A compound and use thereof

Abstract

Provided is a compound represented by General Formula (A), a stereoisomer, a cis-trans isomer, or a pharmaceutically acceptable salt thereof.

Description

A compound and its application

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims priority to and the benefit of Chinese Patent Application No. 202311630342.7, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to the fields of organic chemistry and medicinal chemistry. Background Art

[0004] Cancer is a major threat to human health. Currently, chemotherapy remains one of the main treatments for cancer. However, traditional chemotherapy drugs lack tumor cell specificity. While killing tumor cells, they are also highly toxic to normal cells, leading to serious systemic side effects. Furthermore, many chemotherapy drugs suffer from poor water solubility and low bioavailability, limiting their clinical application. Summary of the Invention

[0005] In a first aspect of the present disclosure, provided are compounds represented by general formula (A), stereoisomers, cis-trans isomers, or pharmaceutically acceptable salts thereof:

[0006] in,

[0007] R1 is selected from hydroxyl, C1-C 10 Hydroxyl, -O - Alkali metal ions, -O - Ammonium ions and -O - ;

[0008] R2 is selected from hydrogen and C1-C 10 hydrocarbon group;

[0009] R3, at each occurrence, is independently selected from hydrogen, halogen, C1-C 10 Hydrocarbon, C1-C 10 Halogenated hydrocarbon, C1-C 10 Alkyloxy, C1-C 10 Halogenated alkyloxy, C6-C 18 Aryl, nitro, -NR 21 R 22 ;

[0010] R4 is selected from C1-C 10 Alkylidene, C1-C 10 Hydrocarbyleneoxy, C6-C 12 Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene, C1-C 10Alkylidene-C6-C 12 Arylene-C1-C 10 Hydrocarbylene, (C1-C 10 alkyleneoxy) d -C1-C 10 Alkylidene, C1-C 10 Hydrocarbyleneoxy-C6-C 12 Arylene, -(CH2) m -CO-NR 23 -(CHR 24 ) j -(CO-NR 25 -(CHR 26 ) k ) p -(CH2) n -, and -((CH2) m -NR 23 -(CHR 24 ) j ) q -(CH2) n -;

[0011] R5 and R6, when present, are independently selected from hydrogen, halogen, C1-C 10 Hydrocarbon, C1-C 10 Halogenated hydrocarbon, C1-C 10 Alkyloxy, C1-C 10 Halogenated alkyloxy and C6-C 18 aryl;

[0012] R7 is selected from:

[0013] R8 is selected from R 10 、R 11 、R 12 、R 17 、-OCO-R 10 、-OCO-R 12 and-OCO-R 17 :

[0014] R 13 and R 14 Each independently selected from hydrogen, C1-C8 hydrocarbon group, C6-C 12 Aryl and C1-C8 alkylene C6-C12 aryl, R 13 and R 14 Optionally, together with the nitrogen atom to which they are attached, they form a 3- to 17-membered nitrogen-containing heterocyclic ring;

[0015] R9 and R 16are each independently selected from hydrogen, alkali metal ions, and ammonium ions;

[0016] R 21 and R 22 are each independently selected from hydrogen and C1-C6 hydrocarbon groups;

[0017] R 23 and R 25 Each independently selected from hydrogen, C1-C6 hydrocarbon group and C1-C6 hydrocarbonoxy group;

[0018] R 24 and R 26 Each independently selected from hydrogen, C1-C6 hydrocarbon group, C1-C6 alkoxy group, C6-C 12 Aryl and C7-C 13 aromatic hydrocarbon groups;

[0019] x is 0 or 1; a is an integer of 0-3; b and c are each independently an integer of 0-4; d is an integer of 0-4; j, k, m, n and p are each independently an integer of 0-5, and q is an integer of 1-5;

[0020] in Indicates the attachment site.

[0021] In some embodiments, a compound represented by the general formula (I), a stereoisomer, a cis-trans isomer, or a pharmaceutically acceptable salt thereof is provided:

[0022] in,

[0023] R1 is selected from hydroxyl, C1-C 10 Hydroxyl, -O - Alkali metal ions, -O - Ammonium ions and -O - ;

[0024] R2 is selected from hydrogen and C1-C 10 hydrocarbon group;

[0025] R3, at each occurrence, is independently selected from hydrogen, halogen, C1-C 10 Hydrocarbon, C1-C 10 Halogenated hydrocarbon, C1-C 10 Alkyloxy, C1-C 10 Halogenated alkyloxy, C6-C 18 Aryl, nitro, -NR 21 R 22 ;

[0026] R4 is selected from C1-C 10 Alkylidene, C1-C 10 Hydrocarbyleneoxy, C6-C 12Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene-C1-C 10 Alkylidene, C1-C 10 Hydrocarbyleneoxy-C6-C 12 Arylene, -(CH2) m -CO-NR 23 -(CHR 24 ) j -(CO-NR 25 -(CHR 26 ) k ) p -(CH2) n -, and -((CH2) m -NR 23 -(CHR 24 ) j ) q -(CH2) n -; or alternatively, R4 is selected from C1-C 10 Alkylidene, C1-C 10 Hydrocarbyleneoxy, C6-C 12 Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene-C1-C 10 Hydrocarbylene, (C1-C 10 alkyleneoxy) d -C1-C 10 Alkylidene, C1-C 10 Hydrocarbyleneoxy-C6-C 12 Arylene, -(CH2) m -CO-NR 23 -(CHR 24 ) j -(CO-NR 25 -(CHR 26 ) k ) p -(CH2) n -, and -((CH2) m -NR 23 -(CHR 24 ) j ) q -(CH2) n -;

[0027] R5 and R6, when present, are independently selected from hydrogen, halogen, C1-C 10 Hydrocarbon, C1-C 10 Halogenated hydrocarbon, C1-C 10 Alkyloxy, C1-C 10 Halogenated alkyloxy and C6-C 18 aryl;

[0028] R7 is selected from:

[0029] R8 is selected from R 10 、R 11 、R 12 、R 17 、-OCO-R 10 、-OCO-R 12 and-OCO-R 17 :

[0030] R 13 and R 14 Each independently selected from hydrogen, C1-C8 hydrocarbon group, C6-C 12 Aryl and C1-C8 alkylene C6-C12 aryl, R 13 and R 14 Optionally, together with the nitrogen atom to which they are attached, they form a 3- to 17-membered nitrogen-containing heterocyclic ring;

[0031] R9 and R 16 are each independently selected from hydrogen, alkali metal ions, and ammonium ions;

[0032] R 21 and R 22 are each independently selected from hydrogen and C1-C6 hydrocarbon groups;

[0033] R 23 and R 25 Each independently selected from hydrogen, C1-C6 hydrocarbon group and C1-C6 hydrocarbonoxy group;

[0034] R 24 and R 26 Each independently selected from hydrogen, C1-C6 hydrocarbon group, C1-C6 alkoxy group, C6-C 12 Aryl and C7-C 13 aromatic hydrocarbon groups;

[0035] a is an integer from 0 to 3; b and c are each independently an integer from 0 to 4; j, k, m, n and p are each independently an integer from 0 to 5, and q is an integer from 1 to 5; or alternatively, a is an integer from 0 to 3; b and c are each independently an integer from 0 to 4; d is an integer from 0 to 4; j, k, m, n and p are each independently an integer from 0 to 5, and q is an integer from 1 to 5;

[0036] in Indicates the attachment site.

[0037] In some embodiments, provided are compounds represented by formula (II), stereoisomers, cis-trans isomers, or pharmaceutically acceptable salts thereof:

[0038] in,

[0039] R1 is selected from hydroxyl, C1-C 10 Hydroxyl, -O - Alkali metal ions, -O - Ammonium ions and -O - ;

[0040] R2 is selected from hydrogen and C1-C 10 hydrocarbon group;

[0041] R3, at each occurrence, is independently selected from hydrogen, halogen, C1-C 10 Hydrocarbon, C1-C 10 Halogenated hydrocarbon, C1-C 10 Alkyloxy, C1-C 10 Halogenated alkyloxy, C6-C 18 Aryl, nitro, -NR 21 R 22 ;

[0042] R4 is selected from C1-C 10 Alkylidene, C1-C 10 Hydrocarbyleneoxy, C6-C 12 Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene-C1-C 10 Hydrocarbylene, (C1-C 10 alkyleneoxy) d -C1-C 10 Alkylidene, C1-C 10 Hydrocarbyleneoxy-C6-C 12 Arylene, -(CH2) m -CO-NR 23 -(CHR 24 )j -(CO-NR 25 -(CHR 26 ) k ) p -(CH2) n -, and -((CH2) m -NR 23 -(CHR 24 ) j ) q -(CH2) n -;

[0043] R5 and R6, when present, are independently selected from hydrogen, halogen, C1-C 10 Hydrocarbon, C1-C 10 Halogenated hydrocarbon, C1-C 10 Alkyloxy, C1-C 10 Halogenated alkyloxy and C6-C 18 aryl;

[0044] R7 is selected from:

[0045] R8 is selected from R 10 、R 11 、R 12 、R 17 、-OCO-R 10 、-OCO-R 12 and-OCO-R 17 :

[0046] R 13 and R 14 Each independently selected from hydrogen, C1-C8 hydrocarbon group, C6-C 12 Aryl and C1-C8 alkylene C6-C12 aryl, R 13 and R 14 Optionally, together with the nitrogen atom to which they are attached, they form a 3- to 17-membered nitrogen-containing heterocyclic ring;

[0047] R9 and R 16 are each independently selected from hydrogen, alkali metal ions, and ammonium ions;

[0048] R 21 and R 22 are each independently selected from hydrogen and C1-C6 hydrocarbon groups;

[0049] R 23 and R 25 Each independently selected from hydrogen, C1-C6 hydrocarbon group and C1-C6 hydrocarbonoxy group;

[0050] R24 and R 26 Each independently selected from hydrogen, C1-C6 hydrocarbon group, C1-C6 alkoxy group, C6-C 12 Aryl and C7-C 13 aromatic hydrocarbon groups;

[0051] a is an integer of 0-3; b and c are each independently an integer of 0-4; d is an integer of 0-4; j, k, m, n and p are each independently an integer of 0-5, and q is an integer of 1-5;

[0052] in Indicates the attachment site.

[0053] In some embodiments, in the formulae described herein,

[0054] R1 is selected from hydroxyl, C1-C 10 Alkoxy, -O - Li + 、-O - Na + 、-O - K + 、-O - Cs + 、-O - NH4 + and -O - ;

[0055] R2 is selected from hydrogen and C1-C 10 alkyl;

[0056] R3, at each occurrence, is independently selected from hydrogen, F, Cl, Br, I, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C6-C 18 Aryl, nitro, -NR 21 R 22 ;

[0057] R4 is selected from C1-C 10 Alkylene, C1-C 10 Alkyleneoxy, C6-C 12 Arylene, C1-C 10 Alkylene-C6-C 12 Arylene, C1-C 10 Alkylene-C6-C 12 Arylene-C1-C 10 Alkylene, C1-C 10 Alkyleneoxy-C6-C 12 Arylene, -(CH2)m -CO-NR 23 -(CHR 24 ) j -(CO-NR 25 -(CHR 26 ) k ) p -(CH2) n -, and -((CH2) m -NR 23 -(CHR 24 ) j ) q -(CH2) n -;

[0058] R5 and R6, when present, are each independently selected from hydrogen, F, Cl, Br, I, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy and C6-C 18 aryl;

[0059] R7 is selected from:

[0060] R8 is selected from R 10 、R 11 、R 12 、R 17 、-OCO-R 10 、-OCO-R 12 and-OCO-R 17 :

[0061] R 13 and R 14 Each independently selected from hydrogen, C1-C8 alkyl, C6-C 12 Aryl and C1-C8 alkylene C6-C12 aryl, R 13 and R 14 Optionally, together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic ring;

[0062] R9 and R 16 Each independently selected from hydrogen, Li + 、Na + , K + 、Cs + and NH4 + ;

[0063] R 21 and R 22are each independently selected from hydrogen and C1-C6 alkyl;

[0064] R 23 and R 25 Each independently selected from hydrogen, C1-C6 alkyl and C1-C6 alkoxy;

[0065] R 24 and R 26 Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C 12 Aryl and C7-C 13 Aralkyl;

[0066] a is an integer of 0-3; b and c are each independently an integer of 0-4; j, k, m, n and p are each independently an integer of 0-5, and q is an integer of 1-5;

[0067] in Indicates the attachment site.

[0068] In other embodiments, in the formulae described herein,

[0069] R1 is selected from hydroxyl, -OCH3, -OCH2CH3, -O - Li + 、-O - Na + 、-O - K + 、-O - Cs + 、-O - NH4 + and -O - ;

[0070] R2 is selected from hydrogen, -CH3 and -CH2CH3;

[0071] R3, at each occurrence, is independently selected from hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, phenyl, -NO2, -NH2, -NH(CH3), -N(CH3)2;

[0072] R4 is selected from -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, -(CH2CH2O)3CH2-, -(CH2CH2CH2O)2CH2CH2-, -(CH2CH2NH)3CH2-, -CH2CH2C6H4-, -CH2CH2C 10H6-, -CH2CH2C6H4C6H4-, -CH2CH2C6H4CH2CH2CH2-, -CH2CH2OCH2CH2-, -CH2CH2OCH2CH2CH2-, -CH2CH2CH2OCH2CH2C H2-, -(CON(CH3)CH2)2-, -(CH2CONH)2CH2-, -CH2CONHCH(CH3)CONHCH(CH3)-, -CH2CONHCH(CH3)CONHCH(CH2C6H5)-;

[0073] R5 and R6, at each occurrence, are each independently selected from hydrogen, F, Cl, Br, -CH3, -CH2CH3, -OCH3, -OCH2CH3 and phenyl;

[0074] R7 is selected from:

[0075] R8 is selected from R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 17 、-OCO-R 10 、-OCO-R 12 and-OCO-R 17 ;

[0076] R 13 and R 14 are each independently selected from hydrogen, methyl, ethyl, isopropyl, butyl, phenyl, benzyl and phenethyl,

[0077] When R 13 and R 14 When forming a ring with the nitrogen atom to which they are attached, R 12 for:

[0078] R9 and R 16 Each independently selected from hydrogen, Li + 、Na + , K + 、Cs + and NH4 + ;

[0079] a is an integer from 0 to 3; b and c are each independently an integer from 0 to 4;

[0080] in Indicates the attachment site.

[0081] In yet other embodiments, the compound described herein may be any one of the compounds listed in Table 1 below.

[0082] A second aspect of the present disclosure provides a pharmaceutical composition comprising a compound represented by the general formula described herein, a stereoisomer, a cis-trans isomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0083] In some embodiments, the pharmaceutical composition comprises an effective amount (e.g., a therapeutically effective amount) of a compound represented by the general formula described herein, its stereoisomers, cis-trans isomers, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient. In other embodiments, the excipient can be a sodium chloride solution carrier. In yet other embodiments, the pharmaceutical composition described herein is prepared as an injection preparation. In still other embodiments, the pharmaceutical composition described herein is configured as an injection, sterile powder for injection, and concentrated solution for injection.

[0084] A third aspect of the present disclosure provides use of a compound represented by the general formula described herein, a stereoisomer, a cis-trans isomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein in the preparation of a medicament for treating tumors or cancer.

[0085] In some embodiments, the tumor or cancer is selected from colorectal cancer, liver cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, bladder cancer, liver cancer, intestinal cancer, head and neck cancer, uterine cancer, urothelial carcinoma, osteosarcoma, sarcoma, kidney cancer, melanoma, prostate cancer, glioma, neuroglioma and leukemia.

[0086] A fourth aspect of the present disclosure provides a compound represented by the general formula described herein, a stereoisomer, a cis-trans isomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for use in treating tumors or cancer.

[0087] In some embodiments, the tumor or cancer is selected from colorectal cancer, liver cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, bladder cancer, liver cancer, intestinal cancer, head and neck cancer, uterine cancer, urothelial carcinoma, osteosarcoma, sarcoma, kidney cancer, melanoma, prostate cancer, glioma, neuroglioma and leukemia.

[0088] A fifth aspect of the present disclosure provides a method for treating tumors or cancer, comprising administering to an individual in need thereof an effective amount (e.g., a therapeutically effective amount) of a compound represented by the general formula (A), (I) and (II) as described herein, its stereoisomers, cis-trans isomers, or pharmaceutically acceptable salts, or a pharmaceutical composition as described herein.

[0089] In some embodiments, the tumor or cancer is selected from colorectal cancer, liver cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, bladder cancer, liver cancer, intestinal cancer, head and neck cancer, uterine cancer, urothelial carcinoma, osteosarcoma, sarcoma, kidney cancer, melanoma, prostate cancer, glioma, neuroglioma and leukemia. DETAILED DESCRIPTION

[0090] The present disclosure is described in detail below by way of specific embodiments, but this does not mean that there is any adverse limitation on the present disclosure. The present disclosure has been described in detail herein by way of specific embodiments, and it will be apparent to those skilled in the art that various changes can be made to these specific embodiments without departing from the spirit and scope of the present disclosure.

[0091] Unless otherwise required in this disclosure, throughout the specification and claims, the words "include" and "comprising" should be interpreted in an open, inclusive sense, ie, "including, but not limited to."

[0092] References herein to "one embodiment" or "another embodiment" or "an embodiment" or "some embodiments" or the like mean that the specific referenced elements, structures, or features described in connection with that embodiment are included in at least one embodiment. Thus, appearances of the phrases "one embodiment" or "an embodiment" or "another embodiment" in different places herein do not necessarily all refer to the same embodiment. Furthermore, the specific elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0093] It is to be understood that as used throughout the specification and claims, the singular forms of the words "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0094] definition

[0095] Accordingly, unless otherwise indicated to the contrary, the following terms used in the specification and appended claims shall have the following meanings:

[0096] The abbreviations placed before certain chemical groups named in this disclosure represent the total number of carbon atoms present in the indicated chemical group. For example, C1-C 10 Alkyl describes an alkyl group as defined below having a total of 1 to 10 carbon atoms, while C3-C 10 Cycloalkyl describes a cycloalkyl group as defined below having a total of 3 to 10 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may be present in substituents of the group being described.

[0097] In this disclosure, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0098] In this disclosure, the term "hydroxyl" refers to an -OH group.

[0099] In the present disclosure, the term "amino" refers to a -NH2 group.

[0100] In this disclosure, the term "carboxyl" refers to a -COOH group.

[0101] In this disclosure, the term "cyano" refers to a -CN group.

[0102] In this disclosure, the term "nitro" refers to a -NO2 group.

[0103] In the present disclosure, the term "alkali metals" refers to the six metal elements in Group IA of the periodic table except hydrogen (H), namely lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs), and francium (Fr).

[0104] In this disclosure, the term "ammonium ion" refers to an ammonia proton derived from ammonia, + In this disclosure, the term "hydrocarbyl" refers to an aliphatic hydrocarbon group. The hydrocarbyl portion may be a "saturated hydrocarbyl" group, meaning that it does not contain any alkene or alkyne moieties. The hydrocarbyl portion may also be an "unsaturated hydrocarbyl" portion, meaning that it contains at least one alkene or alkyne moiety. An "alkene" portion refers to a straight or branched hydrocarbon chain group consisting of 2 to 10 carbon atoms and at least one carbon-carbon double bond, and connected to the rest of the molecule by a single bond, such as vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc., and an "alkyne" portion refers to a straight or branched hydrocarbon chain group consisting of 2 to 10 carbon atoms and at least one carbon-carbon triple bond, and connected to the rest of the molecule by a single bond. The hydrocarbyl portion, whether saturated or unsaturated, may be branched or straight-chain.

[0105] The hydrocarbyl group can have from 1 to 10 carbon atoms (each occurrence in this disclosure of a numerical range such as "1 to 8" refers to each integer in the given range; e.g., "1 to 10" means that the hydrocarbyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms, although this definition also covers occurrences of the term "hydrocarbyl" without specifying a numerical range).

[0106] The hydrocarbyl group may be optionally substituted, i.e., substituted or unsubstituted. When substituted, the substituent groups are individually and independently selected from the group consisting of cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, hydrocarbyloxy, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl groups as defined herein), or amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Typical hydrocarbyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, ethynyl, propynyl and butynyl. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above.

[0107] In some embodiments, "C1-C4 hydrocarbyl" refers to a hydrocarbyl group as defined above containing one to four carbon atoms. The C1-C4 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0108] In some embodiments, "C1-C6 hydrocarbyl" refers to a hydrocarbyl group as defined above containing one to six carbon atoms. The C1-C6 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0109] In some embodiments, "C1-C 10 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing one to ten carbon atoms. 10 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0110] In some embodiments, "C2-C6 hydrocarbyl" refers to a hydrocarbyl group as defined above containing two to six carbon atoms. The C2-C6 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0111] In some embodiments, "C3-C6 hydrocarbyl" refers to a hydrocarbyl group as defined above containing three to six carbon atoms. A C3-C6 hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0112] In some embodiments, "C3-C 10 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing three to ten carbon atoms. 12The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0113] In some embodiments, "C6-C 10 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing six to ten carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0114] In some embodiments, "C7-C 12 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing seven to twelve carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0115] In some embodiments, "haloalkyl" refers to an alkyl group whose substituent groups are one or more groups individually and independently selected from halogens.

[0116] In some embodiments, "alkylene" refers to an alkyl group formed by dropping two hydrogen atoms from an alkyl group molecule. Illustrative examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, and -CH2CH2CH2-.

[0117] In the present disclosure, the term "hydrocarbyl" refers to the general formula -O-hydrocarbyl, wherein hydrocarbyl is as defined in the present disclosure. Illustrative examples of hydrocarbyl include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and tert-pentoxy.

[0118] In the present disclosure, the term "aryl" refers to a carbocyclic ring (all carbon) or two or more fused rings (rings sharing two adjacent carbon atoms) having a completely delocalized pi electron system. Aryl groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. Aryl groups can, for example, have six to twelve carbon atoms. The aryl groups of the present disclosure can be substituted or unsubstituted. When substituted, the hydrogen atoms are replaced by one or more groups independently selected from the group consisting of hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, hydrocarbyl, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl as defined in the present disclosure), or protected amino. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above.

[0119] In the present disclosure, the term "arylene" refers to a carbocyclic ring (all carbon) or two or more fused rings (rings sharing two adjacent carbon atoms) having a completely delocalized pi electron system. Arylene groups include, but are not limited to, fluorenylene, phenylene, and naphthylene. Arylene groups can, for example, have six to twelve carbon atoms. The arylene groups of the present disclosure can be substituted or unsubstituted. When substituted, the hydrogen atoms are replaced by one or more groups independently selected from the group consisting of hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, hydrocarbyl, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl as defined in the present disclosure), or protected amino. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above. The arylene group can be attached to the rest of the molecule and to the residue group through one carbon atom in the group or through any two carbon atoms in the group.

[0120] In the present disclosure, the term "aromatic ring group" refers to a carbocyclic ring (all carbon) or two or more fused rings (rings sharing two adjacent carbon atoms) having a completely delocalized pi electron system. Aryl groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. An aromatic ring group can, for example, have six to twelve carbon atoms. The aromatic ring groups of the present disclosure can be substituted or unsubstituted. When substituted, the hydrogen atoms are replaced by one or more groups independently selected from the group consisting of hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, hydrocarbyl, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl as defined in the present disclosure), or protected amino. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above.

[0121] In the present disclosure, the term "heteroaryl" refers to a 5- to 18-membered aromatic ring group consisting of one to seventeen carbon atoms and one to ten heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. Illustrative examples of heteroaryl groups include, but are not limited to, azaquinolyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, diphenyl The heteroaryl groups of the present disclosure may be substituted or unsubstituted. When substituted, the hydrogen atoms are replaced by one or more groups independently selected from the group consisting of hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, hydrocarbyl, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl as defined in the present disclosure), or protected amino. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above.

[0122] In the present disclosure, the term "heteroarylene" refers to a 5- to 18-membered aromatic ring subunit consisting of one to seventeen carbon atoms and one to ten heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroarylene may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroarylene may be optionally oxidized; the nitrogen atom may be optionally quaternized. Illustrative examples of heteroarylene groups include, but are not limited to, azazepine group, acridinium group, benzimidazole group, benzothiazol group, benzindole group, benzodioxole group, benzofuran group, benzoxazolyl group, benzothiazol group, benzothiadiazol group, benzo[b][1,4]dioxepane group, 1,4-benzodioxane group, benzonaphthofuran group, benzoxazolyl group, benzodioxole group, benzodioxin group, benzopyran group, benzopyrone group, benzofuran group, benzofuranone group, benzothiophene group, benzotriazole group, benzo[4,6]imidazo[1,2-a]pyridine group, carbazole group, cinnolin group, dibenzofuran group, dibenzothiophene group, furan group, yl, furanone subunit, isothiazole subunit, imidazole subunit, indazole subunit, indole subunit, indazole subunit, isoindole subunit, indolin subunit, isoindolin subunit, isoquinolin subunit, indole oxadiazole subunit, isoxazole subunit, naphthyridine subunit, oxadiazole subunit, 2-oxoazepine subunit, oxazole subunit, oxirane subunit, 1-phenyl-1H-pyrrol subunit, phenanthrazine subunit, phenanthiazine subunit The heteroaryl groups of the present disclosure may be substituted or unsubstituted. When substituted, the hydrogen atoms are replaced by one or more groups independently selected from the group consisting of hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, hydrocarbyl, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl as defined in the present disclosure), or protected amino. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above. The heteroarylene group can be attached to the rest of the molecule and to the residue group through one carbon atom in the group or through any two carbon atoms in the group.

[0123] In the present disclosure, the term "heteroaryl" refers to a 5- to 18-membered aromatic ring group consisting of one to seventeen carbon atoms and one to ten heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. Illustrative examples of heteroaromatic ring groups include, but are not limited to, azepine, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxadiazolyl, 1-phenyl-1H-pyrrolyl, phenanthrazinyl, phenanthiazinyl, phenanthroxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thienyl. The heteroaryl ring radical group of the present disclosure can be substituted or unsubstituted. When substituted, the hydrogen atoms are replaced by one or more groups independently selected from the group consisting of hydrocarbyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, hydrocarbyl, aryloxy, mercapto, hydrocarbylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbyl as defined in the present disclosure), or protected amino. Whenever a substituent is described as being "optionally substituted," the substituent may be substituted by one of the substituents described above.

[0124] In the present disclosure, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, in some embodiments from three to twelve carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl, and the like. Unless otherwise expressly stated in the present disclosure, the term "cycloalkyl" is intended to include cycloalkyl as defined above optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, aryl, heteroaryl, aromatic ring group, heteroaromatic ring group, heteroalicyclic group, hydroxy, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfinylamino, N-sulfinylamino, C-carboxyl, O-carboxyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are alkyl as defined in the present disclosure), or amino including mono- and di-substituted amino groups, and protected derivatives thereof.

[0125] In some embodiments, "C3-C6 cycloalkyl" refers to a cycloalkyl group as defined above having three to six carbon atoms. The C3-C6 cycloalkyl group may be optionally substituted as defined above for cycloalkyl.

[0126] In some embodiments, "C3-C 10 "Cycloalkyl" refers to a cycloalkyl group as defined above having three to ten carbon atoms. 10 The cycloalkyl group may be optionally substituted as defined above for a cycloalkyl group.

[0127] In the present disclosure, the heterocycle may contain at least one of B, O, N, P, Si or S as a heteroatom for forming the ring. When the heterocycle contains two or more heteroatoms, the two or more heteroatoms may be the same or different. The heterocycle may be a monocyclic heterocycle or a polycyclic heterocycle and may include a heterocyclic hydrocarbon group, such as a heteroaryl group and. The carbon number of the ring for forming the heterocycle may be 2 to 30, 2 to 20, or 2 to 10. The heteroatoms for forming the heterocycle may be 1 to 10, 1 to 5 or 1 to 3, such as 1, 2, 3, 4, 5, 6, 7, 8 or 9. Examples of heterocycles may include thiophene, furan, pyrrole, imidazole, thiazole, oxazole, oxadiazole, triazole, pyridine, bipyridine, pyrimidine, triazine, acridine, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, thiadiazole, phenothiazine, dibenzosilole, dibenzofuran, and the like, but are not limited thereto.

[0128] As used herein, the term "alkylene" or "alkylene group" refers to a divalent hydrocarbon chain consisting solely of carbon and hydrogen, and may be a straight, branched, or cyclic alkyl group. That is, a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a residual group, such as methylene, ethylene, propylene, n-butylene, vinylene, propenylene, or n-butylene. The alkylene chain may be connected to the remainder of the molecule and the residual group through a single carbon atom or through any two carbon atoms in the chain.

[0129] In the present disclosure, the term "C1-C9 alkylene" refers to a difunctional straight, branched, or cyclic alkyl group having one to nine carbon atoms. That is, "C1-C9 alkylene" refers to a straight or branched divalent hydrocarbon chain composed solely of carbon and hydrogen and having one to nine carbon atoms, connecting the remainder of the molecule to the residual group, such as methylene, ethylene, propylene, n-butylene, vinylene, propenylene, and n-butylene. The alkylene chain can be connected to the remainder of the molecule and the residual group through one carbon in the chain or through any two carbons in the chain. In the present disclosure, the terms "alkyleneoxy," "alkyleneoxy," or "alkyleneoxy" refer to the general formula alkylene-O-, where alkylene or alkylene is as defined in the present disclosure. Illustrative examples of alkyleneoxy include, but are not limited to, methyleneoxy, ethyleneoxy, and n-propyleneoxy. In the present disclosure, the term "C1-C9 alkyleneoxy", "C1-C9 alkyleneoxy" or "C1-C9 hydrocarbyleneoxy" refers to a difunctional linear, branched, or cyclic alkoxy group having one to nine carbon atoms.

[0130] In the present disclosure, the term "cycloalkyloxy" refers to -O-cycloalkyl, wherein cycloalkyl is as defined in the present disclosure. Illustrative examples of cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and cyclodecyloxy.

[0131] In the present disclosure, the term "alkylcarbonylamino" refers to -NHC(=O)-alkyl, wherein alkyl is as defined in the present disclosure. Illustrative examples of alkylcarbonylamino include, but are not limited to, acetamido, propionamido, butyranamido, and pentanoylamino.

[0132] In the present disclosure, the term "alkylcarbonyloxy" refers to -OC(=O)-alkyl, wherein alkyl is as defined in the present disclosure. Illustrative examples of alkylcarbonyloxy include, but are not limited to, acetoxy, propionyloxy, butyryloxy, and pentanoyloxy.

[0133] In the present disclosure, the term "hydrocarbyloxycarbonylamino" refers to -NHC(=O)O-hydrocarbyl, wherein the hydrocarbyl group is as defined in the present disclosure. Illustrative examples of hydrocarbyloxycarbonylamino include, but are not limited to, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, and tert-butoxycarbonylamino.

[0134] In the present disclosure, the term "hydrocarbyloxy" refers to -C(=O)O-hydrocarbyl, wherein the hydrocarbyl group is as defined in the present disclosure. Illustrative examples of hydrocarbyloxy include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, and butoxycarbonyl.

[0135] In the present disclosure, the term "carbonylamino" refers to -C(=O)-NH-.

[0136] In addition, when the prefix is ​​named sequentially, it means that the substituents are listed in the order in which they are first described. For example, arylalkoxy means an alkoxy group substituted by an aryl group, alkoxycarbonyl means a carbonyl group substituted by an alkoxy group, and arylcarbonylalkenyl also means an alkenyl group substituted by an arylcarbonyl group, wherein the arylcarbonyl group can be a carbonyl group substituted by an aryl group.

[0137] In the present disclosure, when “—NH—”, “—NR—” or similar expressions are used, it means that two chemical bonds of the N atom are connected to the rest of the moiety, and should not be interpreted as “—NH—R—”.

[0138] In the present disclosure, when a variable in a defined general formula is represented as 0 or does not exist, it means that the general formula should skip the group in which the variable is represented as 0 or does not exist and continue to connect the group connected to the group in which the variable is represented as 0 or does not exist, and should not be interpreted as no longer connecting any group.

[0139] In the present disclosure, when general formula A, I or II is a quaternary ammonium salt, the general formula compound can be combined with negative ions, and the negative ions include: halogen negative ions (fluorine, chloride, bromide, iodine), nitrate, sulfate, phosphate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, citrate, fumarate, lactate, malate, oxalate, formate, acetate, maleate, succinate, tartrate, ascorbate, benzoate, gentisate, oleate, pamoate, stearate, sorbate, etc.

[0140] In this disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans, etc. In some embodiments, the mammal includes humans.

[0141] In this disclosure, the term "patient" refers to animals (e.g., humans), companion animals (e.g., dogs, cats, or horses), and livestock (e.g., cattle, pigs, and sheep). In some embodiments, the patient is a mammal, including males and females. In some embodiments, the patient is a human.

[0142] In the present disclosure, the term "pharmaceutically acceptable" refers to the carrier, diluent and / or salt which must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0143] In this disclosure, the terms “optional” or “optionally” mean that the subsequently described event or circumstance can or cannot occur, and the description includes instances where the event or circumstance occurs and instances where it does not.

[0144] In the present disclosure, the term "pharmaceutically acceptable excipient" includes but is not limited to any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals and having no side effects on the composition of the pharmaceutical composition.

[0145] In the present disclosure, the term "carrier" is defined as a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it facilitates the introduction of certain organic compounds into cells or tissues of an organism.

[0146] In the present disclosure, the term "pharmaceutically acceptable salt" includes "acceptable acid addition salts" and "acceptable base addition salts".

[0147] In the present disclosure, the term "acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases and 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, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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, glycerophosphate, 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, etc.

[0148] In this disclosure, the term "acceptable base addition salts" refers to salts that retain the biological effectiveness and properties of the free acids, and are biologically or otherwise suitable. These salts are prepared by adding inorganic or organic bases to the free acids. 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. In some embodiments, the 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, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, benzylamine, phenylethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. In some embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0149] In the present disclosure, the term "solvent or solvent mixture" refers to any and all solvents. In some embodiments, the solvent or solvent mixture is an organic solvent and water, including but not limited to methanol, ethanol, 2-propanol, n-butanol, isobutanol, acetone, methyl ethyl ketone, ethyl acetate, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, N,N-dimethylformamide, cyclohexane, cyclopentane, n-hexane, n-heptane, n-pentane, toluene, o-xylene, p-xylene, dimethyl sulfoxide (DMSO), pyridine, acetic acid, anisole, butyl acetate, isopropyl benzene, ethyl formate, formic acid, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone, 2-methyl-1-propanol, 1-pentanol, propyl acetate, ethylene glycol and 1-methyl-2-pyrrolidone, as well as mixtures of any and all two or more such solvents. In some embodiments, the solvent or solvent mixture is a single solvent and a binary mixture. In some embodiments, the solvent or solvent mixture is a single solvent of water and an organic solvent and a binary mixture of water and an organic solvent.

[0150] In the present disclosure, the term "pharmaceutical composition" refers to a formulation of a compound described herein and a medium generally accepted in the art for delivering the bioactive compound to mammals such as humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, and the like.

[0151] In the present disclosure, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds that ameliorates, reduces, or eliminates a particular disease or condition and the symptoms of a particular disease or condition, or prevents or delays the onset of a particular disease or condition or the symptoms of a particular disease or condition. The amount of a compound described in the present disclosure that constitutes an "effective amount" or "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, and the age, weight, etc. of the mammal to be treated, but the amount of a compound described in the present disclosure can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0152] As used herein, "treating" or "treatment" encompasses treating a relevant disease or condition in a mammal, such as a human, suffering from the relevant disease or condition, and includes:

[0153] (i) preventing a disease or disease state from occurring in a mammal, particularly where the mammal is susceptible to said disease state but has not yet been diagnosed with such disease state;

[0154] (ii) inhibiting the disease or disease state, i.e., preventing its occurrence; or

[0155] (iii) ameliorating the disease or condition, even if the disease or condition regresses or does not progress.

[0156] As used in this disclosure, the terms "disease" and "disease state" may be used interchangeably, or may be distinct in that a particular disease or disease state may have no known causative agent (and therefore cannot be explained etiologically) and therefore is not recognized as a disease, but rather is considered an undesirable disease state or condition in which clinicians have identified a more or less specific constellation of symptoms.

[0157] In this disclosure, the term "physiologically acceptable" refers to a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0158] The compounds described in this disclosure, or their pharmaceutically acceptable salts, can contain one or more asymmetric centers and, therefore, can produce enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. The disclosure is intended to include all of these possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using chiral columns. When the compounds described in this disclosure contain olefinic double bonds or other geometric asymmetric centers, unless otherwise indicated, it is intended that the compounds include E and Z geometric isomers. Likewise, it is also intended to include all tautomeric forms.

[0159] In the present disclosure, the term "stereoisomer" refers to a compound composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers and mixtures thereof.

[0160] General formula compound

[0161] The present disclosure relates to compounds represented by the general formulae (A), (I) and (II), stereoisomers, cis-trans isomers, or pharmaceutically acceptable salts thereof:

[0162] in,

[0163] R1 is selected from hydroxyl, C1-C 10 Hydroxyl groups, -O-alkali metal ions, -O-ammonium ions and -O - ;

[0164] R2 is selected from hydrogen and C1-C 10 hydrocarbon group;

[0165] R3, at each occurrence, is independently selected from hydrogen, halogen, C1-C 10 Hydrocarbon, C1-C 10 Halogenated hydrocarbon, C1-C 10 Alkyloxy, C1-C 10 Halogenated alkyloxy, C6-C 18 Aryl, nitro, -NR 21 R 22 ;

[0166] R4 is selected from C1-C 10 Alkylidene, C1-C 10 Hydrocarbyleneoxy, C6-C 12 Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene-C1-C 10 Hydrocarbylene, (C1-C 10 alkyleneoxy) d -C1-C 10 Alkylidene, C1-C 10 Hydrocarbyleneoxy-C6-C 12 Arylene, -(CH2) m -CO-NR 23 -(CHR 24 ) j -(CO-NR 25 -(CHR 26 ) k ) p -(CH2) n -, and -((CH2) m -NR 23 -(CHR 24 ) j ) q -(CH2) n -;

[0167] R5 and R6, when present, are independently selected from hydrogen, halogen, C1-C 10 Hydrocarbon, C1-C 10 Halogenated hydrocarbon, C1-C 10 Alkyloxy, C1-C 10 Halogenated alkyloxy and C6-C 18 aryl;

[0168] R7 is selected from:

[0169] R8 is selected from R10 、R 11 、R 12 、R 17 、-OCO-R 10 、-OCO-R 12 and-OCO-R 17 :

[0170] R 13 and R 14 Each independently selected from hydrogen, C1-C8 hydrocarbon group, C6-C 12 Aryl and C1-C8 alkylene C6-C12 aryl, R 13 and R 14 Optionally, together with the nitrogen atom to which they are attached, they form a 3- to 17-membered nitrogen-containing heterocyclic ring;

[0171] R9 and R 16 are each independently selected from hydrogen, alkali metal ions, and ammonium ions;

[0172] R 21 and R 22 are each independently selected from hydrogen and C1-C6 hydrocarbon groups;

[0173] R 23 and R 25 Each independently selected from hydrogen, C1-C6 hydrocarbon group and C1-C6 hydrocarbonoxy group;

[0174] R 24 and R 26 Each independently selected from hydrogen, C1-C6 hydrocarbon group, C1-C6 alkoxy group, C6-C 12 Aryl and C7-C 13 aromatic hydrocarbon groups;

[0175] x is 0 or 1; a is an integer of 0-3; b and c are each independently an integer of 0-4; d is an integer of 0-4; j, k, m, n and p are each independently an integer of 0-5, and q is an integer of 1-5;

[0176] in Indicates the attachment site.

[0177] In some embodiments, R1 can be selected from hydroxyl, C1-C 10 Alkoxy, -O - Li + 、-O - Na + 、-O - K + 、-O - Cs + 、-O -NH4 + and -O - For example, C1-C 10 Alkoxy groups may be methoxy, ethoxy, propoxy, butoxy, etc. Where appropriate, R1 may also be a C2-C 10 Hydrocarbyloxy.

[0178] In some embodiments, R2 can be selected from hydrogen and C1-C 10 Alkyl. For example, C1-C 10 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or the like.

[0179] In some embodiments, each occurrence of R3 may be the same or different and may be independently selected from hydrogen, F, Cl, Br, I, Cl-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C6-C 18 Aryl, nitro, -NR 21 R 22 For example, C1-C 10 Alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. 10 The haloalkyl group may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, etc. substituted by one or more fluorine groups, chlorine groups, bromine groups, iodine groups or a combination thereof. 10 Alkoxy can be methoxy, ethoxy, propoxy, butoxy, etc., and C1-C 10 The haloalkoxy group may be substituted by one or more fluorine, chlorine, bromine, iodine or a combination thereof, such as methoxy, ethoxy, propoxy, butoxy, etc. 18 Aryl can be phenyl, naphthyl, biphenyl, etc. 21 R 22 In, R 21 and R 22 Each is independently selected from hydrogen and C1-C6 alkyl, such as hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.

[0180] In some embodiments, R4 can be selected from C1-C 10 Alkylene, C1-C 10 Alkyleneoxy, C6-C 12 Arylene, C1-C 10 Alkylene-C6-C 12 Arylene, C1-C 10 Alkylene-C6-C12 Arylene-C1-C 10 Alkylene, C1-C 10 Alkyleneoxy-C6-C 12 Arylene, -(CH2) m -CO-NR 23 -(CHR 24 ) j -(CO-NR 25 -(CHR 26 ) k ) p -(CH2) n -, and -((CH2) m -NR 23 -(CHR 24 ) j ) q -(CH2) n -. For example, C1-C 10 Alkylene can be methylene, ethylene, propylene, butylene, tert-butylene, etc. 10 Alkyleneoxy may be methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, etc. 12 Arylene can be phenylene, naphthylene, biphenylene, etc. 10 Alkylene-C6-C 12 Arylene, C1-C 10 Alkylene-C6-C 12 Arylene-C1-C 10 Alkylene, C1-C 10 Alkyleneoxy-C6-C 12 The alkylene, alkyleneoxy and arylene groups in the arylene group may be C1-C 10 Alkylene, C1-C 10 Alkyleneoxy and C6-C 12 Arylene. In -(CH2) m -CO-NR 23 -(CHR 24 ) j -(CO-NR 25 -(CHR 26 ) k ) p -(CH2) n -and-((CH2) m -NR 23 -(CHR 24 ) j ) q -(CH2) n -Middle, R 23 and R 25are each independently selected from hydrogen, C1-C6 alkyl and C1-C6 alkoxy, and R 24 and R 26 Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C 12 Aryl and C7-C 13 Aralkyl, for example, C1-C6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., C1-C6 alkoxy can be methoxy, ethoxy, propoxy, butoxy, etc., C6-C 12 Aryl can be phenyl, naphthyl and biphenyl, while C7-C 13 Aralkyl groups include benzyl, phenethyl and the like.

[0181] In some embodiments, R5 and R6 may be the same or different at each occurrence and may be independently selected from hydrogen, F, Cl, Br, I, Cl-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy and C6-C 18 Aryl. C1-C 10 Alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. 10 The haloalkyl group may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, etc. substituted by one or more fluorine groups, chlorine groups, bromine groups, iodine groups or a combination thereof. 10 Alkoxy can be methoxy, ethoxy, propoxy, butoxy, etc., and C1-C 10 The haloalkoxy group may be substituted by one or more fluorine, chlorine, bromine, iodine or a combination thereof, such as methoxy, ethoxy, propoxy, butoxy, etc. 18 Aryl groups may include phenyl, naphthyl, biphenyl and the like.

[0182] In some embodiments, R7 can be selected from: Among them R9 and R 16 can be independently selected from hydrogen, Li + 、Na + , K + 、Cs + and NH4 + .

[0183] In some embodiments, R8 can be selected from R 10 、R 11 、R 12 、R 17、-OCO-R 10 、-OCO-R 12 and-OCO-R 17 :

[0184] Among them, R 13 and R 14 Each independently selected from hydrogen, C1-C8 hydrocarbon group, C6-C 12 Aryl and C1-C8 alkylene C6-C 12 Aryl, for example, hydrogen, C1-C8 alkyl, C6-C 12 Aryl and C1-C8 alkylene C6-C 12 More specifically, R 13 and R 14 Each is independently selected from hydrogen, methyl, ethyl, isopropyl, butyl, phenyl, benzyl and phenethyl.

[0185] In addition, R 13 and R 14 They can also form a 3- to 17-membered nitrogen-containing heterocycle together with the nitrogen atom to which they are attached; for example, a 3- to 15-membered, 3- to 12-membered, 3- to 10-membered, 3- to 6-membered, or 3- to 5-membered nitrogen-containing heterocycle. 12 for:

[0186] Pharmaceutical composition

[0187] In some embodiments, a pharmaceutical composition comprises a compound herein, a stereoisomer, a cis-trans isomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0188] In some embodiments, the compound, its stereoisomers, cis-trans isomers, or pharmaceutically acceptable salts thereof, when administered to a mammal for treating a tumor or cancer, may be administered by injection.

[0189] The compounds described in the present disclosure can be obtained in any suitable form, such as an injectable formulation. Illustrative examples of the injectable formulation include, but are not limited to, injections, sterile powders for injection, and concentrated solutions for injection. Injections include solution-type, emulsion-type (such as fat emulsion injections), or suspension-type injections (such as some liposome injections, cortisone acetate injections, etc.), which can be used for intramuscular injection, intravenous injection, intravenous drip, etc. Among them, large-volume (generally not less than 100 ml unless otherwise specified) injections for intravenous injection are also called intravenous infusions. Ampoules are commonly known as small water injections, which are distinguished from large infusions. Sterile powders for injection include lyophilized powder injections and aseptic subpackaging. Concentrated solutions for injection are sterile concentrated solutions diluted before use. Examples of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions herein include, but are not limited to, any adjuvants, carriers, carrier substances, solvents, osmotic pressure regulators, pH regulators, solubilizers, cosolvents, antioxidants, bacteriostats, emulsifiers, suspending agents, fillers, complexing agents, and chelating agents approved by the U.S. Food and Drug Administration for use in humans or animals, which have no side effects on the composition of the pharmaceutical composition. Acceptable carriers for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), the entire contents of which are incorporated herein by reference.

[0190] The pharmaceutical compositions herein can be administered by any method that achieves its intended purpose. The pharmaceutical compositions herein can be administered by injection, such as intradermal injection, subcutaneous injection, intramuscular injection, intravenous drip, intraarterial injection, intracardiac injection, intraarticular injection, subcutaneous infusion and the like. The dosage administered will depend on the age, health and weight of the recipient, if any concurrent treatment is being taken, the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.

[0191] Suitable dosage forms include, but are not limited to, injections, sterile powders for injection, and concentrated solutions for injection. Injections include solution-type, emulsion-type (such as fat emulsion injection), or suspension-type injections (such as some liposome injections, cortisone acetate injection, etc.), which can be used for intramuscular injection, intravenous injection, intravenous drip, etc. Injections for intravenous injection include intravenous infusion and small water injection. Sterile powders for injection include lyophilized powder injection and aseptic packaging. Concentrated solutions for injection are sterile concentrated solutions diluted before use, which can be prepared according to methods known in the art.

[0192] The pharmaceutical composition may contain suitable carriers, solvents, osmotic pressure regulators, pH regulators, solubilizers, cosolvents, antioxidants, antibacterial agents, emulsifiers, suspending agents, fillers, complexing agents, and chelating agents. For example, water for injection, vegetable oils such as soybean oil for injection, ethanol, propylene glycol, and polyethylene glycol may be added as solvents; sodium chloride, glucose, and the like may be added as osmotic pressure regulators; inorganic acids or bases, organic acids or bases such as hydrochloric acid, sodium hydroxide, sodium citrate, and citric acid may be added for pH adjustment; polyoxyethylene castor oil, polysorbate, cyclodextrins such as hydroxypropyl-β-cyclodextrin may be added as solubilizers; organic acids and their sodium salts such as sodium benzoate may be added; acylglycerols, hydroxypropyl-β-cyclodextrins, and the like may be added as solubilizers. Amines and amines, such as meglumine, can be used as solubilizers; ascorbic acid, sodium sulfite, sodium bisulfite and sodium metabisulfite can be added as antioxidants; phenol, cresol, chlorobutanol, thimerosal, etc. can be added as antibacterial agents; lecithin, poloxamer, etc. can be added as emulsifiers; polyvinyl pyrrolidone, methylcellulose, etc. can be added as suspending agents; mannitol, glucose, etc. can be added as fillers; ethylenediaminetetraacetate, etc. can be added as complexing agents and chelating agents, etc.

[0193] Suitable routes of administration can, for example, include parenteral delivery including intradermal injection, subcutaneous injection, intramuscular injection, intravenous drip, intraarterial injection, intracardiac injection, intraarticular injection, subcutaneous infusion, intramedullary injection, and intrathecal injection, direct intraventricular injection, intraperitoneal injection, intranasal injection, or intraocular injection. The compound can also be extended and / or timed, pulsed, in a sustained-release or controlled-release dosage form including reservoir injection, osmotic pumps, pills, transdermal (including electromigration) patches, etc., at a predetermined rate.

[0194] The pharmaceutical composition herein can be produced according to known methods, for example, by conventional mixing, preparation, filtration, filling, sterilization and other operation methods.

[0195] Therefore, according to the present disclosure, the pharmaceutical composition used can be prepared in a conventional manner using one or more physiologically acceptable carriers comprising adjuvants that facilitate processing the active compound into a pharmaceutically usable formulation. Suitable formulations depend on the selected route of administration. Any known techniques, carriers, etc. can be used as suitable and understood in the art.

[0196] Injection can be prepared into the following conventional forms: as a solution or suspension, a solid dosage form suitable for making a solution or suspension before injection, or as an emulsion. Suitable excipients are, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine ​​hydrochloride, etc. In addition, if necessary, the injection pharmaceutical composition can contain a small amount of non-toxic adjuvants, such as wetting agents, pH buffers, etc. Physiologically suitable buffers include but are not limited to Hank's solution, Ringer's solution, or physiological saline buffer. If necessary, absorption enhancing preparations (such as liposomes) can be used.

[0197] In some embodiments, the pharmaceutical compositions herein may contain 0.1%-95% of a compound herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, the pharmaceutical compositions herein may contain 1%-70% of a compound herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0199] In any case, the composition or formulation to be administered will contain an amount of a compound herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0200] In any case, the administration contains a compound herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the disease / condition in the subject being treated.

[0201] Dosage

[0202] At least one compound herein, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound herein, stereoisomer thereof, or pharmaceutically acceptable salt thereof, can be administered to a patient by any method suitable for systemic and / or local delivery of a compound herein, stereoisomer thereof, or pharmaceutically acceptable salt thereof. Non-limiting examples of methods of administration include (a) oral administration, including administration in the form of capsules, tablets, granules, sprays, syrups or other such forms; (b) non-oral administration, such as rectal, vaginal, intraurethral, ​​intraocular, intranasal or intraaural, including administration in the form of aqueous suspensions, oily preparations, etc. or in the form of drops, sprays, suppositories, ointments, ointments, etc.; (c) administration by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracapsular injection, intraspinal injection, intrasternal injection, etc., including delivery by infusion pump; (d) local administration, such as injection directly in the kidney area or heart area, for example, by reservoir implantation; and (e) topical administration; as recognized by those skilled in the art, an appropriate mode of administration is contact of the compounds described in the present disclosure with living tissue.

[0203] The most suitable route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining the method of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, appropriate pharmaceutical excipients and other matters related to delivering the compound, its stereoisomer or its pharmaceutically acceptable salt to a subject in need.

[0204] Pharmaceutical compositions suitable for administration include compositions containing an effective amount of an active ingredient to achieve their desired effect. The dosage required for a therapeutically effective amount of the pharmaceutical compositions described in this disclosure depends on the route of administration, the type of animal being treated, including humans, and the physical characteristics of the particular animal being considered. The dosage can be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent medications, and other factors recognized by those skilled in the art of medicine. More specifically, a therapeutically effective amount refers to an amount of a compound that effectively prevents, alleviates, or ameliorates symptoms of a disease, or prolongs the lifespan of the individual being treated. A therapeutically effective amount is well within the skill of those skilled in the art, particularly in light of the detailed disclosure provided herein.

[0205] As will be apparent to those skilled in the art, the dosage and specific mode of administration for in vivo administration will vary depending on the age, weight, and type of mammal being treated, the specific compound being used, and the specific purpose of the compound being used. Conventional pharmacological methods can be used by those skilled in the art to determine effective dosage levels, i.e., dosage levels necessary for the desired effect. Typically, clinical use of the product in humans is initiated at lower dosage levels, with the dosage levels increasing until the desired effect is achieved. Alternatively, using established pharmacological methods, acceptable in vitro studies can be used to establish effective dosages and routes of administration for the compositions identified by the present method.

[0206] In non-human animal studies, the use of potential products is initiated at higher dose levels, with the dose being reduced until the desired effect is no longer achieved or the adverse side effects disappear. Depending on the desired effect and the therapeutic indication, the dosage range can be relatively wide. Typically, the dosage can be from about 10 μg / kg body weight to 1000 mg / kg body weight, and in some embodiments, from about 100 μg / kg body weight to 300 mg / kg body weight. Alternatively, as will be appreciated by those skilled in the art, the dosage can be based on and calculated according to the patient's body surface area.

[0207] Each physician will be able to select the exact formulation, route of administration, and dosage of the pharmaceutical compositions described herein based on the patient's condition. Typically, the composition administered to a patient may be administered in a dosage range of about 0.05 mg / kg to 3000 mg / kg of the patient's body weight. Depending on the patient's needs, the dosage may be administered once alone or twice or more frequently over a day or several days. In cases where human dosages for a compound have been established for at least some conditions, the present disclosure will use those same dosages, or dosages ranging from about 0.1% to 500% of the established human dosage, and in some embodiments, from 25% to 250% of the established human dosage. In cases where there is no established human dosage, such as in the case of a newly discovered pharmaceutical compound, an appropriate human dosage can be inferred from the median effective dose or infective dose, or other appropriate values ​​from in vitro or in vivo studies, as quantified in animal toxicity studies and efficacy studies.

[0208] It should be noted that due to toxicity and organ dysfunction, the attending physician will know how and when to terminate, interrupt or adjust the administration. On the contrary, if the clinical response is insufficient (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The size of the dosage in the treatment of the disease being paid attention to will change with the severity of the disease state to be treated and the change of the route of administration. For example, the severity of the disease state can be evaluated in part by a standard prognostic evaluation method. In addition, the dosage and possible dosage frequency will also change according to the age, body weight, and reaction of the individual patient. A scheme comparable to the above-mentioned discussion scheme can be used in veterinary medicine.

[0209] Although the exact dosage can be determined based on a drug-by-drug analysis, in most cases, some generalizations can be made about the medicament. The daily dosing regimen for adult patients is, for example, an oral dose of 0.1 mg to 2000 mg of each active ingredient, in some embodiments 1 mg to 2000 mg of each active ingredient, for example 5 mg to 1500 mg of each active ingredient. In other embodiments, the intravenous, subcutaneous or intramuscular dose of each active ingredient used is 0.01 mg to 1000 mg, in some embodiments 0.1 mg to 1000 mg, for example 1 mg to 800 mg. In the case of administering a pharmaceutically acceptable salt, the dosage can be calculated as the free base. In some embodiments, the composition is administered 1 to 4 times a day. Alternatively, the composition described in the present disclosure can be administered by continuous intravenous infusion, in some embodiments administered at a dose of up to 2000 mg of each active ingredient per day. As will be appreciated by those skilled in the art, in certain instances, it may be necessary to administer the compounds described herein in amounts exceeding or far exceeding the above dosage ranges in order to effectively and rapidly treat rapidly developing diseases or infections. In some embodiments, the compounds are administered over a continuous treatment period, e.g., one or more weeks, or months, or years.

[0210] Dosage and dosing interval can be adjusted individually to provide a plasma level of the active moiety sufficient to maintain the adjustment effect or minimum effective concentration (MEC). The MEC of each compound is different, but it is possible to estimate the MEC from in vitro data. The required dosage to reach the MEC depends on individual characteristics and route of administration. However, plasma concentration can be determined using HPLC (high performance liquid chromatography) assays or bioassays.

[0211] Dosage intervals can also be determined using the MEC. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, in some embodiments 30-90% of the time, and in some embodiments 50-90% of the time.

[0212] In cases of local administration or selective uptake, the effective local concentration of the drug is independent of plasma concentration.

[0213] The amount of composition administered will, of course, be dependent on the individual being treated, on the individual's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0214] The efficacy and toxicity of the compounds described in this disclosure can be assessed using known methods. For example, the toxicology of a specific compound, or a subset of compounds sharing certain chemical moieties, can be established by in vitro toxicity assays in cell lines, such as mammalian cell lines, and in some embodiments, human cell lines. The results of such studies can generally predict toxicity in animals such as mammals, or more specifically, in humans. Alternatively, the toxicity of a specific compound can be assessed in animal models such as mice, rats, rabbits, or monkeys using known methods. The efficacy of a specific compound can be determined using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every disease state, including but not limited to cancer, cardiovascular disease, and various immune disorders. Similarly, acceptable animal models can be used to determine the efficacy of chemical agents used to treat these disease states. When choosing a model to determine efficacy, the skilled artisan can select an appropriate model, dosage, route of administration, and treatment regimen, guided by existing knowledge in the art. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0215] If desired, the composition can be placed in a package or dispensing device that can contain one or more unit dosage forms containing the active ingredient. The package can, for example, include metal or plastic foil, such as a blister pack. The package or dispensing device can be provided with instructions for administration. The package or dispensing device can also include precautions associated with the container, which are provided by a government agency that manages drug production, use, or sales, reflecting that the drug form has been approved by the agency for human or veterinary administration. Such precautions, for example, can be labels for prescription drugs approved by the State Food and Drug Administration or the U.S. Food and Drug Administration, or approved product instructions. Compositions comprising the compounds herein, their stereoisomers, or pharmaceutically acceptable salts thereof, can also be prepared in suitable containers and placed in compatible pharmaceutical carriers and labeled for use in the treatment of specified disease states.

[0216] Hereinafter, the present disclosure will be explained in detail through the following examples in order to better understand various aspects of the present application and its advantages. However, it should be understood that the following examples are non-limiting and are only used to illustrate some embodiments of the present application.

[0217] Example

[0218] Compound abbreviations: aq: aqueous solution ml: milliliter g: gram V: volume / weight eq: equivalent ratio L: liter M: mole / liter mg: milligram μl: microliter HOBt: 1-hydroxybenzotriazole DIEA: diisopropylethylamine DCM: dichloromethane PE: petroleum ether EA: ethyl acetate DMSO: dimethyl sulfoxide ACN: acetonitrile MeOH: methanol DMF: N,N-dimethylformamide PPh3: triphenylphosphine THF: tetrahydrofuran VCNa: sodium ascorbate NaH: sodium hydride CuSO 4： Anhydrous copper sulfate HCl: hydrochloric acid NaOH: sodium hydroxide CBr 4： Carbon tetrabromide AcOH: glacial acetic acid N2: nitrogen NaCl: sodium chloride Na2CO3: sodium carbonate Na2SO4: sodium sulfate CHCl3: chloroform NaBH4: sodium borohydride IPA: isopropyl alcohol MTBE: methyl tert-butyl ether HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate NH4Cl: ammonium chloride EtOH: ethanol Py: pyridine DBU: 1,8-diazabicycloundec-7-ene Zn: zinc powder DMAP: 4-dimethylaminopyridine H 3PO4: phosphoric acid TEA: triethylamine Ac2O: acetic anhydride H2SO4: concentrated sulfuric acid TBSCl: tert-butyldimethylchlorosilane KMnO4: potassium permanganate HF: hydrogen fluoride SOCl2: dichlorothionyl EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HPLC: high performance liquid chromatography MS: mass spectrometry 1HNMR: hydrogen nuclear magnetic resonance DMSO-d6: a form of dimethyl sulfoxide (DMSO(CH3)2S=O) in which the hydrogen (H) is replaced by another isotope deuterium (D).

[0219] Example 1

[0220] 1-1: N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-6-bromohexanamide

[0221] A solution of 6-bromohexanoic acid (2g, dissolved in 40ml of dichloromethane) was added dropwise to a mixture of 3,3'-dimethylbenzidine (2.177g), EDCI (2.359g), HOBt (1.663g), DIEA (1.590g), and dichloromethane (60ml) at 0-5°C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. Saturated aqueous sodium bicarbonate (20ml) was added, stirred, and the mixture separated. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried, and concentrated under reduced pressure to yield a crude product. The crude product was purified by column chromatography to yield 2.047g of the product. HPLC purity was 93.09%.

[0222] MS (m / e): 389.20 [M+H] + .1 HNMR (DMSO-d6, 400MHz) δ: 9.214 (s, 1H), 7.373~7.295 (m, 3H), 7.245 (s, 1H), 7.218~7.193 (dd, 1H), 6.673~6.652 (d, 1H), 4.962 (s, 2H), 3.581~3.548(t, 2H), 2.365~2.328(t, 2H), 2.227(s, 3H), 2.118(s, 3H), 1.893~1.823(m, 2H), 1.662~1.606(m, 2H), 1.500~1.443(m, 2H).

[0223] 1-2: N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-6-azidohexanamide

[0224] N-(4'-Amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-6-bromohexanamide (7.3g) and dimethyl sulfoxide (51ml) were stirred at room temperature until completely dissolved. Sodium azide (1.83g) was added and stirred at room temperature overnight. Extraction was performed with dichloromethane (200ml) and water (200ml). The aqueous phase was extracted twice with dichloromethane (200ml). The combined organic phases were washed four times with saturated sodium chloride (100ml) solution. The organic phases were dried and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to yield 2.808g of the product. HPLC purity was 93.32%.

[0225] MS (m / e): 352.24 [M+H] + . 1 H NMR (DMSO-d6, 400MHz) δ: 9.202 (s, 1H), 7.367 ~ 7.292 (m, 3H), 7.238 ~ 7.190 (m, 2H), 6.666 ~ 6.646 (d, 1H), 4.937 (s, 2H) ), 3.362~3.327(m,2H), 2.358~2.322(t,2H), 2.220(s,3H), 2.112(s,3H), 1.653~1.566(m,4H), 1.427~1.369(m,2H).

[0226] 1-3: (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium

[0227] Step 1: Add acetonitrile (16 ml) to N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-6-azidohexamide (1 g, 1.0 eq), stir under argon protection until completely dissolved, cool to 0-5°C in an ice-salt bath, add hydrochloric acid solution (0.712 ml of 12M hydrochloric acid, dissolved in 24 ml of deionized water) dropwise, and stir for 5 minutes after the addition is complete; maintain the system at 0-5°C, add sodium nitrite solution (392 mg of sodium nitrite, dissolved in 12 ml of deionized water) dropwise, and maintain the system at 0-5°C and stir for 30 minutes.

[0228] Step 2: 4-Amino-5-hydroxy-1,3-naphthalene disulfonic acid monosodium salt (970 mg) was added to deionized water (19.4 ml), stirred under argon protection, and cooled to 0-5°C in an ice-salt bath; while maintaining the system at 0-5°C, sodium bicarbonate solution (956 mg of sodium bicarbonate dissolved in 20 ml of deionized water) was added dropwise. After the addition was complete, the system was maintained at 0-5°C and stirred for 5 minutes.

[0229] Step 3: Maintaining the system at 0-5°C, slowly add the reaction solution from Step 1 to the reaction system from Step 2. Maintaining the system at 0-5°C, stir and react for 3 hours. Add 76 ml of 20% aqueous sodium chloride solution to the system and stir at room temperature overnight. Centrifuge the reaction solution and collect the filter cake to obtain a purple solid. Purify the product using medium-pressure preparative pressure to obtain 1.64 g of the product. HPLC purity: 98.95%.

[0230] MS (m / e): 682.31 [M-2Na+3H] + . 1 HNMR (DMSO-d6, 600MHz) δ: 15.954 (s, 1H), 9.643 (s, 1H), 9.277 (s, 1H), 8.362 ( s, 1H), 8.042~8.025(d, 1H), 7.902~7.887(d, 1H), 7.652~7.650(m, 2H), 7.572( s, 1H), 7.500 (s, 2H), 7.003 ~ 6.987 (d, 1H), 3.366 ~ 3.344 (t, 2H), 2.517 (s, 3H), 2.385~2.361(t, 2H), 2.277(s, 3H), 1.661~1.581(m, 4H), 1.422~1.397(m, 2H).

[0231] 1-4: (2S,3S,4S,5R,6S)-2-(methoxycarbonyl)-6-(4-((((4-nitrophenoxy)carbonyl)oxy)methyl)-3-(prop-2-yn-1-yloxy)phenoxy)tetrahydro-2H-pyran-3,4,5-triacetate

[0232] (2S,3R,4S,5S,6S)-2-(4-(hydroxymethyl)-3-(prop-2-yn-1-yloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate (4.0 g), dichloromethane (240 ml), p-nitrophenyl chloroformate (3.26 g), and triethylamine (2.46 g) were stirred at room temperature overnight under nitrogen. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to obtain 2.94 g of the product with an HPLC purity of 97.05%. MS (m / e): 682.36 [M+Na] + .

[0233] 1-5: (2S,3R,4S,5S,6S)-2-(4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0234] (2S,3S,4S,5R,6S)-2-(methoxycarbonyl)-6-(4-((((4-nitrophenoxy)carbonyl)oxy)methyl)-3-(prop-2-yn-1-yloxy)phenoxy)tetrahydro-2H-pyran-3,4,5-triacetate (138 mg) and (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1- The reaction mixture was stirred overnight at room temperature with 100 mg of N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide (100 mg), DMF (5 ml), HOBt (19 mg), DIEA (22 mg), and pyridine (1.25 ml). The reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography to yield 124 mg of the product with an HPLC purity of 98.26%. MS (m / e): 1238.78 [M+H] + .

[0235] 1-6: (2S,3S,4S,5R,6S)-6-(4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0236] (2S,3R,4S,5S,6S)-2-(4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9 To a solution of 50 mg of (-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate (50 mg) and tetrahydrofuran (0.65 ml) was added dropwise with an aqueous solution of sodium hydroxide (6.5 mg dissolved in 0.65 ml of deionized water) maintained at 0-5°C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 1.5 hours. The reaction was then cooled to 0°C and quenched by the addition of 1 M hydrochloric acid (pH ≈ 4). The reaction solution was concentrated under reduced pressure and purified by medium pressure preparative purification to yield 40 mg of the product. HPLC purity was 98.60%. MS (m / e): 1098.66 [M+H] + .

[0237] 1-7: (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12- Trisodium (2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0238] (2S,3S,4S,5R,6S)-6-(4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4 ,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (36 mg), (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium (29 mg) were added to the mixture in the dark, and the mixture was dissolved and stirred at room temperature in dimethyl sulfoxide (2 ml). An aqueous solution of copper sulfate (4.2 mg, dissolved in 0.3 ml of deionized water) and an aqueous solution of sodium ascorbate (10.4 mg, dissolved in 0.3 ml of deionized water) were added sequentially. Deionized water (1.6 ml) was added, and the mixture was stirred at room temperature under argon for 1 hour. The crude reaction solution was purified by medium pressure preparative purification to obtain 25 mg of the product. HPLC purity was 93.85%. MS (m / e): 1779.67 [M-3Na+4H] + .

[0239] Example 2:

[0240] 2-1: (2S,3S,4S,5R,6S)-2-(methoxycarbonyl)-6-(3-(prop-2-yn-1-yloxy)-4-((2,2,2-trichloro-1-iminoethoxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triacetate

[0241] (2S,3R,4S,5S,6S)-2-(4-(hydroxymethyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate (1 g) was added to dichloromethane (10 ml) until completely dissolved. Trichloroacetonitrile (365 mg) and DBU (30.8 mg) were added sequentially with stirring, and the mixture was stirred at room temperature for 4 hours. The product was obtained and the reaction solution was used directly in the next reaction. The yield is calculated as 100%.

[0242] 2-2: (2S,3R,4S,5S,6S)-2-(4-(((1S,2R)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionamido)-1-phenylpropoxy)methyl)-3-(prop-2-yn-1-yloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0243] (2S,3S,4S,5R,6S)-2-(methoxycarbonyl)-6-(3-(prop-2-yn-1-yloxy)-4-((2,2,2-trichloro-1-iminoethoxy)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triacetate (52 mg) and (S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-1-((S)-2-( (1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptane-4-yl)-N,3-dimethylbutanamide (30 mg) was dissolved in anhydrous dichloromethane (2 ml). D-camphorsulfonic acid (1.1 mg) was added with stirring at room temperature, and the mixture was stirred at room temperature for 4 hours under argon atmosphere. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative thin-layer chromatography to yield 30 mg of the product with an HPLC purity of 78.44%. MS (m / e): 1208.85 [M+H] + .

[0244] 2-3: (2S,3S,4S,5R,6S)-6-(4-(((1S,2R)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionamido)-1-phenylpropoxy)methyl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0245] (2S,3R,4S,5S,6S)-2-(4-(((1S,2R)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2- To a solution of 30 mg of (1-phenylpropoxy)methyl)-3-(prop-2-yn-1-yloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate (30 mg) and methanol (2 ml) was stirred; an aqueous solution of sodium hydroxide (10 mg dissolved in 2 ml of deionized water) was added dropwise at 0-5°C. After the addition was complete, the mixture was naturally warmed to room temperature and stirred for 2 hours. The reaction was then cooled to 0°C and quenched by the addition of 1 M hydrochloric acid (pH ≈ 4). The reaction solution was concentrated under reduced pressure and purified by medium pressure to yield 27 mg of the product. HPLC purity was 72.35%. MS (m / e): 1068.92 [M+H] + .

[0246] 2-4: (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-(((1S,2R)-2-((2R,3 trisodium 3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutyramido)-N,3-dimethylbutyramido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionamido)-1-phenylpropoxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0247] Using the synthesis method of Example 1-7, (2S,3S,4S,5R,6S)-6-(4-(((1S,2R)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutyramido)-N,3-dimethylbutyramido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3- The product (14 mg) was synthesized from (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt (methoxy-2-methylpropionamido)-1-phenylpropoxy)methyl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid. HPLC purity was 91.58%. MS (m / e): 1749.80 [M-3Na+4H] + .

[0248] Example 3:

[0249] 3-1: (2S,3R,4S,5S,6S)-2-(4-(bromomethyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0250] (2S,3R,4S,5S,6S)-2-(4-(hydroxymethyl)-3-(prop-2-yn-1-yloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate (1.0 g), carbon tetrabromide (1.01 g), and dichloromethane (8 ml) were stirred and added portionwise with triphenylphosphine (796 mg) at 0-5°C. After addition, the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to yield 743 mg of the product. HPLC purity was 98.43%.

[0251] MS (m / e): 579.15 [M+Na] + . 1HNMR (CDCl3, 400MHz) δ: 7.277~7.263 (d, 1H), 6.752~6.721 (d, 1H), 6.640~ 6.586(dd, 1H), 5.354~5.337(m, 2H), 5.292~5.263(m, 1H), 5.159~5.146(d , 1H), 4.758~4.754(d, 2H), 4.542~4.506(d, 2H), 4.189~4.173(m, 1H), 3.7 30(s, 3H), 2.541~2.533(t, 1H), 2.064(s, 3H), 2.051(s, 3H), 2.043(s, 3H).

[0252] 3-2: (2S,3R,4S,5S,6S)-2-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0253] (2S,3R,4S,5S,6S)-2-(4-(bromomethyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate (116 mg) and (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide (50 mg) were dissolved in dichloromethane (5 ml), DIEA (27 mg) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by preparative thin-layer chromatography to obtain 62 mg of the product with an HPLC purity of 99.36%. MS (m / e): 1194.74 [M+H] + .

[0254] 3-3: (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0255] Using the synthetic method of Example 1-6, 55 mg of the product was obtained by hydrolyzing (2S,3R,4S,5S,6S)-2-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate. HPLC purity: 79.39%. MS (m / e): 1054.79 [M+H] + .

[0256] 3-4: (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((3S,6S,9S,10R)-9-((S)-sec-butyl)- Trisodium 10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0257] Using the synthesis method of Example 1-7, (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropyl-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl The product was prepared by adding (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt to obtain 20 mg of the product. HPLC purity was 96.89%. MS (m / e): 1735.77 [M-3Na+4H] + .

[0258] Example 4:

[0259] 4-1: (S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-N,N,3-trimethyl-1-oxo-N-(2-(prop-2-yn-1-yloxy)-4-(((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)benzyl)butyl-2-ammonium bromide

[0260] (2S,3R,4S,5S,6S)-2-(4-(bromomethyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate (114 mg), (S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide (100 mg) and 2-butanone (10 ml) were stirred at 80 degrees for 12 hours. The reaction solution was concentrated under reduced pressure and purified by medium pressure to obtain 70 mg of the product. HPLC purity was 97.09%. MS (m / e): 1208.75 [M-Br] + .

[0261] 4-2: (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,2,8-trimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodec-2-ammonium-1-yl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate ion

[0262] Using the synthesis method of Example 1-6, (S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropyl-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptane-4-yl)bromide was prepared. Hydrolysis of (((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)benzyl)butyl)-2-ammonium (methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-N,N,3-trimethyl-1-oxo-N-(2-(prop-2-yn-1-yloxy)-4-(((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)benzyl)butyl)-2-ammonium chloride afforded 36 mg of the product. HPLC purity: 98.38%. MS (m / e): 1068.78 [M+H] + .

[0263] 4-3: (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-10-(2 Disodium ((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,2,8-trimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodec-2-ammonium-1-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0264] Using the synthesis method of Example 1-7, (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropyl-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,2,8 The product was obtained by adding (E)-4-amino-6-((4'-(6-azidohexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt to obtain 54 mg of the product. HPLC purity was 99.16%. MS (m / e): 1749.86 [M-2Na+3H] + .

[0265] Example 5:

[0266] 5-1: ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butyrylamino)butyrylamino)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoyl)-L-phenylalanine methyl ester

[0267] ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-L-phenylalanine (100 mg) was added dropwise to methanol (5 ml) at 0-5°C. After the addition was complete, the system was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to yield 101 mg of the product. HPLC purity: 95.40%. MS (m / e): 746.63 [M+H] + .

[0268] 5-2: (2S,3R,4S,5S,6S)-2-(4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-5,8-diisopropyl-12-(2-((S)-2-((1R,2R)-1-methoxy-3-(((S)-1-methoxy-1-oxo-3-phenylpropan-2-yl)amino)-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0269] Using the synthetic method of Example 1-5, 40 mg of the product was obtained from ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butyrylamino)butyrylamino)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoyl)-L-phenylalanine methyl ester and (2S,3S,4S,5R,6S)-2-(methoxycarbonyl)-6-(4-((((4-nitrophenoxy)carbonyl)oxy)methyl)-3-(prop-2-yn-1-yloxy)phenoxy)tetrahydro-2H-pyran-3,4,5-triacetate. HPLC purity was 81.73%. MS (m / e): 1266.81 [M+H]. + .

[0270] 5-3: (2S,3S,4S,5R,6S)-6-(4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((S)-1-carboxy-2-phenylethyl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0271] Using the synthesis method of Example 1-6, 7 mg of the product was obtained from (2S,3R,4S,5S,6S)-2-(4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-5,8-diisopropyl-12-(2-((S)-2-((1R,2R)-1-methoxy-3-(((S)-1-methoxy-1-oxo-3-phenylpropan-2-yl)amino)-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate. HPLC purity 97.20%. MS (m / e): 1112.82 [M+H] + .

[0272] 5-4: (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)- Tetrasodium 12-(2-((S)-2-((1R,2R)-3-(((S)-1-carboxylate-2-phenylethyl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0273] Using the synthesis method of Example 1-7, (2S,3S,4S,5R,6S)-6-(4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((S)-1-carboxy-2-phenylethyl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10- The product was obtained by the addition of (E)-4-amino-6-((4'-(6-azidohexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt to give 1 mg of product. The purity was 89.97% by HP LC. MS (m / e): 1793.88 [M-4Na+5H]. + .

[0274] Example 6

[0275] 6-1(2S,3R,4S,5S,6S)-2-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-3,6-diisopropyl-10-(2-((S)-2-((1R,2R)-1-methoxy-3-(((S)-1-methoxy-1-oxo-3-phenylpropan-2-yl)amino)-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0276] (2S,3R,4S,5S,6S)-2-(4-(bromomethyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate and ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butyrylamino)butyrylamino)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoyl)-L-phenylalanine methyl ester (50 mg) were dissolved in DMF (1 ml) and DIEA (26 mg). The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by medium pressure preparative purification to obtain 40 mg of the product with an HPLC purity of 94.66%. MS (m / e): 1222.80 [M+H] + .

[0277] 6-2(2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((S)-1-carboxy-2-phenylethyl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0278] Using the synthesis method of Example 1-6, 23 mg of the product was obtained by hydrolyzing (2S,3R,4S,5S,6S)-2-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-3,6-diisopropyl-10-(2-((S)-2-((1R,2R)-1-methoxy-3-(((S)-1-methoxy-1-oxo-3-phenylpropan-2-yl)amino)-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate. HPLC purity 91.34%. MS (m / e): 1068.72 [M+H] + .

[0279] 6-3(2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)4-((3S,6S,9S,10R)-9-((S)-sec-butyl) Tetrasodium 10-(2-((S)-2-((1R,2R)-3-(((S)-1-carboxylate-2-phenylethyl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0280] Using the synthesis method of Example 1-7, (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((S)-1-carboxyl-2-phenylethyl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-diol The product was prepared by the following methods: (1) (1,2-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecyl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid and (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt to give 4 mg of the product. HPLC purity was 89.39%. MS (m / e): 1749.91 [M-4Na+5H] + .

[0281] Example 7

[0282] 7-1(S)-2-((S)-2-(Benzyl(methyl)amino)-3-methylbutanamido)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxohept-4-yl)-N,3-dimethylbutanamide

[0283] At room temperature, (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide (200 mg) and sodium triacetoxyborohydride (590 mg) were dissolved in a 10:1 N,N-dimethylformamide:acetic acid solution (2.2 ml) with stirring and clarified. Benzaldehyde (355 mg) was then added and the reaction was allowed to proceed for 16 hours. Pump concentration was then performed to obtain a crude product. The crude product was purified by column chromatography to obtain 211 mg of the product, MS (m / e): 808.64 [M+H] + .

[0284] 7-2: (2S)-N-Benzyl-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-N,3-dimethyl-1-oxo-N-(2-(prop-2-yn-1-yloxy)-4-(((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)benzyl)butyl-2-ammonium bromide

[0285] [Corrected 25.12.2024 in accordance with Rule 26] (S)-2-((S)-2-(Benzyl(methyl)amino)-3-methylbutyramido)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5 ... To the mixture of (2S,3R,4S,5S,6S)-2-(4-(bromomethyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate (1.36 g), and potassium carbonate (56 mg) were dissolved in acetonitrile (6.5 ml) and refluxed in an oil bath at 80°C with stirring for 20 hours. After the reaction was complete, the mixture was reduced to dryness and the crude product was purified by column chromatography to yield 171 mg of the product. MS (m / e): 1285.06 [M-Br] + .

[0286] 7-3: (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-2-benzyl-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodec-2-ammonium-1-yl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate ion

[0287] Using the synthesis method of Example 1-6, (2S)-N-benzyl-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropyl-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptane bromide was prepared. Hydrolysis of butyl-2-(((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)benzyl)butyl)-4-(((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)benzyl)butyl)-2-ammonium chloride afforded 70 mg of the product. MS (m / e): 1144.71 [M+H] + .

[0288] 7-4: (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((3S,6S,9S,10R)-2-benzyl-9-((S)-sec-butyl)-1 Disodium 0-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodec-2-ammonium-1-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0289] Using the synthesis method of Example 1-7, (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-2-benzyl-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-diol The product was obtained by the addition of (1-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecane-2-ammonium-1-yl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate ion and compound (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. 83 mg of the product was obtained. MS (m / e): 1825.76 [M-2Na+3H] + .

[0290] Example 8:

[0291] 8-1: (S)-2-((S)-2-(ethyl(methyl)amino)-3-methylbutanamido)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxohept-4-yl)-N,3-dimethylbutanamide

[0292] Using the synthetic method of Example 7-1, 247 mg of the product was obtained from (S)-N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptane-4-yl)-N,3-dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide and acetaldehyde. MS (m / e): 746.68 [M+H]. + .

[0293] 8-2: (2S)-N-ethyl-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-N,3-dimethyl-1-oxo-N-(2-(prop-2-yn-1-yloxy)-4-(((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)benzyl)butyl-2-ammonium bromide

[0294] (2S,3R,4S,5S,6S)-2-(4-(bromomethyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate (201 mg), (S)-2-((S)-2-(ethyl(methyl)amino)-3-methylbutyramido)-N-((3R,4S,5S)-1-((S)-2-(( 1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxohept-4-yl)-N,3-dimethylbutanamide (207 mg), acetone (4 ml), and N,N-diisopropylethylamine (9 mg) were stirred at 55°C for 17 hours. The reaction mixture was dried to dryness. The crude product was purified by column chromatography to obtain 87 mg of the product. MS (m / e): 1223.05 [M-Br] + .

[0295] 8-3: (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-2-ethyl-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodec-2-ammonium-1-yl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate ion

[0296] Using the synthesis method of Example 1-6, (2S)-N-ethyl-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropyl-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxopropyl)bromide was prepared. 54 mg of the product was obtained by adding (heptane-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-N,3-dimethyl-1-oxo-N-(2-(prop-2-yn-1-yloxy)-4-(((2S,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)benzyl)butyl-2-ammonium. MS (m / e): 1082.74 [M+H] + .

[0297] 8-4: (2S,3S,4S,5R,6S)-6-(3-((1-(2-(3-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-2-ethyl Disodium 10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodec-2-ammonium-1-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0298] Using the synthesis method of Example 1.7, (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-2-ethyl-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-diol 70 mg of the product was obtained by the reaction of (4,7-dioxo-11-oxa-2,5,8-triazadodecane-2-ammonium-1-yl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate ion and (E)-4-amino-6-((4'-(3-(2-azidoethoxy)propionamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. MS (m / e): 1765.98 [M-2Na+3H] + .

[0299] Example 9:

[0300] 9-1: tert-Butyl (4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate

[0301] Dissolve 3,3'-dimethylbenzidine (10g) and 1,4-dioxane (170ml) with stirring. Then, di-tert-butyl dicarbonate (11ml) was diluted with 1,4-dioxane (30ml) and slowly added dropwise to the reaction mixture. Stir at room temperature under nitrogen for 20 hours. The crude product was purified by column chromatography to obtain 7.4g of the product.

[0302] 9-2: tert-Butyl (4'-(3-(2-bromoethoxy)propionamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate

[0303] Tert-butyl (4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate (1.2 g), 3-(2-bromoethoxy)propionic acid (0.84 g), tetrahydrofuran (20 ml), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.7 g), and diisopropylethylamine (0.46 g) were stirred at room temperature for 18 hours. After the reaction was complete, the reaction was extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated to dryness. Column chromatography purification afforded 1.6 g of the product. MS (m / e): 491.21 [M+H] + .

[0304] 9-3: N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-3-(2-bromoethoxy)propionamide

[0305] Tert-butyl (4'-(3-(2-bromoethoxy)propionamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate (1.6 g) was dissolved in dichloromethane (19.2 ml), and trifluoroacetic acid (1.92 ml) was added. The mixture was stirred at room temperature for 17 hours. After the reaction was complete, the mixture was dried to dryness. The crude product was purified by column chromatography to obtain 1.2 g of the product. MS (m / e): 391.27 [M+H] + .

[0306] 9-4: N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-3-(2-azidoethoxy)propionamide

[0307] Using the synthetic method of Example 1-2, 770 mg of the product was obtained from N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-3-(2-bromoethoxy)propionamide. MS (m / e): 354.32 [M+H] + .

[0308] 9-5: (E)-4-amino-6-((4'-(3-(2-azidoethoxy)propionamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt

[0309] Using the synthetic method of Example 1-3, 379 mg of the product was obtained from N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-3-(2-azidoethoxy)propionamide and 4-amino-5-hydroxy-1,3-naphthalenedisulfonic acid monosodium salt. MS (m / e): 684.63 [M-2Na+3H] + .

[0310] 9-6: (2S,3S,4S,5R,6S)-6-(3-((1-(2-(3-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-1 Disodium 0-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,2,8-trimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodec-2-ammonium-1-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0311] Using the synthesis method of Example 1-7, (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropyl-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,2,8-trimethyl The product was obtained by the addition of (E)-4-amino-6-((4'-(3-(2-azidoethoxy)propionamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt to give 109 mg of the product. MS (m / e): 1751.81 [M-2Na+3H] + .

[0312] Example 10:

[0313] 10-1: 2-(3-chloropropoxy)acetic acid

[0314] Ethyl 2-(3-chloropropoxy)acetate (2.5 g) and tetrahydrofuran (25 ml) were stirred and dissolved, then cooled to 0°C in an ice-salt bath. Sodium hydroxide (665 mg) was dissolved in water (25 ml) and slowly added dropwise to the reaction mixture, stirring for 1.5 hours. After the reaction was complete, the reaction mixture was concentrated and the pH was adjusted to 1 with 1 mol / L HCl. Extraction was performed three times with ethyl acetate, and the layers were separated. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 1.7 g of the product.

[0315] 10-2: tert-Butyl (4'-(2-(3-chloropropoxy)acetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate

[0316] Using the synthetic method of Example 9-2, 2.87 g of the product was obtained from tert-butyl (4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate and 2-(3-chloropropoxy)acetic acid.

[0317] 10-3: N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(3-chloropropoxy)acetamide: Using the synthetic method of Example 9-3, 1.315 g of the product was obtained from tert-butyl (4'-(2-(3-chloropropoxy)acetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate. MS (m / e): 347.32 [M+H].

[0318] 10-4: N-(4'-Amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(3-azidopropoxy)acetamide. N-(4'-Amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(3-chloropropoxy)acetamide (1.315 g) was stirred in dimethyl sulfoxide (10 ml) at room temperature until completely dissolved. Sodium azide (287 mg) and sodium iodide (441 mg) were added, and the mixture was stirred in an oil bath at 80°C for 15 hours. After the reaction was complete, dichloromethane (200 ml) and water (200 ml) were added, and the mixture was separated by extraction. The aqueous phase was extracted twice with dichloromethane (200 ml). The organic phases were combined and washed four times with saturated sodium chloride solution. The organic phases were dried and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 914 mg of the product. MS (m / e): 354.32 [M+H] + .

[0319] 10-5: (E)-4-amino-6-((4'-(2-(3-azidopropoxy)acetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium

[0320] Using the synthetic method of Example 1-3, 345 mg of the product was obtained from N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(3-azidopropoxy)acetamide and 4-amino-5-hydroxy-1,3-naphthalenedisulfonic acid monosodium salt. MS (m / e): 684.34 [M-2Na+3H]+.

[0321] 10-6: (2S,3S,4S,5R,6S)-6-(3-((1-(3-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxoethoxy)propyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-1 Disodium 0-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,2,8-trimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodec-2-ammonium-1-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0322] Using the synthesis method of Example 1-7, (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropyl-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,2,8-trimethyl The product was obtained by the addition of (E)-4-amino-6-((4'-(2-(3-azidopropoxy)acetamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt to give 128 mg of the product. MS (m / e): 1752.15 [M-2Na+3H] + .

[0323] Example 11:

[0324] Using the synthesis method of Example 1-7, (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-2-ethyl-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-diol (2S, 3S,4S,5R,6S)-6-(3-((1-(3-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxoethoxy)propyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-2-ethyl-10-(2 106 mg of disodium ((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodec-2-ammonium-1-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate. MS (m / e): 1766.04 [M-2Na+3H] + .

[0325] Example 12:

[0326] Using the synthesis method of Example 1-7, (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-2-ethyl-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl- The product (2S) was obtained by the reaction of 2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecane-2-ammonium-1-yl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate ion and (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. ,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((3S,6S,9S,10R)-9-((S)-sec-butyl)-2-ethyl-10-(2-( 51 mg of (S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodec-2-ammonium-1-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid disodium salt. MS (m / e): 1763.98 [M-2Na+3H] + .

[0327] Example 13:

[0328] Using the synthesis method of Example 1-7, (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-2-benzyl-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8- The product (2S) was obtained by mixing (E)-4-amino-6-((4'-(3-(2-azidoethoxy)propionamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt with dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecane-2-ammonium-1-yl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate ion and (E)-4-amino-6-((4'-(3-(2-azidoethoxy)propionamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. ,3S,4S,5R,6S)-6-(3-((1-(2-(3-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((3S,6S,9S,10R)-2-benzyl-9-((S)-sec-butyl)-10-( 40 mg of 2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodec-2-ammonium-1-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid disodium salt. MS (m / e): 1827.99 [M-2Na+3H] + .

[0329] Example 14:

[0330] Using the synthesis method of Example 1-7, (2S,3S,4S,5R,6S)-6-(4-((3S,6S,9S,10R)-2-benzyl-9-((S)-sec-butyl)-10-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8- The product (2S) was obtained by mixing (E)-4-amino-6-((4'-(2-(3-azidopropoxy)acetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt with dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodecane-2-ammonium-1-yl)-3-(prop-2-yn-1-yloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate ion and (E)-4-amino-6-((4'-(2-(3-azidopropoxy)acetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. ,3S,4S,5R,6S)-6-(3-((1-(3-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxoethoxy)propyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((3S,6S,9S,10R)-2-benzyl-9-((S)-sec-butyl)-10-( 51 mg of 2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-3,6-diisopropyl-2,8-dimethyl-4,7-dioxo-11-oxa-2,5,8-triazadodec-2-ammonium-1-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid disodium salt. MS (m / e): 1827.95 [M-2Na+3H] + .

[0331] Biological Example 1: Study on the Inhibitory Effect on Human Tumor Cells in Vitro

[0332] 1. Test materials

[0333] 1.1 Test sample

[0334] The compounds obtained according to Examples 1 to 14 of the present disclosure were respectively named Example Compounds 1 to 14 for use in experiments, and may be referred to as test compounds hereinafter.

[0335] 1.2 Test cells

[0336] Human colorectal cancer cell lines HCT116 and SW620, human hepatoma cell line HepG2, human gastric cancer cell line NCI-N87, human triple-negative breast cancer cell line MDA-MB-468, human pharyngeal squamous cell carcinoma line Fadu, human ovarian cancer cell line SK-OV-3, human pancreatic cancer cell line BxPC-3, human prostate cancer cell line 22RV1, human non-small cell carcinoma NCI-H1975 and HCC827, and human malignant melanoma A375 were all purchased from the Cell Bank of the Chinese Academy of Sciences.

[0337] 1.3 Main reagents and equipment

[0338] RPMI-1640 medium: Gibco, originally in the form of dry powder, was prepared into liquid medium according to the instructions, and 2 g / L NaHCO3 and 5.958 g / L HEPES were added as required for cell culture.

[0339] EMEM (Minimum Essential Medium with Earle's salts) culture medium: Gibco, the original dry powder was prepared into liquid culture medium according to the instructions, and 2.2 g / L NaHCO3 and 5.958 g / L HEPES were added according to the needs of cell culture.

[0340] L-15 medium: Gibco, originally in the form of dry powder, was prepared into liquid medium according to the instructions, and 2 g / L NaHCO3 and 5.958 g / L HEPES were added as required for cell culture.

[0341] McCoy'5A medium: Sigma, originally in the form of dry powder, was prepared into liquid medium according to the instructions, and 1.5 g / L NaHCO3 and 2.383 g / L HEPES were added as required for cell culture.

[0342] DMEM (Minimum Essential Medium with Earle's salts) culture medium: Gibco, the original dry powder was prepared into liquid culture medium according to the instructions, and 2.2 g / L NaHCO3 and 5.958 g / L HEPES were added according to the needs of cell culture.

[0343] FBS (fetal bovine serum): Biological Industries (BI).

[0344] βGU (β-glucuronidase): Sigma-Aldrich, prepared as a 2 mg / ml stock solution in PBS.

[0345] MTT (tetrazolium salt): Sigma-Aldrich, prepared into 5 mg / ml stock solution in PBS.

[0346] SRB (sulforhodamine): Sigma-Aldrich, prepared as a 0.4% (weight / volume) working solution in 1% acetic acid.

[0347] Vertical pressure steam sterilizer: Shanghai Shen'an Medical Instrument Factory, model LDZX-50KBS.

[0348] CO2 cell culture incubator: Thermo, model 311, model 371.

[0349] Clean bench: Donglian Har Instrument Manufacturing Co., Ltd., model DL-CJ-2N, model DL-CJ-1ND.

[0350] Microplate reader: Bio-Rad, model 680.

[0351] 96-well plate washer: Thermo Corporation, model N21535.

[0352] 2. Test methods

[0353] Cell culture medium was prepared according to the formulation shown in Table 2 below. Cells were cultured at 37° C., 5% CO 2 , and saturated humidity until the logarithmic growth phase (usually, adherent cells were nearly completely confluent). Adherent cells were removed by trypsin / EDTA digestion and then collected for subsequent experiments.

[0354] According to the number shown in Table 2, cells were seeded into 96-well cell culture plates (hereinafter referred to as 96-well plates), cultured overnight to allow the cells to adhere, and different concentrations of the test compounds were added. The cells were cultured for 3 days. Finally, the total amount of cellular protein in the test wells was determined by the SRB method, or the cell viability was measured by the MTT method:

[0355] 2.1 SRB method for measuring total cellular protein: This method was modified based on the literature (V. Vichai and K. Kirtikara. Sulfo rhodamine B colorimetric assay for cytotoxicity screening. Nature Protocols. 2006, 1: 1112-1116). Specific procedures: Aspirate the culture medium from the wells and fix the cells with 10% trichloroacetic acid for at least 1 hour. Remove the trichloroacetic acid, wash with H2O, and stain with 0.4% SRB for 15-30 minutes. Remove excess SRB and wash with 1% acetic acid. Add 100 μl of 10 mM Tris (tris(hydroxymethyl)aminomethane)) to dissolve protein-bound SRB, and detect at a wavelength of 570 nm.

[0356] 2.2 MTT assay for cell viability: The method was modified according to the literature (J. Carmichael, W. DeGraff, A. Gazdar et al., Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Research. 1987, 47: 936-942). The specific method is as follows:

[0357] For firmly adherent cells: Aspirate the culture medium and add 100 μl / well of basal culture medium (without fetal bovine serum (FBS) or other additives) containing 0.5 mg / ml MTT. Continue culturing for 3 hours. Aspirate the basal culture medium containing MTT and add 100 μl / well of DMSO to dissolve the formazan. Detect at a wavelength of 490 nm.

[0358] For cells that are not firmly attached: directly add MTT solution to a concentration of 0.5 mg / ml, continue culturing for 3 hours, add a volume of triplicate solvent equal to the system to dissolve the formazan, and detect at a wavelength of 570 nm.

[0359] 2.3: Weigh 1-2 mg of β-glucuronidase and dissolve it in PBS to a 2 mg / ml stock solution. Upon use, dilute it to a 12.5 μg / ml working solution in complete culture medium. For test wells requiring enzyme, add 80 μl of the working solution at a concentration of 1 μg β-glucuronidase per well. For test wells not requiring enzyme, add 80 μl of complete culture medium.

[0360] Weigh 1-3 mg of the test compound and dissolve it in DMSO to a 20 mM stock solution. Perform a 3-fold serial dilution in DMSO, followed by a 100-fold dilution in RPMI1640 basal medium to obtain a 10x working solution, for a total of eight concentrations. Add 20 μl of the 10x working solution to each test well, for a final volume of 200 μl per well. The DMSO concentration is 0.1%.

[0361] 2.4 Calculation of compound inhibitory activity: The test includes a compound test group, a positive solvent control group (PC) without compound, and a negative solvent control group (NC) without cells and compound. Inhibition rate = [1-(test value-NC mean) / (PC mean-NC mean)] × 100%

[0362] The mean and SD of the inhibition rate were obtained from repeated test wells. The compound concentration was plotted as the horizontal axis and distributed in logarithmic form, and the mean inhibition rate was plotted as the vertical axis. The curve was fitted with the logistic 4-parameter equation. The compound concentration corresponding to 50% inhibition rate on the curve was the IC 50value.

[0363] Table 2: Culture medium formulations and cell seeding concentrations for human tumor cell lines

[0364] 3. Test results

[0365] Inhibitory IC of the test compounds on human tumor cell lines 50 The values ​​are shown in Table 3-7.

[0366] Biological Example 2: In vivo study of the human gastric cancer NCI-N87 xenograft model

[0367] 1. Test materials

[0368] Example compound 1, purity 98.08%, 2-8°C, light-shielded and sealed

[0369] Experimental animals: SPF (specific pathogen-free) Balb / c-nu male nude mice, weighing 18-20 g, housed in an SPF barrier system with a controlled temperature of 20-26°C, relative humidity of 40-70%, and a 12 / 12 hour light / dark cycle.

[0370] Test tumor line: Human gastric cancer NCI-N87 cell line, introduced from Shanghai Cell Bank.

[0371] 2. Test methods and dosing regimen

[0372] First, a human gastric cancer NCI-N87 xenograft model was established subcutaneously in nude mice using a cell-mixed gel inoculation method. After the xenograft tumor grew to a volume of 100-300 mm 3 When tumor growth remains stable, animals are randomly divided into groups using the remainder method according to tumor volume and dosed. Tumor volume is measured two to three times per week. After the dosing period, animals are sacrificed, and subcutaneous tumors are removed and weighed. Tumor volume and weight are used to evaluate the antitumor activity of the drug in this model.

[0373] Table 8: Experimental animal groups and dosing schedule Note: “-” indicates that the field is not filled in or there is no valid data. The dosage or administration cycle can be adjusted according to the animal tolerance and tumor growth during the administration process.

[0374] Example compound 1 was fully dissolved in sterile 0.9% sodium chloride injection to prepare a 1.5 mg / ml solution, which was kept away from light and prepared immediately before use.

[0375] 3. Evaluation indicators

[0376] The formula for calculating tumor volume is: volume = 0.5 × long diameter × short diameter 2 .

[0377] Relative tumor volume (RTV): RTV = V t / V0

[0378] Among them, V0 is the tumor volume measured at the time of group administration (i.e., d0), V t is the tumor volume at each measurement.

[0379] Relative tumor proliferation rate T / C: T / C = T RTV / C RTV ×100%

[0380] Where T is the mean RTV of the test substance and C is the mean RTV of the model control group. Tumor inhibition rate (%) = (mean tumor weight of the model control group - mean tumor weight of the drug group) / mean tumor weight of the model control group × 100%. Percentage change in body weight = W n / W0×100%

[0381] Among them, W n : the average body weight of the experimental animals in each group on the nth day, W0: the average body weight of the experimental animals in each group on the 0th day.

[0382] Statistical methods:

[0383] Tumor volume and animal body weight data were statistically analyzed using the general linear model test in SPSS 22.0 software. Repeated measures analysis of variance was first used for sphericity testing. If P > 0.05, the repeated measurements were considered to be non-correlated, and one-way analysis of variance was used for inter-group statistical analysis. If P ≤ 0.05, the repeated measurements were considered to be correlated, and multivariate analysis of variance was used for inter-group statistical analysis.

[0384] Tumor weight data were tested for homogeneity of variance using Levene's Test in SPSS 22.0 software. If the variances were homogeneous (P>0.05), one-way analysis of variance (One-Way Anova test) was used for inter-group statistical analysis. If the variances were unequal (P≤0.05), the Kruskal-Wallis nonparametric test was performed. If the result of the Kruskal-Wallis nonparametric test was significant (P≤0.05), the Mann-Whitney U test method of the nonparametric test was used for pairwise comparisons between groups.

[0385] 4. Test process and results

[0386] After the experimental animals were purchased, they were kept in a balanced environment for 3 days. The xenograft model was established in nude mice using the cell-mixed gel inoculation method: conventionally cultured NCI-N87 cells in the logarithmic growth phase were collected and digested, and the cell density was adjusted to 6×10 7 In an ice water bath, slowly add the cell suspension to an equal volume of matrix gel, mix well, and then inoculate subcutaneously in the right axilla of male nude mice, 0.15 ml per mouse, with a cell inoculation volume of approximately 4.5 million per mouse, to establish an allogeneic transplantation model.

[0387] Regularly observe the tumor growth of the model animals. When the average tumor volume of the model nude mice reaches about 100-300mm 3 At day 0, the experimental animals were randomly divided into groups according to tumor volume using the remainder method and dosed. The day of grouping was designated as day 0. After grouping, the groups were dosed according to Table 8. The dosage or dosing cycle was adjusted appropriately based on tumor growth and the animal's condition. Following dosing, the tumor volume of the experimental animals was measured 2-3 times per week until the end of the trial. The day after the dosing cycle, the experimental animals were sacrificed, and the subcutaneous tumors were removed and weighed. The antitumor activity of each compound in this model was evaluated based on tumor volume and weight. The experimental results are shown below.

[0388] Table 9: Effects on the growth of human gastric cancer NCI-N87 xenograft model Note: “-” indicates no valid data or no field, ***p<0.001 compared with the model control group.

[0389] Biological Example 3: In vivo study of the human gastric cancer NCI-N87 xenograft model

[0390] The test was performed using the method of Biological Example 2 and the dosage regimen in Table 10.

[0391] Table 10: Dosage regimen “-” means no entry

[0392] The test results are shown below.

[0393] Table 11 Effects on the growth of human gastric cancer NCI-N87 xenograft model Note: “-” indicates no valid data or no field; *p<0.05, **p<0.01 compared with the model control group.

[0394] Biological Example 4: In vivo study of the human gastric cancer NCI-N87 xenograft model

[0395] The test was carried out according to the method of biological example 2 and the dosage regimen in Table 12.

[0396] Table 12 Experimental animal grouping and dosing regimen Note: “-” means no valid data or no entry;

[0397] The test results are shown below.

[0398] Table 13 Effects on the growth of human gastric cancer NCI-N87 xenograft model Note: “-” indicates no valid data or no field; *p<0.05, **p<0.01 compared with the model control group.

[0399] Biological Example 5: In vivo study of a human ovarian cancer SK-OV-3 xenograft model

[0400] The test was performed using the method of Biological Example 2 and the dosage regimen in Table 14:

[0401] Table 14: Experimental animal groups and dosing schedule Note: “-” means no valid data or no entry;

[0402] The test results are shown below.

[0403] Table 15 Effects on the growth of human ovarian cancer SK-OV-3 xenograft model Note: "-" indicates no valid data or left blank; **p < 0.01 compared with the model control group. One animal in the G5 group died on day 18. During the experiment, an animal fight and bite occurred in this group on day 7, resulting in weight loss in some animals. However, other animals in the same group recovered well during the subsequent experiment, suggesting that the death was unrelated to drug administration.

[0404] Biological Example 6: In vivo study of a human ovarian cancer SK-OV-3 xenograft model

[0405] The test was carried out according to the method of Biological Example 2 and the dosage regimen in Table 16.

[0406] Table 16: Experimental animal groups and dosing schedule Note: “-” means no valid data or no entry;

[0407] The test results are shown below.

[0408] Table 17 Effects on the growth of human ovarian cancer SK-OV-3 xenograft model Note: “-” indicates no valid data or no field; **p<0.01, ***p<0.001, compared with the model control group.

[0409] Biological Example 7: In vivo study on human non-small cell lung cancer NCI-H1975 xenograft model The method of Biological Example 2 was used to test the dosage regimen in accordance with Table 18.

[0410] Table 18: Experimental animal groups and dosing regimens Note: “-” means no valid data or no entry;

[0411] The test results are shown below.

[0412] Table 19 Effects on the growth of human non-small cell lung cancer NCI-H1975 xenograft model Note: “-” indicates no valid data or no field; **p<0.01 compared with the model control group.

[0413] Biological Example 8: In vivo study of human non-small cell lung cancer NCI-H1975 xenograft model

[0414] The test was carried out according to the method of Biological Example 2 and the dosage regimen in Table 20.

[0415] Table 20: Experimental animal groups and dosing regimens Note: “-” means no valid data or no entry;

[0416] The test results are shown below.

[0417] Table 21 Effects on the growth of human non-small cell lung cancer NCI-H1975 xenograft model Note: “-” indicates no valid data or no entry; *p<0.05, **p<0.01 compared with the model control group,

[0418] Biological Example 9: In vivo study on human non-small cell lung cancer NCI-H1975 xenograft model The method of Biological Example 2 was used to test the dosage regimen in accordance with Table 22.

[0419] Table 22: Experimental animal groups and dosing regimens Note: “-” means no valid data or no entry;

[0420] The test results are shown below.

[0421] Table 23 Effects on the growth of human non-small cell lung cancer NCI-H1975 xenograft model Note: “-” indicates no valid data or no entry; *p<0.05, **p<0.01, ***p<0.001 compared with the model control group;

[0422] Biological Example 10: In vivo study on human non-small cell lung cancer NCI-H1975 xenograft model The method of Biological Example 2 was used to test the dosage regimen in accordance with Table 24.

[0423] Table 24: Experimental animal groups and dosing regimens Note: “-” means no valid data or no entry;

[0424] The test results are shown below.

[0425] Table 25 Effects on the growth of human non-small cell lung cancer NCI-H1975 xenograft model Note: “-” indicates no valid data or no entry; **p<0.01, ***p<0.001 compared with the model control group;

[0426] The above content is only an exemplary embodiment of the present disclosure and is not intended to limit the scope of the present disclosure. Any modifications, equivalent substitutions, improvements, etc. made within the concepts and principles of the present disclosure should be included in the scope of protection of the present disclosure.

Claims

1. A compound represented by the general formula (A), a stereoisomer, a cis-trans isomer, or a pharmaceutically acceptable salt thereof: in, R1 is selected from hydroxyl, C1-C 10 Alkyloxy, -O - Alkali metal ions, -O - Ammonium ions and -O - ; R2 is selected from hydrogen and C1-C 10 Hydrocarbon; R3, at each occurrence, is independently selected from hydrogen, halogen, C1-C 10 Hydrocarbon, C1-C 10 Halogenated hydrocarbon, C1-C 10 Alkyloxy, C1-C 10 Halogenated alkyloxy, C6-C 18 Aryl, Nitro, -NR 21 R 22 ; R4 is selected from C1-C 10 Alkylidene, C1-C 10 Oxyalkylene, C6-C 12 Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene-C1-C 10 Alkylene, (C1-C 10 Hydrocarbyleneoxy) d -C1-C 10 Alkylidene, C1-C 10 Hydrocarbyleneoxy-C6-C 12 Arylene, -(CH2) m -CO-NR 23 -(CHR 24 ) j -(CO-NR 25 -(CHR 26 ) k ) p -(CH2) n -, and -((CH2) m -NR 23 -(CHR 24 ) j ) q -(CH2) n -; R5 and R6, when present, are independently selected from hydrogen, halogen, C1-C 10 Hydrocarbon, C1-C 10 Halogenated hydrocarbon, C1-C 10 Alkyloxy, C1-C 10 Halogenated alkyloxy and C6-C 18 Aryl; R7 is selected from: R8 is selected from R 10 , R 11 , R 12 , R 17 、-OCO-R 10 、-OCO-R 12 and-OCO-R 17 : R 13 and R 14 Each independently selected from hydrogen, C1-C8 hydrocarbon, C6-C 12 Aryl and C1-C8 alkylene C6-C 12 Aryl, R 13 and R 14 Optionally, they are combined with the nitrogen atom to which they are attached to form a 3- to 17-membered nitrogen-containing heterocyclic ring; R9 and R 16 are each independently selected from hydrogen, alkali metal ions and ammonium ions; R 21 and R 22 Each is independently selected from hydrogen and C1-C6 hydrocarbon group; R 23 and R 25 Each is independently selected from hydrogen, C1-C6 hydrocarbon group and C1-C6 hydrocarbonoxy group; R 24 and R 26 Each independently selected from hydrogen, C1-C6 hydrocarbon group, C1-C6 alkoxy group, C6-C 12 Aryl and C7-C 13 Aromatic hydrocarbon group; x is 0 or 1; a is an integer of 0-3; b and c are each independently an integer of 0-4; d is an integer of 0-4; j, k, m, n and p are each independently an integer of 0-5, and q is an integer of 1-5; in Indicates the connection site.

2. The compound represented by the general formula (A) according to claim 1, its stereoisomers, cis-trans isomers, or pharmaceutically acceptable salts thereof, wherein the general formula (A) is the general formula (I): in, R1 is selected from hydroxyl, C1-C 10 Alkyloxy, -O - Alkali metal ions, -O - Ammonium ions and -O - ; R2 is selected from hydrogen and C1-C 10 Hydrocarbon; R3, at each occurrence, is independently selected from hydrogen, halogen, C1-C 10 Hydrocarbon, C1-C 10 Halogenated hydrocarbon, C1-C 10 Alkyloxy, C1-C 10 Halogenated alkyloxy, C6-C 18 Aryl, Nitro, -NR 21 R 22 ; R4 is selected from C1-C 10 Alkylidene, C1-C 10 Oxyalkylene, C6-C 12 Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene, C1-C 10 Alkylidene-C6-C 12 Arylene-C1-C 10 Alkylene, (C1-C 10 Hydrocarbyleneoxy) d -C1-C 10 Alkylidene, C1-C 10 Hydrocarbyleneoxy-C6-C 12 Arylene, -(CH2) m -CO-NR 23 -(CHR 24 ) j -(CO-NR 25 -(CHR 26 ) k ) p -(CH2) n -, and -((CH2) m -NR 23 -(CHR 24 ) j ) q -(CH2) n -; R5 and R6, when present, are independently selected from hydrogen, halogen, C1-C 10 Hydrocarbon, C1-C 10 Halogenated hydrocarbon, C1-C 10 Alkyloxy, C1-C 10 Halogenated alkyloxy and C6-C 18 Aryl; R7 is selected from: R8 is selected from R 10 , R 11 , R 12 , R 17 、-OCO-R 10 、-OCO-R 12 and-OCO-R 17 : R 13 and R 14 Each independently selected from hydrogen, C1-C8 hydrocarbon, C6-C 12 Aryl and C1-C8 alkylene C6-C 12 Aryl, R 13 and R 14 Optionally, they are combined with the nitrogen atom to which they are attached to form a 3- to 17-membered nitrogen-containing heterocyclic ring; R9 and R 16 are each independently selected from hydrogen, alkali metal ions and ammonium ions; R 21 and R 22 Each is independently selected from hydrogen and C1-C6 hydrocarbon group; R 23 and R 25 Each is independently selected from hydrogen, C1-C6 hydrocarbon group and C1-C6 hydrocarbonoxy group; R 24 and R 26 Each independently selected from hydrogen, C1-C6 hydrocarbon group, C1-C6 alkoxy group, C6-C 12 Aryl and C7-C 13 Aromatic hydrocarbon group; a is an integer of 0-3; b and c are each independently an integer of 0-4; d is an integer of 0-4; j, k, m, n and p are each independently an integer of 0-5, and q is an integer of 1-5; in Indicates the connection site.

3. The compound represented by the general formula (A) according to claim 1 or 2, its stereoisomers, cis-trans isomers, or pharmaceutically acceptable salts thereof, wherein: R1 is selected from hydroxyl, C1-C 10 Alkoxy, -O - Li + , -O - Na + , -O - K + , -O - Cs + , -O - NH4 + and -O - ; R2 is selected from hydrogen and C1-C 10 alkyl; R3, at each occurrence, is independently selected from hydrogen, F, Cl, Br, I, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, C6-C 18 Aryl, Nitro, -NR 21 R 22 ; R4 is selected from C1-C 10 Alkylene, C1-C 10 Alkyleneoxy, C6-C 12 Arylene, C1-C 10 Alkylene-C6-C 12 Arylene, C1-C 10 Alkylene-C6-C 12 Arylene-C1-C 10 Alkylene, (C1-C 10 Hydrocarbyleneoxy) d -C1-C 10 Alkylidene, C1-C 10 Alkyleneoxy-C6-C 12 Arylene, -(CH2) m -CO-NR 23 -(CHR 24 ) j -(CO-NR 25 -(CHR 26 ) k ) p -(CH2) n -, and -((CH2) m -NR 23 -(CHR 24 ) j ) q -(CH2) n -; R5 and R6, when present, are each independently selected from hydrogen, F, Cl, Br, I, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy and C6-C 18 Aryl; R7 is selected from: R8 is selected from R 10 , R 11 , R 12 , R 17 、-OCO-R 10 、-OCO-R 12 and-OCO-R 17 : R 13 and R 14 Each independently selected from hydrogen, C1-C8 alkyl, C6-C 12 Aryl and C1-C8 alkylene C6-C 12 Aryl, R 13 and R 14 Optionally, they are combined with the nitrogen atom to which they are attached to form a 3- to 6-membered nitrogen-containing heterocyclic ring; R9 and R 16 Each independently selected from hydrogen, Li + 、Na + , K + , Cs + and NH4 + ; R 21 and R 22 Each independently selected from hydrogen and C1-C6 alkyl; R 23 and R 25 Each independently selected from hydrogen, C1-C6 alkyl and C1-C6 alkoxy; R 24 and R 26 Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C 12 Aryl and C7-C 13 Aralkyl; a is an integer of 0-3; b and c are each independently an integer of 0-4; d is an integer of 0-4; j, k, m, n and p are each independently an integer of 0-5, and q is an integer of 1-5; in Indicates the connection site.

4. The compound represented by general formula (A) according to any one of claims 1 to 3, its stereoisomer, cis-trans isomer, or pharmaceutically acceptable salt, wherein: R1select -OH, -OCH3, -OCH2CH3, -O - Li + , -O - Na + , -O - K + , -O - Cs + , -O - NH4 + sum-o - ; R2 is selected from hydrogen, -CH3 and -CH2CH3; R3, at each occurrence, is independently selected from hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, phenyl, -NO2, -NH2, -NH(CH3), -N(CH3)2; R4 is selected from -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, -(CH2CH2O)3CH2-, -(CH2CH2CH2O)2CH2CH2-, -(CH2CH2NH)3CH2-, -CH2CH2C6H4-, -CH2CH2C 10 H6-, -CH2CH2C6H4C6H4-, -CH2CH2C6H4CH2CH2CH2-, -CH2CH2OCH2CH2-, -CH2CH2OCH2CH2CH2-, -CH2CH2CH2OCH2CH2CH2-, -(CON(CH3)CH2)2-, -(CH2CONH)2CH2-, -CH2CONHCH(CH3)CONHCH(CH3)-, -CH2CONHCH(CH3)CONHCH(CH2C6H5)-; R5 and R6, at each occurrence, are each independently selected from hydrogen, F, Cl, Br, -CH3, -CH2CH3, -OCH3, -OCH2CH3 and phenyl; R7 is selected from: R8 is selected from R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 17 、-OCO-R 10 、-OCO-R 12 and-OCO-R 17 : R 13 and R 14 are each independently selected from hydrogen, methyl, ethyl, isopropyl, butyl, phenyl, benzyl and phenethyl, When R 13 and R 14 When forming a ring with the nitrogen atom to which they are attached, R 12 for: R9 and R 16 Each independently selected from hydrogen, Li + 、Na + , K + , Cs + and NH4 + ; a is an integer from 0 to 3; b and c are each independently an integer from 0 to 4; in Indicates the connection site.

5. A compound, a stereoisomer, a cis-trans isomer, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from:

6. [Corrected 24.12.2024 in accordance with Rule 91] A compound, its stereoisomers, cis- and trans-isomers, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from:

7. [Corrected 24.12.2024 in accordance with Rule 91] A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, its stereoisomers, cis-trans isomers, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. [Corrected 24.12.2024 as per Rule 91] A pharmaceutical composition as claimed in claim 7, wherein the excipient is a sodium chloride solution carrier.

9. [Corrected on 24.12.2024 according to Rule 91] The pharmaceutical composition as claimed in claim 7, which is prepared as an injection preparation.

10. [Corrected on 24.12.2024 according to Rule 91] The pharmaceutical composition as claimed in claim 9, wherein the injection preparation is an injection solution, a sterile powder for injection and a concentrated solution for injection.

11. [Corrected 24.12.2024 in accordance with Rule 91] Use of a compound as claimed in any one of claims 1 to 6, its stereoisomers, cis-trans isomers, or pharmaceutically acceptable salts, or a pharmaceutical composition as claimed in any one of claims 7 to 10 in the preparation of a medicament for the treatment of tumors or cancer.

12. [Corrected on 24.12.2024 in accordance with Rule 91] The use as claimed in claim 11, wherein the tumor or cancer is selected from colorectal cancer, liver cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, bladder cancer, liver cancer, intestinal cancer, head and neck cancer, uterine cancer, urothelial carcinoma, osteosarcoma, sarcoma, kidney cancer, melanoma, prostate cancer, glioma, neuroglioma and leukemia.

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