CN107033157B

CN107033157B - Bisbenzylisoquinoline derivative and application thereof in preparing medicament for treating or preventing tumor

Info

Publication number: CN107033157B
Application number: CN201610396617.9A
Authority: CN
Inventors: 潘卫东; 雅科夫; 刘杰麟; 蓝俊杰; 刘亚洲; 骆衡; 张荣红; 娄华勇; 肖潇; 晏文涛; 易平; 刘唐婧君; 刘晟; 李小刚; 刘柏岑
Original assignee: Key Laboratory of Natural Product Chemistry of Guizhou Academy of Sciences; Guizhou Medical University
Current assignee: Key Laboratory of Natural Product Chemistry of Guizhou Academy of Sciences; Guizhou Medical University
Priority date: 2016-02-03
Filing date: 2016-06-07
Publication date: 2020-05-05
Anticipated expiration: 2036-06-07
Also published as: CN107033157A

Abstract

The application relates to a bisbenzylisoquinoline derivative and application thereof in preparing a medicament for treating or preventing tumors. Specifically, the application discloses an application of a compound of a general formula (I), a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a metabolite thereof, or a pharmaceutical composition thereof, or a combination of the compound and another anti-tumor drug in preparing a drug for treating or preventing tumors; the application also discloses a compound of the general formula (II), a single stereoisomer thereof, a mixture of the stereoisomers, a prodrug thereof, a pharmaceutically acceptable salt thereof or a metabolite thereof, a pharmaceutical composition thereof and application thereof in preparing a medicament for treating or preventing tumors:

wherein, X₁‑X₆、R₁‑R₄X, y, z and n are as defined herein.

Description

Bisbenzylisoquinoline derivative and application thereof in preparing medicament for treating or preventing tumor

Technical Field

The present application relates generally to the field of pharmaceutical chemistry.

Background

The bisbenzylisoquinoline alkaloid has various biological activities, mainly including antibiosis, anti-inflammation, blood pressure reduction, tumor resistance, platelet aggregation resistance, immunity regulation, arrhythmia resistance, hepatic fibrosis resistance and the like.

Tetrandrine, also called tetrandrine, has a chemical formula of (6,6 ', 7, 12-tetramethoxy-2, 2' -dimethyl berbamine), is a bisbenzylisoquinoline alkaloid extracted from the root tuber of the traditional Chinese medicine, namely tetrandrine, and has the following chemical structural formula:

disclosure of Invention

One aspect of the present application relates to the use of a compound of general formula (I), a single stereoisomer thereof, a mixture of its stereoisomers, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a metabolite thereof, in the manufacture of a medicament for the treatment or prevention of a tumour:

wherein the content of the first and second substances,

X₁selected from hydrogen, halogen, nitro, nitroso, -SO₃H or optionally substituted sulfonyl;

X₂、X₃and X₄Each independently selected from hydrogen, halogen, nitro, nitroso, -SO₃H. Optionally substituted amino or optionally substituted sulfonyl;

R₁and R₂Each independently selected from the group consisting of hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substitutedAn alkylcarbonyl group, an optionally substituted alkenylcarbonyl group or an optionally substituted alkynylcarbonyl group of (a);

x is an integer from 1 to 3;

y is an integer from 1 to 4; and

z is an integer from 1 to 2;

with the following conditions:

X₁、X₂、X₃and X₄Not hydrogen at the same time; and

when X is present₁、X₂、X₃And X₄When one of them is halogen, the rest X₁Selected from hydrogen, nitro, nitroso, -SO₃H or optionally substituted sulfonyl; the rest of X₂、X₃And X₄Each independently selected from hydrogen, nitro, nitroso, -SO₃H. Optionally substituted amino or optionally substituted sulfonyl, but not both.

Another aspect of the present application relates to the use of a compound of general formula (Ia), a single stereoisomer thereof, a mixture of its stereoisomers, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a metabolite thereof, in the manufacture of a medicament for the treatment or prevention of a tumor:

wherein the content of the first and second substances,

R₁selected from the group consisting of nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, optionally substituted alkynylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylcarbonyl, or optionally substituted heteroarylcarbonyl or substituted sulfonyl; and

R₂selected from the group consisting of hydrogen, optionally substituted alkyl, nitroso, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, optionally substituted alkynylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, or substituted sulfonyl.

Yet another aspect of the present application relates to the use of a compound, a single stereoisomer thereof, a mixture of its stereoisomers, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a metabolite thereof, in the manufacture of a medicament for the treatment or prevention of a tumor, wherein the compound is selected from the group consisting of:

yet another aspect of the present application relates to the use of a pharmaceutical composition comprising a compound of formula (I), a compound of formula (Ia), a compound of any one of compounds H-01 to H-55, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a metabolite thereof, and a pharmaceutically acceptable carrier for the manufacture of a medicament for the treatment or prevention of a tumor.

Yet another aspect of the present application relates to the use of a compound of formula (I), a compound of formula (Ia), a compound of any one of compounds H-01 to H-55, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a metabolite thereof in combination with another anti-neoplastic drug in the manufacture of a medicament for the treatment or prevention of a neoplasm.

Another aspect of the present application relates to compounds of general formula (II), single stereoisomers thereof, mixtures of stereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, and metabolites thereof:

wherein the content of the first and second substances,

X₅selected from hydrogen, halogen, nitro, nitroso, -SO₃H or optionally substituted sulfonyl;

X₆selected from-OH, halogen, -CN, -NH-C (═ O) -NH-R₈、-O-C(＝O)-R₉、-O-S(＝O)₂-R₁₀、-NH-C(＝S)-NH-R₁₁、-NH-C(＝O)OR₁₂、-OC(＝O)NHR₁₃、-OC(＝O)OR₁₄、-OR₁₅、-NH-P(＝O)R₁₆R₁₇、-NHC(＝S)R₁₈、-NHC(＝O)R₁₉or-OC (═ O) R₂₀；

R₈To R₂₀Each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, optionally substituted alkynylcarbonyl, optionally substituted amino or optionally substituted aryloxy;

n is 0, 1,2 or 3;

R₃and R₄Each independently selected from the group consisting of hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, or optionally substituted alkynylcarbonyl;

with the following conditions:

when X is present₅N is not 0 when hydrogen or halogen;

optionally, when X₆When it is halogen, X₅Is not hydrogen.

Another aspect of the present application relates to compounds, single stereoisomers thereof, mixtures of stereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, and metabolites thereof, wherein the compounds are selected from the group consisting of:

another aspect of the present application relates to a pharmaceutical composition comprising a compound of formula (II), any one of compounds H-56 to H-106, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, and a metabolite thereof, and a pharmaceutically acceptable carrier.

The application relates to application of a compound in a general formula (II), a compound in any one of compounds H-56 to H-106, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof or a pharmaceutical composition in preparation of medicines for preventing or treating tumors.

The application relates to application of a compound in a general formula (II), any one of compounds H-56 to H-106, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof and a metabolite thereof, or a combination of the pharmaceutical composition and another anti-tumor drug in preparation of drugs for preventing or treating tumors.

Detailed description of the preferred embodiments

In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to be open-ended, inclusive meaning that "includes but is not limited to".

Reference throughout this specification to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" means that a particular reference element, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

It should be understood that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a reaction comprising "a catalyst" includes one catalyst, or two or more catalysts. It will also be understood that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.

Definition of

Certain chemical groups named herein are identified above by shorthand symbols indicating the total number of carbon atoms found in the chemical group shown. E.g. C₇-C₁₂Alkyl describes an alkyl group as defined below having a total number of carbon atoms from 7 to 12, and C₄-C₁₂The cycloalkyl alkyl group being described as having a total numberIs a cycloalkylalkyl group of 4 to 12 carbon atoms as defined below. The total number of carbon atoms in the shorthand notation does not include carbons that may be present in a substituent of the group.

Accordingly, unless indicated to the contrary, the following terms used in the specification and appended claims have the following meanings:

"hydroxy" refers to an-OH group.

"cyano" refers to the group-CN.

"nitro" means-NO₂A group.

"nitroso" refers to the group-N ═ O.

"amino" means-NH₂A group.

"alkyl" means a straight or branched hydrocarbon chain radical consisting exclusively of carbon and hydrogen atoms, free of unsaturation, having from one to twelve carbon atoms, especially from one to eight carbon atoms or from one to six carbon atoms, and attached by single bonds to the rest of the molecule, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (tert-butyl), and the like.

The alkyl group may be optionally substituted, i.e., substituted or unsubstituted. When substituted, the substituent groups are one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, or amino including mono-and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted with one of the substituents described above.

“C₁-C₄Alkyl "refers to an alkane as defined above containing from one to four carbon atomsA radical group. C₁-C₄The alkyl group may be optionally substituted as defined for the alkyl group.

“C₁-C₆Alkyl "refers to an alkyl group as defined above containing one to six carbon atoms. C₁-C₆The alkyl group may be optionally substituted as defined for the alkyl group.

“C₁-C₁₂Alkyl "refers to an alkyl group as defined above containing from one to twelve carbon atoms. C₁-C₁₂The alkyl group may be optionally substituted as defined for the alkyl group.

In certain embodiments, alkyl is C₁-C₄An alkyl group.

In certain embodiments, alkyl is C₁-C₆An alkyl group.

In certain embodiments, alkyl is C₁-C₁₂An alkyl group.

"alkenyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, especially from two to eight carbon atoms or from two to six carbon atoms, and which is attached to the remainder of the molecule by a single bond, for example vinyl, prop-1-enyl, but-1-enyl, pent-1, 4-dienyl, and the like. The alkenyl groups herein may be substituted or unsubstituted. When substituted, the substituent groups are one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, or amino including mono-and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted with one of the substituents described above.

“C₂-C₆Alkenyl "means an alkenyl group as defined above containing two to six carbon atoms. C₂-C₆The alkenyl group may be optionally substituted as defined for the alkenyl group.

“C₂-C₈Alkenyl "refers to an alkenyl group as defined above containing from two to eight carbon atoms. C₂-C₈The alkenyl group may be optionally substituted as defined for the alkenyl group.

“C₂-C₁₂Alkenyl "refers to an alkenyl group as defined above containing from two to twelve carbon atoms. C₂-C₁₂The alkenyl group may be optionally substituted as defined for the alkenyl group.

In certain embodiments, alkenyl is C₂-C₆An alkenyl group.

In certain embodiments, alkenyl is C₂-C₈An alkenyl group.

In certain embodiments, alkenyl is C₂-C₁₂An alkenyl group.

"alkynyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having two to twelve carbon atoms, especially having two to eight carbon atoms or two to six carbon atoms, and which is attached to the remainder of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The alkynyl groups herein may be substituted or unsubstituted. When substituted, the substituent groups are one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, or amino including mono-and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted with one of the substituents described above.

“C₂-C₆Alkynyl "refers to an alkynyl group as defined above containing two to six carbon atoms. C₂-C₆The alkynyl group may be optionally substituted as defined for the alkynyl group.

“C₂-C₈Alkynyl "refers to alkynyl groups as defined above containing from two to eight carbon atoms. C₂-C₈The alkynyl group may be optionally substituted as defined for the alkynyl group.

“C₂-C₁₂Alkynyl "refers to alkynyl groups as defined above containing from two to twelve carbon atoms. C₂-C₁₂The alkynyl group may be optionally substituted as defined for the alkynyl group.

In certain embodiments, alkynyl is C₂-C₆Alkynyl.

In certain embodiments, alkynyl is C₂-C₈Alkynyl.

In certain embodiments, alkynyl is C₂-C₁₂Alkynyl.

The term "halogen" as used herein refers to bromine, chlorine, fluorine or iodine.

"haloalkyl" refers to an alkyl group as defined above substituted with one or more halogens as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl moiety of the haloalkyl group may be optionally substituted as defined for alkyl above.

"alkoxy" means an-OR group, wherein R is an alkyl group as defined above.

"cycloalkyl" means a stable, non-aromatic, monocyclic or polycyclic alkyl group consisting only of carbon and hydrogen atoms, which may contain a fused or bridged ring system having from three to eighteen carbon atoms, especially from three to fifteen carbon atoms or from three to ten carbon atoms, which is saturated and connected to the remainder of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7-dimethyl-bicyclo [2.2.1] heptanyl, and the like. The cycloalkyl groups herein may be substituted or unsubstituted. When substituted, the substituent groups are one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, or amino including mono-and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted with one of the substituents described above.

“C₃-C₁₈Cycloalkyl "refers to a cycloalkyl group as defined above containing from three to eighteen carbon atoms. C₃-C₁₈The cycloalkyl group may be optionally substituted as defined for the cycloalkyl group.

“C₃-C₁₅Cycloalkyl "means a cycloalkyl group as defined above containing from three to fifteen carbon atoms. C₃-C₁₅The cycloalkyl group may be optionally substituted as defined for the cycloalkyl group.

“C₃-C₁₀Cycloalkyl "refers to a cycloalkyl group as defined above containing from three to ten carbon atoms. C₃-C₁₀The cycloalkyl group may be optionally substituted as defined for the cycloalkyl group.

In certain embodiments, cycloalkyl is C₃-C₁₈A cycloalkyl group.

In certain embodiments, cycloalkyl is C₃-C₁₅A cycloalkyl group.

In certain embodiments, cycloalkyl is C₃-C₁₀A cycloalkyl group.

"aryl" means an aromatic monocyclic or polycyclic hydrocarbon ring system consisting exclusively of hydrogen and carbon and containing six to eighteen carbon atoms, especially having six to twelve carbon atoms or six to ten carbon atoms, wherein the ring system may be partially saturated. Aryl groups include, but are not limited to, groups such as phenyl, naphthyl, and fluorenyl. The aryl groups herein may be substituted or unsubstituted. When substituted, the substituent groups are one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, or amino including mono-and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted with one of the substituents described above.

“C₆-C₁₈Aryl "refers to an aryl group as defined above containing six to eighteen carbon atoms. C₆-C₁₈The aryl group may be optionally substituted as defined for the aryl group.

“C₆-C₁₂Aryl "refers to an aryl group as defined above containing six to twelve carbon atoms. C₆-C₁₂The aryl group may be optionally substituted as defined for the aryl group.

“C₆-C₁₀Aryl "refers to an aryl group as defined above containing six to ten carbon atoms. C₆-C₁₀The aryl radical may be as defined for the aryl radicalAre intentionally substituted.

In certain embodiments, aryl is C₆-C₁₈And (4) an aryl group.

In certain embodiments, aryl is C₆-C₁₂And (4) an aryl group.

In certain embodiments, aryl is C₆-C₁₀And (4) an aryl group.

"heteroaryl" refers to a five to eighteen membered aromatic ring group consisting of carbon atoms and one to five heteroatoms selected from nitrogen, oxygen and sulfur. The heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may comprise fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atoms may optionally be quaternized. Examples include, but are not limited to, azanyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothiophenyl (benzothiophenyl), benzotriazolyl, benzo [4,6] imidazo [1,2-a ] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, thienyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazatrolyl, oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl, and benzoxazinyl, 2, 3-naphthyridinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl.

Heteroaryl groups may be optionally substituted, i.e., substituted or unsubstituted. When substituted, the substituent groups are one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, or amino including mono-and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted with one of the substituents described above.

"five-to eighteen-membered heteroaryl" refers to a five-to eighteen-membered aromatic ring group consisting of carbon atoms and one to five heteroatoms selected from nitrogen, oxygen, and sulfur. Five-to eighteen-membered heteroaryl groups may be optionally substituted as defined for heteroaryl groups.

"five-to twelve-membered heteroaryl" refers to a five-to twelve-membered aromatic ring group consisting of carbon atoms and one to five heteroatoms selected from nitrogen, oxygen, and sulfur. Five-to twelve-membered heteroaryl groups may be optionally substituted as defined for heteroaryl groups.

"five-to ten-membered heteroaryl" refers to a five-to ten-membered aromatic ring group consisting of carbon atoms and one to five heteroatoms selected from nitrogen, oxygen, and sulfur. Five-to ten-membered heteroaryl groups may be optionally substituted as defined for heteroaryl groups.

In certain embodiments, heteroaryl is a five to eighteen membered heteroaryl.

In certain embodiments, heteroaryl is a five to twelve membered heteroaryl.

In certain embodiments, heteroaryl is a five-to ten-membered heteroaryl.

"heterocyclyl" refers to a stable 3 to 18 membered non-aromatic ring group consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless specifically stated otherwise in the specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and optionally oxidizing the nitrogen, carbon or sulfur atom of the heterocyclic group; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclyl groups include, but are not limited to, dioxolane, thienyl [1,3] dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trioxanyl, trithianyl, triazinyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl.

"carbonyl" refers to a group in which a carbon atom is double bonded to an oxygen atom (i.e., a C (═ O) group).

"alkylcarbonyl" refers to-C (═ O) R, where R is an alkyl group as defined above. Examples of alkylcarbonyl include, but are not limited to, -C (═ O) CH₃、-C(＝O)CH₂CH₃、-C(＝O)CF₃、-C(＝O)CCl₃、-C(＝O)CClH₂and-C (═ O) CH₂And (C) CN. The alkylcarbonyl groups herein may be substituted or unsubstituted. When substituted, the substituent groups are one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, or amino including mono-and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted with one of the substituents described above.

"alkenylcarbonyl" refers to-C (═ O) R, where R is an alkenyl group as defined above. Examples of alkenylcarbonyl include, but are not limited to, -C (═ O) CH ═ CH₂、-C(＝O)CH＝CHCH₃、-C(＝O)CH＝CF₂、-C(＝O)CH＝CCl₂and-C (═ O) CH ═ CHCH₂And (C) CN. The alkenylcarbonyl groups herein may be substituted or unsubstituted. When substituted, the substituent groups are one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, or amino including mono-and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted with one of the substituents described above.

"alkynylcarbonyl" refers to-C (═ O) R, where R is an alkynyl group as defined above. Examples of alkynylcarbonyls include, but are not limited to, -C (═ O) C ≡ CH, -C (═ O) CH₂C ≡ CH, -C (═ O) C ≡ CF, and-C (═ O) C ≡ CCH₂And (C) CN. The alkynyl carbonyl groups of the present application may be substituted or unsubstituted. When substituted, the substituent groups are one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, or amino including mono-and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted with one of the substituents described above.

"Arylcarbonyl" refers to-C (═ O) R, whichWherein R is an aryl group as defined above. Examples of arylcarbonyl include, but are not limited to, -C (═ O) Ph, -C (═ O) (PhCF)₃) -C (═ O) (PhOMe) and-C (═ O) (PhNO)₂). The arylcarbonyl groups herein can be substituted or unsubstituted. When substituted, the substituent groups are one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, or amino including mono-and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted with one of the substituents described above.

"heteroarylcarbonyl" refers to — C (═ O) R, where R is a heteroaryl group as defined above. Examples of heteroarylcarbonyl groups include, but are not limited to, 2-thenoyl, 2-furoyl groups the heteroarylcarbonyl groups of the parent application may be substituted or unsubstituted. When substituted, the substituent groups are one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, or amino including mono-and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted with one of the substituents described above.

' Sulfonyl groupRadical "means-S (═ O)₂R groups, wherein R may be alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, amino, and the like groups as defined above. Examples of sulfonyl include, but are not limited to-S (═ O)₂CH₃(methylsulfonyl), -S (═ O)₂CF₃、-S(＝O)₂CH₂CH₃And 4-methylbenzenesulfonyl (tosyl). When substituted, the substituent groups are one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, or amino including mono-and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted", the substituent may be substituted with one of the substituents described above.

"prodrug" is intended to mean a compound that can be converted under physiological conditions or by solvolysis to the biologically active compound of the present application. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the present application. A prodrug may be inactive when administered to a subject in need thereof, but may be converted to the active compound of the application in vivo. Prodrugs can generally be rapidly converted in vivo to yield the parent compound of the application, for example, by hydrolysis in blood. Prodrug compounds generally provide the advantages of solubility, histocompatibility, or sustained release in mammalian organisms (see Bundgard, h., Design of Prodrugs (1985), pp.7-9,21-24(Elsevier, Amsterdam)).

A discussion of prodrugs is provided in Higuchi, t, et al, "Pro-drugs as Novel Delivery Systems (prodrugs as Novel Delivery Systems)," a.c.s.symposium Series, (1975), vol.14 and Bioreversible Carriers in drug Design, ed.edward b.roche, American pharmaceutical association and Pergamon Press,1987, the entire contents of both of which are incorporated herein by reference.

The term "prodrug" is also intended to include any covalently bonded carriers that release the active compounds of the present application in vivo when the prodrug is administered to a mammalian subject. Prodrugs of the compounds of the present application may be prepared by modifying functional groups present in the compounds of the present application in such a way that the cleavage to the parent compound of the present application is modified, either by routine manipulation or in vivo. Prodrugs comprise compounds of the present application wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the compound of the present application is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amine functional groups in the compounds of the present application, and the like.

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the recitation includes both substituted aryl groups and unsubstituted aryl groups.

"pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been recognized by the U.S. food and drug administration as being useful in humans or animals in a variety of forms that do not have adverse effects on the resulting pharmaceutical composition.

"pharmaceutically acceptable salts" include "pharmaceutically acceptable acid addition salts" and "pharmaceutically acceptable base addition salts".

"pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and are formed using inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexylsulfamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, Glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

"pharmaceutically acceptable base addition salts" refers to those salts that retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, salts of cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzylamine, phenylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

Crystallization often results in solvates of the compounds of the present application. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compound of the present application with one or more molecules of a solvent. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present application may exist in the form of hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as in the corresponding solvated forms. The compounds of the present application may be true solvates, but in other cases the compounds of the present application may retain only adventitious water or the compounds may be mixtures of water and some adventitious solvent.

"polymorph" refers to a component having the same chemical formula but a different structure.

"pharmaceutical composition" refers to a formulation of a compound of the present application with a vehicle generally accepted in the art for delivery of biologically active compounds to mammals such as humans. Such media include all pharmaceutically acceptable carriers, diluents or excipients.

Pharmaceutical compositions containing a compound of formula (I) or formula (Ia) may be formulated and used as the following dosage forms: tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions for administration by injection, suspensions; patches for transdermal administration, subcutaneous deposits, and the like. Injections can be prepared in the following conventional forms: solutions or suspensions, solid dosage forms suitable for constitution with a solution or suspension prior to injection, or emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of non-toxic adjuvants such as wetting agents, pH buffering agents and the like. Absorption enhancers (e.g., liposomes) can also be used if desired.

Formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Alternatively, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean oil, grapefruit oil or almond oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, for example sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

Pharmaceutical preparations for oral use can be obtained by the following method: combining the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, if desired after addition of suitable auxiliaries, to give tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, for example cross-linked polyvinylpyrrolidone, agar or alginic acid or alginates such as sodium alginate. Sugar-coated cores are suitably coated. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings in order to identify or characterize different combinations of active compound doses. These formulations can be made using methods well known in the art.

The present application also relates to various pharmaceutical compositions for delivery, including intraocular, intranasal, and otic delivery, which are well known in the pharmaceutical arts. Pharmaceutical formulations include aqueous ophthalmic solutions of the active compounds, which may be present in water-soluble form, such as eye drops, or as gellan gum or hydrogels; ophthalmic ointments; ophthalmic suspensions, such as microparticles, small polymeric particles comprising a drug suspended in a liquid carrier medium, liposoluble formulations, and microspheres; and an ocular insert. These suitable pharmaceutical formulations are most often and preferably manufactured as sterile, isotonic and buffered formulations for stability and comfort. Pharmaceutical compositions also include drops and sprays, which often mimic nasal secretions in many ways to ensure maintenance of normal ciliary action. As is well known to those skilled in the art, suitable formulations are most often and preferably isotonic, maintaining a mild buffer at pH 5.5 to 6.5, and most often and preferably include an antimicrobial preservative and a suitable pharmaceutical stabilizer. Pharmaceutical formulations for intra-aural delivery include suspensions and ointments that are applied topically in the ear. Common solvents for these otic formulations include glycerin and water.

The compound of formula (I), the compound of formula (Ia) or the pharmaceutical composition comprising the compound of formula (I) or the compound of formula (Ia) may be administered by the oral or non-oral route. When administered orally, it may be administered in capsules, tablets, granules, sprays, syrups, or other dosage forms. When administered parenterally, it may be administered in the form of an aqueous suspension, an oily preparation, etc., or in the form of drops, suppositories, salves, ointments, etc., and when administered by injection, it may be administered subcutaneously, intraperitoneally, intravenously, intramuscularly, etc.

"therapeutically effective amount" means an amount of a compound of the present application sufficient to effectively treat (as defined below) a disease or condition in a mammal when administered to the mammal, preferably a human. The amount of the compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, and the age of the mammal to be treated, but can be determined routinely by those skilled in the art, given their own knowledge and this disclosure.

As used herein, "treating" or "treatment" encompasses treating a related disease or condition in a mammal, preferably a human, suffering from the related disease or condition and includes:

(i) preventing the occurrence of a disease or condition in a mammal, particularly when the mammal is susceptible to said disease condition but has not been diagnosed as having such a disease condition;

(ii) inhibiting a disease or disease state, i.e., preventing its occurrence; or

(iii) Alleviating the disease or condition, i.e., causing regression of the disease or condition.

As used herein, the terms "disease" and "disease state" may be used interchangeably, or may be different, in that a particular disease or disease state may not have a known causative agent (and therefore cannot be explained by etiology), and is therefore not recognized as a disease, but rather is considered an undesirable disease state or condition, in which a clinician has identified a more or less specific series of symptoms.

The compounds of the present application, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as (R) -or (S) -or (D) -or (L) -of amino acids, in terms of absolute stereochemistry. The present application is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R) -and (S) -, or (D) -and (L) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using a chiral column. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise indicated, it is meant that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also meant to be included.

"stereoisomers" refers to compounds consisting of the same atoms bonded by the same bonds, but having different three-dimensional structures that are not interchangeable. The present application encompasses various stereoisomers and mixtures thereof.

As used herein, "contacting" refers to bringing two or more substances into close proximity for interaction.

wherein the content of the first and second substances,

R₁and R₂Each independently selected from the group consisting of hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, or optionally substituted alkynylcarbonyl;

x is an integer from 1 to 3;

y is an integer from 1 to 4; and

z is an integer from 1 to 2;

with the following conditions:

X₁、X₂、X₃and X₄Not hydrogen at the same time; and

when X is present₁、X₂、X₃And X₄When one of them is halogen, the rest X₁Selected from hydrogen, nitro, nitroso, -SO₃H or an optionally substituted sulfonyl group, the remainder of X₂、X₃And X₄Each independently selected from hydrogen, nitro, nitroso, -SO₃H. Optionally substituted amino or optionally substituted sulfonyl, but not both.

In certain embodiments, X₁Selected from hydrogen, halogen, nitro, nitroso, -SO₃H or-S (═ O)₂-R₇，X₂、X₃And X₄Each independently selected from hydrogen, halogen, nitro, nitroso, amino, -SO₃H、-NR₃-C(＝O)-R₄、-NR₅-S(＝O)₂-R₆or-S (═ O)₂-R₇；

R₃and R₅Each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;

R₄selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl or optionally substituted alkynylcarbonyl;

R₆and R₇Each is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted amino;

x is an integer from 1 to 3;

y is an integer from 1 to 4;

z is an integer from 1 to 2; and

with the following conditions:

X₁、X₂、X₃and X₄Not hydrogen at the same time; and

when X is present₁、X₂、X₃And X₄When one of them is halogen, the rest X₁Selected from hydrogen, nitro, nitroso, -SO₃H or-S (═ O)₂-R₇And the remainder of X₂、X₃And X₄Each independently selected from hydrogen, nitro, nitroso, amino and-SO₃H、-NR₃-C(＝O)-R₄、-NR₅-S(＝O)₂-R₆or-S (═ O)₂-R₇But not both.

In certain embodiments, x is 1,2, or 3.

In certain embodiments, y is 1,2, 3, or 4.

In certain embodiments, z is 1 or 2.

In certain embodiments, X₁Independently selected from hydrogen, halogen, nitro, nitroso, -SO₃H. Optionally substituted arylamino-substituted sulfonyl or optionally substituted alkyl-substituted sulfonyl, X₂、X₃And X₄Each independently selected from hydrogen, halogen, nitro, nitroso, -SO₃H. Optionally substituted alkylcarbonyl-substituted amino, optionally substituted alkenylcarbonyl-substituted amino, optionally substituted alkynylcarbonyl-substituted amino, optionally substituted alkoxycarbonyl-substituted amino, optionally substituted cycloalkylcarbonyl-substituted amino, optionally substituted arylcarbonyl-substituted amino, optionally substituted heterocyclylcarbonyl-substituted amino, optionally substituted aminocarbonyl-substituted amino, optionally substituted heteroarylcarbonyl-substituted amino, optionally substituted alkoxycarbonylcarbonyl-substituted amino, optionally substituted alkylsulfonyl-substituted amino, optionally substituted alkenylsulfonyl-substituted amino, optionally substituted alkynylsulfonyl-substituted amino, optionally substituted alkoxysulfonyl-substituted amino, optionally substituted arylsulfonyl-substituted aminoAmino, optionally substituted heterocyclylsulfonyl substituted amino, optionally substituted heteroarylsulfonyl substituted amino, optionally substituted aminosulfonyl substituted amino, optionally substituted arylamino substituted sulfonyl or optionally substituted alkyl substituted sulfonyl.

In certain embodiments, X₁Selected from hydrogen, halogen, nitro, nitroso, -SO₃H. An arylamino-substituted sulfonyl group or an alkoxy-substituted alkyl-substituted sulfonyl group; x₂、X₃And X₄Each independently selected from hydrogen, halogen, nitro, nitroso, -SO₃H. Alkylcarbonyl-substituted amino, hydroxy-substituted alkylcarbonyl-substituted amino, ester-substituted alkylcarbonyl-substituted amino, alkenylcarbonyl-substituted amino, alkoxycarbonyl-substituted amino, aryl-substituted alkoxycarbonyl-substituted amino, halogen-substituted arylcarbonyl-substituted amino, alkoxy-substituted arylcarbonyl-substituted amino, haloalkyl-substituted arylcarbonyl-substituted amino, alkoxycarbonyl carbonyl substituted amino, heterocyclylcarbonyl substituted amino, alkylsulfonyl substituted amino, aralkylsulfonyl substituted amino, arylsulfonyl substituted amino, nitro substituted arylsulfonyl substituted amino, alkyl substituted arylsulfonyl substituted amino, halogen substituted arylsulfonyl substituted amino, alkyl substituted aminosulfonyl substituted amino, arylamino substituted sulfonyl or alkoxy substituted alkyl substituted sulfonyl.

In certain embodiments, R₁Selected from hydrogen, nitroso, alkyl, aryl-substituted alkyl, aryl, alkylcarbonyl or arylcarbonyl.

In certain embodiments, X is 1, and X is₂Selected from halogen, nitro, nitroso, amino, -SO₃H. Alkylcarbonyl-substituted amino, hydroxy-substituted alkylcarbonyl-substituted amino, ester-substituted alkylcarbonyl-substituted amino, alkenylcarbonyl-substituted amino, aryl-substituted alkenylcarbonyl-substituted amino, alkoxycarbonyl-substituted amino, aryl-substituted alkoxycarbonyl-substituted amino, arylcarbonyl-substituted amino, halogen-substituted aminoAn arylcarbonyl-substituted amino group, an alkoxy-substituted arylcarbonyl-substituted amino group, a haloalkyl-substituted arylcarbonyl-substituted amino group, an alkoxycarbonylcarbonyl-substituted amino group, a heterocyclylcarbonyl-substituted amino group, a heteroarylcarbonyl-substituted amino group, an alkylsulfonyl-substituted amino group, an aralkylsulfonyl-substituted amino group, an arylsulfonyl-substituted amino group, a nitro-substituted arylsulfonyl-substituted amino group, an alkyl-substituted arylsulfonyl-substituted amino group, a halogen-substituted arylsulfonyl-substituted amino group, an alkyl-substituted aminosulfonyl-substituted amino group, an arylamino-substituted sulfonyl group, or an alkoxy-substituted alkyl-substituted sulfonyl group of (b).

In certain embodiments, y is 4, and X is₃Is hydrogen.

In certain embodiments, z is 2, and X₄Is hydrogen.

In certain embodiments, X₁Is hydrogen, nitro or halogen.

In certain embodiments, X is 2, and X is₂One of them is hydrogen, X₂Is selected from amino, nitro, nitroso, -SO₃H. Br, Cl, methylcarbonylamino, isopropylcarbonylamino, isobutylcarbonylamino, vinylcarbonylamino, styrylcarbonylamino, 2-methylpropenylcarbonylamino, 2-methylpropyloxycarbonylamino, hydroxymethylcarbonylamino, methylcarbonyloxymethylcarbonylamino, methoxycarbonylcarbonylamino, furanylcarbonylamino, thienylcarbonylamino, morpholinocarbonylamino, phenylcarbonylamino, 2-chlorophenylcarbonylamino, 4-methoxyphenylcarbonylamino, trifluoromethylphenylcarbonylamino, phenylmethyloxycarbonylamino, methylsulfonylamino, phenylsulfonylamino, 2-nitrophenylsulfonylamino, 4-methylphenylsulfonylamino, 4-chlorophenylsulfonylamino, isobutylcarbonylamino, vinylcarbonylamino, 2-methylpropenylcarbonylamino, 2-chlorophenylcarbonylamino, 4-nitrophenylcarbonylamino, 4-methylphenylsulfonylamino, 4-chlorophenylsulfonylamino, 2, 4-dichlorophenylsulfonylamino, phenylmethylsulfonylamino, dimethylaminosulfonylamino, phenylaminosulfonyl or methoxymethylsulfonyl.

In certain embodiments, R₂Is an alkyl group.

In certain embodiments, R₂Is C₁-C₆An alkyl group.

In certain embodiments, R₂Is methyl.

In certain embodiments, R₁Is alkyl, and R₂Is an alkyl group.

In certain embodiments, R₁Is C₁-C₆Alkyl, and R₂Is C₁-C₆An alkyl group.

In certain embodiments, R₁Methyl, and R₂Is methyl.

In certain embodiments, R₁Is alkyl, and R₂Is hydrogen.

In certain embodiments, R₁Is C₁-C₆Alkyl, and R₂Is hydrogen.

In certain embodiments, R₁Is methyl, and R₂Is hydrogen.

In certain embodiments, X₁Is halogen, X₂、X₃And X₄Each independently selected from nitro, nitroso, amino, -SO₃H、-NR₃-C(＝O)-R₄、-NR₅-S(＝O)₂-R₆or-S (═ O)₂-R₇。

In certain embodiments, X₁Is halogen, X₂Selected from nitro and/or sulfonic acid groups, X₃And X₄Is hydrogen and x is 1.

In certain embodiments, X is 1, X₂Is located at C-14 position.

In certain embodiments, X is 2 and X is₂Respectively located at the C-10 position and the C-14 position.

In certain embodiments, X₃And X₄Is hydrogen.

In certain embodiments, R₁Selected from hydrogen, nitroso, optionally substituted C₁-C₆Alkyl, optionally substituted phenylcarbonyl or optionally substituted C₁-C₆An alkylcarbonyl group.

In certain embodiments, R₁Selected from hydrogen, methyl, benzyl, benzoyl, nitroso or acetyl.

In certain embodiments, R₁Selected from hydrogen, methyl, benzyl, benzoyl, nitroso or acetyl; and/or

R₂Is methyl; and/or

X₁Hydrogen, nitro or halogen (halogen is preferably Br or Cl); and/or

X is 1 or 2, and at least one X₂Is hydrogen, amino, nitro, nitroso, -SO₃H. Br, Cl, methylcarbonylamino, isobutylcarbonylamino, vinylcarbonylamino, styrylcarbonylamino, 2-methylpropenylcarbonylamino, 2-methylpropyloxycarbonylamino, hydroxymethylcarbonylamino, methylcarbonyloxymethylcarbonylamino, methoxycarbonylcarbonylamino, furylcarbonylamino, thienylcarbonylamino, morpholinylcarbonylamino, phenylcarbonylamino, 2-chlorophenylcarbonylamino, 4-methoxyphenylcarbonylamino, trifluoromethylphenylcarbonylamino, phenylmethyloxycarbonylamino, methylsulfonylamino, phenylsulfonylamino, 2-nitrophenylsulfonylamino, 4-methylphenylsulfonylamino, 4-chlorophenylsulfonylamino, isobutylcarbonylamino, vinylcarbonylamino, styrylcarbonylamino, 2-methylpropenylcarbonylamino, 2-chlorophenylcarbonylamino, 4-methylphenylsulfonylamino, 4-chlorophenylsulfonylamino, 2-nitrophenylsulfonyl, 2, 4-dichlorophenylsulfonylamino, phenylmethylsulfonylamino, dimethylaminosulfonylamino, phenylaminosulfonyl or methoxymethylsulfonyl; and/or

y is 3, and X₃Is hydrogen; and/or

z is 2, and X₄Is a hydrogen atom, and is,

with the following conditions:

X₁、X₂、X₃and X₄Not simultaneously being hydrogen, and

when X is present₁、X₂、X₃And X₄When one of them is halogen, the rest X₁、X₂、X₃And X₄Not hydrogen at the same time.

wherein the content of the first and second substances,

R₁selected from the group consisting of nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, optionally substituted alkynylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, or optionally substituted sulfonyl; and

R₂selected from the group consisting of hydrogen, optionally substituted alkyl, nitroso, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, optionally substituted alkynylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted arylcarbonyl or optionally substituted heteroarylcarbonyl or optionally substituted sulfonyl.

In certain embodiments, R₁Selected from the group consisting of halogen-substituted alkylcarbonyl, halogen-substituted alkenylcarbonyl, halogen-substituted alkynylcarbonyl, halogen-substituted cycloalkylcarbonyl, halogen-substituted arylcarbonyl, or halogen-substituted heteroarylcarbonyl.

In certain embodiments, R₁Selected from cyano-substituted alkylcarbonyl, cyano-substituted alkenylcarbonyl, cyano-substituted alkynylcarbonyl, cyano-substituted cycloalkylcarbonyl, cyano-substituted arylcarbonyl or cyano-substituted heteroarylcarbonyl.

In certain embodiments, R₁Selected from the group consisting of hydroxy-substituted alkylcarbonyl, hydroxy-substituted alkenylcarbonyl, hydroxy-substituted alkynylcarbonyl, hydroxy-substituted cycloalkylcarbonyl, hydroxy-substituted arylcarbonyl, or hydroxy-substituted heteroarylcarbonyl.

In certain embodiments, R₁Selected from nitro-substituted alkylcarbonyl, nitro-substituted alkenylcarbonyl, nitro-substituted alkynylcarbonyl, nitro-substituted cycloalkaneAlkylcarbonyl, nitro-substituted arylcarbonyl or nitro-substituted heteroarylcarbonyl.

In certain embodiments, R₁Selected from optionally substituted alkyl-substituted alkylcarbonyl, optionally substituted alkyl-substituted alkenylcarbonyl, optionally substituted alkyl-substituted alkynylcarbonyl, optionally substituted alkyl-substituted cycloalkylcarbonyl, optionally substituted alkyl-substituted arylcarbonyl or optionally substituted alkyl-substituted heteroarylcarbonyl.

In certain embodiments, R₁Selected from optionally substituted alkoxy-substituted alkylcarbonyl, optionally substituted alkoxy-substituted alkenylcarbonyl, optionally substituted alkoxy-substituted alkynylcarbonyl, optionally substituted alkoxy-substituted cycloalkylcarbonyl, optionally substituted alkoxy-substituted arylcarbonyl or optionally substituted alkoxy-substituted heteroarylcarbonyl.

In certain embodiments, R₁Selected from the group consisting of trifluoromethylcarbonyl, chloromethylcarbonyl and 3-trifluoromethylphenylcarbonyl.

The various groups or substituents in the above embodiments may be combined in any combination.

Yet another aspect of the present application relates to the use of a compound, a single stereoisomer thereof, a mixture of its stereoisomers, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a metabolite thereof, in the manufacture of a medicament for the treatment or prevention of a tumor, wherein the compound is selected from the group consisting of: compound H-01 to compound H-55.

Illustrative examples of dosage forms that can be used in the pharmaceutical compositions of the present application include, but are not limited to, tablets, capsules, pills, suppositories, emulsions, ointments, injections, and infusions.

The other anti-tumor drug can be selected from cyclophosphamide, daunorubicin, podophyllotoxin, vinblastine, paclitaxel, adriamycin and the like. In certain embodiments, the additional anti-neoplastic agent is doxorubicin or paclitaxel. The compound of the general formula (I) and adriamycin or paclitaxel can obtain synergistic effect in the aspect of treating tumor.

Another aspect of the present application relates to a method for the treatment or prevention of a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), a compound of formula (Ia), a compound of any one of compounds H-01 to H-55, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a metabolite thereof, or a pharmaceutical composition thereof.

In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

Yet another aspect of the present application relates to a compound of formula (I), a compound of formula (Ia), a compound of any one of compounds H-01 to H-55, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a metabolite thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of a tumor.

Yet another aspect of the present application relates to a method of inhibiting tumor cell growth, comprising contacting a tumor cell with a therapeutically effective amount of a compound of formula (I), a compound of formula (Ia), a compound of any one of compounds H-01 to H-55, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a metabolite thereof, or a pharmaceutical composition thereof.

In aspects related to the above application, the tumor may be selected from tongue cancer, pancreatic adenocarcinoma, cervical cancer, laryngeal cancer, kidney cancer, erythroleukemia, leukemia, breast cancer, melanoma, prostate cancer, sarcoma, ovarian cancer, ureter cancer, bladder cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, endocrine cancer, skin cancer, hemangioma, brain cancer or Central Nervous System (CNS) cancer and metastatic cancers thereof, preferably tongue cancer, pancreatic adenocarcinoma, cervical cancer, laryngeal cancer, kidney cancer, erythroleukemia, leukemia, breast cancer, melanoma or prostate cancer.

In aspects of the disclosure directed to above, the tumor may be a drug-resistant tumor. The drug-resistant tumor can be drug-resistant breast cancer, melanoma, human prostate cancer, tongue cancer, pancreatic adenocarcinoma, cervical cancer, laryngeal cancer, kidney cancer, erythroleukemia, leukemia, sarcoma, ovarian cancer, ureteral cancer, bladder cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, endocrine cancer, skin cancer, hemangioma or glioma and the like, and is preferably drug-resistant breast cancer, melanoma, leukemia or human prostate cancer. The drug-resistant tumor can be resistant to cyclophosphamide, daunorubicin, podophyllotoxin, vinblastine, taxol, adriamycin, progestogen, tamoxifen, etc., such as cyclophosphamide, daunorubicin, podophyllotoxin, vinblastine, taxol, adriamycin, etc. Specific examples of drug resistant cell lines include, but are not limited to, the breast cancer cell line MDA-MB-231, the melanoma cell line WM9 and the human prostate cancer cell line PC 3.

wherein the content of the first and second substances,

n is 0, 1,2 or 3;

with the following conditions:

when X is present₅N is not 0 when hydrogen or halogen;

optionally, when X₆When it is halogen, X₅Is not hydrogen.

In certain embodiments, X₅Selected from hydrogen, halogen, nitro, nitroso, -SO₃H or-S (═ O)₂-R₂₁，R_,21Is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted amino.

In certain embodiments, R₃And R₄Each independently selected from hydrogen, nitroso, optionally substitutedOptionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl or optionally substituted alkynylcarbonyl.

In certain embodiments, R₈To R₂₀Each independently selected from the group consisting of 1-3 selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆C substituted by substituents of haloalkoxy and nitro₆-C₁₈An aryl group; optionally substituted by 1-3 substituents selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆C substituted by substituents of haloalkoxy₃-C₁₀A cycloalkyl group; optionally substituted by 1-3 substituents selected from halogen, -OC (═ O) C₁-C₆Alkyl, -OC (═ O) C₂-C₆Alkenyl or C₆-C₁₈Aryl substituted C₁-C₆An alkyl group; optionally substituted by 1-3 substituents selected from halogen and C₆-C₁₈Aryl substituted C₂-C₆An alkenyl group; optionally substituted by 1-3 substituents selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆3-18 membered heterocyclic group substituted with the substituents of haloalkoxy and nitro; optionally substituted by 1-3 substituents selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆5-18 membered heteroaryl substituted with substituents of haloalkoxy and nitro; optionally substituted by 1-3 substituents selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆C substituted by substituents of haloalkoxy and nitro₆-C₁₈An aryloxy group; optionally substituted by 1-3 substituents selected from halogen, -OC (═ O) C₁-C₆Alkyl, -OC (═ O) C₂-C₆Alkenyl or C₆-C₁₈Aryl substituted C₁-C₆An alkoxycarbonyl group; and optionally substituted N (C)₁-C₆Alkyl radical)₂。

In certain embodiments, R₈To R₂₀Each independently selected from the group consisting of 1-3 selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆Phenyl or naphthyl substituted with substituents of haloalkoxy and nitro; optionally substituted by 1-3 substituents selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆Cyclopentyl or cyclohexyl substituted with a substituent of haloalkoxy; optionally substituted by 1-3 substituents selected from halogen, -OC (═ O) C₁-C₆Alkyl, -OC (═ O) C₂-C₆Alkenyl, phenyl or naphthyl substituted C₁-C₆An alkyl group; c optionally substituted by 1-3 substituents selected from halogen, phenyl or naphthyl₂-C₆An alkenyl group; optionally substituted by 1-3 substituents selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆A 5-membered heterocyclic group substituted with a substituent of haloalkoxy and nitro; optionally substituted by 1-3 substituents selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆5-membered heteroaryl substituted with substituents of haloalkoxy and nitro; optionally substituted by 1-3 substituents selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆Phenoxy or naphthoxy substituted with a substituent of haloalkoxy and nitro; optionally substituted by 1-3 substituents selected from halogen, -OC (═ O) C₁-C₆Alkyl, -OC (═ O) C₂-C₆Alkenyl, phenyl or naphthyl substituted C₁-C₆An alkoxycarbonyl group; and N (C)₁-C₆Alkyl radical)₂。

In certain embodiments, R₃And R₄Each independently selected from hydrogen, nitroso, C₁-C₆Alkyl, benzyl, benzoyl or acetyl.

In certain embodiments, R₈To R₂₀Each independently selected from-OH, -F, -CN, -CH₂Ph、-CH₂CH₂Ph, cyclopentyl, cyclohexyl, -CH₂CH₂Cl、-CH＝C(CH₃)₂、-C(＝O)OC₂H₅T-butyl, -CH₂CH₂OC(＝O)C(＝CH₂)CH₃Phenyl, 4-methylphenyl, 4-trifluoromethoxyphenyl, 4-nitrophenyl, 2-trifluoromethyl-4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 2,4, 6-trichlorophenyl, -CH ═ CH-Ph, 2-nitrophenyl, 4-nitrophenyl, 2, 4-dichlorophenyl, naphthyl, -N (CH)₃)₂2-oxazolidonyl or thienyl.

In certain embodiments, R₃And R₄Each independently selected from methyl, benzyl, acetyl, benzoyl or substituted benzoyl.

In certain embodiments, n is 1 and X₆At position C14.

In certain embodiments, X₅Is hydrogen.

In certain embodiments, X₆Selected from-OH, -F, -CN, -NH-C (═ O) -NH-R₈、-O-C(＝O)-R₉or-O-S (═ O)₂-R₁₀、-NH-C(＝S)-NH-R₁₁、-NH-C(＝O)OR₁₂、-OC(＝O)NHR₁₃、-OC(＝O)OR₁₄、-NH-P(＝O)R₁₆R₁₇、-NHC(＝S)R₁₈、-NHC(＝O)R₁₉or-OC (═ O) R₂₀；

R₈Is selected from-CH₂Ph, 4-chlorophenyl, cyclopentyl, cyclohexyl, -CH₂CH₂Cl, tert-butyl, -CH₂CH₂OC(＝O)C(＝CH₂)CH₃4-methylphenyl, 4-trifluoromethoxyphenyl, 4-nitroPhenyl, 2-trifluoromethyl-4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-trifluoromethylphenyl, -CH₂CH₂Ph, 2-methoxyphenyl, 4-methoxyphenyl, or naphthyl;

R₉selected from phenyl, 4-fluorophenyl, -CH ═ C (CH)₃)₂3-chlorophenyl, 2,4, 6-trichlorophenyl, 2-chlorophenyl, 4-methoxyphenyl, tert-butyl, -CH ═ CH-Ph, naphthyl, or thienyl;

R₁₀selected from 2-nitrophenyl, 2, 4-dichlorophenyl or 4-methylphenyl;

R₁₁is selected from-C (═ O) OC₂H₅；

R₁₂Selected from phenyl or 4-nitrophenyl;

R₁₃selected from benzyl, tert-butyl or cyclohexyl;

R₁₄selected from 4-nitrophenyl, phenyl or benzyl;

R₁₆and R₁₇Are each 2-oxazolidone, phenoxy or phenyl;

R₁₈to R₂₀is-N (CH)₃)₂；

n is 1 and X₆At position C14;

R₃is methyl, benzyl, acetyl, benzoyl or substituted benzoyl; and

R₄is methyl.

The present application also relates to compounds, single stereoisomers thereof, mixtures of stereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, and metabolites thereof, wherein the compounds are selected from the group consisting of: compound H-56 to compound H-106.

The present application also relates to pharmaceutical compositions comprising a compound of formula (II), its single stereoisomers, mixtures thereof, its prodrugs, its pharmaceutically acceptable salts and its metabolites, and a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition is a tablet, capsule, pill, suppository, emulsion, paste, injection, or infusion.

The application also relates to the application of the compound in the general formula (II), single stereoisomer thereof, mixture of the stereoisomers thereof, prodrug thereof, pharmaceutically acceptable salt thereof and metabolite thereof or the pharmaceutical composition in the preparation of medicines for preventing or treating tumors.

The application also relates to the application of the compound in the general formula (II), a single stereoisomer thereof, a mixture of the stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof and a metabolite thereof, or the combination of the pharmaceutical composition and another anti-tumor drug in the preparation of drugs for preventing or treating tumors.

In certain embodiments, the additional anti-neoplastic agent is selected from the group consisting of doxorubicin, paclitaxel, cyclophosphamide, daunorubicin, podophyllotoxin, vinblastine, and the like, preferably doxorubicin or paclitaxel.

In certain embodiments, the tumor is selected from tongue cancer, pancreatic adenocarcinoma, cervical cancer, laryngeal cancer, renal cancer, erythroleukemia, leukemia, breast cancer, melanoma, prostate cancer, liver cancer, sarcoma, ovarian cancer, ureteral cancer, bladder cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, endocrine cancer, skin cancer, hemangioma, brain cancer, or central nervous system cancer or a metastatic cancer thereof, preferably tongue cancer, pancreatic adenocarcinoma, cervical cancer, laryngeal cancer, kidney cancer, erythroleukemia, leukemia, breast cancer, melanoma, prostate cancer, or liver cancer.

In certain embodiments, the tumor is a drug-resistant tumor.

In certain embodiments, the drug-resistant tumor is a drug-resistant breast cancer, melanoma, human prostate cancer, tongue cancer, pancreatic adenocarcinoma, cervical cancer, laryngeal cancer, renal cancer, erythroleukemia, leukemia, liver cancer, sarcoma, ovarian cancer, ureteral cancer, bladder cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, endocrine cancer, skin cancer, hemangioma, or glioma, and the like, preferably a drug-resistant breast cancer, melanoma, or human prostate cancer; preferably drug-resistant breast cancer, melanoma, human prostate cancer, tongue cancer, pancreatic adenocarcinoma, cervical cancer, laryngeal cancer, renal cancer, erythroleukemia or leukemia. The drug-resistant tumor can be resistant to cyclophosphamide, daunorubicin, podophyllotoxin, vinblastine, taxol, adriamycin, progestogen, tamoxifen, etc., such as cyclophosphamide, daunorubicin, podophyllotoxin, vinblastine, taxol, adriamycin, etc. Specific examples of drug-resistant cell lines include, but are not limited to, breast cancer cell line MDA-MB-231, melanoma cell line WM9, human prostate cancer cell line PC3, human erythroleukemia drug-resistant cell line HEL, leukemia drug-resistant cell line K562, human pancreatic cancer drug-resistant cell line BxPC-3, human tongue cancer drug-resistant cell line Tca8113, cervical cancer drug-resistant cell line HeLa, renal cancer drug-resistant cell line GRC-1, laryngeal cancer drug-resistant cell line Hep-2.

Another aspect of the present application relates to a method for treating or preventing a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (II), a compound of any one of compounds H-56 to H-106, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a metabolite thereof, or a pharmaceutical composition thereof.

Yet another aspect of the present application relates to a compound of general formula (II), a compound of any one of compounds H-56 to H-106, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a metabolite thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of a tumor.

Yet another aspect of the present application relates to a method of inhibiting the growth of a tumor cell, comprising contacting a tumor cell with a therapeutically effective amount of a compound of formula (II), a compound of any one of compounds H-56 to H-106, a single stereoisomer thereof, a mixture of stereoisomers thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a metabolite thereof, or a pharmaceutical composition thereof.

The following are examples of various methods for preparing the compounds of general formula (I) of the present application.

A process for the preparation of a compound of general formula (I), its single stereoisomers, mixtures thereof, prodrugs thereof, pharmaceutically acceptable salts thereof or metabolites thereof,

wherein the content of the first and second substances,

X₁、X₂、X₃and X₄Each independently is nitro; or X₁、X₂、X₃And X₄Each independently hydrogen or nitro, with the proviso that: x₁、X₂、X₃And X₄Not hydrogen at the same time;

x is an integer from 1 to 3;

y is an integer from 1 to 4; and

z is an integer from 1 to 2;

wherein the method comprises the step of carrying out nitration reaction on berbamine, tetrandrine or tetrandrine.

In certain embodiments, the nitration is carried out using a mixed acid of acetic anhydride and nitric acid.

In certain embodiments, the nitration reaction is carried out using a non-polar solvent as the solvent.

Illustrative examples of non-polar solvents that can be used in the above nitration reaction include, but are not limited to, dichloromethane, chloroform, and 1, 2-dichloroethane.

In certain embodiments, the nitration reaction is carried out at a temperature of from about-10 ℃ to about 5 ℃.

In certain embodiments, the nitration reaction is carried out at about 0 ℃.

In certain embodiments, the nitration reaction is carried out in an atmosphere of an inert gas.

Illustrative examples of inert gases that can be used in the nitration reaction described above include, but are not limited to, argon, helium, and nitrogen.

wherein the content of the first and second substances,

X₁、X₂、X₃and X₄Each independently is an amino group; or X₁、X₂、X₃And X₄Each independently hydrogen or amino, with the proviso that: x₁、X₂、X₃And X₄Not hydrogen at the same time;

x is an integer from 1 to 3;

y is an integer from 1 to 4; and

z is an integer from 1 to 2;

wherein the method comprises the steps of carrying out nitration reaction on berbamine, tetrandrine or tetrandrine, and then carrying out reduction reaction on the obtained nitration product.

In certain embodiments, NaBH is used₄The reduction reaction is carried out.

In certain embodiments, NiCl is used₂·6H₂And O is a catalyst to carry out the reduction reaction.

In certain embodiments, the reduction reaction is carried out at a temperature of from about-15 ℃ to about 0 ℃.

In certain embodiments, the reduction reaction is performed in an ice bath.

In certain embodiments, the reduction reaction is carried out using a polar aprotic solvent as the solvent.

Illustrative examples of aprotic solvents that can be used in the above reduction reaction include, but are not limited to, tetrahydrofuran, 1, 4-dioxane, and dimethylformamide.

wherein the content of the first and second substances,

X₁、X₂、X₃and X₄Each independently is a carbonyl-substituted amino group; or X₁、X₂、X₃And X₄Each independently is hydrogen or-NR₃-C(＝O)-R₄The conditions are as follows: x₁、X₂、X₃And X₄Not hydrogen at the same time;

R₁selected from the group consisting of hydrogen, optionally substituted alkyl, nitroso, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted sulfonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, or optionally substituted alkynylcarbonyl;

x is an integer from 1 to 3;

y is an integer from 1 to 4; and

z is an integer from 1 to 2;

the method comprises the steps of carrying out nitration reaction on berbamine, tetrandrine or tetrandrine, carrying out reduction reaction on the obtained nitration product, and carrying out acylation reaction on the obtained reduction product.

In certain embodiments, the acylation is carried out using an acid halide compound or a sulfonyl halide compound.

In certain embodiments, the acylation reaction is carried out using a basic solvent as the solvent.

Illustrative examples of basic solvents that can be used for the above acylation reaction include, but are not limited to, pyridine, a dichloromethane solution of diethylamine, and a dichloromethane solution of triethylamine.

In certain embodiments, the acylation reaction is carried out at a temperature of about 0 ℃ to room temperature.

In certain embodiments, the acylation reaction is carried out in an ice bath.

In certain embodiments, the acylation reaction is carried out in an inert gas atmosphere.

Illustrative examples of inert gases that can be used for the above acylation reaction include, but are not limited to, argon, helium, and nitrogen.

wherein the content of the first and second substances,

X₁、X₂、X₃and X₄Each independently is a sulfonic acid group; or X₁、X₂、X₃And X₄Each independently is hydrogen or-SO₃H, with the proviso that: x₁、X₂、X₃And X₄Not hydrogen at the same time;

R₁and R₂Each independently selected from hydrogen, nitroso, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl or optionally substituted alkynylcarbonyl;

x is an integer from 1 to 3;

y is an integer from 1 to 4; and

z is an integer from 1 to 2;

wherein the method comprises the step of carrying out sulfonation reaction on berbamine, tetrandrine or tetrandrine.

In certain embodiments, the sulfonation reaction is carried out using sulfate and concentrated sulfuric acid.

In certain embodiments, the sulfonation reaction is carried out using a non-polar solvent as the solvent.

Illustrative examples of non-polar solvents that can be used in the present application include, but are not limited to, dichloromethane, chloroform, and 1, 2-dichloroethane.

In certain embodiments, the sulfonation reaction is conducted at a temperature of from about-15 ℃ to about 0 ℃.

In certain embodiments, the sulfonation reaction is carried out in an ice bath.

wherein the content of the first and second substances,

X₁、X₂、X₃and X₄Each independently is hydrogen or-NH-S (═ O)₂-R₆The conditions are as follows: x₁、X₂、X₃And X₄Not hydrogen at the same time;

R₆selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted ringAn alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocyclic group or an optionally substituted amino group;

x is an integer from 1 to 3;

y is an integer from 1 to 4; and

z is an integer from 1 to 2;

the method comprises the steps of carrying out nitration reaction on berbamine, tetrandrine or tetrandrine and concentrated nitric acid, carrying out reduction reaction on the reaction product and iron powder to generate amino, and carrying out reaction on the amino and acyl chloride under the catalysis of alkali to obtain the compound with the general formula (I).

Examples

Although any person skilled in the art can prepare the compounds of the present application in accordance with the general techniques disclosed above, more detailed synthetic techniques for the compounds of the present application are provided elsewhere in the specification for convenience. In addition, all reagents and reaction conditions used in the synthesis are known to those skilled in the art and can be obtained from common commercial sources.

Example 1

Preparation of tetrandrine nitration derivative H-27

Preparing mixed acid solution at 0 ℃, adding 1.5mL (CH) into a 10mL round-bottom flask under the protection of Ar₃CO)₂And O, slowly dropwise adding 0.6mL of concentrated nitric acid while stirring, cooling to-10 ℃ after stirring for 5min, slowly dropwise adding 3mL of anhydrous chloroform solution of 500mg (0.8mmol) of tetrandrine into the mixed acid solution, completing dropwise adding for 15min, detecting by TLC, completing reaction for 70min, and adding water to stop the reaction. Adjusting pH to alkaline with concentrated ammonia water, extracting with chloroform completely, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering and evaporating to dryness, and recovering chloroform solution to obtain solid 610 mg. The pure compound H-27 was purified by column chromatography with 50:1 methanol (496mg, 92% yield).

H-28 (yield 43%) was obtained in a similar manner to example 1, except that the amount of the mixed acid added was changed to 4mL, and the reaction time was prolonged to 200 min.

Example 2

Preparation of tetrandrine nitration reduction derivative H-29

Taking 100mg (0.15mmol) of H-27 dry sample in a 25mL round-bottom flask, adding 2mL tetrahydrofuran, stirring until the sample is completely dissolved, adding 1mL methanol dissolved 10.8mg (0.046mmol) NiCl into the reaction system at 0 DEG C₂·6H₂O, stirring, adding 28.4mg (0.75mmol) NaBH₄Reacting the solid in ice bath for 20min, detecting the reaction completion by TLC, stopping the reaction, pouring the reactant into ice water, extracting the reactant with chloroform for three times, washing with saturated NaCl solution, and carrying out anhydrous MgSO₄Drying, filtering, evaporating to dryness, and recovering chloroform solution to obtain solid 96 mg. Chloroform: purification on a column with 50:1 methanol gave H-29(78mg, yield 78%), H-30(12mg, yield 12%).

Example 3

Preparation of tetrandrine amidated and sulfonylaminated derivatives

Taking 50mg (0.08mmol) of a dried H-29 sample, putting the dried H-29 sample into a 10mL round-bottom flask, adding 1.5mL of pyridine at 0 ℃ under the protection of Ar, stirring to dissolve the sample, adding 1.5 times of acyl chloride, detecting the reaction by TLC, reacting completely for 3-4H, and stopping the reaction. Pouring the mixed reaction solution into ice water and saturated NaHCO₃Adjusting pH to alkaline with water solution, extracting with chloroform for 3 times, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering and evaporating to dryness, and recovering a chloroform solution to obtain solid chloroform: passing through a column with the ratio of 40:1, and separating to obtain a pure product.

26 (H-01 to H-26, yield 40% -80%) of the methyl amide and the sulfonamide compound were obtained in the same manner as in example 3, except that the corresponding acid chloride raw material was used.

Example 4

Preparation of tetrandrine benzyl derivatives

And (3) experimental operation: taking 50mg (0.08mmol) of tetrandrine dried sample in a 10mL round-bottom flask, adding 2mL of anhydrous D under the protection of ArMF, 7mg NaH (0.16mmol, 55%) was added, the mixture was stirred uniformly, 20. mu.L of BnBr (0.16mmol) was added dropwise, the reaction was carried out at room temperature for 8 hours, and the reaction was stopped when the reaction was completed by TLC. Adding saturated NH₄The reaction was stopped with Cl, the mixture was poured into ice water, extracted with chloroform 3 times, washed with saturated NaCl solution, and anhydrous MgSO₄Drying, filtration and evaporation to dryness, recovering the chloroform solution, passing the resulting solid through 200 to 300 mesh silica gel (15g), chloroform: pure H-31(15mg, 21% yield) was obtained with methanol 30: 1.

Example 5

Preparation of tetrandrine nitrated derivative

And (3) experimental operation: preparing mixed acid solution at 0 ℃, adding 0.8mL (CH) into a 10mL round-bottom flask under the protection of Ar₃CO)₂And O, slowly dropwise adding 0.5mL of concentrated nitric acid while stirring, cooling to-10 ℃ after stirring for 5min, slowly dropwise adding 1mL of anhydrous chloroform solution of 50mg (0.07mmol) of H-31 into the mixed acid solution, completing dropwise adding for 10min, detecting by TLC for 1.5H, completely reacting, and adding water to stop the reaction. Adjusting pH to alkaline with concentrated ammonia water, extracting with chloroform completely, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, evaporating to dryness, and recovering chloroform solution to obtain solid 48 mg. Chloroform: methanol: purification on a column with diethylamine (40: 1: 0.1) gave pure H-32(46mg, 92% yield).

Taking 500mg (0.8mmol) of tetrandrine dried sample, putting the sample in a 10mL round-bottom flask, adding 10mL of anhydrous DMF under the protection of Ar, adding 70mg of NaH (1.6mmol, 55%), stirring uniformly, dropwise adding 180 mu L of benzoyl chloride (1.6mmol), reacting for 8h at room temperature, detecting the reaction by TLC, and stopping the reaction. Adding saturated NH₄The reaction was stopped with Cl, the mixture was poured into ice water, extracted with chloroform 3 times, washed with saturated NaCl solution, and anhydrous MgSO₄Drying, filtration and evaporation to dryness, recovering the chloroform solution, passing the resulting solid through 200 to 300 mesh silica gel (18g), chloroform: the pure product (508mg) was obtained at 30: 1.

Prepare mixed acid solution at 0 ℃, add 0.8mL (CH3CO) after the 10mL round bottom flask under Ar protection₂O, slowly dripping 0.5mL of concentrated nitric acid under stirring, stirring for 5min, cooling to-10 deg.C, slowly dripping 1mL of anhydrous chloroform solution of 50mg (0.07mmol) benzoylated tetrandrine into the mixed acid solution, and dripping for 10minAfter the addition, TLC detection is carried out for 1.5h, the reaction is complete, and water is added to stop the reaction. Adjusting pH to alkaline with concentrated ammonia water, extracting with chloroform completely, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, evaporating to dryness, and recovering chloroform solution to obtain solid 48 mg. Chloroform: methanol: purification on a column with diethylamine (40: 1: 0.1) gave pure H-33(48mg, 94% yield).

Example 6

Preparation of reduced derivative of tetrandrine nitration product

And (3) experimental operation:

a. taking a dry sample H-33100 mg (0.13mmol) to a 10mL round-bottom flask, adding 2.0mL AcOH, stirring until the sample is completely dissolved, adding 74mg (1.32mmol) of reduced iron powder in three times, heating to 60 ℃, detecting by TLC, and completing the reaction for 5.5H. Stirring was stopped, the temperature was reduced to room temperature, and the reaction mixture was poured into ice water and saturated with Na₂CO₃Adjusting pH of the aqueous solution to alkaline, extracting with chloroform, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering and evaporating to dryness, and recovering chloroform solution to obtain solid 79 mg. Chloroform: methanol: purification on a column at a ratio of 40:1:0.1 gave pure H-33 reduced product H-34(60mg, 65%).

b. Taking the reaction dry sample H-3460 mg (0.08mmol) in the previous step, putting the sample in a 10mL round-bottom flask, adding 1.5mL pyridine at 0 ℃ under the protection of Ar, stirring to dissolve the sample, adding 16 mu L (0.12mmol) o-chlorobenzoyl chloride, detecting the reaction by TLC, reacting for 4H completely, and stopping the reaction. Pouring the mixed reaction solution into ice water and saturated NaHCO₃Adjusting pH to alkaline with water solution, extracting with chloroform for 3 times, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering and evaporating to dryness, and recovering chloroform solution to obtain solid 58mg, chloroform: methanol: the diethylamine was passed through a column at a ratio of 40:1:0.1 to obtain pure H-35(35mg, yield: 50%).

Example 7

Nitrated mixed substituted derivatives

And (3) experimental operation: taking a dry sample H-27100 mg (0.15mmol) in a 10mL round-bottom flask, adding 2.0mL trifluoroacetic acid, stirring until the sample is completely dissolved, adding 57mg (0.32mmol) of N-bromosuccinimide twice in ice bath, continuing to perform ice bath reaction for 30min, then heating to room temperature, and after 4H, completing the reaction. The reaction mixture was poured into ice water and saturated with Na₂CO₃Adjusting pH to 10, extracting with chloroform, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, and recovering chloroform under reduced pressure to obtain crude product 102 mg. Adding chloroform: methanol: purification on a column with 50:1:0.1 of diethylamine yielded H-36(83mg, yield 75%) as a pure product of H-27.

Example 8

Preparation of Compounds H-37, H-38 and H-39

Taking 100mg (0.15mmol) of tetrandrine as a dry sample, adding 2.13mg (0.015mmol) of anhydrous Na into a 10mL round-bottom flask₂SO₄And then adding 2.0mL of dichloromethane, stirring until the sample is completely dissolved, dropwise adding 27 mu L (1.5mmol) of concentrated sulfuric acid within 15min under ice bath, continuing to react in ice bath for 1h, then heating to room temperature, and completely reacting after 10 h. The reaction mixture was poured into ice water and saturated with Na₂CO₃Adjusting pH to 10, extracting with chloroform, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, and recovering chloroform under reduced pressure to obtain crude product 102 mg. Adding chloroform: methanol: purification on a column with diethylamine ═ 50:1:0.1 yielded compound H-37(95mg, yield 90%).

Taking a dry sample compound H-37100 mg (0.15mmol) to a 10mL round-bottom flask, adding 2.0mL of dimethylformamide, stirring until the sample is completely dissolved, dropwise adding 11 mu L (1.5mmol) of thionyl chloride within 15min under ice bath, continuing to react for 1H in ice bath, dropwise adding 1mL of dimethylformamide solution dissolved with 14mg of aniline, heating to 100 ℃, reacting for 10H, and then completely reacting. The reaction mixture was poured into ice water and saturated NaHCO₃Adjusting pH of the aqueous solution to 7, extracting with chloroform, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, and recovering chloroform under reduced pressure to obtain crude product 102 mg. Adding chloroform: methanol: purification on a column with diethylamine at 50:1:0.1 yielded compound H-38(87mg, yield 75%).

Compound H-39 was prepared using the procedure for the preparation of compound H-38 except that a solution of dimethylformamide having 9.0. mu.L of methanol dissolved therein was used instead of 1mL of a solution of dimethylformamide having 14mg of aniline dissolved therein (yield 81%).

Example 9

Preparation of Compound H-40, Compound H-41, Compound H-43, and Compound H-44

Taking a dry sample compound H-37100 mg (0.15mmol) to a 10mL round-bottom flask, adding 2.0mL trifluoroacetic acid, stirring until the sample is completely dissolved, adding 50mg of N-bromosuccinimide in two batches under ice bath, continuing to react in ice bath for 30min, then returning to room temperature, and reacting completely after 5H. The reaction mixture was poured into ice water and saturated NaHCO₃Adjusting pH of the aqueous solution to 7, extracting with chloroform, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, and recovering chloroform under reduced pressure to obtain crude product 93 mg. Adding chloroform: methanol: purification on a column at 50:1:0.1 afforded compound H-40(78 mg).

Compound H-41 was prepared using the procedure for preparation of compound H-40 except that 65mg of N-bromosuccinimide was used instead of 32mg of N-bromosuccinimide and concentrated sulfuric acid was used instead of the mixed acid.

Except using mixed acid to replace concentrated sulfuric acid and Na₂SO₄In addition, compound H-43 was prepared using the procedure for the preparation of compound H-40, except that 32mg of N-chlorosuccinimide was used instead of 32mg of N-bromosuccinimide.

Except using mixed acid to replace concentrated sulfuric acid and Na₂SO₄In addition, compound H-44 was prepared using the procedure for the preparation of compound H-40, except that 65mg of N-chlorosuccinimide was used instead of 32mg of N-bromosuccinimide.

Example 10

Preparation of Compound H-42

Adding 50mg of an A sample dissolved in 2mL of dichloromethane into a 10mL round-bottom flask at 0 ℃ under the protection of Ar, stirring for 5min, then cooling to-10 ℃, slowly dropwise adding 0.6mL of concentrated nitric acid into the mixture, finishing dropwise adding for 15min, detecting by TLC, reacting for 13h completely, and adding water to stop the reaction. Adjusting pH to alkaline with concentrated ammonia water, extracting with chloroform completely, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering and evaporating to dryness, and recovering chloroform solution to obtain solid 610 mg. Chloroform: purification with 50:1 methanol column chromatography gave pure H-42(33mg, 65% yield).

Example 11

Preparation of Compound H-45 and Compound H-52

1. Taking 500mg (0.8mmol) of tetrandrine dried sample, putting the sample in a 10mL round-bottom flask, adding 10mL of anhydrous DMF under the protection of Ar, adding 70mg of NaH (1.6mmol, 55%), stirring uniformly, dropwise adding 180 mu L of benzoyl chloride (1.6mmol), reacting for 8h at room temperature, detecting the reaction by TLC, and stopping the reaction. Adding saturated NH₄The reaction was stopped with Cl, the mixture was poured into ice water, extracted with chloroform 3 times, washed with saturated NaCl solution, and anhydrous MgSO₄Drying, filtration and evaporation to dryness, recovering the chloroform solution, passing the resulting solid through 200 to 300 mesh silica gel (15g), chloroform: the pure product (512mg) was obtained with methanol 30: 1.

2. 100mg (0.15mmol) of the first-step dried sample was taken in a 10mL round-bottom flask, and 2.2mg (0.015mmol) of anhydrous Na was added₂SO₄And then adding 2.0mL of dichloromethane, stirring until the sample is completely dissolved, dropwise adding 27 mu L (1.5mmol) of concentrated sulfuric acid within 15min under ice bath, continuing to react in ice bath for 1h, then heating to room temperature, and completely reacting after 10 h. The reaction mixture was poured into ice water and saturated with Na₂CO₃Adjusting pH to 10, extracting with chloroform, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, and recovering chloroform under reduced pressure to obtain crude product 102 mg. Adding chloroform: methanol: purification on a column with diethylamine ═ 50:1:0.1 yielded compound H-45(95mg, yield 80%).

Except that the mixed acid described in example 1 was used in place of concentrated sulfuric acid and Na₂SO₄In addition, Compound H-52 was prepared using the procedure for preparation of Compound H-45 (yield 87%).

Example 12

Preparation of Compound H-46, Compound H-47, Compound H-48, Compound H-49, Compound H-50 and Compound H-51

The experimental method comprises the following steps: 1. taking 500mg (0.8mmol) of tetrandrine dried sample, putting the sample in a 10mL round-bottom flask, adding 10mL of anhydrous DMF under the protection of Ar, adding 70mg of NaH (1.6mmol, 55%), stirring uniformly, dropwise adding 180 mu L of benzoyl chloride (1.6mmol), reacting for 8h at room temperature, detecting the reaction by TLC, and stopping the reaction. Adding saturated NH₄The reaction was stopped with Cl, the mixture was poured into ice water, extracted with chloroform 3 times, washed with saturated NaCl solution, and anhydrous MgSO₄Drying, filtration and evaporation to dryness, recovering the chloroform solution, passing the resulting solid through 200 to 300 mesh silica gel (15g), chloroform: the pure product (512mg) was obtained with methanol 30: 1.

2. And (3) taking 100mg (0.15mmol) of the first-step dried sample into a 10mL round-bottom flask, adding 2.0mL of trifluoroacetic acid, stirring until the sample is completely dissolved, adding 25mg of N-chlorosuccinimide in two batches in ice bath, continuing to perform ice bath reaction for 30min, then returning to the room temperature, and completely reacting after 5 h. The reaction mixture was poured into ice water and saturated NaHCO₃Adjusting pH of the aqueous solution to 7, extracting with chloroform, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, and recovering chloroform under reduced pressure to obtain crude product 93 mg. Adding chloroform: methanol: purification on a column with diethylamine ═ 50:1:0.1 yielded compound H-46(56mg, yield 51%).

Compound H-47 was prepared using the procedure for the preparation of compound H-46 except that 50mg of N-chlorosuccinimide was used instead of 25mg of N-chlorosuccinimide (yield 46%).

Compound H-48 was prepared using the procedure for preparation of compound H-46 except that acetic anhydride was used instead of benzoyl chloride and 32mg of N-bromosuccinimide was used instead of 25mg of N-chlorosuccinimide (yield 63%).

Compound H-49 was prepared using the procedure for preparation of compound H-46 except that acetic anhydride was used instead of benzoyl chloride and 65mg of N-bromosuccinimide was used instead of 25mg of N-chlorosuccinimide (yield 49%).

Compound H-50 was prepared using the procedure for preparation of compound H-46 except that acetic anhydride was used instead of benzoyl chloride and 50mg of N-chlorosuccinimide was used instead of 25mg of N-chlorosuccinimide (yield 41%).

Compound H-51 was prepared using the procedure for preparation of compound H-46 except that acetic anhydride was used instead of benzoyl chloride and 80mg of N-chlorosuccinimide was used instead of 25mg of N-chlorosuccinimide (yield 38%).

Example 13

Preparation of Compound H-53

1. Taking 500mg (0.8mmol) of tetrandrine dried sample in a 10mL round-bottom flask, adding 10mL anhydrous DMF under the protection of Ar, and adding 70mg NaH (1.6mmol, 55%) was stirred well, 113. mu.L acetyl chloride (1.6mmol) was added dropwise, the reaction was carried out at room temperature for 9h, the reaction was completed by TLC detection, and the reaction was stopped. Adding saturated NH₄The reaction was stopped with Cl, the mixture was poured into ice water, extracted with chloroform 3 times, washed with saturated NaCl solution, and anhydrous MgSO₄Drying, filtration and evaporation to dryness, recovering the chloroform solution, passing the resulting solid through 200 to 300 mesh silica gel (15g), chloroform: methanol 30:1 to give acetylacetin (512 mg).

2. Taking 100mg (0.15mmol) of acetylated tetrandrine obtained in the first step into a 10mL round bottom flask, adding 2.13mg (0.015mmol) of anhydrous Na₂SO₄And then adding 2.0mL of dichloromethane, stirring until the sample is completely dissolved, dropwise adding 27 mu L (1.5mmol) of concentrated sulfuric acid within 15min under ice bath, continuing to react in ice bath for 1h, then heating to room temperature, and completely reacting after 10 h. The reaction mixture was poured into ice water and saturated with Na₂CO₃Adjusting pH to 10, extracting with chloroform, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, and recovering chloroform under reduced pressure to obtain crude product 102 mg. Adding chloroform: methanol: purification on a column at 50:1:0.1 afforded compound H-53(82mg, 79% yield).

Example 14

Preparation of Compound H-54

1. Taking 100mg (0.15mmol) of tetrandrine as a dry sample, adding 2.0mL of trifluoroacetic acid into a 10mL round-bottom flask, stirring until the sample is completely dissolved, adding 25mg of N-chlorosuccinimide in two batches under ice bath, continuing to react in ice bath for 30min, then returning to room temperature, and reacting completely after 5 h. The reaction mixture was poured into ice water and saturated NaHCO₃Adjusting pH of the aqueous solution to 7, extracting with chloroform, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, and recovering chloroform under reduced pressure to obtain crude product 93 mg. Adding chloroform: methanol: purifying with 50:1:0.1 column chromatography to obtain tetrandrine chloride (86 mg).

2. Taking 50mg (0.08mmol) of the dried sample of the chlorotetrandrine in a 10mL round-bottom flask, adding 2.0mL of trifluoroacetic acid, stirring until the sample is completely dissolved, adding 25mg of N-bromosuccinimide in two batches under ice bath, continuing to react in the ice bath for 30min, then recovering to room temperature, reacting for 5h, and then carrying out reverse reactionIt should be complete. The reaction mixture was poured into ice water and saturated NaHCO₃Adjusting pH of the aqueous solution to 7, extracting with chloroform, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, and recovering chloroform under reduced pressure to obtain crude product 41 mg. Adding chloroform: methanol: purification on a column with diethylamine ═ 50:1:0.1 yielded compound H-54(35mg, yield 48%).

Example 15

Preparation of Compound H-55

1. Taking 100mg (0.15mmol) of tetrandrine sample to a 10mL round-bottom flask, adding 2.13mg (0.015mmol) of anhydrous Na₂SO₄And then adding 2.0mL of dichloromethane, stirring until the sample is completely dissolved, dropwise adding 27 mu L (1.5mmol) of concentrated sulfuric acid within 15min under ice bath, continuing to react in ice bath for 1h, then heating to room temperature, and completely reacting after 10 h. The reaction mixture was poured into ice water and saturated with Na₂CO₃Adjusting pH to 10, extracting with chloroform, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, and recovering chloroform under reduced pressure to obtain crude product 102 mg. Adding chloroform: methanol: purification on a column with diethylamine ═ 50:1:0.1 yielded compound H-37(95 mg).

Preparing mixed acid solution at 2.0 ℃, adding 0.15mL (CH) into a 10mL round bottom flask under the protection of Ar₃CO)₂And O, slowly dropwise adding 0.06mL of concentrated nitric acid while stirring, cooling to-10 ℃ after stirring for 5min, slowly dropwise adding 3mL of anhydrous chloroform solution of 50mg (0.08mmol) of H-37 into the mixed acid solution, completing dropwise adding for 15min, detecting by TLC, completing reaction for 70min, and adding water to stop the reaction. Adjusting pH to alkaline with concentrated ammonia water, extracting with chloroform completely, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering and evaporating to dryness, and recovering chloroform solution to obtain solid 610 mg. Chloroform: purification with 50:1 methanol column chromatography gave pure H-55(39mg, 65% yield).

Example 16

Preparation of hard capsules

Taking compound H-325 g, medicinal starch 75g and microcrystalline cellulose 20g, drying the medicinal starch, sieving with a 120-mesh sieve, mixing with the compound H-32 and the microcrystalline cellulose, sieving with the 120-mesh sieve twice, filling into hard capsules, and preparing 1000 capsules. Each hard capsule contains 0.5mg of main drug component.

Example 17

Preparation of coated tablets

Taking compound H-285 g, hydroxypropyl methylcellulose 6g, carboxymethyl starch sodium 10g, microcrystalline cellulose 8g, lactose 115g, starch 50g and magnesium stearate 1 g; mixing the main materials and adjuvants, adding into high speed stirrer, spraying water, granulating, controlling water content to 3-4%, tabletting, making 1000 tablets, and coating film.

Example 18

Preparation of the solution

Dissolving compound H-305 g in 400mL of polyethylene glycol 200, diluting with appropriate amount of distilled water, adding appropriate amount of sucrose, adjusting volume to 1000mL, stirring, filtering, packaging into 10mL or 20mL each, sterilizing, and packaging.

Biological examples 1 to 5

1.Breast cancer drug-resistant cell strain MDA-MB-231 model screening

Test compounds: bisbenzylisoquinoline derivatives of the present application as listed in tables 1-1, 1-2, 1-3

The screening method comprises the following steps: tetrazolium salt reduction process (MTT process)

(1) Inoculating cells: cells in the logarithmic growth phase were collected, prepared into a single cell suspension using DMEM medium containing 10% fetal bovine serum, and seeded into a 96-well plate in a volume of 200. mu.L per well at 5000 cells per well.

(2) Administration: the adherent cells need to be attached for 24 hours before administration. The test should be provided with a positive control group, a negative control group and a blank control, wherein the positive control is an anti-tumor drug with similar chemical structure and the same or similar action mechanism, cisplatin (DDP), tetrandrine (HJ), tetrandrine (HY), Adriamycin (ADM) and Paclitaxel (PTX) are selected as the positive control in the test, and the negative control is a solvent control (a compound solvent is DMSO, and the influence of a solvent DMSO on cells can be ignored when the DMSO is prepared to be less than or equal to 1 per thousand).

(3) Color generation: after the subjects were co-cultured with the cells for 72 hours, 20 μ L of MTT solution (with PBS < pH 7.4) was added per well. Incubation is continued for 1-4 hours, the culture is terminated, the culture supernatant in the wells is carefully aspirated, centrifugation is required for the suspended cells, and the culture supernatant in the wells is aspirated again. Add 150. mu.L DMSO/well and shake for 15 minutes to dissolve the crystals well.

(4) Color comparison: the 490nm wavelength is selected, the optical absorption value (OD value) of each well is measured on an enzyme-linked immunosorbent instrument, the result is recorded, the OD value is taken as a parameter reflecting the activity and the metabolic condition of the cell, and the result is expressed as mean +/-standard deviation (chi +/-s).

(5) And (3) calculating an inhibition rate: statistical analysis was performed by t-test for group comparisons. Each experimental group and control group were provided with 6 wells, and each experiment was repeated at least 3 times. The growth inhibition rate was calculated by the following formula:

model principle: in mitochondria of living cells, dehydrogenase associated with NADP is present to reduce yellow MTT to insoluble blue-violet formazan (Formanzan), and in dead cells, this enzyme disappears and MTT is not reduced. The model detects the action condition of the sample on the tumor cells according to the reduction degree of MTT.

The experimental results are as follows: using the methods described above, several compounds prepared herein were tested for their inhibitory effects on MDA cells, with the specific results shown in tables 1-1, 1-2, and 1-3 below.

TABLE 1-1

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

Tables 1 to 2

HY represents tetrandrine; HJ represents tetrandrine; ADM represents doxorubicin; the concentration of doxorubicin (ADM) was 3.5. mu.M, and the concentration of the compound of the present application was 5. mu.M.

Tables 1 to 3

HY represents tetrandrine; HJ represents tetrandrine; PTX represents paclitaxel; paclitaxel (PTX) was at a concentration of 3.5. mu.M, and the compound of the present application was at a concentration of 5. mu.M.

2.Melanoma drug-resistant cell line WM9 model screening

Test compounds: bisbenzylisoquinoline derivatives of the present application as listed in tables 2-1, 2-2, 2-3

The experimental results are as follows: using the above method, several compounds prepared herein were tested for inhibition of WM9 cells, with the specific results shown in tables 2-1, 2-2, and 2-3 below.

TABLE 2-1

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

Tables 2 to 2

Tables 2 to 3

3.Screening of human prostate cancer drug-resistant cell strain PC3 model

Test compounds: bisbenzylisoquinoline derivatives of the present application as listed in tables 3-1, 3-2, 3-3

(2) Administration: the adherent cells need to be attached for 24 hours before administration. The test should be provided with a positive control group, a negative control group and a blank control, wherein the positive control is an anti-tumor drug with similar chemical structure and the same or similar action mechanism, cisplatin (DDP), tetrandrine (HJ), tetrandrine (HY), Adriamycin (ADM) and Paclitaxel (PTX) are selected as the positive control in the test, and the negative control is a solvent control (the compound solvent is DMSO, and the influence of the solvent DMSO on cells can be ignored when the DMSO is prepared to be less than or equal to 1 per thousand).

The experimental results are as follows: using the above method, several compounds prepared herein were tested for their inhibitory effect on PC3 cells, with the specific results shown in tables 3-1, 3-2, and 3-3 below.

TABLE 3-1

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

TABLE 3-2

Tables 3 to 3

4.Screening of human erythroleukemia cell strain HEL and leukemia cell strain K562 model

Test compounds: bisbenzylisoquinoline derivatives of the present application as listed in tables 4, 5

(2) Administration: the adherent cells need to be attached for 24 hours before administration. The test should be provided with a positive control group, a negative control group and a blank control, wherein the positive control is an anti-tumor drug with similar chemical structure and the same or similar action mechanism, cisplatin (DDP), tetrandrine (HJ) and tetrandrine (HY) are selected as the positive control in the test, and the negative control is a solvent control (a compound solvent is DMSO, and the influence of a solvent DMSO on cells can be ignored when the DMSO is prepared to be less than or equal to 1 per mill).

The experimental results are as follows: using the above method, several compounds prepared in the present application were tested for their inhibitory effects on HEL cell line and K562 cell line, and the specific results are shown in tables 4 and 5 below.

TABLE 4

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

TABLE 5

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

5.Hep-2 of human larynx cancer cell strain, Tca8113 of human tongue cancer cell strain, BxPC-3 of human pancreas cancer cell strain, and cervical cancer cell Cell strain HeLa and kidney cancer cell strain GRC-1 model screening

Test compounds: bisbenzylisoquinoline derivatives of the present application as listed in tables 6-10

The experimental results are as follows: using the above method, several compounds prepared in the present application were tested for their inhibitory effects on Hep-2 cell line, Tca8113 cell line, BxPC-3 cell line, HeLa cell line, and GRC-1 cell line, and the specific results are shown in the following tables 6-10.

TABLE 6

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

TABLE 7

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

TABLE 8

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

TABLE 9

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

Watch 10

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

Example 19

Preparation of tetrandrine phosphoric amide derivative

And (3) experimental operation:

taking a dry sample H-29100 mg (0.13mmol) into a 10mL round-bottom flask, adding 2.0mL DCM at room temperature, stirring until the sample is completely dissolved, adding corresponding phosphorus oxychloride 0.15mmol, detecting by TLC, and reacting completely for 2H. The stirring was stopped and the reaction mixture was poured into saturated NaHCO₃Adjusting pH to alkaline, extracting with DCM, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, evaporating to dryness, and recovering DCM to obtain solid 80 mg. Chloroform: methanol: purifying with 50:1:0.1 column to obtain pure products H-56 to H-58 (yield is 75-55%).

Example 20

Preparation of tetrandrine urea or thiourea derivatives

And (3) experimental operation:

taking a dry sample H-29100 mg (0.13mmol) into a 10mL round-bottom flask, adding 2.0mL DCM into the round-bottom flask, stirring the mixture at room temperature until the sample is completely dissolved, adding 0.15mmol of corresponding isocyanate or isothiocyanate, detecting by TLC, and completing the reaction for 2H. The stirring was stopped and the reaction mixture was poured into saturated NaHCO₃Adjusting pH to alkaline, extracting with DCM, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, evaporating to dryness, and recovering DCM to obtain solid 80 mg. Chloroform: methanol: purifying with 50:1:0.1 column to obtain pure products H-59 to H-79 (yield is 75-55%).

Example 21

Preparation of tetrandrine diazo derivative

And (3) experimental operation:

a taking a dry sample H-29200 mg in a 10mL round bottom flask, adding 5mL (4M) H₂SO₄Stirring at room temperature until the sample is completely dissolved, placing in an ice bath, cooling to 0-5 ℃, and quickly dropwise adding 28mg of NaNO₂Checking the reaction with potassium iodide, dripping 0.6mmol fluoroboric acid until white solid is sucked out, stirring for 30min, filtering the reaction solution, and drying the residue at 150 deg.C. After the dried solid was placed in a 250ml beaker and a certain amount of DCM was added, saturated NaHCO was used₃Adjusting pH to alkaline, extracting with DCM, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering and evaporating to dryness, and recovering DCM to obtain solid 128 mg. Chloroform: methanol: purification on a column with 50:1:0.1 diethylamine yielded pure H-80(90mg, 45%).

b taking a dry sample H-29200 mg in a 10mL round-bottom flask, adding 5mL (4M) H₂SO₄Stirring at room temperature until the sample is completely dissolved, placing in an ice bath, cooling to 0-5 ℃, and quickly dropwise adding 28mg of NaNO₂The reaction was checked for completion with potassium iodide starch in an aqueous solution, and the reaction was completed after dropping 1.2mmol of CuCN containing a large amount of saturated sodium carbonate by TLC detection and counting for 3. The reaction was poured into a 250ml beaker and a defined amount of DCM was added and saturated NaHCO was used₃Adjusting pH to alkaline, extracting with DCM, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering and evaporating to dryness, and recovering DCM to obtain solid 110 mg. Chloroform: methanol: purification on a column with 50:1:0.1 diethylamine yielded pure H-81(80mg, 40%).

Example 22

Preparation of tetrandrine hydroxyl derivative

And (3) experimental operation:

taking a dry sample H-29500 mg in a 25mL round-bottom flask, adding 10mL (4N) H₂SO₄Stirring at room temperature until the sample is completely dissolved, placing in an ice bath, cooling to 0-5 ℃, and quickly dropwise adding 70mg of NaNO₂The aqueous solution is checked for complete reaction with potassium iodide starch, and the diazonium salt is added dropwise to 10ml (10N) H at 110 deg.C₂SO₄Stirring, detecting by TLC, and finishing the reaction for 30 min. The reaction was poured into a 250ml beaker and a defined amount of DCM was added and saturated NaHCO was used₃Adjusting pH to alkaline, extracting with DCM, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering and evaporating to dryness, and recovering DCM to obtain solid 300 mg. Chloroform: methanol: purification on a column (50: 1: 0.1) gave pure H-82(280mg, 56%).

Taking a dry sample H-91100mg and DMAP (0.05mmol) in a 10mL round bottom flask, 2.0mL DCM was added and stirred at room temperature until the sample was completely dissolved, the corresponding acid chloride 0.2mmol was added, TLC check, 2h reaction was complete. The stirring was stopped and the reaction mixture was poured into saturated NaHCO₃Adjusting pH to alkaline, extracting with DCM, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering, evaporating to dryness, and recovering DCM to obtain solid 80 mg. Chloroform: methanol: purifying with 50:1:0.1 column to obtain pure products H-83 to H-97 (yield is 75-55%).

Example 23

Preparation of tetrandrine carbamate and carbonate derivatives

And (3) experimental operation:

a taking a dry sample H-29100 mg (0.13mmol) in a 10mL round bottom flask, adding 2.0mL DCM, stirring at room temperature until the sample is completely dissolved, adding corresponding 0.20mmol of chloroformate, detecting by TLC, and completing the reaction for 4H. The stirring was stopped and the reaction mixture was poured into saturated NaHCO₃Adjusting pH to alkaline, extracting with DCM, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering and evaporating to dryness, and recovering DCM to obtain solid. Chloroform: methanol: purifying with 50:1:0.1 column to obtain pure products H-98 to H-99 (yield 60-45%).

b, taking a dried sample H-91100 mg (0.13mmol) into a 10mL round-bottom flask, adding 2.0mL toluene, stirring until the sample is completely dissolved, adding corresponding 0.20mmol isocyanate, heating in an oil bath to 95 ℃, refluxing, stirring, detecting by TLC, and completing the reaction for 5 hours. Stirring was stopped, toluene was removed from the reaction mixture, DCM was added and the mixture was dissolved and poured into saturated NaHCO₃Adjusting pH to alkaline, extracting with DCM, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering and evaporating to dryness, and recovering DCM to obtain solid. Chloroform: methanol: diethylamine is 50:1:0.1 pure through columnThe pure products H-100 to H-103 are obtained (the yield is 60 percent to 50 percent).

c, taking a dry sample H-91100 mg (0.13mmol) into a 10mL round-bottom flask, adding 2.0mL DCM into the round-bottom flask, stirring the mixture at room temperature until the sample is completely dissolved, adding 0.20mmol of corresponding chloroformate, detecting by TLC, and completing the reaction for 4H. The stirring was stopped and the reaction mixture was poured into saturated NaHCO₃Adjusting pH to alkaline, extracting with DCM, washing with saturated NaCl solution, and removing anhydrous MgSO₄Drying, filtering and evaporating to dryness, and recovering DCM to obtain solid. Chloroform: methanol: purifying with 50:1:0.1 column to obtain pure H-104 to H-106 (65-45% yield).

Biological example 6

Screening of human liver cancer cell strain MHCC97L model

Test compounds: bisbenzylisoquinoline derivatives of the present application as listed in Table 11

(1) Inoculating cells: a culture solution containing 10% fetal calf serum is used for preparing a single cell suspension, and 1000-10000 cells per well are inoculated to a 96-well plate, wherein the volume of each well is 200 mu L.

(2) Culturing the cells: culturing for 3-5 days (the culture time can be determined according to the purpose and requirements of the experiment) like the common culture conditions.

(3) Color generation: after 3-5 days of incubation, 20 μ L of MTT solution (5mg/mL with PBS < pH 7.4) was added per well. Incubation was continued for 4 hours, the culture was terminated, and the culture supernatant in the wells was carefully aspirated, after centrifugation was required for suspension cells, and the culture supernatant in the wells was aspirated. Add 150. mu.L DMSO/well and shake for 10 minutes to dissolve the crystals well.

(4) Color comparison: selecting 490nm wavelength, measuring the light absorption value of each well on an enzyme linked immunosorbent assay, recording the result, and drawing a cell growth curve by taking time as an abscissa and the light absorption value as an ordinate.

Model principle: in mitochondria of living cells, NADP-related dehydrogenase is present to reduce yellow MTT to insoluble blue-violet formazan (Formanzan), and in dead cells, this enzyme disappears and MTT is not reduced. The model detects the action condition of the sample on the tumor cells according to the reduction degree of MTT.

The experimental results are as follows: using the above procedure, several compounds prepared herein were tested for inhibition of MHCC97L cell line, with the specific results shown in Table 11 below.

TABLE 11

HY represents tetrandrine; HJ represents tetrandrine; sora represents the positive control sorafenib.

Biological example 7

Breast cancer drug-resistant cell line MDA-MB-231, melanoma drug-resistant cell line WM9 and human prostate cancer drug-resistant cell line PC3 model screening

Test compounds: bisbenzylisoquinoline derivatives of the present application as listed in tables 12-14

(3) Color generation: after the subjects were co-cultured with the cells for 72 hours, 20 μ L of MTT solution (5mg/mL with PBS < pH 7.4) was added per well. Incubation is continued for 1-4 hours, the culture is terminated, the culture supernatant in the wells is carefully aspirated, centrifugation is required for the suspended cells, and the culture supernatant in the wells is aspirated again. Add 150. mu.L DMSO/well and shake for 15 minutes to dissolve the crystals well.

The experimental results are as follows: using the above method, several compounds prepared in this application were tested for their inhibitory effects on MDA-MB-231, WM9 and PC3 cell lines, and the specific results are shown in tables 12-14 below.

TABLE 12-1

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

TABLE 12-2

TABLE 13-1

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

TABLE 13-2

TABLE 14-1

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

TABLE 14-2

Biological example 8

Screening of human erythroleukemia HEL and leukemia cell K562 model

Test compounds: bisbenzylisoquinoline derivatives of the present application as listed in tables 15-16

The experimental results are as follows: by using the method, the inhibition effect of a plurality of compounds prepared by the application on HEL cell strains and K562 cell strains is tested, and the specific results are shown in the following tables 15-16.

Watch 15

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

TABLE 16

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

Biological example 9

Human pancreatic cancer cell line BxPC-3, human tongue cancer cell line Tca8113, cervical cancer cell line HeLa and kidney cancer cell line Model screening of cell strain GRC-1 and laryngeal cancer cell strain Hep-2

Test compounds: bisbenzylisoquinoline derivatives of the present application as listed in table 12

The experimental results are as follows: using the above method, several compounds prepared in the present application were tested for their inhibitory effects on BxPC-3 cell line, Tca8113 cell line, HeLa cell line, GRC-1 cell line, and Hep-2 cell line, and the specific results are shown in the following tables 17-21.

TABLE 17

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

Watch 18

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

Watch 19

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

Watch 20

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

TABLE 21

HY represents tetrandrine; HJ represents tetrandrine; DDP denotes cisplatin.

Compound spectral data:

(one) mass spectral data of the compound:

(II) Compound Hydrogen Spectroscopy data:

H-01¹H-NMR(CDCl₃,400MHz)δ(ppm):12.02(1H,s,-CONH-),7.90(1H,s,H-13),7.30(1H,dd,J＝1.6,8.0Hz,H-14′),7.22(1H,dd,J＝2.4,8.0Hz,H-13′),6.59(1H,d,J＝2.8Hz,H-11′),6.57(1H,s,H-10),6.47(1H,s,H-5′),6.32(1H,s,H-5),6.13(1H,dd,J＝2.0,8.4Hz,H-10′),5.89(1H,s,H-8′),3.99(1H,d,J＝9.2Hz,H-1′),3.94(3H,s,12-OCH₃),3.82(1H,dd,J＝5.2,11.2Hz,H-1),3.75(3H,s,6-OCH₃),3.37(3H,s,6′-OCH₃),3.10(3H,s,7-OCH₃),2.61(3H,s,2′-NCH₃),2.51(3H,s,2-NCH₃)。

H-02¹H-NMR(CDCl₃,400MHz)δ(ppm):12.27(1H,s,-CONH-),7.81(1H,s,H-13),7.36(1H,dd,J＝1.6,10.0Hz,H-14′),7.24(1H,dd,J＝2.4,10.4Hz,H-13′),6.63(1H,d,J＝2.4Hz,H-11′),6.62(1H,s,H-10),6.48(1H,s,H-5′),6.25(1H,s,H-5),6.15(1H,dd,J＝2.0,8.4Hz,H-10′),5.90(1H,s,H-8′),4.04(1H,d,J＝9.2Hz,H-1′),3.97(3H,s,12-OCH₃),3.84(1H,d,J＝6.0Hz,H-1),3.72(3H,s,6-OCH₃),3.37(3H,s,6′-OCH₃),3.10(3H,s,7-OCH₃),2.62(3H,s,2′-NCH₃),2.47(3H,s,2-NCH₃)。

H-03¹H-NMR(CDCl₃,400MHz)δ(ppm):12.80(1H,s,-CONH-),8.10(1H,s,H-13),7.31(1H,dd,J＝2.0,8.4Hz,H-14′),7.23(1H,dd,J＝2.4,8.0Hz,H-13′),6.60(1H,d,J＝2.4Hz,H-11′),6.59(1H,s,H-10),6.45(1H,s,H-5′),6.21(1H,s,H-5),6.14(1H,dd,J＝1.6,8.4Hz,H-10′),5.88(1H,s,H-8′),4.00(3H,s,12-OCH₃),3.93(1H,d,J＝9.2Hz,H-1′),3.81(1H,dd,J＝5.2,11.2Hz,H-1),3.71(3H,s,6-OCH₃),3.33(3H,s,6′-OCH₃),3.07(3H,s,7-OCH₃),2.60(3H,s,2′-NCH₃),2.17(3H,s,2-NCH₃)。

H-04¹H-NMR(CDCl₃,400MHz)δ(ppm):7.76(1H,s,H-13),7.32(1H,dd,J＝1.6,7.6Hz,H-14′),7.23(1H,dd,J＝2.8,8.0Hz,H-13′),6.63(1H,d,J＝2.8Hz,H-11′),6.61(1H,s,H-10),6.49(1H,s,H-5′),6.26(1H,s,H-5),6.15(1H,dd,J＝2.0,8.4Hz,H-10′),5.90(1H,s,H-8′),4.04(1H,d,J＝9.2Hz,H-1′),3.96(3H,s,12-OCH₃),3.84(1H,dd,J＝5.2,10.4Hz,H-1),3.72(3H,s,6-OCH₃),3.37(3H,s,6′-OCH₃),3.10(3H,s,7-OCH₃),2.63(3H,s,2′-NCH₃),2.49(3H,s,2-NCH₃)。

H-05¹H-NMR(CDCl₃,400MHz)δ(ppm):12.42(1H,s,CONH),7.80(1H,s,H-13),7.32(1H,dd,J＝2.4,8.4Hz,H-14′),7.23(1H,dd,J＝2.4,8.0Hz,H-13′),6.63(1H,s,H-10),6.61(1H,dd,J＝2.8,8.4Hz,H-11′),6.48(1H,s,H-5′),6.25(1H,s,H-5),6.15(1H,dd,J＝2.0,8.4Hz,H-10′),5.89(1H,s,H-8′),4.04(1H,d,J＝9.2Hz,H-1′),3.97(3H,s,12-OCH₃),3.80(1H,dd,J＝5.6,10.8Hz,H-1),3.72(3H,s,6-OCH₃),3.37(3H,s,6′-OCH₃),3.08(3H,s,7-OCH₃),2.60(3H,s,2′-NCH₃),2.47(3H,s,2-NCH₃)。

H-06¹H-NMR(CDCl₃,400MHz)δ(ppm):12.30(1H,s,CONH),7.75(1H,s,H-13),7.32(1H,dd,J＝2.0,8.4Hz,H-14′),7.23(1H,dd,J＝2.4,8.0Hz,H-13′),6.62(1H,s,H-10),6.60(1H,d,J＝2.4Hz,H-11′),6.48(1H,s,H-5′),6.26(1H,s,H-5),6.15(1H,dd,J＝2.0,8.4Hz,H-10′),5.89(1H,s,H-8′),4.04(1H,d,J＝9.2Hz,H-1′),3.96(3H,s,12-OCH₃),3.82(1H,dd,J＝5.6,11.2Hz,H-1),3.75(3H,s,6-OCH₃),3.37(3H,s,6′-OCH₃),3.09(3H,s,7-OCH₃),2.61(3H,s,2′-NCH₃),2.47(3H,s,2-NCH₃)。

H-07¹H-NMR(CDCl₃,400MHz)δ(ppm):10.39(1H,s,CONH),7.82(1H,s,H-13),7.31(1H,d,J＝7.2Hz,H-14′),7.20(1H,d,J＝8.0Hz,H-13′),6.62(1H,s,H-10),6.61(1H,s,H-11′),6.47(1H,s,H-5′),6.32(1H,s,H-5),6.15(1H,d,J＝8.0Hz,H-10′),5.87(1H,s,H-8′),3.98(1H,d,J＝8.8Hz,H-1′),3.95(3H,s,12-OCH₃),3.82(1H,dd,J＝5.2,10.4Hz,H-1),3.75(3H,s,6-OCH₃),3.36(3H,s,6′-OCH₃),3.08(3H,s,7-OCH₃),2.61(3H,s,2′-NCH₃),2.41(3H,s,2-NCH₃)。

H-08¹H-NMR(CDCl₃,400MHz)δ(ppm):11.93(1H,s,CONH),7.72(1H,s,H-13),7.30(1H,dd,J＝2.0,8.4Hz,H-14′),7.21(1H,dd,J＝2.8,8.4Hz,H-13′),6.60(1H,dd,J＝2.4,8.4Hz,H-11′),6.52(1H,s,H-10),6.48(1H,s,H-5′),6.31(1H,s,H-5),6.15(1H,dd,J＝2.0,8.4Hz,H-10′),5.90(1H,s,H-8′),3.97(1H,s,H-1′),3.94(3H,s,12-OCH₃),3.92(2H,m,CH₂),3.83(1H,m,H-1),3.74(3H,s,6-OCH₃),3.37(3H,s,6′-OCH₃),3.11(3H,s,7-OCH₃),2.61(3H,s,2′-NCH₃),2.46(3H,s,2-NCH₃)。

H-09¹H-NMR(CDCl₃,400MHz)δ(ppm):12.36(1H,s,CONH),8.11(1H,s,H-13),7.78(1H,d,J＝15.6Hz,CH＝CH),7.30(1H,dd,J＝2.0,8.4Hz,H-14′),7.23(1H,dd,J＝2.4,8.0Hz,H-13′),6.61(1H,s,H-10),6.58(1H,d,J＝2.4,8.4Hz,H-11′),6.51(1H,s,CH＝CH),6.47(1H,s,H-5′),6.33(1H,s,H-5),6.13(1H,dd,J＝2.0,8.4Hz,H-10′),5.89(1H,s,H-8′),4.06(1H,d,J＝8.8Hz,H-1′),3.98(3H,s,12-OCH₃),3.80(1H,m,H-1),3.75(3H,s,6-OCH₃),3.48(3H,s,6′-OCH₃),3.09(3H,s,7-OCH₃),2.60(3H,s,2′-NCH₃),2.58(3H,s,2-NCH₃)。

H-10¹H-NMR(CDCl₃,400MHz)δ(ppm):12.24(1H,s,CONH),8.05(1H,s,H-13),7.30(1H,d,J＝7.6Hz,H-14′),7.22(1H,dd,J＝2.4,8.4Hz,H-13′),6.59(1H,s,H-10),6.56(1H,s,H-11′),6.47(1H,s,H-5′),6.31(1H,s,H-5),6.13(1H,d,J＝7.6Hz,H-10′),5.89(1H,s,H-8′),4.01(1H,d,J＝9.2Hz,H-1′),3.95(3H,s,12-OCH₃),3.80(1H,dd,J＝5.2,10.8Hz,H-1),3.74(3H,s,6-OCH₃),3.36(3H,s,6′-OCH₃),3.09(3H,s,7-OCH₃),2.60(3H,s,2′-NCH₃),2.51(3H,s,2-NCH₃)。

H-11¹H-NMR(CDCl₃,400MHz)δ(ppm):11.88(1H,s,CONH),7.99(1H,s,H-13),7.29(1H,dd,J＝2.4,8.0Hz,H-14′),7.21(1H,dd,J＝2.4,8.4Hz,H-13′),6.59(1H,d,J＝2.4Hz,H-11′),6.57(1H,s,H-10),6.47(1H,s,H-5′),6.31(1H,s,H-5),6.12(1H,dd,J＝2.0,8.4Hz,H-10′),5.88(1H,s,H-8′),3.99(1H,d,J＝9.2Hz,H-1′),3.96(3H,s,12-OCH₃),3.80(1H,dd,J＝5.6,11.2Hz,H-1),3.75(3H,s,6-OCH₃),3.36(3H,s,6′-OCH₃),3.10(3H,s,7-OCH₃),2.60(3H,s,2′-NCH₃),2.50(3H,s,2-NCH₃)。

H-12¹H-NMR(CDCl₃,400MHz)δ(ppm):12.47(1H,s,CONH),7.88(1H,s,H-13),7.31(1H,dd,J＝2.0,8.0Hz,H-14′),7.22(1H,dd,J＝2.4,8.0Hz,H-13′),6.58(1H,dd,J＝2.4,8.4Hz,H-11′),6.57(1H,s,H-10),6.47(1H,s,H-5),6.31(1H,s,H-5′),6.14(1H,dd,J＝2.0,8.4Hz,H-10′),5.89(1H,s,H-8′),3.98(1H,s,H-1′),3.95(3H,s,12-OCH₃),3.81(1H,dd,J＝5.6,11.2Hz,H-1),3.75(3H,s,6-OCH₃),3.36(3H,s,6′-OCH₃),3.10(3H,s,7-OCH₃),2.60(3H,s,2′-NCH₃),2.47(3H,s,2-NCH₃)。

H-13¹H-NMR(CDCl₃,400MHz)δ(ppm):12.36(1H,s,CONH),7.86(1H,s,H-13),7.30(1H,dd,J＝2.0,8.0Hz,H-14′),7.21(1H,dd,J＝2.8,8.0Hz,H-13′),6.58(1H,dd,J＝2.8,8.4Hz,H-11′),6.57(1H,s,H-10),6.47(1H,s,H-5),6.31(1H,s,H-5′),6.13(1H,dd,J＝2.4,8.8Hz,H-10′),5.89(1H,s,H-8′),3.98(1H,m,H-1′),3.93(3H,s,12-OCH₃),3.79(1H,m,H-1),3.75(3H,s,6-OCH₃),3.36(3H,s,6′-OCH₃),3.10(3H,s,7-OCH₃),2.60(3H,s,2′-NCH₃),2.50(3H,s,2-NCH₃)。

H-14¹H-NMR(CDCl₃,400MHz)δ(ppm):13.49(1H,s,CONH),7.90(1H,s,H-13),7.33(1H,dd,J＝2.0,8.0Hz,H-14′),7.22(1H,dd,J＝2.8,8.0Hz,H-13′),6.61(1H,dd,J＝2.8,8.4Hz,H-11′),6.60(1H,s,H-10),6.49(1H,s,H-5′),6.32(1H,s,H-5),6.14(1H,dd,J＝2.0,8.8Hz,H-10′),5.90(1H,s,H-8′),3.96(3H,s,12-OCH₃),3.87(1H,dd,J＝5.6,11.2Hz,H-1′),3.75(3H,s,6-OCH₃),3.37(3H,s,6′-OCH₃),3.11(3H,s,7-OCH₃),2.62(3H,s,2′-NCH₃),2.49(3H,s,2-NCH₃)。

H-15¹H-NMR(CDCl₃,400MHz)δ(ppm):12.44(1H,s,CONH),7.86(1H,s,H-13),7.31(1H,dd,J＝2.0,8.0Hz,H-14′),7.22(1H,dd,J＝3.2,8.4Hz,H-13′),6.64(1H,d,J＝2.8Hz,H-11′),6.62(1H,s,H-10),6.48(1H,s,H-5′),6.31(1H,s,H-5),6.14(1H,dd,J＝2.0,8.4Hz,H-10′),5.90(1H,s,H-8′),4.03(1H,d,J＝8.8Hz,H-1′),3.96(3H,s,12-OCH₃),3.81(1H,dd,J＝5.6,11.2Hz,H-1),3.75(3H,s,6-OCH₃),3.37(3H,s,6′-OCH₃),3.10(3H,s,7-OCH₃),2.60(3H,s,2′-NCH₃),2.54(3H,s,2-NCH₃)。

H-16¹H-NMR(CDCl₃,400MHz)δ(ppm):12.07(1H,s,-CONH-),7.68(1H,s,H-13),7.31(1H,dd,J＝2.0,8.4Hz,H-14′),7.23(1H,dd,J＝3.2,8.4Hz,H-13′),6.23(1H,s,H-10),6.30(1H,d,J＝2.4Hz,H-11′),6.48(1H,s,H-5′),6.28(1H,s,H-5),6.15(1H,dd,J＝2.0,10.4Hz,H-10′),5.89(1H,s,H-8′),4.06(1H,d,J＝9.2Hz,H-1′),3.95(3H,s,12-OCH₃),3.81(1H,dd,J＝5.6,11.2Hz,H-1),3.73(3H,s,6-OCH₃),3.38(3H,s,6′-OCH₃),3.09(3H,s,7-OCH₃),2.60(3H,s,2′-NCH₃),2.54(3H,s,2-NCH₃)。

H-17¹H-NMR(CDCl₃,400MHz)δ(ppm):7.36(1H,dd,J＝2.4,8.4Hz,H-14′),7.06(1H,dd,J＝2.4,8.0Hz,H-13′),6.96(1H,s,H-13),6.88(1H,dd,J＝2.8,8.4Hz,H-11′),6.80(1H,s,H-10),6.52(1H,s,H-5′),6.35(1H,d,J＝2.0Hz,H-10′),6.33(1H,s,H-5),5.93(1H,s,H-8′),3.96(3H,s,12-OCH₃),3.85(1H,m,H-1′),3.75(3H,s,6-OCH₃),3.36(3H,s,6′-OCH₃),3.20(3H,s,7-OCH₃),2.17(3H,s,2′-NCH₃),2.07(3H,s,2-NCH₃)。

H-20¹H-NMR(CDCl₃,400MHz)δ(ppm):7.28(1H,d,J＝6.8Hz,H-14′),7.25(1H,s,H-13),7.15(1H,d,J＝8.0Hz,H-13′),6.55(1H,dd,J＝1.6,8.0Hz,H-11′),6.46(1H,s,H-10),6.40(1H,s,H-5′),6.30(1H,s,H-5),6.12(1H,d,J＝7.6Hz,H-10′),5.84(1H,s,H-8′),3.93(3H,s,12-OCH₃),3.84(1H,d,J＝9.2Hz,H-1′),3.79(1H,dd,J＝5.2,11.2Hz,H-1),3.73(3H,s,6-OCH₃),3.35(3H,s,6′-OCH₃),3.07(3H,s,7-OCH₃),2.59(3H,s,2′-NCH₃),2.49(3H,s,2-NCH₃)。

H-21¹H-NMR(CDCl₃,400MHz)δ(ppm):7.25(1H,d,J＝2.0Hz,H-14′),7.16(1H,dd,J＝2.4,8.0Hz,H-13′),6.90(1H,s,H-13),6.50(1H,dd,J＝2.4,8.4Hz,H-11′),6.48(1H,s,H-10),6.44(1H,s,H-5′),6.36(1H,s,H-5),6.11(1H,dd,J＝1.6,8.4Hz,H-10′),5.88(1H,s,H-8′),4.14(1H,d,J＝9.6Hz,H-1′),3.88(1H,m,H-1),3.79(3H,s,12-OCH₃),3.77(3H,s,6-OCH₃),3.38(3H,s,6′-OCH₃),3.11(3H,s,7-OCH₃),2.69(3H,s,2′-NCH₃),2.58(3H,s,2-NCH₃)。

H-22¹H-NMR(CDCl₃,400MHz)δ(ppm):7.27(1H,dd,J＝2.0,8.0Hz,H-14′),7.16(1H,dd,J＝2.4,8.0Hz,H-13′),6.84(1H,s,H-13),6.51(1H,dd,J＝2.8,8.4Hz,H-11′),6.48(1H,s,H-10),6.45(1H,s,H-5′),6.33(1H,s,H-5),6.12(1H,dd,J＝2.0,8.4Hz,H-10′),5.88(1H,s,H-8′),4.02(1H,d,J＝9.2Hz,H-1′),3.78(3H,s,12-OCH₃),3.77(1H,s,H-1),3.75(3H,s,6-OCH₃),3.38(3H,s,6′-OCH₃),3.10(3H,s,7-OCH₃),2.61(3H,s,2′-NCH₃),2.58(3H,s,2-NCH₃)。

H-23¹H-NMR(CDCl₃,400MHz)δ(ppm):7.33-7.29(7H,m,H-Ph,13,14′),7.22(1H,dd,J＝2.4,8.0Hz,H-13′),6.54(1H,dd,J＝2.8,8.4Hz,H-11′),6.49(1H,s,H-10),6.46(1H,s,H-5′),6.24(1H,s,H-5),6.14(1H,dd,J＝2.0,8.8Hz,H-10′),5.86(1H,s,H-8′),3.94(3H,s,12-OCH₃),3.78(2H,m,H-1′,1),3.73(3H,s,6-OCH₃),3.34(3H,s,6′-OCH₃),3.08(3H,s,7-OCH₃),2.58(3H,s,2′-NCH₃),2.30(3H,s,2-NCH₃)。

H-24¹H-NMR(CDCl₃,400MHz)δ(ppm):7.29(1H,dd,J＝2.0,8.4Hz,H-14′),7.24(1H,s,H-13),7.18(1H,dd,J＝2.4,8.0Hz,H-13′),6.56(1H,dd,J＝2.8,8.4Hz,H-11′),6.46(1H,s,H-10),6.41(1H,s,H-5′),6.30(1H,s,H-5),6.13(1H,dd,J＝2.0,8.4Hz,H-10′),5.85(1H,s,H-8′),3.94(3H,s,12-OCH₃),3.83(2H,m,H-1′,1),3.74(3H,s,6-OCH₃),3.35(3H,s,6′-OCH₃),3.08(3H,s,7-OCH₃),2.58(3H,s,2′-NCH₃),2.50(3H,s,2-NCH₃)。

H-25¹H-NMR(CDCl₃,400MHz)δ(ppm):7.28(1H,dd,J＝2.4,8.0Hz,H-14′),7.18(1H,dd,J＝2.4,8.0Hz,H-13′),6.61(1H,dd,J＝2.4,8.0Hz,H-11′),6.50(1H,s,H-13),6.46(1H,s,H-10),6.31(1H,s,H-5′),6.29(1H,s,H-5),6.12(1H,dd,J＝2.0,8.4Hz,H-10′),5.87(1H,s,H-8′),3.94(1H,m,H-1′),3.88(3H,s,12-OCH₃),3.81(1H,m,H-1),3.74(3H,s,6-OCH₃),3.35(3H,s,6′-OCH₃),3.11(3H,s,7-OCH₃),2.88(6H,s,CH₃),2.59(3H,s,2′-NCH₃),2.42(3H,s,2-NCH₃)。

H-26¹H-NMR(CDCl₃,400MHz)δ(ppm):10.19(1H,s,-CONH-),7.32(1H,s,H-13),7.29(1H,dd,J＝1.6,8.0Hz,H-14′),7.21(1H,dd,J＝2.4,8.0Hz,H-13′),6.59(1H,s,H-10),6.58(1H,d,J＝2.4Hz,H-11′),6.46(1H,s,H-5′),6.30(1H,s,H-5),6.12(1H,dd,J＝2.0,8.4Hz,H-10′),5.87(1H,s,H-8′),3.98(1H,d,J＝9.2Hz,H-1′),3.93(3H,s,12-OCH₃),3.74(3H,s,6-OCH₃),3.35(3H,s,6′-OCH₃),3.09(3H,s,7-OCH₃),2.60(3H,s,2′-NCH₃),2.43(3H,s,2-NCH₃)。

H-27¹H-NMR(CDCl₃,400MHz)δ(ppm):7.42(1H,s,H-13),7.37(1H,dd,J＝2.0,8.0Hz,H-14′),7.12(1H,dd,J＝2.4,8.0Hz,H-13′),6.77(1H,dd,J＝2.8,8.4Hz,H-11′),6.54(1H,s,H-10),6.52(1H,s,H-5′),6.30(1H,s,H-5),6.28(1H,d,J＝2.0Hz,H-10′),5.98(1H,s,H-8′),3.98(3H,s,12-OCH₃),3.91(1H,dd,J＝6.0,10.8Hz,H-1′),3.75(3H,s,6-OCH₃),3.66(1H,m,H-1),3.38(3H,s,6′-OCH₃),3.18(3H,s,7-OCH₃),2.63(3H,s,2′-NCH₃),2.21(3H,s,2-NCH₃)。

H-28¹H-NMR(CDCl₃,400MHz)δ(ppm):7.42(1H,s,H-13),7.39(1H,dd,J＝2.4,8.4Hz,H-14′),7.15(1H,dd,J＝2.8,8.4Hz,H-13′),6.77(1H,dd,J＝2.4,8.4Hz,H-11′),6.55(1H,s,H-10),6.52(1H,s,H-5′),6.30(1H,dd,J＝2.0,8.4Hz,H-10′),6.00(1H,s,H-8′),3.99(3H,s,12-OCH₃),3.79(3H,s,6-OCH₃),3.44(3H,s,6′-OCH₃),3.21(3H,s,7-OCH₃),2.66(3H,s,2′-NCH₃),2.20(3H,s,2-NCH₃)。

H-29¹H-NMR(CDCl₃,400MHz)δ(ppm):7.28(1H,d,J＝9.6Hz,H-14′),7.18(1H,dd,J＝2.0,8.0Hz,H-13′),6.60(1H,dd,J＝2.0,8.4Hz,H-11′),6.50(1H,s,H-10),6.46(1H,s,H-5′),6.31(1H,s,H-5),6.29(1H,s,H-13),6.12(1H,dd,J＝1.6,8.0Hz,H-10′),5.87(1H,s,H-8′),3.94(1H,d,J＝9.2Hz,H-1′),3.87(3H,s,12-OCH₃),3.80(1H,dd,J＝5.2,11.2Hz,H-1),3.73(3H,s,6-OCH₃),3.35(3H,s,6′-OCH₃),3.11(3H,s,7-OCH₃),2.61(3H,s,2′-NCH₃),2.42(3H,s,2-NCH₃)。

H-30¹H-NMR(CDCl₃,400MHz)δ(ppm):7.33(1H,dd,J＝2.4,8.4Hz,H-14′),7.21(1H,dd,J＝2.4,8.0Hz,H-13′),6.60(1H,dd,J＝2.8,8.4Hz,H-11′),6.50(1H,s,H-13),6.47(1H,s,H-10),6.32(1H,s,H-5),6.31(1H,s,H-5′),6.04(1H,dd,J＝2.4,8.4Hz,H-10′),5.89(1H,s,H-8′),3.92(1H,m,H-1′),3.88(3H,s,12-OCH₃),3.80(1H,m,H-1),3.75(3H,s,6-OCH₃),3.49(3H,s,6′-OCH₃),3.36(3H,s,7-OCH₃),2.66(3H,s,2′-NCH₃),2.42(3H,s,2-NCH₃)。

H-31¹H-NMR(CDCl₃,400MHz)δ(ppm):7.02(1H,dd,J＝2.4,8.0Hz,H-14′),6.98(1H,d,J＝8.0Hz,H-13′),6.90(1H,d,J＝2.0Hz,H-14),6.88(1H,d,J＝4.0Hz,H-13),6.65(1H,s,H-10),6.55(1H,dd,J＝2.4,8.0Hz,H-11′),6.53(1H,s,H-5′),6.48(1H,dd,J＝2.4,8.0Hz,H-10′),6.33(1H,s,H-5),5.68(1H,s,H-8′),3.89(3H,s,12-OCH₃),3.80(3H,s,6-OCH₃),3.76(1H,d,J＝4.8Hz,H-1′),3.44(3H,s,6′-OCH₃),2.83(3H,s,2′-NCH₃),2.60(3H,s,2-NCH₃)。

H-32¹H-NMR(CDCl₃,400MHz)δ(ppm):7.42(1H,s,H-13),7.37(1H,dd,J＝2.0,8.0Hz,H-14′),7.13(1H,dd,J＝2.4,8.0Hz,H-13′),6.75(1H,dd,J＝2.4,8.0Hz,H-11′),6.52(1H,s,H-10),6.51(1H,s,H-5′),6.33(1H,s,H-5),6.29(1H,dd,J＝2.0,8.4Hz,H-10′),5.85(1H,s,H-8′),3.99(3H,s,12-OCH₃),3.81(2H,m,H-1′,1),3.72(3H,s,6-OCH₃),3.38(3H,s,6′-OCH₃),2.49(3H,s,2′-NCH₃),2.22(3H,s,2-NCH₃)。

H-33¹H-NMR(CDCl₃,400MHz)δ(ppm):7.42(1H,s,H-13),7.34(1H,d,J＝7.6Hz,H-14′),7.30(1H,d,J＝3.2Hz,H-13′),6.74(1H,d,J＝3.2Hz,H-11′),6.60(1H,s,H-10),6.46(1H,s,H-5′),6.40(1H,s,H-5),6.22(1H,m,H-10′),5.75(1H,s,H-8′),3.98(3H,s,12-OCH₃),3.74(1H,m,H-1′),3.69(3H,s,6-OCH₃),3.59(1H,m,H-1),3.53(3H,s,6′-OCH₃),2.24(3H,s,2′-NCH₃),1.91(3H,s,2-NCH₃)。

H-34¹H-NMR(CDCl₃,400MHz)δ(ppm):7.37(1H,d,J＝8.0Hz,H-14′),7.24(1H,s,H-13),7.17(1H,d,J＝6.8Hz,H-13′),6.56(1H,m,H-11′),6.41(1H,s,H-10),6.34(1H,s,H-5′),6.31(1H,s,H-5),6.03(1H,dd,J＝8.0,3.2Hz,H-10′),5.80(1H,s,H-8′),4.00(3H,s,12-OCH₃),3.63(3H,s,6-OCH₃),3.39(3H,s,6′-OCH₃),2.22(3H,s,2′-NCH₃),2.05(3H,s,2-NCH₃)。

H-35¹H-NMR(CDCl₃,400MHz)δ(ppm):12.77(1H,s,-CONH-),7.56-8.07(5H,m,H-Bz),7.37(1H,d,J＝8.0Hz,H-14′),7.24(1H,s,H-13),7.17(1H,d,J＝6.8Hz,H-13′),6.56(1H,m,H-11′),6.41(1H,s,H-10),6.34(1H,s,H-5′),6.31(1H,s,H-5),6.03(1H,dd,J＝2.0,8.4Hz,H-10′),5.80(1H,s,H-8′),4.00(3H,s,12-OCH₃),3.96-3.67(3H,m,H-1′,1,3b),3.63(3H,s,6-OCH₃),3.43(1H,s,H-3′b),3.39(3H,s,6′-OCH₃),2.22(3H,s,2′-NCH₃),2.14(2H,m,H-15b,4a),2.05(3H,s,2-NCH₃)。

H-36¹H-NMR(CDCl₃,400MHz)δ(ppm):7.45(1H,s,H-13),7.43(1H,dd,J＝2.4,8.4Hz,H-14′),7.17(1H,dd,J＝2.4,8.4Hz,H-13′),6.78(1H,dd,J＝2.0,8.0Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝2.0,8.4Hz,H-10′),6.13(1H,s,H-8′),4.00(3H,s,12-OCH₃),3.63(3H,s,6-OCH₃),3.39(3H,s,6′-OCH₃),2.22(3H,s,2′-NCH₃),2.05(3H,s,2-NCH₃)。

H-37¹H-NMR(CDCl₃,500MHz)δ(ppm):12.32(1H,s,H-S),7.81(1H,s,H-13),7.35(1H,dd,J＝1.6,8.2Hz,H-14′),7.18(1H,dd,J＝2.5,8.2Hz,H-13’),6.75(1H,s,H-10),6.68(1H,dd,J＝2.5,8.4Hz,H-11’),6.52(1H,s,H-5’),6.43(1H,s,H-5),6.19(1H,dd,J＝1.7,8.4Hz,H-10’),5.94(1H,s,H-8’),3.97(3H,s,12-OCH₃),3.91(1H,dd,J＝5.9,10.6Hz,H-1’),3.78(3H,s,6-OCH₃),3.42(1H,m,H-1),3.38(3H,s,6′-OCH₃),3.18(3H,s,7-OCH₃),2.84(3H,s,2′-NCH₃),2.65(3H,s,2-NCH₃)。

H-38¹H-NMR(CDCl₃,400MHz)δ(ppm):7.55(2H,dd,J＝2.2,8.8Hz,H-Ph),7.35(1H,dd,J＝7.4,14.8Hz,H-Ph),7.18(2H,t,J＝8.0,15.2Hz,H-Ph),7.09(1H,d,J＝2.0Hz,H-14′),7.05(1H,s,H-13),7.01(1H,dd,J＝2.8,8.0Hz,H-13′),6.55(1H,dd,J＝2.4,8.4Hz,H-11′),6.46(1H,s,H-10),6.40(1H,s,H-5′),6.29(1H,s,H-5),6.12(1H,dd,J＝2.0,8.8Hz,H-10′),5.84(1H,s,H-8′),3.93(3H,s,12-OCH₃),3.85(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.73(3H,s,6-OCH₃),3.42(1H,m,H-15′b),3.35(3H,s,6′-OCH₃),3.07(3H,s,7-OCH₃),＝2.58(3H,s,2′-NCH₃),2.50(3H,s,2-NCH₃)。

H-39¹H-NMR(CDCl₃,400MHz)δ(ppm):7.78(1H,s,H-13),7.50(1H,dd,J＝2.0,8.4Hz,H-14’),7.25(1H,dd,J＝2.8,8.4Hz,H-13’),6.75(1H,dd,J＝2.8,8.4Hz,H-11’),6.66(1H,s,H-10),6.65(1H,s,H-5’),6.45(1H,s,H-5),6.24(1H,dd,J＝2.0,8.4Hz,H-10’),6.02(1H,s,H-8’),4.00(3H,s,12-OCH₃),3.82(1H,dd,J＝5.7,10.6Hz,H-1′),3.79(3H,s,6-OCH₃),3.48(1H,m,H-1),3.45(3H,s,14-SO₂-OCH₃),3.20(3H,s,6′-OCH₃),3.06(3H,s,7-OCH₃),2.78(3H,s,2′-NCH₃),2.57(3H,s,2-NCH₃)。

H-40¹H-NMR(CDCl₃,400MHz)δ(ppm):7.45(1H,s,H-13),7.43(1H,dd,J＝2.0,8.4Hz,H-14′),7.11(1H,dd,J＝2.0,8.4Hz,H-13′),6.86(1H,s,H-10),6.78(1H,dd,J＝2.0,6.8Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝1.6,6.8Hz,H-10′),6.04(1H,s,H-8′),4.00(3H,s,12-OCH₃),3.85(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝2.4,8.0Hz,H-1),3.71(3H,s,6-OCH₃),3.45(1H,m,H-15′b),3.29(3H,s,6′-OCH₃),3.28(3H,s,7-OCH₃),2.64(3H,s,2′-NCH₃),2.21(3H,s,2-NCH₃).

H-41¹H-NMR(CDCl₃,400MHz)δ(ppm):7.36(1H,s,H-13),7.32(1H,dd,J＝2.0,8.4Hz,H-14′),7.21(1H,dd,J＝2.0,6.8Hz,H-13′),6.78(1H,dd,J＝1.6,6.8Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝2.4,8.4Hz,H-10′),6.04(1H,s,H-8′),4.00(3H,s,12-OCH₃),3.85(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.71(3H,s,6-OCH₃),3.45(1H,m,H-15′b),3.29(3H,s,6′-OCH₃),3.28(3H,s,7-OCH₃),2.65(3H,s,2′-NCH₃),2.24(3H,s,2-NCH₃).

H-42¹H-NMR(CDCl₃,400MHz)δ(ppm):7.40(1H,dd,J＝1.6,6.4Hz,H-14′),7.23(1H,dd,J＝2.0,6.4Hz,H-13′),6.86(1H,s,H-14),6.85(1H,s,H-13),6.76(1H,s,H-10),6.74(1H,dd,J＝2.0,6.8Hz,H-11′),6.51(1H,s,H-5′),6.37(1H,dd,J＝1.2,6.0Hz,H-10′),5.78(1H,s,H-5),5.42(1H,s,H-8′),3.93(3H,s,12-OCH₃),3.80(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.54(3H,s,6-OCH₃),3.45(1H,m,H-15′b),3.14(3H,m,6′-OCH₃),2.62(3H,s,2′-NCH₃),2.20(3H,s,2-NCH₃)。

H-43¹H-NMR(CDCl₃,400MHz)δ(ppm):7.47(1H,s,H-13),7.41(1H,dd,J＝2.0,8.0Hz,H-14′),7.35(1H,dd,J＝2.0,8.0Hz,H-13′),7.02(1H,s,H-10),6.77(1H,dd,J＝1.6,6.8Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝1.6,6.8Hz,H-10′),6.04(1H,s,H-8′),4.03(3H,s,12-OCH₃),3.86(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.71(3H,s,6-OCH₃),3.45(1H,m,H-15′b),3.29(3H,s,6′-OCH₃),3.28(3H,s,7-OCH₃),2.64(3H,s,2′-NCH₃),2.25(3H,s,2-NCH₃)。

H-44¹H-NMR(CDCl₃,400MHz)δ(ppm):7.47(1H,s,H-13),7.41(1H,dd,J＝2.0,8.0Hz,H-14′),7.35(1H,dd,J＝2.0,8.0Hz,H-13′),6.77(1H,dd,J＝1.6,6.8Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝1.6,6.8Hz,H-10′),6.04(1H,s,H-8′),4.03(3H,s,12-OCH₃),3.80(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.54(3H,s,6-OCH₃),3.45(1H,m,H-15′b),3.14(3H,m,6′-OCH₃),2.62(3H,s,2′-NCH₃),2.20(3H,s,2-NCH₃)。

H-45¹H-NMR(CDCl₃,400MHz)δ(ppm):12.32(1H,s,14-SO₃H),7.47-7.78(5H,m,H-Bz),7.34(2H,m,H-13′,14′),7.10(1H,s,H-13),6.87(1H,s,H-14),6.77(1H,m,H-11′),6.60(1H,s,H-10),6.44(1H,s,H-5′),6.39(1H,s,H-5),6.24(1H,m,H-10′),5.57(1H,s,H-8′),3.92(3H,s,12-OCH₃),3.69(3H,s,6-OCH₃),3.55(3H,m,H-1′,1,4b),3.48(3H,s,6′-OCH₃),3.14(3H,m,6′-OCH₃),2.62(3H,s,2′-NCH₃),2.20(3H,s,2-NCH₃)。

H-46¹H-NMR(CDCl₃,400MHz)δ(ppm):7.37-7.66(5H,m,H-Bz),7.34(2H,m,H-13′,14′),7.10(1H,s,H-13),7.06(1H,s,H-14),6.77(1H,m,H-11′),6.60(1H,s,H-10),6.44(1H,s,H-5′),6.39(1H,s,H-5),6.24(1H,m,H-10′),5.57(1H,s,H-8′),3.92(3H,s,12-OCH₃),3.69(3H,s,6-OCH₃),3.55(3H,m,H-1′,1,4b),3.49(3H,s,6′-OCH₃),3.17(3H,s,2′-NCH₃),2.68(2H,m,H-15b,4a),2.46(3H,s,2-NCH₃)。

H-47¹H-NMR(CDCl₃,400MHz)δ(ppm):7.37-7.66(5H,m,H-Bz),7.34(2H,m,H-13′,H-14′),7.10(1H,s,H-13),6.77(1H,m,H-11′),6.60(1H,s,H-10),6.44(1H,s,H-5′),6.39(1H,s,H-5),6.24(1H,m,H-10′),5.57(1H,s,H-8′),3.92(3H,s,12-OCH₃),3.69(3H,s,6-OCH₃),3.55(3H,m,H-1′,1,4b),3.48(3H,s,6′-OCH₃),3.20(3H,s,2′-NCH₃),2.58(2H,m,H-15b,4a),2.17(3H,s,2-NCH₃)。

H-48¹H-NMR(CDCl₃,400MHz)δ(ppm):7.35(1H,dd,J＝1.6,6.4Hz,H-14′),7.14(1H,dd,J＝2.0,6.4Hz,H-13′),6.86(2H,m,H-13,H-14),6.80(1H,dd,J＝2.0,6.8Hz,H-11′),6.54(1H,s,H-10),6.45(1H,s,H-5′),6.28(1H,dd,J＝2.0,6.8Hz,H-10′),5.95(1H,s,H-8′),3.93(3H,s,12-OCH₃),3.82(1H,m,H-1′),3.28(1H,dd,J＝5.6,11.2Hz,H-1),3.00(3H,s,6-OCH₃),2.85(1H,m,H-15′b),2.73(3H,m,6′-OCH₃),2.50(3H,m,2′-NCH₃),2.15(3H,s,2-NCH₃)。

H-49¹H-NMR(CDCl₃,400MHz)δ(ppm):7.36(1H,dd,J＝2.4,8.4Hz,H-14′),7.08(1H,m,H-13,H-14),7.02(1H,dd,J＝2.8,8.4Hz,H-13′),6.85(1H,dd,J＝2.8,8.0Hz,H-11′),6.55(1H,s,H-10),6.53(1H,s,H-5′),6.32(1H,dd,J＝2.0,8.4Hz,H-10′),5.93(1H,s,H-8′),3.85(3H,s,12-OCH₃),3.50(1H,m,H-1′),3.15(1H,d,J＝3.2Hz,H-1),2.80(3H,s,6-OCH₃),2.63(1H,m,H-15′b),2.48(3H,m,6′-OCH₃),2.35(3H,m,2′-NCH₃),2.11(3H,s,2-NCH₃)。

H-50¹H-NMR(CDCl₃,400MHz)δ(ppm):7.41(1H,s,H-13),7.36(1H,dd,J＝2.0,6.4Hz,H-14′),7.12(1H,dd,J＝2.0,6.4Hz,H-13′),6.75(1H,dd,J＝2.0,6.8Hz,H-11′),6.55(1H,s,H-10),6.52(1H,s,H-5′),6.28(1H,dd,J＝2.0,6.8Hz,H-10′),6.01(1H,s,H-8′),3.98(3H,s,12-OCH₃),3.93(1H,m,H-1′),3.73(3H,s,6-OCH₃),3.68(1H,d,J＝2.0Hz,H-1),3.45(1H,m,H-15′b),3.37(3H,m,6′-OCH₃),3.19(3H,m,2′-NCH₃),2.65(3H,s,2-NCH₃)。

H-51¹H-NMR(CDCl₃,400MHz)δ(ppm):7.43(1H,s,H-13),7.41(1H,dd,J＝2.0,6.4Hz,H-14′),7.16(1H,dd,J＝2.0,6.8Hz,H-13′),6.78(1H,dd,J＝2.0,6.4Hz,H-11′),6.51(1H,s,H-5′),6.32(1H,dd,J＝1.6,6.4Hz,H-10′),6.04(1H,s,H-8′),4.00(3H,s,12-OCH₃),3.92(1H,m,H-1′),3.71(3H,s,6-OCH₃),3.67(1H,s,H-1),3.42(1H,m,H-15′b),3.27(3H,m,6′-OCH₃),2.64(3H,m,2′-NCH₃),2.21(3H,s,2-NCH₃)。

H-52¹H-NMR(CDCl₃,400MHz)δ(ppm):7.41(1H,s,H-13),7.36(1H,dd,J＝2.0,8.4Hz,H-14′),7.11(1H,dd,J＝2.4,8.0Hz,H-13′),6.75(1H,dd,J＝2.8,8.4Hz,H-11′),6.55(1H,s,H-10),6.49(1H,s,H-5′),6.35(1H,s,H-5),6.24(1H,dd,J＝1.6,8.0Hz,H-10′),6.04(1H,s,H-8′),3.98(3H,s,12-OCH₃),3.85(1H,m,H-1′),3.72(3H,s,6-OCH₃),3.66(1H,s,H-1),3.42(1H,m,H-15′b),3.45(3H,s,6′-OCH₃),3.11(3H,s,7-CH₃),2.59(3H,s,2′-NCH₃),2.32(3H,s,2′-NCH₃)。

H-53¹H-NMR(CDCl₃,400MHz)δ(ppm):12.31(1H,s,14-SO₃H),7.83(1H,s,H-13),7.32(1H,dd,J＝2.0,8.4Hz,H-14′),7.11(1H,dd,J＝2.0,8.0Hz,H-13′),6.77(1H,s,H-10),6.67(1H,dd,J＝2.8,8.4Hz,H-11′),6.50(1H,s,H-5′),6.39(1H,s,H-5),6.24(1H,dd,J＝1.6,6.8Hz,H-10′),5.97(1H,s,H-8′),3.98(3H,s,12-OCH₃),3.90(1H,m,H-1′),3.81(3H,s,6-OCH₃),3.36(3H,s,6′-OCH₃),3.23(1H,m,H-15′b),2.79(3H,s,2′-NCH₃),2.64(3H,s,2′-NCH₃)。

H-54¹H-NMR(CDCl₃,400MHz)δ(ppm):7.38(1H,dd,J＝1.6,8.0Hz,H-14′),7.16(1H,dd,J＝2.0,6.8Hz,H-13′),7.08(1H,s,H-13),6.86(1H,dd,J＝2.4,8.8Hz,H-11′),6.57(1H,s,H-5′),6.56(1H,s,H-5′),6.35(1H,dd,J＝1.6,6.4Hz,H-10′),6.03(1H,s,H-8′),4.00(3H,s,12-OCH₃),3.85(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.71(3H,s,6-OCH₃),3.45(1H,m,H-15′b),3.29(3H,s,6′-OCH₃),3.28(3H,s,7-OCH₃),2.64(3H,s,2′-NCH₃),2.21(3H,s,2-NCH₃)。

H-55¹H-NMR(CDCl₃,400MHz)δ(ppm):7.41(1H,dd,J＝2.0,8.0Hz,H-14′),7.14(1H,dd,J＝2.0,6.8Hz,H-13′),7.08(1H,s,H-13),6.86(1H,dd,J＝2.4,8.8Hz,H-11′),6.57(1H,s,H-5′),6.56(1H,s,H-5′),6.35(1H,dd,J＝1.6,6.4Hz,H-10′),6.03(1H,s,H-8′),4.00(3H,s,12-OCH₃),3.92(1H,d,J＝10.0Hz,H-1′),3.78(1H,dd,J＝5.6,11.2Hz,H-1),3.71(3H,s,6-OCH₃),3.45(1H,m,H-15′b),3.29(3H,s,6′-OCH₃),3.28(3H,s,7-OCH₃),2.80(3H,s,2′-NCH₃),2.17(3H,s,2-NCH₃).

H-57¹H-NMR(CDCl₃,400MHz)δ(ppm):7.54(10H,m,2″(-O-Ph)₂),7.30(1H,dd,J＝4.0,8.0Hz,H-14′),7.25(1H,s,H-13),7.20(1H,dd,J＝4.0,8.0Hz,H-13′),6.58(1H,dd,J＝4.0,8.0Hz,H-11′),6.47(1H,s,H-10),6.46(1H,s,H-5′),6.26(1H,s,H-5),6.14(1H,dd,J＝4.0,8.0Hz,H-10′),5.87(1H,s,H-8′),3.94(3H,s,21-OCH₃),3.83(1H,d,J＝16.0Hz,H-1),3.72(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.6,12.8Hz,H-15′α),3.33(3H,s,18′-OCH₃),3.09(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.58(3H,s,16′-OCH₃),2.49(1H,d,J＝13.6Hz,H-15b),2.32(3H,s,16-OCH₃).

H-58¹H-NMR(CDCl₃,500MHz)δ(ppm):7.94(5H,m,2″-Ph),7.49(5H,m,2″-Ph′),7.24(1H,dd,J＝5.0,10.0Hz,H-14′),7.14(1H,dd,J＝5.0,10.0Hz,H-13′),6.87(1H,s,H-13),6.51(1H,s,H-10),6.48(1H,dd,J＝5.0,10.0Hz,H-11′),6.44(1H,s,H-5′),6.20(1H,s,H-5),6.07(1H,dd,J＝5.0,10.0Hz,H-10′),5.83(1H,s,H-8′),3.77(1H,d,J＝20.0Hz,H-1),3.70(3H,s,21-OCH₃),3.59(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.0,15.0Hz,H-15′α),3.33(3H,s,18′-OCH₃),3.04(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.58(3H,s,16′-OCH₃),2.32(1H,d,J＝13.6Hz,H-15b),2.08(3H,s,16-OCH₃).

H-59¹H-NMR(CDCl₃,500MHz)δ(ppm):7.45(1H,s,H-6″),7.35(2H,s,H-5″,H-7″),7.34(2H,s,H-4″,H-8″),7.30(1H,dd,J＝5.0,10.0Hz,H-14′),7.29(1H,s,H-13),7.18(1H,dd,J＝5.0,10.0Hz,H-13′),6.60(1H,dd,J＝5.0,10.0Hz,H-11′),6.54(1H,s,H-10),6.46(1H,s,H-5′),6.29(1H,s,H-5),6.15(1H,dd,J＝5.0,10.0Hz,H-10′),5.89(1H,s,H-8′),3.96(3H,s,21-OCH₃),3.93(1H,dd,J＝7.0,14.0Hz,H-1′),3.72(3H,s,18-OCH₃),3.73(1H,s,H-1),3.52(1H,m,H-3β),3.43(1H,m,H-3′α),3.37(3H,s,18′-OCH₃),3.24(1H,dd,J＝7.0,16.0Hz,H-15′α),3.08(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.87(1H,s,NH),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.60(3H,s,16′-OCH₃),,2.54(3H,s,16-OCH₃),2.51(1H,d,J＝17.0Hz,H-15b),2.25(1H,dd,J＝6.5,20.0Hz,H-4α).

H-60¹H-NMR(CDCl₃,400MHz)δ(ppm):7.39(1H,dd,J＝4.0,8.0Hz,H-14′),7.28(2H,dd,J＝4.0,12.0Hz,H-6″,H-8″),7.25(2H,dd,J＝4.0,12.0Hz,H-5″,H-9″),7.13(1H,dd,J＝4.0,8.0Hz,H-13′),6.92(1H,dd,J＝4.0,8.0Hz,H-11′),6.74(1H,s,H-13),6.71(1H,s,H-10),6.54(1H,s,H-5),6.38(1H,dd,J＝4.0,8.0Hz,H-10′),6.24(1H,s,H-5′),5.97(1H,s,H-8′),3.95(1H,d,J＝8.0Hz,H-1),3.91(3H,s,21-OCH₃),3.77(1H,dd,J＝8.0,16.0Hz,H-1′),3.71(3H,s,18-OCH₃),3.60(1H,m,H-3β),3.45(1H,m,H-3′α),3.36(3H,s,18′-OCH₃),3.20(1H,dd,J＝5.6,12.8Hz,H-15′α),3.18(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.64(3H,s,16′-OCH₃),2.51(1H,d,J＝13.6Hz,H-15b),2.41(1H,dd,J＝5.2,16.0Hz,H-4α),2.18(3H,s,16-OCH₃).

H-61¹H-NMR(CDCl₃,500MHz)δ(ppm):7.52(1H,s,H-13),7.29(1H,dd,J＝5.0,10.0Hz,H-14′),7.19(1H,dd,J＝5.0,10.0Hz,H-13′),6.58(1H,dd,J＝5.0,10.0Hz,H-11′),6.54(1H,s,H-10),6.46(1H,s,H-5′),6.29(1H,s,H-5),6.14(1H,dd,J＝5.0,10.0Hz,H-10′),5.87(1H,s,H-8′),3.96(3H,s,21-OCH₃),3.93(1H,dd,J＝7.0,14.0Hz,H-1′),3.72(3H,s,18-OCH₃),3.73(1H,s,H-1),3.52(1H,m,H-3β),3.43(1H,m,H-3′α),3.37(3H,s,18′-OCH₃),3.24(1H,dd,J＝7.0,16.0Hz,H-15′α),3.08(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.87(1H,s,NH),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.60(3H,s,16′-OCH₃),,2.54(3H,s,16-OCH₃),2.51(1H,d,J＝17.0Hz,H-15b),2.25(1H,dd,J＝6.5,20.0Hz,H-4α),2.15(2H,m,H-5″),1.68(2H,m,H-9″),1.60(1H,m,H-7″),2.24(2H,m,H-6″),2.21(2H,m,H-8″).

H-63¹H-NMR(CDCl₃,400MHz)δ(ppm):7.48(1H,s,H-13),7.29(1H,dd,J＝4.0,8.0Hz,H-14′),7.19(1H,dd,J＝4.0,8.0Hz,H-13′),6.59(1H,dd,J＝4.0,8.0Hz,H-11′),6.54(1H,s,H-10),6.46(1H,s,H-5),6.30(1H,s,H-5′),6.31(1H,dd,J＝4.0,8.0Hz,H-10′),6.13(1H,m,H-9″b),5.88(1H,s,H-8′),5.61(1H,m,H-9″a),4.33(2H,t,J＝4.0,8.0Hz,H-4″CH₂),4.26(2H,t,J＝4.0,8.0Hz,H-5″CH₂),3.95(1H,d,J＝8.0Hz,H-1),3.91(3H,s,21-OCH₃),3.77(1H,dd,J＝8.0,16.0Hz,H-1′),3.71(3H,s,18-OCH₃),3.60(1H,m,H-3β),3.45(1H,m,H-3′α),3.36(3H,s,18′-OCH₃),3.20(1H,dd,J＝5.6,12.8Hz,H-15′α),3.18(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.64(3H,s,16′-OCH₃),2.51(1H,d,J＝13.6Hz,H-15b),2.41(1H,dd,J＝5.2,16.0Hz,H-4α),2.18(3H,s,16-OCH₃),1.95(3H,m,H-10″-CH₃).

H-64¹H-NMR(CDCl₃,400MHz)δ(ppm):7.51(1H,s,H-13),7.30(1H,dd,J＝4.0,8.0Hz,H-14′),7.20(1H,dd,J＝4.0,8.0Hz,H-13′),6.58(1H,dd,J＝4.0,8.0Hz,H-11′),6.55(1H,s,H-10),6.47(1H,s,H-5),6.30(1H,s,H-5′),6.14(1H,dd,J＝4.0,8.0Hz,H-10′),5.88(1H,s,H-8′),3.95(1H,d,J＝8.0Hz,H-1),3.92(3H,s,21-OCH₃),3.82(1H,dd,J＝8.0,16.0Hz,H-1′),3.76(3H,s,18-OCH₃),3.60(1H,m,H-3β),3.45(1H,m,H-3′α),3.37(3H,s,18′-OCH₃),3.20(1H,dd,J＝5.6,12.8Hz,H-15′α),3.08(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.60(3H,s,16′-OCH₃),2.51(1H,d,J＝13.6Hz,H-15b),2.49(3H,s,16-OCH₃),2.41(1H,dd,J＝5.2,16.0Hz,H-4α).

H-65¹H-NMR(CDCl₃,500MHz)δ(ppm):7.53(1H,s,H-13),7.28(1H,dd,J＝5.0,10.0Hz,H-14′),7.19(1H,dd,J＝5.0,10.0Hz,H-13′),6.57(1H,dd,J＝5.0,10.0Hz,H-11′),6.54(1H,s,H-10),6.46(1H,s,H-5′),6.30(1H,s,H-5),6.13(1H,dd,J＝5.0,10.0Hz,H-10′),5.87(1H,s,H-8′),3.96(3H,s,21-OCH₃),3.93(1H,dd,J＝7.0,14.0Hz,H-1′),3.72(3H,s,18-OCH₃),3.73(1H,s,H-1),3.52(1H,m,H-3β),3.43(1H,m,H-3′α),3.37(3H,s,18′-OCH₃),3.24(1H,dd,J＝7.0,16.0Hz,H-15′α),3.08(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.87(1H,s,NH),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.60(3H,s,16′-OCH₃),,2.54(3H,s,16-OCH₃),2.51(1H,d,J＝17.0Hz,H-15b),2.25(1H,dd,J＝6.5,20.0Hz,H-4α),1.40(9H,s,H-3″C(CH₃)₃).

H-66¹H-NMR(CDCl₃,400MHz)δ(ppm):7.47(1H,s,H-13),7.31(2H,d,J＝8.0Hz,H-5″,H-7″)7.35(1H,dd,J＝4.0,8.0Hz,H-14′),7.20(1H,dd,J＝4.0,8.0Hz,H-13′),7.12(2H,d,J＝8.0Hz,H-4″,H-8″),6.61(1H,dd,J＝4.0,8.0Hz,H-11′),6.57(1H,s,H-10),6.47(1H,s,H-5′),6.29(1H,s,H-5),6.15(1H,dd,J＝4.0,8.0Hz,H-10′),5.90(1H,s,H-8′),4.03(1H,d,J＝16.0Hz,H-1),3.96(3H,s,21-OCH₃),3.82(1H,m,H-3β),3.69(3H,s,18-OCH₃),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.6,12.8Hz,H-15′α),3.34(3H,s,18′-OCH₃),3.11(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.65(3H,s,16′-OCH₃),2.51(1H,d,J＝13.6Hz,H-15b),2.47(3H,s,16-OCH₃),2.41(1H,dd,J＝5.2,16.0Hz,H-4α),2.31(3H,s,7″-CH₃).

H-67¹H-NMR(CDCl₃,400MHz)δ(ppm):7.45(1H,d,J＝8.0Hz,H-6″),7.43(1H,d,J＝4.0Hz,H-8″),7.31(1H,dd,J＝4.0,8.0Hz,H-14′),7.20(1H,dd,J＝4.0,8.0Hz,H-13′),7.18(1H,dd,J＝4.0,12.0Hz,H-5″),7.16(1H,dd,J＝4.0,12.0Hz,H-5″),6.61(1H,dd,J＝4.0,8.0Hz,H-11′),6.58(1H,s,H-10),6.47(1H,s,H-5′),6.38(1H,s,H-13),6.30(1H,s,H-5),6.16(1H,dd,J＝4.0,8.0Hz,H-10′),5.90(1H,s,H-8′),3.96(1H,d,J＝16.0Hz,H-1),3.93(3H,s,21-OCH₃),3.74(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.6,12.8Hz,H-15′α),3.36(3H,s,18′-OCH₃),3.10(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.59(3H,s,16′-OCH₃),2.51(1H,d,J＝13.6Hz,H-15b),2.48(3H,s,16-OCH₃).

H-68¹H-NMR(CDCl₃,400MHz)δ(ppm):8.19(1H,s,H-5″),8.17(1H,s,H-7″),7.60(1H,s,H-4″),7.58(1H,s,H-8″),7.43(1H,s,H-13),7.31(1H,dd,J＝4.0,8.0Hz,H-14′),7.20(1H,dd,J＝4.0,8.0Hz,H-13′),6.60(1H,dd,J＝4.0,8.0Hz,H-11′),6.59(1H,s,H-10),6.47(1H,s,H-5′),6.31(1H,s,H-5),6.16(1H,dd,J＝4.0,8.0Hz,H-10′),5.90(1H,s,H-8′),3.98(1H,d,J＝16.0Hz,H-1),3.93(3H,s,21-OCH₃),3.74(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.6,12.8Hz,H-15′α),3.37(3H,s,18′-OCH₃),3.09(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.59(3H,s,16′-OCH₃),2.56(1H,d,J＝13.6Hz,H-15b),2.53(3H,s,16-OCH₃).

H-69¹H-NMR(CDCl₃,400MHz)δ(ppm):7.73(1H,d,J＝4.0Hz,H-7″),7.64(1H,dd,J＝4.0,8.0Hz,H-8″),7.41(1H,d,J＝8.0Hz,H-4″),7.38(1H,s,H-13),7.31(1H,dd,J＝4.0,8.0Hz,H-14′),7.20(1H,dd,J＝4.0,8.0Hz,H-13′),6.61(1H,dd,J＝4.0,8.0Hz,H-11′),6.58(1H,s,H-10),6.48(1H,s,H-5′),6.31(1H,s,H-5),6.16(1H,dd,J＝4.0,8.0Hz,H-10′),5.90(1H,s,H-8′),3.98(1H,d,J＝16.0Hz,H-1),3.93(3H,s,21-OCH₃),3.74(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.6,12.8Hz,H-15′α),3.37(3H,s,18′-OCH₃),3.09(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.59(3H,s,16′-OCH₃),2.56(1H,d,J＝13.6Hz,H-15b),2.53(3H,s,16-OCH₃).

H-70¹H-NMR(CDCl₃,500MHz)δ(ppm):7.44(1H,s,H-13),7.37(1H,m,H-5″),7.36(1H,m,H-7″),7.31(1H,dd,J＝5.0,10.0Hz,H-14′),7.20(1H,dd,J＝5.0,10.0Hz,H-13′),7.01(2H,m,H-4″,H-8″),6.61(1H,dd,J＝5.0,10.0Hz,H-11′),6.58(1H,s,H-10),6.47(1H,s,H-5′),6.30(1H,s,H-5),6.16(1H,dd,J＝5.0,10.0Hz,H-10′),5.90(1H,s,H-8′),3.95(1H,dd,J＝5.0,10.0Hz,H-1′),3.93(3H,s,21-OCH₃),3.74(3H,s,18-OCH₃),3.73(1H,s,H-1),3.52(1H,m,H-3β),3.43(1H,m,H-3′α),3.36(3H,s,18′-OCH₃),3.24(1H,dd,J＝7.0,16.0Hz,H-15′α),3.10(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.87(1H,s,NH),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.59(3H,s,16′-OCH₃),2.35(1H,d,J＝17.0Hz,H-15b),2.32(3H,s,16-OCH₃),2.22(1H,dd,J＝6.5,20.0Hz,H-4α).

H-71¹H-NMR(CDCl₃,500MHz)δ(ppm):7.52(1H,m,H-4″),7.45(1H,s,H-13),7.31(1H,dd,J＝5.0,10.0Hz,H-14′),7.28(1H,s,H-6″),7.20(1H,s,H-7″),7.20(1H,dd,J＝5.0,10.0Hz,H-13′),7.01(1H,m,H-8″),6.61(1H,dd,J＝5.0,10.0Hz,H-11′),6.58(1H,s,H-10),6.47(1H,s,H-5′),6.30(1H,s,H-5),6.16(1H,dd,J＝5.0,10.0Hz,H-10′),5.90(1H,s,H-8′),3.95(1H,dd,J＝5.0,10.0Hz,H-1′),3.93(3H,s,21-OCH₃),3.74(3H,s,18-OCH₃),3.73(1H,s,H-1),3.52(1H,m,H-3β),3.43(1H,m,H-3′α),3.36(3H,s,18′-OCH₃),3.24(1H,dd,J＝7.0,16.0Hz,H-15′α),3.10(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.87(1H,s,NH),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.59(3H,s,16′-OCH₃),2.49(3H,s,16-OCH₃),2.35(1H,d,J＝17.0Hz,H-15b),2.22(1H,dd,J＝6.5,20.0Hz,H-4α).

H-72¹H-NMR(CDCl₃,400MHz)δ(ppm):7.55(4H,m,H-4″,H-5″,H-7″,H-8″),7.45(1H,s,H-13),7.31(1H,dd,J＝4.0,8.0Hz,H-14′),7.21(1H,dd,J＝4.0,8.0Hz,H-13′),6.61(1H,dd,J＝4.0,8.0Hz,H-11′),6.59(1H,s,H-10),6.47(1H,s,H-5′),6.31(1H,s,H-5),6.16(1H,dd,J＝4.0,8.0Hz,H-10′),5.90(1H,s,H-8′),3.98(1H,d,J＝16.0Hz,H-1),3.94(3H,s,21-OCH₃),3.74(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.6,12.8Hz,H-15′α),3.37(3H,s,18′-OCH₃),3.10(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.60(3H,s,16′-OCH₃),2.56(1H,d,J＝13.6Hz,H-15b),2.52(3H,s,16-OCH₃).

H-73¹H-NMR(CDCl₃,500MHz)δ(ppm):7.44(1H,s,H-13),7.32(5H,m,5″-Ph),7.29(1H,dd,J＝5.0,10.0Hz,H-14′),7.18(1H,dd,J＝5.0,10.0Hz,H-13′),6.58(1H,dd,J＝5.0,10.0Hz,H-11′),6.51(1H,s,H-10),6.45(1H,s,H-5′),6.28(1H,s,H-5),6.13(1H,dd,J＝5.0,10.0Hz,H-10′),5.87(1H,s,H-8′),3.98(1H,d,J＝20.0Hz,H-1),3.87(3H,s,21-OCH₃),3.74(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.0,15.0Hz,H-15′α),3.34(3H,s,18′-OCH₃),3.09(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.59(3H,s,16′-OCH₃),2.56(1H,d,J＝17.0Hz,H-15b),2.31(3H,s,16-OCH₃).

H-74¹H-NMR(CDCl₃,500MHz)δ(ppm):7.92(3H,m,H-8″，H-9″，H-10″),7.68(1H,d,J＝5.0Hz,H-7″),7.57(1H,s,H-13),7.53(3H,m,H-5″，H-6″，H-7″),7.31(1H,dd,J＝5.0,10.0Hz,H-14′),7.22(1H,dd,J＝5.0,10.0Hz,H-13′),6.63(1H,dd,J＝5.0,10.0Hz,H-11′),6.59(1H,s,H-10),6.47(1H,s,H-5′),6.24(1H,s,H-5),6.16(1H,dd,J＝5.0,10.0Hz,H-10′),5.90(1H,s,H-8′),3.98(1H,d,J＝20.0Hz,H-1),3.92(3H,s,21-OCH₃),3.74(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.0,15.0Hz,H-15′α),3.34(3H,s,18′-OCH₃),3.09(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.60(3H,s,16′-OCH₃),2.56(1H,d,J＝17.0Hz,H-15b),2.29(3H,s,16-OCH₃).

H-75¹H-NMR(CDCl₃,400MHz)δ(ppm):7.48(1H,s,H-13),7.33(1H,m,H-5″),7.31(1H,m,H-9″),7.29(1H,dd,J＝4.0,8.0Hz,H-14′),7.20(1H,dd,J＝4.0,8.0Hz,H-13′),6.88(1H,m,H-6″),6.86(1H,m,H-8″),6.61(1H,dd,J＝4.0,8.0Hz,H-11′),6.57(1H,s,H-10),6.47(1H,s,H-5′),6.29(1H,s,H-5),6.16(1H,dd,J＝4.0,8.0Hz,H-10′),5.90(1H,s,H-8′),3.98(1H,d,J＝16.0Hz,H-1),3.94(3H,s,21-OCH₃),3.79(3H,s,6″-OCH₃),3.74(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.6,12.8Hz,H-15′α),3.37(3H,s,18′-OCH₃),3.10(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.60(3H,s,16′-OCH₃),2.56(1H,d,J＝13.6Hz,H-15b),2.44(3H,s,16-OCH₃).

H-76¹H-NMR(CDCl₃,500MHz)δ(ppm):7.48(1H,s,H-13),7.30(1H,dd,J＝5.0,10.0Hz,H-14′),7.28(1H,s,H-5″),7.21(1H,dd,J＝5.0,10.0Hz,H-13′),7.20(1H,m,H-7″),7.18(1H,m,H-9″),6.87(1H,m,H-8″),6.61(1H,dd,J＝5.0,10.0Hz,H-11′),6.58(1H,s,H-10),6.47(1H,s,H-5′),6.29(1H,s,H-5),6.16(1H,dd,J＝5.0,10.0Hz,H-10′),5.90(1H,s,H-8′),3.98(1H,d,J＝20.0Hz,H-1),3.94(3H,s,21-OCH₃),3.74(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.0,15.0Hz,H-15′α),3.36(3H,s,18′-OCH₃),3.10(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.59(3H,s,16′-OCH₃),2.56(1H,d,J＝17.0Hz,H-15b),2.47(3H,s,6″-CH₃),2.35(3H,s,16-OCH₃).

H-77¹H-NMR(CDCl₃,500MHz)δ(ppm):7.50(1H,s,H-13),7.28(1H,dd,J＝5.0,10.0Hz,H-14′),7.18(1H,dd,J＝5.0,10.0Hz,H-13′),6.58(1H,dd,J＝5.0,10.0Hz,H-11′),6.54(1H,s,H-10),6.45(1H,s,H-5′),6.29(1H,s,H-5),6.13(1H,dd,J＝5.0,10.0Hz,H-10′),5.87(1H,s,H-8′),3.98(1H,d,J＝20.0Hz,H-1),3.94(3H,s,21-OCH₃),3.74(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.0,15.0Hz,H-15′α),3.35(3H,s,18′-OCH₃),3.08(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.58(3H,s,16′-OCH₃),2.56(1H,d,J＝17.0Hz,H-15b),2.46(3H,s,16-OCH₃),2.01(1H,m,H-4″),1.64(4H,m,5″-2H,8″-2H),1.37(4H,m,6″-2H,7″-2H).

H-79¹H-NMR(CDCl₃,500MHz)δ(ppm):7.35(1H,s,H-13),7.28(1H,dd,J＝5.0,10.0Hz,H-14′),7.19(1H,dd,J＝5.0,10.0Hz,H-13′),6.59(1H,dd,J＝5.0,10.0Hz,H-11′),6.58(1H,s,H-10),6.45(1H,s,H-5′),6.29(1H,s,H-5),6.11(1H,dd,J＝5.0,10.0Hz,H-10′),5.86(1H,s,H-8′),3.98(1H,d,J＝20.0Hz,H-1),3.91(3H,s,21-OCH₃),3.73(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.0,15.0Hz,H-15′α),3.34(3H,s,18′-OCH₃),3.08(3H,s,19-OCH₃),3.03(6H,S,3″(-CH₃)₂),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.59(3H,s,16′-OCH₃),2.56(1H,d,J＝13.6Hz,H-15b),2.42(3H,s,16-OCH₃).

H-82¹H-NMR(CDCl₃,400MHz)δ(ppm):7.28(1H,dd,J＝4.0,8.0Hz,H-14′),7.20(1H,dd,J＝4.0,8.0Hz,H-13′),6.57(1H,dd,J＝4.0,8.0Hz,H-11′),6.52(1H,s,H-13),6.47(1H,s,H-10),6.37(1H,s,H-5),6.30(1H,s,H-5′),6.15(1H,dd,J＝4.0,8.0Hz,H-10′),5.89(1H,s,H-8′),3.92(1H,d,J＝8.0Hz,H-1),3.89(3H,s,21-OCH₃),3.77(1H,dd,J＝8.0,16.0Hz,H-1′),3.75(3H,s,18-OCH₃),3.60(1H,m,H-3β),3.45(1H,m,H-3′α),3.38(3H,s,18′-OCH₃),3.20(1H,dd,J＝5.6,12.8Hz,H-15′α),3.18(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.61(3H,s,16′-OCH₃),2.51(1H,d,J＝17.0Hz,H-15b),2.41(1H,dd,J＝5.2,16.0Hz,H-4α),2.33(3H,s,16-OCH₃).

H-84¹H-NMR(CDCl₃,500MHz)δ(ppm):8.05(1H,d,J＝5.0Hz,H-8″),7.84(1H,s,H-5″),7.82(1H,s,H-7″),7.72(1H,m,H-6″),7.36(1H,dd,J＝5.0,10.0Hz,H-14′),7.08(1H,dd,J＝5.0,10.0Hz,H-13′),6.82(1H,dd,J＝5.0,10.0Hz,H-11′),6.63(1H,s,H-13),6.54(1H,s,H-10),6.51(1H,s,H-5′),6.34(1H,dd,J＝5.0,10.0Hz,H-10′),6.29(1H,s,H-5),5.97(1H,s,H-8′),3.96(3H,s,21-OCH₃),3.93(1H,dd,J＝7.0,14.0Hz,H-1′),3.72(3H,s,18-OCH₃),3.73(1H,s,H-1),3.52(1H,m,H-3β),3.43(1H,m,H-3′α),3.37(3H,s,18′-OCH₃),3.24(1H,dd,J＝7.0,16.0Hz,H-15′α),3.08(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.87(1H,s,NH),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.60(3H,s,16′-OCH₃),,2.54(3H,s,16-OCH₃),2.51(1H,d,J＝17.0Hz,H-15b),2.25(1H,dd,J＝6.5,20.0Hz,H-4α).

H-85¹H-NMR(CDCl₃,400MHz)δ(ppm):7.33(1H,dd,J＝4.0,8.0Hz,H-14′),7.13(1H,dd,J＝4.0,8.0Hz,H-13′),6.82(1H,dd,J＝4.0,8.0Hz,H-11′),6.64(1H,s,H-13),6.57(1H,s,H-10),6.49(1H,s,H-5′),6.37(1H,s,H-3″),6.28(1H,dd,J＝4.0,8.0Hz,H-10′),6.25(1H,s,H-5),5.95(1H,s,H-8′),4.03(1H,d,J＝16.0Hz,H-1),3.95(3H,s,21-OCH₃),3.82(1H,m,H-3β),3.72(3H,s,18-OCH₃),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.6,12.8Hz,H-15′α),3.36(3H,s,18′-OCH₃),3.08(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.60(3H,s,16′-OCH₃),2.51(1H,d,J＝13.6Hz,H-15b),2.46(3H,s,16-OCH₃),2.41(1H,dd,J＝5.2,16.0Hz,H-4α),2.24(6H,s,H-5″,H-6″).

H-86¹H-NMR(CDCl₃,400MHz)δ(ppm):8.26(2H,dd,J＝4.0,8.0Hz,H-5″,H-7″)7.34(1H,dd,J＝4.0,8.0Hz,H-14′)7.20(2H,dd,J＝4.0,8.0Hz,H-4″,H-8″),7.17(1H,dd,J＝4.0,8.0Hz,H-13′),6.81(1H,dd,J＝4.0,8.0Hz,H-11′),6.72(1H,s,H-13),6.66(1H,s,H-10),6.48(1H,s,H-5′),6.25(1H,dd,J＝4.0,8.0Hz,H-10′),6.19(1H,s,H-5),5.95(1H,s,H-8′),4.03(1H,d,J＝16.0Hz,H-1),3.91(3H,s,21-OCH₃),3.82(1H,m,H-3β),3.69(3H,s,18-OCH₃),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.6,12.8Hz,H-15′α),3.33(3H,s,18′-OCH₃),3.10(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.64(3H,s,16′-OCH₃),2.51(1H,d,J＝13.6Hz,H-15b),2.41(1H,dd,J＝5.2,16.0Hz,H-4α),2.13(3H,s,16-OCH₃).

H-87¹H-NMR(CDCl₃,400MHz)δ(ppm):8.24(1H,m,H-4″),8.12(1H,d,J＝8.0Hz,H-6″),7.60(1H,m,H-8″),7.47(1H,t,J＝8.0,16.0Hz,H-6″),7.34(1H,dd,J＝4.0,8.0Hz,H-14′),7.18(1H,dd,J＝4.0,8.0Hz,H-13′),6.81(1H,dd,J＝4.0,8.0Hz,H-11′),6.72(1H,s,H-13),6.66(1H,s,H-10),6.48(1H,s,H-5′),6.25(1H,dd,J＝4.0,8.0Hz,H-10′),6.20(1H,s,H-5),5.95(1H,s,H-8′),4.03(1H,d,J＝16.0Hz,H-1),3.96(3H,s,21-OCH₃),3.82(1H,m,H-3β),3.69(3H,s,18-OCH₃),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.6,12.8Hz,H-15′α),3.34(3H,s,18′-OCH₃),3.11(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.65(3H,s,16′-OCH₃),2.51(1H,d,J＝13.6Hz,H-15b),2.13(3H,s,16-OCH₃),1.91(1H,dd,J＝5.2,16.0Hz,H-4α).

H-88¹H-NMR(CDCl₃,500MHz)δ(ppm):7.44(2H,s,H-5″,H-7″),7.36(1H,dd,J＝5.0,10.0Hz,H-14′),7.10(1H,dd,J＝5.0,10.0Hz,H-13′),6.89(1H,s,H-13),6.87(1H,dd,J＝5.0,10.0Hz,H-11′),6.61(1H,s,H-10),6.51(1H,s,H-5′),6.36(1H,dd,J＝5.0,10.0Hz,H-10′),6.27(1H,s,H-5),5.99(1H,s,H-8′),3.95(3H,s,21-OCH₃),3.93(1H,dd,J＝7.0,14.0Hz,H-1′),3.75(3H,s,18-OCH₃),3.73(1H,s,H-1),3.52(1H,m,H-3β),3.43(1H,m,H-3′α),3.37(3H,s,18′-OCH₃),3.24(1H,dd,J＝7.0,16.0Hz,H-15′α),3.21(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.87(1H,s,NH),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.65(3H,s,16′-OCH₃),2.35(1H,d,J＝17.0Hz,H-15b),2.24(3H,s,16-OCH₃),2.04(1H,dd,J＝6.5,20.0Hz,H-4α).

H-89¹H-NMR(CDCl₃,500MHz)δ(ppm):8.20(1H,s,H-4″),8.18(1H,s,H-8″),7.33(1H,dd,J＝5.0,10.0Hz,H-14′),7.16(1H,dd,J＝5.0,10.0Hz,H-13′),7.00(1H,s,H-5″),6.99(1H,s,H-7″),6.83(1H,dd,J＝5.0,10.0Hz,H-11′),6.73(1H,s,H-13),6.64(1H,s,H-10),6.48(1H,s,H-5′),6.26(1H,dd,J＝5.0,10.0Hz,H-10′),6.19(1H,s,H-5),5.96(1H,s,H-8′),3.95(3H,s,21-OCH₃),3.91(3H,s,6″-OCH₃),3.83(1H,dd,J＝7.0,14.0Hz,H-1′),3.75(3H,s,18-OCH₃),3.73(1H,s,H-1),3.52(1H,m,H-3β),3.43(1H,m,H-3′α),3.37(3H,s,18′-OCH₃),3.24(1H,dd,J＝7.0,16.0Hz,H-15′α),3.21(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.87(1H,s,NH),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.65(3H,s,16′-OCH₃),2.35(1H,d,J＝17.0Hz,H-15b),2.16(3H,s,16-OCH₃),2.04(1H,dd,J＝6.5,20.0Hz,H-4α).

H-92¹H-NMR(CDCl₃,400MHz)δ(ppm):7.94(1H,d,J＝8.0Hz,H-5″),7.65(1H,d,J＝4.0Hz,H-6″),7.40(1H,dd,J＝4.0,12.0Hz,H-7″),7.36(1H,dd,J＝4.0,8.0Hz,H-14′),7.07(1H,dd,J＝4.0,8.0Hz,H-13′),6.82(1H,dd,J＝4.0,8.0Hz,H-11′),6.54(1H,s,H-13),6.51(1H,s,H-10),6.40(1H,s,H-5′),6.34(1H,dd,J＝4.0,8.0Hz,H-10′),6.30(1H,s,H-5),5.95(1H,s,H-8′),4.03(1H,d,J＝16.0Hz,H-1),3.76(3H,s,21-OCH₃),3.70(3H,s,18-OCH₃),3.82(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.6,12.8Hz,H-15′α),3.37(3H,s,18′-OCH₃),3.21(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.63(3H,s,16′-OCH₃),2.51(1H,d,J＝13.6Hz,H-15b),2.25(3H,s,16-OCH₃),1.91(1H,dd,J＝5.2,16.0Hz,H-4α).

H-93¹H-NMR(CDCl₃,500MHz)δ(ppm):7.69(1H,s,H-4″),7.68(1H,s,H-8″),7.26(1H,dd,J＝5.0,10.0Hz,H-14′),7.22(1H,s,H-5″),7.23(1H,s,H-7″),6.99(1H,dd,J＝5.0,10.0Hz,H-13′),6.71(1H,dd,J＝5.0,10.0Hz,H-11′),6.40(1H,s,H-13),6.41(1H,s,H-10),6.25(1H,s,H-5′),6.23(1H,dd,J＝5.0,10.0Hz,H-10′),6.20(1H,s,H-5),5.84(1H,s,H-8′),3.79(1H,dd,J＝5.0,10.0Hz,H-1′),3.66(3H,s,21-OCH₃),3.58(3H,s,18-OCH₃),3.73(1H,s,H-1),3.52(1H,m,H-3β),3.43(1H,m,H-3′α),3.26(3H,s,18′-OCH₃),3.24(1H,dd,J＝7.0,16.0Hz,H-15′α),3.10(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.87(1H,s,NH),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.53(3H,s,16′-OCH₃),2.35(1H,d,J＝17.0Hz,H-15b),2.34(3H,s,16-OCH₃),2.22(1H,dd,J＝6.5,20.0Hz,H-4α),2.15(3H,s,6″-CH₃).

H-95¹H-NMR(CDCl₃,400MHz)δ(ppm):9.29(1H,d,J＝8.0Hz,H-4″),8.64(1H,d,J＝8.0Hz,H-6″),8.12(1H,d,J＝8.0Hz,H-10″),7.94(1H,d,J＝8.0Hz,H-5″),7.60(3H,m,H-7″,H-8″,H-9″),7.37(1H,dd,J＝4.0,8.0Hz,H-14′),7.19(1H,dd,J＝4.0,8.0Hz,H-13′),6.86(1H,dd,J＝4.0,8.0Hz,H-11′),6.82(1H,s,H-13),6.69(1H,s,H-10),6.49(1H,s,H-5′),6.28(1H,dd,J＝4.0,8.0Hz,H-10′),6.14(1H,s,H-5),5.98(1H,s,H-8′),3.98(1H,d,J＝16.0Hz,H-1),3.94(3H,s,21-OCH₃),3.74(3H,s,18-OCH₃),3.72(1H,m,H-3β),3.45(1H,m,H-3′α),3.40(1H,dd,J＝5.6,12.8Hz,H-15′α),3.37(3H,s,18′-OCH₃),3.10(3H,s,19-OCH₃),2.97(1H,m,H-4′α),2.92(1H,m,H-4β),2.89(1H,m,H-3α),2.86(1H,m,H-3′β),2.79(1H,m,H-15′b),2.72(1H,m,H-4′β),2.68(1H,m,H-15a),2.66(3H,s,16′-OCH₃),2.49(1H,d,J＝13.6Hz,H-15b),2.16(3H,s,16-OCH₃).

from the foregoing it will be appreciated that, although specific embodiments of the application have been described herein for purposes of illustration, various modifications or improvements may be made by those skilled in the art without departing from the spirit and scope of the application. Such variations and modifications are intended to fall within the scope of the appended claims.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a combination thereof with another anti-neoplastic drug, in the manufacture of a medicament for the treatment or prevention of a neoplasm:

wherein the content of the first and second substances,

X₁selected from hydrogen, halogen or nitro;

X₂each independently selected from hydrogen, halogen, nitro, nitroso, -SO₃H. Alkylcarbonyl-substituted amino, hydroxy-substituted alkylcarbonyl-substituted amino, methylcarbonyloxymethylcarbonylamino, alkenylcarbonyl-substituted amino, aryl-substituted alkenylcarbonyl-substituted amino, alkoxycarbonyl-substituted amino, aryl-substituted alkoxycarbonyl-substituted amino, arylcarbonyl-substituted amino, halogen-substituted arylcarbonyl-substituted amino, alkoxy-substituted arylcarbonyl-substituted amino, haloalkyl-substituted arylcarbonyl-substituted amino, alkoxycarbonyl-carbonyl-substituted amino, heterocyclylcarbonyl-substituted amino, heteroarylcarbonyl-substituted amino, alkylsulfonyl-substituted amino, aralkylsulfonyl-substituted amino, arylsulfonyl-substituted amino, nitro-substituted arylsulfonyl-substituted amino, alkyl-substituted arylsulfonyl-substituted amino, halogen-substituted aryl, halogen, An alkyl-substituted aminosulfonyl-substituted amino group, an arylamino-substituted sulfonyl group, or an alkoxy-substituted alkyl-substituted sulfonyl group;

x is 1, X₂At position C-14; or X is 2, X₂Respectively positioned at C-10 position and C-14 position;

y is 4, and X₃Is hydrogen;

z is 2, and X₄Is hydrogen, R₁Selected from hydrogen, nitroso, alkyl, aryl-substituted alkyl, alkylcarbonyl or arylcarbonyl;

R₂is an alkyl group;

with the following conditions:

X₁、X₂、X₃and X₄Not hydrogen at the same time; and

when X is present₁、X₂When one of them is halogen, the rest X₁Selected from hydrogen or nitro; the rest of X₂Each independently selected from hydrogen, nitro, nitroso, -SO₃H. Alkylcarbonyl-substituted amino, hydroxy-substituted alkylcarbonyl-substituted amino, methylcarbonyloxymethylcarbonylamino, alkenylcarbonyl-substituted amino, aryl-substituted alkenylcarbonyl-substituted amino, alkoxycarbonyl-substituted amino, aryl-substituted alkoxycarbonyl-substituted amino, arylcarbonyl-substituted amino, halogen-substituted arylcarbonyl-substituted amino, alkoxy-substituted arylcarbonyl-substituted amino, haloalkyl-substituted arylcarbonyl-substituted amino, alkoxycarbonyl-carbonyl-substituted amino, heterocyclylcarbonyl-substituted amino, heteroarylcarbonyl-substituted amino, alkylsulfonyl-substituted amino, aralkylsulfonyl-substituted amino, arylsulfonyl-substituted amino, nitro-substituted arylsulfonyl-substituted amino, alkyl-substituted arylsulfonyl-substituted amino, halogen-substituted aryl, halogen, An alkyl-substituted aminosulfonyl-substituted amino, an arylamino-substituted sulfonyl or an alkoxy-substituted alkyl-substituted sulfonyl, but not both hydrogen;

wherein the alkyl group contained in the above groups is C₁-C₆An alkyl group; the alkenyl group contained in the above-mentioned groups is C₂-C₆An alkenyl group; the aryl group contained in the above groups is C₆-C₁₈An aryl group; the heteroaryl group contained in the above groups is a five-to eighteen-membered aromatic ring group consisting of carbon atoms and one to five heteroatoms selected from nitrogen, oxygen and sulfur; the heterocyclic group contained in the above-mentioned groups means a 3 to 18-membered non-aromatic ring group consisting of 2 to 12 carbon atoms and 1 to 6 hetero atoms selected from nitrogen, oxygen and sulfur;

wherein the pharmaceutical composition comprises the compound of the general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,

wherein the tumor is selected from tongue cancer, pancreatic cancer, cervical cancer, laryngeal cancer, renal cancer, leukemia, breast cancer, melanoma, prostate cancer, sarcoma, ovarian cancer, ureteral cancer, bladder cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, endocrine cancer, skin cancer, hemangioma, brain cancer, or central nervous system cancer, or metastatic cancer thereof.

2. The use of claim 1, wherein the tumor is a erythroleukemia.

3. The use as claimed in claim 1, wherein

X₂Each independently selected from hydrogen, halogen, nitro, nitroso, -SO₃H. Alkylcarbonyl-substituted amino, hydroxy-substituted alkylcarbonyl-substituted amino, methylcarbonyloxymethylcarbonylamino, alkenylcarbonyl-substituted amino, alkoxycarbonyl-substituted amino, aryl-substituted alkoxycarbonyl-substituted amino, halogen-substituted arylcarbonyl-substituted amino, alkoxy-substituted arylcarbonyl-substituted amino, haloalkyl-substituted arylcarbonyl-substituted amino, alkoxycarbonyl carbonyl substituted amino, heterocyclylcarbonyl substituted amino, alkylsulfonyl substituted amino, aralkylsulfonyl substituted amino, arylsulfonyl substituted amino, nitro substituted arylsulfonyl substituted amino, alkyl substituted arylsulfonyl substituted amino, halogen substituted arylsulfonyl substituted amino, alkyl substituted aminosulfonyl substituted amino, arylamino substituted sulfonyl or alkoxy substituted alkyl substituted sulfonyl;

wherein the alkyl group contained in the above groups is C₁-C₆An alkyl group; the alkenyl group contained in the above-mentioned groups is C₂-C₆An alkenyl group; the aryl group contained in the above groups is C₆-C₁₂An aryl group; the heteroaryl group contained in the above groups is a five-to twelve-membered aromatic ring group composed of carbon atoms and one to five heteroatoms selected from nitrogen, oxygen and sulfur.

4. The use of claim 1, wherein X is 1, and X is₂Selected from halogen, nitro, nitroso, -SO₃H. Alkylcarbonyl-substituted amino, hydroxy-substituted alkylcarbonyl-substituted amino, methylcarbonyloxymethylcarbonylamino, alkenylcarbonyl-substituted amino, aryl-substituted alkenylcarbonyl-substituted amino, alkoxycarbonyl-substituted amino, aryl-substituted alkoxycarbonyl-substituted amino, arylcarbonyl-substituted amino, halogen-substituted arylcarbonyl-substituted amino, alkoxy-substituted arylcarbonyl-substituted amino, haloalkyl-substituted arylcarbonyl-substituted amino, alkoxycarbonyl-carbonyl-substituted amino, heterocyclylcarbonyl-substituted amino, heteroarylcarbonyl-substituted amino, alkylsulfonyl-substituted amino, aralkylsulfonyl-substituted amino, arylsulfonyl-substituted amino, nitro-substituted arylsulfonyl-substituted amino, alkyl-substituted arylsulfonyl-substituted amino, halogen-substituted aryl, halogen, An alkyl-substituted aminosulfonyl-substituted amino group, an arylamino-substituted sulfonyl group, or an alkoxy-substituted alkyl-substituted sulfonyl group.

5. The use of claim 1, wherein X is 2, and X is₂One of them is hydrogen, X₂Is selected from nitro, nitroso, -SO₃H. Br, Cl, methylcarbonylamino, isopropylcarbonylamino, isobutylcarbonylamino, vinylcarbonylamino, styrylcarbonylamino, 2-methylpropenylcarbonylamino, 2-methylpropyloxycarbonylamino, hydroxymethylcarbonylamino, methylcarbonyloxymethylcarbonylamino, methoxycarbonylcarbonylamino, furanylcarbonylamino, thienylcarbonylamino, morpholinocarbonylamino, phenylcarbonylamino, chlorophenylcarbonylamino, methoxyphenylcarbonylamino, trifluoromethylphenylcarbonylamino, benzyloxycarbonylamino, methylsulfonylamino, phenylsulfonylamino, nitrophenylsulfonylamino, methylphenylsulfonylamino, chlorophenylsulfonylamino, dichlorophenylsulfonylamino, phenylmethylsulfonylamino, dimethylaminosulfonylaminoA phenyl aminosulfonyl group or a methoxymethylsulfonyl group.

6. The use according to any one of claims 1 to 4, wherein R is₂Is C₁-C₆An alkyl group.

7. The use of claim 6, wherein R₂Is methyl.

8. The use of claim 1, wherein R₁Is C₁-C₆Alkyl, and R₂Is C₁-C₆An alkyl group.

9. The use of claim 8, wherein R₁Is methyl, and R₂Is methyl.

10. The use of claim 1, wherein R₁Is C₁-C₆Alkyl, and R₂Is hydrogen.

11. The use of claim 10, wherein R₁Is methyl.

12. The use of claim 1, wherein R₁Is hydrogen, and R₂Is C₁-C₆An alkyl group.

13. The use of claim 12, wherein R₂Is methyl.

14. The use as claimed in claim 1, wherein X₁Is halogen, X₂Selected from nitro and sulfonic acid groups, X₃And X₄Is hydrogen and x is 1.

15. The use of claim 1, wherein R₁Selected from hydrogen, nitroso, C₁-C₆Alkyl, aryl substituted C₁-C₆Alkyl, phenylcarbonyl or C₁-C₆An alkylcarbonyl group.

16. The use of claim 1, wherein R₁Selected from hydrogen, nitroso, C₁-C₆Alkyl, phenyl substituted C₁-C₆Alkyl, phenylcarbonyl or C₁-C₆An alkylcarbonyl group.

17. The use of claim 1, wherein R₁Selected from hydrogen, methyl, benzyl, benzoyl, nitroso or acetyl.

18. The use of claim 1, wherein R₁Selected from hydrogen, methyl, benzyl, benzoyl, nitroso or acetyl; and/or

R₂Is methyl; and/or

X₁Is hydrogen, nitro or halogen; and/or

X is 1 or 2, and at least one X₂Is hydrogen, nitro, nitroso, -SO₃H. Br, Cl, methylcarbonylamino, isobutylcarbonylamino, vinylcarbonylamino, styrylcarbonylamino, 2-methylpropenylcarbonylamino, 2-methylpropyloxycarbonylamino, hydroxymethylcarbonylamino, methylcarbonyloxymethylcarbonylamino, methoxycarbonylcarbonylamino, furanylcarbonylamino, thienylcarbonylamino, morpholinylcarbonylamino, phenylcarbonylamino, chlorophenylcarbonylamino, methoxyphenylcarbonylamino, trifluoromethylphenylcarbonylamino, benzyloxycarbonylamino, methylsulfonylamino, phenylsulfonylamino, nitrophenylsulfonylamino, methylphenylsulfonylamino, chlorophenylsulfonylamino, dichlorophenylsulfonylamino, phenylmethylsulfonylamino, dimethylaminosulfonylamino, phenylaminosulfonyl or methoxymethylsulfonyl; and/or

With the following conditions:

X₁、X₂、X₃and X₄Not simultaneously being hydrogen, and

when X is present₁And X₂When one of them is halogen, the rest X₁And X₂Not hydrogen at the same time.

19. The use of the following compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, or combinations thereof with another anti-tumor drug in the preparation of a medicament for treating or preventing tumors:

wherein the pharmaceutical composition comprises a compound as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;

20. The use of claim 19, wherein the tumor is a erythroleukemia.

21. The use of claim 1 or 19, wherein the pharmaceutical composition is a tablet, capsule, pill, suppository, emulsion, ointment, injection, or infusion.

22. The use of claim 1 or 19, wherein the tumor is selected from tongue cancer, pancreatic cancer, cervical cancer, laryngeal cancer, renal cancer, leukemia, breast cancer, melanoma, or prostate cancer.

23. The use of claim 1 or 19, wherein the tumor is a drug resistant tumor.

24. The use of claim 23, wherein the drug-resistant tumor is drug-resistant breast cancer, melanoma, human prostate cancer, tongue cancer, pancreatic cancer, cervical cancer, laryngeal cancer, renal cancer, leukemia, sarcoma, ovarian cancer, ureteral cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, lung cancer, lymphoma, multiple myeloma, endocrine cancer, skin cancer, hemangioma, or glioma.

25. The use of claim 23, wherein the drug resistant tumor is drug resistant erythroleukemia.

26. The use of claim 24, wherein the drug-resistant tumor is drug-resistant breast cancer, melanoma, leukemia, or human prostate cancer.

27. The use as claimed in claim 1 or 19, wherein the further antineoplastic agent is selected from doxorubicin, paclitaxel, cyclophosphamide, daunorubicin, podophyllotoxin or vinblastine.

28. The use of claim 27, wherein the another anti-neoplastic drug is doxorubicin or paclitaxel.

29. A compound of formula (II):

wherein the content of the first and second substances,

X₅selected from hydrogen;

X₆independently selected from-NH-C (═ O) -NH-R₈、-O-C(＝O)-R₉、-O-S(＝O)₂-R₁₀、-NH-C(＝S)-NH-R₁₁、-NH-C(＝O)OR₁₂、-OC(＝O)NHR₁₃、-OC(＝O)OR₁₄、-NH-P(＝O)R₁₆R₁₇、-NHC(＝S)R₁₈、-NHC(＝O)R₁₉or-OC (═ O) R₂₀；

R₈Each independently selected from the group consisting of 1-3 selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆C substituted by substituents of haloalkoxy and nitro₆-C₁₈An aryl group; optionally substituted by 1-3 substituents selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆C substituted by substituents of haloalkoxy₃-C₁₀A cycloalkyl group; and optionally substituted by 1-3 substituents selected from halogen, -OC (═ O) C₁-C₆Alkyl, -OC (═ O) C₂-C₆Alkenyl or C₆-C₁₈Aryl substituted C₁-C₆An alkyl group;

R₉each independently selected from the group consisting of 1-3 selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆C substituted by substituents of haloalkoxy and nitro₆-C₁₈An aryl group; optionally substituted by 1-3 substituents selected from halogen, -OC (═ O) C₁-C₆Alkyl, -OC (═ O) C₂-C₆Alkenyl or C₆-C₁₈Aryl substituted C₁-C₆An alkyl group; optionally substituted by 1-3 substituents selected from halogen and C₆-C₁₈Aryl substituted C₂-C₆An alkenyl group; and is arbitrarily selected by 1-3From halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆5-18 membered heteroaryl substituted with substituents of haloalkoxy and nitro;

R₁₀each independently selected from the group consisting of 1-3 selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆C substituted by substituents of haloalkoxy and nitro₆-C₁₈An aryl group;

R₁₁each independently selected from the group consisting of optionally substituted 1-3 substituents selected from halogen, -OC (═ O) C₁-C₆Alkyl, -OC (═ O) C₂-C₆Alkenyl or C₆-C₁₈Aryl substituted C₁-C₆An alkoxycarbonyl group;

R₁₂each independently selected from the group consisting of 1-3 selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆C substituted by substituents of haloalkoxy and nitro₆-C₁₈An aryl group;

R₁₃each independently selected from the group consisting of 1-3 selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆C substituted by substituents of haloalkoxy₃-C₁₀A cycloalkyl group; and optionally substituted by 1-3 substituents selected from halogen, -OC (═ O) C₁-C₆Alkyl, -OC (═ O) C₂-C₆Alkenyl or C₆-C₁₈Aryl substituted C₁-C₆An alkyl group;

R₁₄each independently selected from the group consisting of 1-3 selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆C substituted by substituents of haloalkoxy and nitro₆-C₁₈An aryl group; and optionally substituted by 1-3 substituents selected from halogen, -OC (═ O) C₁-C₆Alkyl, -OC (═ O) C₂-C₆Alkenyl or C₆-C₁₈Aryl substituted C₁-C₆An alkyl group;

R₁₆and R₁₇Each independently selected from the group consisting of 1-3 selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆C substituted by substituents of haloalkoxy and nitro₆-C₁₈An aryl group; optionally substituted by 1-3 substituents selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆3-18 membered heterocyclic group substituted with the substituents of haloalkoxy and nitro; and optionally 1-3 selected from halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆C substituted by substituents of haloalkoxy and nitro₆-C₁₈An aryloxy group;

R₁₈to R₂₀Each independently selected from N (C)₁-C₆Alkyl radical)₂；

n is 1,2 or 3;

R₃and R₄Each independently selected from hydrogen, nitroso, C₁-C₆Alkyl radical, C₆-C₁₈Aryl substituted C₁-C₆Alkyl radical, C₆-C₁₈Aryl carbonyl group, C₁-C₆An alkylcarbonyl group;

wherein the heteroaryl group is an aromatic ring group consisting of carbon atoms and one to five heteroatoms selected from nitrogen, oxygen and sulfur; said heterocyclyl means a non-aromatic ring group consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur;

with the following conditions:

when X is present₅When hydrogen is used, n is not 0.

30. The compound of claim 29, wherein

R₃And R₄Each independently selected from hydrogen, nitroso, C₁-C₆Alkyl, benzyl, benzoyl or acetyl.

31. The compound of claim 29 or 30, wherein

R₃And R₄Each independently selected from methyl, benzyl, acetyl, or benzoyl.

32. The compound of claim 29 or 30, wherein n is 1 and X₆At position C14.

33. The compound of claim 29 or 30, wherein R₃And R₄Each independently selected from C₁-C₆An alkyl group.

34. The compound of claim 29 or 30, wherein

X₅Is hydrogen;

X₆selected from-NH-C (═ O) -NH-R₈、-O-C(＝O)-R₉or-O-S (═ O)₂-R₁₀、-NH-C(＝S)-NH-R₁₁、-NH-C(＝O)OR₁₂、-OC(＝O)NHR₁₃、-OC(＝O)OR₁₄、-NH-P(＝O)R₁₆R₁₇、-NHC(＝S)R₁₈or-OC (═ O) R₂₀；

R₁₀selected from 2-nitrophenyl, 2, 4-dichlorophenyl or 4-methylphenyl;

R₁₁is selected from-C (═ O) OC₂H₅；

R₁₂Selected from phenyl or 4-nitrophenyl;

R₁₃selected from benzyl, tert-butyl or cyclohexyl;

R₁₄selected from 4-nitrophenyl, phenyl or benzyl;

R₁₆and R₁₇Are each 2-oxazolidone, phenoxy or phenyl;

R₁₈to R₂₀is-N (CH)₃)₂；

n is 1 and X₆At position C14;

R₃is methyl, benzyl, acetyl, or benzoyl; and

R₄is methyl.

35. A compound or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

36. a pharmaceutical composition comprising a compound according to any one of claims 29 to 35, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

37. The pharmaceutical composition of claim 36, which is a tablet, capsule, pill, suppository, emulsion, ointment, injection or infusion.

38. Use of a compound according to any one of claims 29 to 35 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 36 or 37 in the manufacture of a medicament for the prevention or treatment of a tumour.

39. Use of a compound of any one of claims 29 to 35 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 36 or 37 in combination with another anti-neoplastic agent in the manufacture of a medicament for the prevention or treatment of a neoplasm.

40. The use as claimed in claim 39, wherein the another antitumor drug is selected from doxorubicin, paclitaxel, cyclophosphamide, daunorubicin, podophyllotoxin or vinblastine.

41. The use of claim 40, wherein the another anti-neoplastic drug is doxorubicin or paclitaxel.

42. The use of any one of claims 38-41, wherein the tumor is selected from tongue cancer, pancreatic cancer, cervical cancer, laryngeal cancer, renal cancer, leukemia, breast cancer, melanoma, prostate cancer, liver cancer, sarcoma, ovarian cancer, ureteral cancer, bladder cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, endocrine cancer, skin cancer, hemangioma, brain cancer, or central nervous system cancer, or a metastatic cancer thereof.

43. The use of any one of claims 38-41, wherein the tumor is a erythroleukemia.

44. The use of claim 42, wherein the tumor is tongue cancer, pancreatic cancer, cervical cancer, laryngeal cancer, renal cancer, leukemia, breast cancer, melanoma, prostate cancer, or liver cancer.

45. The use of any one of claims 38-41, wherein the tumor is a drug resistant tumor.

46. The use of claim 45, wherein the drug-resistant tumor is drug-resistant breast cancer, melanoma, human prostate cancer, tongue cancer, pancreatic cancer, cervical cancer, laryngeal cancer, renal cancer, leukemia, liver cancer, sarcoma, ovarian cancer, ureteral cancer, bladder cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, endocrine cancer, skin cancer, hemangioma, or glioma.

47. The use of claim 45, wherein the drug resistant tumor is drug resistant erythroleukemia.

48. The use of claim 46, wherein the drug-resistant tumor is tongue cancer, pancreatic cancer, cervical cancer, laryngeal cancer, renal cancer, leukemia, breast cancer, melanoma, prostate cancer, or liver cancer.