NCI-N87 human gastric cancer cells.

[0427] Experimental Example 3. Inhibitory effect of the compound on the proliferation of HCC1954 cells

[0428] 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 5.

[0429] Table 5. Tumor cell origin

[0430] 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.

[0431] 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 perform the assay after an appropriate reaction time. 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 Tables 6-1 and 6-2.

[0432] Table 6-1. Inhibitory activity of compounds on the proliferation of HCC1954 cells

[0433] Table 6-2. Inhibitory activity of compounds on HCC1954 cell proliferation

[0434] Test results show that the compound of the present invention has an inhibitory effect on the proliferation of HCC1954 human breast cancer cells.

[0435] Experimental Example 4. Inhibitory effect of the compound on the proliferation of NCI-H1975 cells

[0436] Cell plating: First, NCI-H1975 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 the tumor cells is shown in Table 7.

[0437] Table 7. Tumor cell origin

[0438] 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.

[0439] 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 perform the assay after an appropriate reaction time. 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 Tables 8-1 and 8-2.

[0440] Table 8-1. Inhibitory activity of compounds on the proliferation of NCI-H1975 cells

[0441] Table 8-2. Inhibitory activity of compounds on NCI-H1975 cell proliferation

[0442] Test results show that the compound of the present invention has an inhibitory effect on the proliferation of NCI-H1975 human non-small cell lung cancer cells.

[0443] Experimental Example 5. Inhibitory effect of the compound on the proliferation of NCI-H358 cells

[0444] Cell plating: First, NCI-H358 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 9.

[0445] Table 9. Tumor cell origin

[0446] 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.

[0447] 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 10.

[0448] Table 10. Inhibitory activity of compounds on the proliferation of NCI-H358 cells

[0449] Test results show that the compound of the present invention has an inhibitory effect on the proliferation of NCI-H358 human non-small cell lung cancer cells.

[0450] Experimental Example 6. Metabolic stability of compounds in liver microsomal incubation system

[0451] Liver microsome incubation system: The test compound, human / monkey liver microsome solution, and PBS were mixed and pre-incubated at 37℃ for 5 min. NADPH solution was then added to bring the final concentration of the test compound to 1 μM and the final concentration of human / monkey liver microsome protein to 0.5 mg / ml. After incubation for 0 and 15 min respectively, acetonitrile containing an internal standard was added to precipitate the protein. After centrifugation, the supernatant was collected and the test compound was detected by LC-MS / MS. The residual rate (%) of the parent drug in the incubation system was calculated as follows: Residual rate (%) = 100 × (AT) 15min / AT 0min )

[0452] Note:AT 15min : Peak area ratio of the analyte to the internal standard in the sample after 15 min of incubation; AT 0min The peak area ratio of the analyte to the internal standard before reaction is shown in Table 11.

[0453] Table 11. Residual fraction of compounds after 15 min of incubation in human and monkey liver microsomes

[0454] *In human and monkey liver microsomal incubation systems, the main metabolite of P-1 was compound P-1-M (P-1-M has an inhibitory activity (IC50) on the proliferation of N87, HT29, H358, and H1975 cells). 50(>1 μM). Therefore, compared with the control compound, the compound of this application, such as P-1, can be rapidly inactivated, significantly reducing the toxic side effects on non-target tissues, and has better safety.

[0455] PNU-EDA can be prepared according to US2018 / 0360985Al.

[0456] The structure of P-1-M is shown below:

[0457] 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-labeled compound, metabolite, or prodrug thereof, wherein the compound has the following structure: in, X is selected from -O-, -S-, and -N(R3)-; L is selected from single bonds and -C(R4)(R5)-; R1 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n - HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n - aryl, benzyl, heteroaryl and heterocyclic groups, the C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2- 6. Acynyl, aryl, benzyl, heteroaryl, and heterocyclic groups may optionally be selected from one or more halogens, C 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 Substituents include alkylamine, hydroxyl, hydroxyalkyl, amino, and aminoalkyl groups; R2 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, haloalkyl, amino, aminoalkyl, hydroxyalkyl, HO-(CH2) n -O-(CH2) n - and H2N-(CH2) n -O-(CH2) n -; n is selected independently from 1-10; R3 is selected from H and C. 1-6 Alkyl, haloalkyl, and hydroxyl; R4 is selected from H and C. 1-6 Alkyl, haloalkyl, and hydroxyl; R5 is selected from H and C. 1-6 Alkyl, haloalkyl, and hydroxyl; or, When X is selected from -N(R3)-, R3 can also be linked with R1 and its attached atoms to form a ring; The condition is that when R2 is methyl, X is NH, and L is -CH2-, R1 is not H2N-(CH2)2-.

2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, R1 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n - HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n -、C 6-10 Aryl, benzyl, 5-10 membered heteroaryl and 3-14 membered heterocyclic groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, benzyl, 5-10 membered heteroaryl, and 3-14 membered heterocyclic groups may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-(OH) n ,amine group, -NH-C 1-6 Alkyl groups are substituted.

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, wherein, R1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2NH2-substituted cyclobutyl, -CH2NH2-substituted cyclohexyl, and HO-(CH2). n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n - HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n - Phenyl, benzyl, amino-substituted phenyl, hydroxy-substituted phenyl, amino-substituted benzyl, hydroxy-substituted benzyl, azacyclobutyl, pyrrolidinyl, piperidinyl, piperazineyl, and morpholinyl.

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, wherein, X is selected from -O-, -S-, and -NH-.

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, wherein, R2 is selected from hydrogen, C 1- 6-alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, amino, HO-(CH2) n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - and H2N-(CH2) n -O-(CH2) n - 6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope-labeled compound, metabolite, or prodrug thereof, wherein, n is independently selected from 1, 2, 3, 4, 5, 6, 7, and 9.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, R3 is selected from H and C. 1- 6-alkyl, halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 can be linked with R1 and the atoms attached to it to form a heterocycle.

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, L is selected from single bond, -CH2-, -CH(CH3)- and -C(CH3)2-.

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, R4 and R5 are each independently selected from H and C. 1-4 alkyl.

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, The compound has one or more of the following characteristics: (1) R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n - HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n -、C 6-10 Aryl, benzyl, 5-10 membered heteroaryl and 3-14 membered heterocyclic groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, benzyl, 5-10 membered heteroaryl, and 3-14 membered heterocyclic groups may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-(OH) n ,amine group, -NH-C 1-6 Substituents of alkyl groups; (2) X is selected from -O- and -S-; (3) R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, HO-(CH2). n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -and amino groups; (4) n is independently selected from 1, 2, 3, 4, 5 and 6; (5) R3 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 may be connected to R1 and the atoms attached thereto to form nitrogen-containing heterocycles, such as 3-14-membered nitrogen-containing heterocycles, such as 3-10-membered nitrogen-containing heterocycles, such as 3-8-membered nitrogen-containing heterocycles, such as 3-6-membered nitrogen-containing heterocycles, such as 3-membered nitrogen-containing heterocycles, 4-membered nitrogen-containing heterocycles, 5-membered nitrogen-containing heterocycles or 6-membered nitrogen-containing heterocycles; (6) L is selected from single bonds and -C(R4)(R5)-; (7) R4 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl; and / or, (8) R5 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite, or prodrug thereof, wherein, X is selected from -O-, -S-, and -NH-; L is selected from single bonds and -C(R4)(R5)-; R1 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, cyano, HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n - HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n -、C 6-10 Aryl, benzyl, 5-10 membered heteroaryl and 3-14 membered heterocyclic groups, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, benzyl, 5-10 membered heteroaryl, and 3-14 membered heterocyclic groups may optionally be replaced by one or more groups selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl -OH, amino, -NH-C 1-6 Substituents of alkyl groups; R2 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, amino, HO-(CH2) n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - and H2N-(CH2) n -O-(CH2) n -; R3 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 can be connected to R1 and the atoms attached thereto to form nitrogen-containing heterocycles, such as 3-14 member nitrogen-containing heterocycles; R4 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; R5 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; n is independently selected from 1, 2, 3, 4, 5, 6, 7, and 8.

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, X is selected from -O-, -S-, and -NH-; R1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2NH2-substituted cyclobutyl, -CH2NH2-substituted cyclohexyl, and HO-(CH2). n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n - HS-(CH2) n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n - Phenyl, benzyl, amino-substituted phenyl, hydroxy-substituted phenyl, amino-substituted benzyl, hydroxy-substituted benzyl, azacyclobutyl, pyrrolidinyl, piperidinyl, piperazineyl, and morpholinyl; R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, and HO-(CH2). n - H2N-(CH2) n -、HO-(CH2) n -O-(CH2) n - H2N-(CH2) n -O-(CH2) n -and amino groups; R3 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 can be connected to R1 and the atoms attached thereto to form nitrogen-containing heterocycles, such as 3-8 membered nitrogen-containing heterocycles, such as 3-6 membered nitrogen-containing heterocycles, such as 3 membered nitrogen-containing heterocycles, 4 membered nitrogen-containing heterocycles, 5 membered nitrogen-containing heterocycles or 6 membered nitrogen-containing heterocycles; R4 is selected from H, methyl, and ethyl; R5 is selected from H, methyl, and ethyl; n is independently selected from 1, 2, 3, 4, and 5.

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, X is selected from -S- and -NH-; L is selected from -CH2- and -CH(CH3)-; R1 is selected from hydrogen, fluorine, methyl, cyclohexyl, -CH2NH2-substituted cyclohexyl, and HO-(CH2). n -O-(CH2) n -、HO-(CH2) n - H2N-(CH2) n - HS-(CH2) n - phenyl, amino-substituted phenyl, aziridine and piperidinyl; R2 is selected from hydrogen, methyl, ethyl, or HO-(CH2). n - and H2N-(CH2) n -; R3 is selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and hydroxyl groups; or, R3 can be connected to R1 and the atoms attached thereto to form 3-6 nitrogen-containing heterocycles, such as 3-membered nitrogen-containing heterocycles, 4-membered nitrogen-containing heterocycles, 5-membered nitrogen-containing heterocycles or 6-membered nitrogen-containing heterocycles; n is independently selected from 1, 2, and 3.

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 the compound has the structure shown in formula (II): in, Y is selected from the following structure:

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, The 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:

16. A pharmaceutical composition comprising the compound of any one of claims 1-15 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitride, isotope label, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

17. A medicine box, comprising: a) at least one compound of any one of claims 1-15, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof, or a pharmaceutical composition of claim 16, 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.

18. The use of the compound of any one of claims 1-15 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug of the same, the pharmaceutical composition of claim 16 or the cassette of claim 17 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, and sarcoma.

19. Use of the compound of any one of claims 1-15, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitride, isotope label, metabolite, or prodrug thereof, for the preparation of an antibody-drug conjugate.

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