Camptothecin prodrug and pharmaceutical composition thereof

Abstract

Disclosed are a compound of general formula (I), and a stereoisomer and a cis-trans isomer thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are as defined in the present disclosure.

Description

Camptothecin prodrug and pharmaceutical composition thereof

[0001] Citation of Related Applications

[0002] This disclosure claims all rights and interests in the Chinese invention patent application with application number 202210602187.7, filed with the State Intellectual Property Office of the People's Republic of China on May 30, 2022, entitled "Camptothecin Prodrugs and Pharmaceutical Compositions Thereof," and incorporates the entire contents thereof into this disclosure by reference.

[0003] field

[0004] The present disclosure relates generally to the fields of organic chemistry and medicinal chemistry.

[0005] background

[0006] Cancer is a major threat to human health. The latest global cancer burden data for 2020, released by the World Health Organization's International Agency for Research on Cancer (IARC), show that 19.29 million new cancer cases were reported worldwide in 2020, of which 4.57 million were in China. Globally, 9.96 million cancer deaths occurred in 2020, of which 3 million were in China. China ranks first in both new cases and deaths. Chemotherapy remains one of the main treatments for cancer, but 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. As one of the essential substances of life, carbohydrates have a wide range of applications in prodrug design. Glycoside modification can not only significantly increase the water solubility of drugs but also achieve tumor cell targeting of chemotherapy drugs through sugar transporters, glycosidases, and other mechanisms. Prodrug modification is an effective strategy to improve the tumor targeting of chemotherapy drugs, reduce drug toxicity, and enhance antitumor activity.

[0007] Camptothecin is an alkaloid anti-tumor drug first extracted in 1966 by American chemist Wall et al. from the bark and fruit of the Chinese plant Camptotheca acuminata (Davidia involucrata). Camptothecin exhibits anti-tumor activity at nanomolar concentrations and has demonstrated promising therapeutic effects against a variety of malignancies, including gastrointestinal tumors, leukemia, and bladder cancer. However, camptothecin has extremely poor water solubility (2.5 μg / ml). Clinically, camptothecin treatment can cause severe side effects such as bone marrow suppression, diarrhea, vomiting, and hematuria. Furthermore, its clinical use faces challenges such as high toxicity, low selectivity, and low water solubility. Research and development of camptothecin derivatives and their prodrugs is ongoing.

[0008] Prijovich et al. used 5,6-dihydro-4H-benzo[de]quinolinecamptothecin (BQC) as a lead compound and coupled glucuronic acid to its 10-hydroxyl group to prepare the glycoconjugate BQC-G. Compared with BQC, BQC-G has significantly improved water solubility at physiological pH.

[0009] 9ACG is a glycoconjugate based on 9-aminocamptothecin (9AC). Toxicity studies have shown that a dose of 50 mg / kg is lethal to mice.

[0010] There is still a need for further improvement in the prodrugs obtained by modifying camptothecin and its derivatives using glycosidases.

[0011] Overview

[0012] In one aspect, the present disclosure relates to compounds of formula (I), stereoisomers, and cis- and trans-isomers thereof:

[0013] in,

[0014] R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids;

[0015] R2 is selected from hydrogen, C1-C8 hydrocarbon group;

[0016] R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 hydrocarbon group, C1-C8 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group;

[0017] R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8) m, C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides;

[0018] R5 is selected from hydrogen, C1-C8 hydrocarbon group;

[0019] R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkyleneamino (C1-C4 alkyl) 2, C1-C8 alkylenethio C1-C8 alkyl, C1-C9 alkylene-oxy-C1-C9 alkyl;

[0020] R5 and R6 can be connected to form a ring, and when R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring;

[0021] R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene;

[0022] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is 0, -(CH2R7)n represents a covalent bond; R8 is selected from carbonylamino, wherein the amino group is substituted by a C1-C8 hydrocarbon group or an aromatic hydrocarbon group, a C1-C8 alkyleneamino C1-C8 alkylene group, a C1-C8 alkylenethio C1-C8 alkylene group, or a C1-C8 alkyleneoxy C1-C8 alkylene group;

[0023] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond;

[0024] R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0025] R 10 One or more substituted hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0026] R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0027] R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0028] R 13 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0029] R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0030] R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0031] R1, R 11 、R 12 The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine.

[0032] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof and a pharmaceutically acceptable carrier:

[0033] in,

[0034] R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids;

[0035] R2 is selected from hydrogen, C1-C8 hydrocarbon group;

[0036] R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 hydrocarbon group, C1-C8 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group;

[0037] R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8) m , C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides;

[0038] R5 is selected from hydrogen, C1-C8 hydrocarbon group;

[0039] R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkyleneamino (C1-C4 alkyl) 2, C1-C8 alkylenethio C1-C8 alkyl, C1-C9 alkylene-oxy-C1-C9 alkyl;

[0040] R5 and R6 can be connected to form a ring, and when R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring;

[0041] R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene;

[0042] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond;

[0043] R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C8 alkyl or aromatic alkyl group, a C1-C8 alkyleneamino C1-C8 alkylene, a C1-C8 alkylenethio C1-C8 alkylene, or a C1-C8 alkyleneoxy C1-C8 alkylene;

[0044] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond;

[0045] R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0046] R 10 One or more substituted hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0047] R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0048] R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0049] R 13 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0050] R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C18 heteroaromatic groups;

[0051] R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0052] R1, R 11 、R 12 The natural or unnatural amino acids are selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine.

[0053] In another aspect, the present disclosure relates to the use of a compound of formula (I) or a stereoisomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof and a pharmaceutically acceptable carrier, in the preparation of a medicament for treating tumors or cancer:

[0054] in,

[0055] R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids;

[0056] R2 is selected from hydrogen, C1-C8 hydrocarbon group;

[0057] R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 hydrocarbon group, C1-C8 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group;

[0058] R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15Aromatic ring group, -(CH2R7)n, -(R8)m, C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides;

[0059] R5 is selected from hydrogen, C1-C8 hydrocarbon group;

[0060] R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkyleneamino (C1-C4 alkyl) 2, C1-C8 alkylenethio C1-C8 alkyl, C1-C9 alkylene-oxy-C1-C9 alkyl;

[0061] R5 and R6 can be connected to form a ring, and when R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring;

[0062] R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene;

[0063] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond;

[0064] R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C8 alkyl or aromatic alkyl group, a C1-C8 alkyleneamino C1-C8 alkylene, a C1-C8 alkylenethio C1-C8 alkylene, or a C1-C8 alkyleneoxy C1-C8 alkylene;

[0065] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond;

[0066] R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0067] R 10 One or more substituted hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0068] R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0069] R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0070] R 13 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0071] R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0072] R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0073] R1, R 11 、R 12 The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine.

[0074] In certain embodiments, illustrative examples of the tumor or cancer include, but are not limited to, colorectal cancer, lung cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, bladder cancer, liver cancer, stomach cancer, intestinal cancer, head and neck cancer, uterine cancer, urothelial carcinoma, osteosarcoma, sarcoma, kidney cancer, melanoma, prostate cancer, glioma, neuroglioma, and leukemia.

[0075] In another aspect, the present disclosure relates to a method for treating tumors or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof and a pharmaceutically acceptable carrier:

[0076] in,

[0077] R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids;

[0078] R2 is selected from hydrogen, C1-C8 hydrocarbon group;

[0079] R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 hydrocarbon group, C1-C8 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group;

[0080] R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8)m, C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides;

[0081] R5 is selected from hydrogen, C1-C8 hydrocarbon group;

[0082] R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkyleneamino (C1-C4 alkyl) 2, C1-C8 alkylenethio C1-C8 alkyl, C1-C9 alkylene-oxy-C1-C9 alkyl;

[0083] R5 and R6 can be connected to form a ring, and when R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring;

[0084] R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene;

[0085] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond;

[0086] R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C8 alkyl or aromatic alkyl group, a C1-C8 alkyleneamino C1-C8 alkylene, a C1-C8 alkylenethio C1-C8 alkylene, or a C1-C8 alkyleneoxy C1-C8 alkylene;

[0087] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond;

[0088] R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0089] R 10 One or more substituted hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0090] R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0091] R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0092] R 13Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0093] R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0094] R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0095] R1, R 11 、R 12 The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine.

[0096] In certain embodiments, illustrative examples of the tumor or cancer include, but are not limited to, colorectal cancer, lung cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, bladder cancer, liver cancer, stomach cancer, intestinal cancer, head and neck cancer, uterine cancer, urothelial carcinoma, osteosarcoma, sarcoma, kidney cancer, melanoma, prostate cancer, glioma, neuroglioma, and leukemia.

[0097] In another aspect, the present disclosure relates to a method for preparing a compound of formula (I) or a stereoisomer or a cis-trans isomer thereof:

[0098] in,

[0099] R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids;

[0100] R2 is selected from hydrogen, C1-C8 hydrocarbon group;

[0101] R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 hydrocarbon group, C1-C8 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group;

[0102] R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8)m, C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides;

[0103] R5 is selected from hydrogen, C1-C8 hydrocarbon group;

[0104] R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkyleneamino (C1-C4 alkyl) 2, C1-C8 alkylenethio C1-C8 alkyl, C1-C9 alkylene-oxy-C1-C9 alkyl;

[0105] R5 and R6 can be connected to form a ring, and when R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring;

[0106] R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene;

[0107] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond;

[0108] R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C8 alkyl or aromatic alkyl group, a C1-C8 alkyleneamino C1-C8 alkylene, a C1-C8 alkylenethio C1-C8 alkylene, or a C1-C8 alkyleneoxy C1-C8 alkylene;

[0109] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond;

[0110] R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0111] R 10 One or more substituted hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0112] R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0113] R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0114] R 13 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0115] R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0116] R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0117] R1, R 11 、R 12The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, homoalanine:

[0118] The preparation method comprises:

[0119] (1) reacting the compound of general formula (AI) with the compound of general formula (A-II) to obtain the compound of general formula (A-III),

[0120] Among them, R4', R9', R 10 ' represents the group and the R4, R9, R 10 The same definition as;

[0121] (2) reacting the compound of general formula (A-III) with sodium azide to obtain the compound of general formula (A-IV),

[0122] Among them, R4', R9', R 10 ' represents the group and the R4, R9, R 10 The same definition as;

[0123] (3) reacting the compound of formula (A-IV) with 4-amino-5-hydroxy-1,3-naphthalene disulfonic acid monosodium salt to obtain the compound of formula (AV),

[0124] Among them, R4', R9', R 10 ' represents the group and the R4, R9, R 10 The same definition as;

[0125] (4) reacting the compound of formula (BI) with carbon tetrabromide to obtain the compound of formula (B-II),

[0126] Wherein, the groups represented by R1', R2', and R3' in the general formula (BI) and the general formula (B-II) are the same as those defined for R1, R2, and R3 in the general formula (I);

[0127] (5) reacting the compound of formula (B-II) with the compound of formula (B-III) to obtain the compound of formula (B-IV)

[0128] Wherein, the groups represented by R1', R2', R3', R5', and R6' in general formula (B-II), general formula (B-III), and general formula (B-IV) have the same definitions as R1, R2, R3, R5, and R6 in general formula (I);

[0129] (6) The compound of general formula (B-IV) is reacted under alkaline conditions to obtain the compound of general formula (BV)

[0130] Wherein, the groups represented by R1', R2', R3', R5', and R6' in the general formula (B-IV) and the general formula (BV) are the same as those defined for R1, R2, R3, R5, and R6 in the general formula (I);

[0131] (7) reacting the compound of formula (AV) with the compound of formula (BV) to obtain the compound of formula (I), or reacting the compound of formula (AV) with the compound of formula (BV) to obtain a product and forming a pharmaceutically acceptable salt thereof with a corresponding acid or base.

[0132] Among them, R2', R3', R4', R5', R6', R9', R 10 ' represents the group and R2, R3, R4, R5, R6, R9, R 10 , have the same definition.

[0133] In yet another aspect, the present disclosure relates to the following compounds, stereoisomers thereof:

[0134] In certain embodiments, the compounds of the present disclosure have good water solubility.

[0135] In certain embodiments, the compounds of the present disclosure have good stability.

[0136] The compounds of the present disclosure have good storage stability.

[0137] The compounds disclosed herein have good stability in the blood circulation of a living body.

[0138] In certain embodiments, the compounds of the present disclosure have good anti-cancer activity.

[0139] In certain embodiments, the compounds of the present disclosure have a good safety profile.

[0140] In certain embodiments, the compounds of the present disclosure are well tolerated.

[0141] In certain embodiments, the compounds of the present disclosure have good anticancer activity against large tumors.

[0142] In certain embodiments, the compounds disclosed herein have good anti-cancer activity against tumors that have previously been poorly treated with irinotecan.

[0143] BRIEF DESCRIPTION OF THE DRAWINGS

[0144] FIG1 shows the tumor volume-time curve after administration of irinotecan before grouping.

[0145] Details

[0146] In the following description, certain specific details are included to provide a thorough understanding of each disclosed embodiment. However, one skilled in the relevant art will recognize that the embodiments can be implemented without one or more of these specific details and with other methods, components, materials, etc.

[0147] Unless otherwise required by this disclosure, throughout this specification and the claims that follow, the words "include" and "comprising" should be construed in an open, inclusive sense, ie, "including, but not limited to."

[0148] Reference throughout this specification to "one embodiment" or "another embodiment" or "an embodiment" or "certain embodiments" means that the particular 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 various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0149] It will be understood that the singular articles “a,” “an,” and “the,” as used in the specification of this disclosure and the appended claims, include plural referents unless the context clearly dictates otherwise.

[0150] definition

[0151] Accordingly, unless otherwise indicated to the contrary, the following terms used in the specification and appended claims shall have the following meanings:

[0152] Certain chemical groups named in this disclosure are preceded by abbreviations indicating the total number of carbon atoms present in the indicated chemical group. For example, C1-C4 alkyl describes an alkyl group as defined below having a total of 1 to 4 carbon atoms, while C3-C4 alkyl describes an alkyl group ... 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.

[0153] In this disclosure, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0154] In this disclosure, the term "hydroxyl" refers to an -OH group.

[0155] In this disclosure, the term "amino" refers to a -NH2 group.

[0156] In this disclosure, the term "carboxyl" refers to a -COOH group.

[0157] In this disclosure, the term "cyano" refers to a -CN group.

[0158] In this disclosure, the term "nitro" refers to a -NO2 group.

[0159] In the present disclosure, the term "hydrocarbyl" refers to an aliphatic hydrocarbon group. The hydrocarbyl portion can be a "saturated hydrocarbyl" group, meaning that it does not contain any alkene or alkyne moieties. The hydrocarbyl portion can also be an "unsaturated hydrocarbyl" portion, meaning that it contains at least one alkene or alkyne moiety. The "alkene" portion refers to a straight or branched hydrocarbon chain group consisting of two to eight 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 the "alkyne" portion refers to a straight or branched hydrocarbon chain group consisting of two to eight 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, can be branched or straight-chain.

[0160] The hydrocarbyl group can have from 1 to 8 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 8" 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 8 carbon atoms, although this definition also covers occurrences of the term "hydrocarbyl" without specifying a numerical range).

[0161] The hydrocarbyl group may be optionally substituted, i.e., substituted or unsubstituted. When substituted, the substituent groups are individually and independently selected from one or more of the following: cycloalkyl, aromatic, heteroaromatic, 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.

[0162] In certain 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.

[0163] In certain 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.

[0164] In certain embodiments, "C1-C 12 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing from one to twelve carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0165] In certain 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.

[0166] In certain 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.

[0167] In certain embodiments, "C3-C 12 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing three to twelve carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0168] In certain embodiments, "C6-C 12 "Hydrocarbyl" refers to a hydrocarbon group as defined above containing six to twelve carbon atoms. 12 The hydrocarbyl group may be optionally substituted as defined for a hydrocarbyl group.

[0169] In certain 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.

[0170] In the present disclosure, the term "alkyloxy" refers to the general formula -O-alkyl, wherein alkyl is as defined in the present disclosure. Illustrative examples of alkyloxy include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and tert-pentoxy.

[0171] In the present disclosure, the term "aromatic" 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. Aromatic groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. An aromatic group can, for example, have five to twelve carbon atoms. The aromatic 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, aromatic, heteroaromatic, heteroalicyclic, hydroxy, protected 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-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.

[0172] In the present disclosure, the term "aromatic subunit" 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. Aromatic subunit groups include, but are not limited to, fluorenyl subunits, phenyl subunits, and naphthyl subunits. Aromatic subunit groups can, for example, have five to twelve carbon atoms. Aromatic subunit 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, aromatic, heteroaromatic, heteroalicyclic, hydroxy, protected 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-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 aromatic subunit 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.

[0173] 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. Aromatic groups include, but are not limited to, fluorenyl, phenyl, and naphthyl. Aromatic ring groups can, for example, have five to twelve carbon atoms. 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, aromatic, heteroaromatic, heteroalicyclic, hydroxy, protected 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-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.

[0174] In the present disclosure, the term "arylalkyloxy" refers to the general formula -O-alkylaryl, wherein the alkyl group and the aryl group are as defined in the present disclosure. Illustrative examples of arylalkyloxy include, but are not limited to, benzyloxy, phenethyloxy, and phenylpropyloxy.

[0175] In certain embodiments, "C6-C 16 "Arylalkyloxy" refers to an aromatic alkyloxy group as defined above containing six to sixteen carbon atoms. 16 An arylalkyloxy group may be optionally substituted as defined for an alkyl group and an aryl group, respectively.

[0176] In certain embodiments, "C6-C 18 "Arylalkyloxy" refers to an aromatic alkyloxy group as defined above containing six to eighteen carbon atoms. 18 An arylalkyloxy group may be optionally substituted as defined for an alkyl group and an aryl group, respectively.

[0177] In certain embodiments, "C7-C 18 "Arylalkyloxy" refers to an aromatic alkyloxy group as defined above containing seven to eighteen carbon atoms. 18 An arylalkyloxy group may be optionally substituted as defined for an alkyl group and an aryl group, respectively.

[0178] In certain embodiments, "C8-C 18"Arylalkyloxy" refers to an aromatic alkyloxy group as defined above containing eight to eighteen carbon atoms. 18 An arylalkyloxy group may be optionally substituted as defined for an alkyl group and an aryl group, respectively.

[0179] In certain embodiments, "C8-C 24 "Arylalkyloxy" refers to an aromatic alkyloxy group as defined above containing eight to twenty-four carbon atoms. 24 An arylalkyloxy group may be optionally substituted as defined for an alkyl group and an aryl group, respectively.

[0180] In certain embodiments, "C 11 -C 24 "Arylalkyloxy" refers to an aromatic alkyloxy group as defined above containing eleven to twenty-four carbon atoms. 11 -C 24 An arylalkyloxy group may be optionally substituted as defined for an alkyl group and an aryl group, respectively.

[0181] In certain embodiments, "C 12 -C 24 "Arylalkyloxy" refers to an aromatic alkyloxy group as defined above containing twelve to twenty-four carbon atoms. 12 -C 24 An arylalkyloxy group may be optionally substituted as defined for an alkyl group and an aryl group, respectively.

[0182] In certain embodiments, "C6-C 24 "Arylalkyloxy" refers to an aromatic alkyloxy group as defined above containing six to twenty-four carbon atoms. 24 An arylalkyloxy group may be optionally substituted as defined for an alkyl group and an aryl group, respectively.

[0183] 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 certain 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 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, The heteroaromatic 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, aromatic, heteroaromatic, heteroalicyclic, hydroxy, protected 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-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.

[0184] In the present disclosure, the term "heteroaromatic subunit" 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 certain embodiments, the heteroaromatic subunit 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 heteroaromatic subunit may be optionally oxidized; and the nitrogen atom may be optionally quaternized. Illustrative examples of heteroaromatic subunits include, but are not limited to, azepine subunits, acridinium subunits, benzimidazole subunits, benzothiazole subunits, benzindole subunits, benzodioxole subunits, benzofuran subunits, benzoxaazole subunits, benzothiazole subunits, benzothiadiazolyl subunits, benzo[b][1,4]dioxepane subunits, 1,4-benzodioxane subunits, benzonaphthofuran subunits, benzoxaazole subunits, benzodioxole subunits, benzodioxin subunits, benzopyran subunits, benzopyrone subunits, benzofuran subunits, benzofuranone subunits, benzothiophene subunits, benzotriazole subunits, benzo[4,6]imidazo[1,2-a]pyridine subunits, carbazole subunits, cinnolin subunits, dibenzofuran subunits, dibenzothiophene subunits, furan subunits, subunit, furanone subunit, isothiazole subunit, imidazole subunit, indazole subunit, indole subunit, indazole subunit, isoindole subunit, indolin subunit, isoindolin subunit, isoquinolin subunit, indoleazine subunit, isoxazole subunit, naphthyridine subunit, oxadiazole subunit, 2-oxoazepine subunit, oxazole subunit, oxirane subunit, 1-phenyl-1H-pyrrol subunit, phenanthrazine subunit, phenathiazine subunit The heteroaromatic subunits 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, aromatic, heteroaromatic, heteroalicyclic, hydroxy, protected 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-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 heteroaromatic subunit 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.

[0185] 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 certain embodiments, the heteroaryl 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 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, aromatic, heteroaromatic, heteroalicyclic, hydroxy, protected 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-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.

[0186] 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 certain embodiments from three to twelve carbon atoms, and which is saturated or unsaturated and is 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, aromatic, heteroaromatic, aromatic ring, heteroaromatic ring, heteroalicyclic, 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.

[0187] In certain 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.

[0188] In certain 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.

[0189] In certain embodiments, "C3-C 12 "Cycloalkyl" refers to a cycloalkyl group as defined above having three to twelve carbon atoms. 12 The cycloalkyl group may be optionally substituted as defined above for a cycloalkyl group.

[0190] As used herein, the term "alkylene" or "alkylene" refers to a divalent hydrocarbon chain consisting solely of carbon and hydrogen, which 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.

[0191] 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 consisting solely of carbon and hydrogen and having one to nine carbon atoms, connecting the rest 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 rest 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-C8 alkyleneoxy" or "C1-C8 hydrocarbyleneoxy" refers to a difunctional linear, branched or cyclic alkoxy group having one to nine carbon atoms.

[0192] In the present disclosure, the term "C1-C8 alkyleneoxy", "C1-C8 alkyleneoxy" or "C1-C8 hydrocarbyleneoxy" refers to a difunctional linear, branched, or cyclic alkoxy group having one to nine carbon atoms.

[0193] 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.

[0194] 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, butyrylamino, and pentanoylamino.

[0195] 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.

[0196] In the present disclosure, the term "alkyloxycarbonylamino" refers to -NHC(=O)O-alkyl, wherein alkyl is as defined in the present disclosure. Illustrative examples of alkyloxycarbonylamino include, but are not limited to, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, and tert-butoxycarbonylamino.

[0197] In the present disclosure, the term "alkyloxycarbonyl" refers to -C(=O)O-alkyl, wherein alkyl is as defined in the present disclosure. Illustrative examples of alkyloxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, and butoxycarbonyl.

[0198] In the present disclosure, the term "carbonylamino" refers to -C(=O)-NH-.

[0199] In the present disclosure, the term "a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof" refers to the compound of the general formula (I) of the present disclosure, a stereoisomer thereof.

[0200] In this disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans, etc. In certain embodiments, the mammal includes humans.

[0201] 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 certain embodiments, the patient is a mammal, including males and females. In certain embodiments, the patient is a human.

[0202] In this disclosure, the term "pharmaceutically acceptable" refers to carriers, vehicles, diluents, excipients and / or salts that must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0203] 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.

[0204] In the present disclosure, the term "pharmaceutically acceptable carrier, diluent or excipient" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and various forms of carriers that have no side effects on the composition of the pharmaceutical composition.

[0205] In this 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.

[0206] In the present disclosure, the term "pharmaceutically acceptable salt" includes "acceptable acid addition salts" and "acceptable base addition salts".

[0207] In this disclosure, the term "acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are biologically or otherwise suitable and are formed using inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2,2-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.

[0208] In this disclosure, the term "acceptable base addition salts" refers to salts that retain the biological effectiveness and properties of the free acids, and the base addition salts 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 certain 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 certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0209] In the present disclosure, the term "solvent or solvent mixture" refers to any and all solvents. In certain embodiments, the solvent or solvent mixture is an organic solvent and water, which includes but is 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 any and all mixtures of two or more such solvents. In certain embodiments, the solvent or solvent mixture is a single solvent and a binary mixture. In certain 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.

[0210] As used herein, 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 any pharmaceutically acceptable carrier, diluent, or excipient.

[0211] In the present disclosure, the term "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 symptoms of a particular disease or condition, or prevents or delays the onset of a particular disease or condition or symptoms of a particular disease or condition. The amount of a compound described in the present disclosure that constitutes a "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.

[0212] 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:

[0213] (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;

[0214] (ii) inhibiting the disease or disease state, i.e., preventing its occurrence; or

[0215] (iii) ameliorating the disease or condition, even if the disease or condition regresses or does not progress.

[0216] 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.

[0217] 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.

[0218] The compounds described in the present 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 as (R)- or (S)-, or (D)- or (L)- of amino acids based on absolute stereochemistry. The present disclosure is intended to include all of these possible isomers, as well as their racemic forms and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or can be separated using conventional techniques, such as HPLC using chiral columns. When the compounds described in the present disclosure contain olefinic double bonds or other geometric asymmetric centers, unless otherwise indicated, it is meant that the compounds include E and Z geometric isomers. Similarly, it is also meant to include all tautomeric forms.

[0219] 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. Specific implementation plan

[0220] In one aspect, the present disclosure relates to compounds of formula (I), stereoisomers, and cis- and trans-isomers thereof:

[0221] in,

[0222] R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids;

[0223] R2 is selected from hydrogen, C1-C8 hydrocarbon group;

[0224] R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkyloxy, cyano, nitro, amino, aromatic, aromatic alkyl, and amino substituted with C1-C4 alkyl;

[0225] R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8)m, C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides;

[0226] R5 is selected from hydrogen, C1-C8 hydrocarbon group;

[0227] R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkyleneamino (C1-C4 alkyl) 2, C1-C8 alkylenethio C1-C8 alkyl, C1-C9 alkylene-oxy-C1-C9 alkyl;

[0228] R5 and R6 can be connected to form a ring, and when R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring;

[0229] R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene;

[0230] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond;

[0231] R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C8 alkyl or aromatic alkyl group, a C1-C8 alkyleneamino C1-C8 alkylene, a C1-C8 alkylenethio C1-C8 alkylene, or a C1-C8 alkyleneoxy C1-C8 alkylene;

[0232] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond;

[0233] R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C12 aromatic groups;

[0234] R 10 One or more substituted hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0235] R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0236] R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0237] R 13 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0238] R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0239] R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0240] R1, R 11 、R 12The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine.

[0241] In one aspect, the present disclosure relates to compounds of formula (I), stereoisomers, and cis- and trans-isomers thereof:

[0242] in,

[0243] R1 is selected from hydrogen, C1-C4 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids;

[0244] R2 is selected from hydrogen, C1-C4 hydrocarbon group;

[0245] R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C4 hydrocarbon group, C1-C4 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group;

[0246] R4 is selected from C1-C6 alkylene, C1-C6 alkyleneoxy, C1-C6 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8)m, C1-C4 alkylene-aromatic subunit, C1-C4 alkylene-aromatic subunit-C1-C4 alkylene, C1-C4 alkylene-aromatic subunit-aromatic subunit, C1-C4 alkylene-heteroaromatic subunit-C1-C4 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides;

[0247] R5 is selected from hydrogen, C1-C4 hydrocarbon group;

[0248] R6 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkyleneamino (C1-C4 alkyl) 2, C1-C4 alkylenethio C1-C4 alkyl, C1-C4 alkylene-oxy-C1-C4 alkyl;

[0249] R5 and R6 can be connected to form a ring, and when R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring;

[0250] R7 is selected from hydrogen, C1-C4 alkyleneoxy, amino C1-C4 alkylene, thio C1-C4 alkylene, oxy C1-C4 alkylene;

[0251] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond;

[0252] R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C4 alkyl or aromatic alkyl group, a C1-C4 alkyleneamino C1-C4 alkylene, a C1-C4 alkylenethio C1-C4 alkylene, or a C1-C4 alkyleneoxy C1-C4 alkylene;

[0253] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond;

[0254] R9 is selected from one or more hydrogen, halogen, cyano, C1-C4 hydrocarbon, C1-C4 alkoxy, C5-C 12 aromatic groups;

[0255] R 10 One or more substituted hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0256] R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0257] R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3+ R 13 , natural or unnatural amino acids;

[0258] R 13 Selected from hydrogen, C1-C4 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0259] R 14 Selected from hydrogen, C1-C4 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0260] R 15 Selected from hydrogen, C1-C4 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0261] R1, R 11 、R 12 The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine.

[0262] In certain embodiments, R1 is selected from hydrogen, -CH3, -CH2CH3, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids.

[0263] In certain embodiments, R2 is selected from hydrogen, -CH3, -CH2CH3.

[0264] In certain embodiments, R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, -F-, -Cl, -Br, -CN, -CH3, -CH2CH 3、-CH2CH2CH3, -CH2CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH2CH2CH3, phenyl, benzyl, -NO2, -NH2, -N(CH3)2.

[0265] In certain embodiments, R4 is selected from

[0266] -CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2CH2CH2CH2CH2-、

[0267] -CH2OCH2-, -CH2OCH2CH2-, -CH2OCH2CH2OCH2-, -CH2OCH2CH2OCH2CH2OCH2-, -CH2OCH2CH2OCH2CH2OCH2CH2OCH2-, -CH2CH2OCH2CH2CH2OCH2-, -CH2CH2OCH2CH2CH2OCH2CH 2CH2OCH2-, -CH2CH2OCH2CH2CH2OCH2CH2CH2OCH2CH2CH2OCH2-, -CH2CH2OCH2-, -CH2CH2OCH2CH2CH2OCH2CH2-, -CH2CH2OCH2CH2CH2OCH2-, -CH2NHCH2CH2NHCH2CH2NHCH2-,

[0268] A polypeptide composed of a combination of natural or non-natural amino acids, such as glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, homoalanine, or any combination thereof; the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides.

[0269] In certain embodiments, R5 is selected from hydrogen, -CH3, -CH2CH3

[0270] In certain embodiments, R6 is selected from hydrogen, -CH3, -CH2OCH3, -CH2N(CH3)2, -CH2SCH(CH3)2.

[0271] In certain embodiments, R5 and R6 can be selected from a five-membered ring or a six-membered ring when forming a ring.

[0272] In certain embodiments, R5 and R6 can be selected from cyclopentyl and cyclohexyl when forming a ring.

[0273] In certain embodiments, R7 is selected from -H, -OCH2-, -OCH2CH2-, -OCH2CH2CH2-, -OCH2CH2CH2CH2-, -NHCH2-, -NHCH2CH2-, -NHCH2CH2CH2-, -NHCH2CH2CH2-, -NHCH2CH2CH2CH2-, -SCH2-, -SCH2CH2-, -SCH2CH2CH2-, -SCH2CH2CH2CH2-, -CH2O-, -CH2CH2O-, -CH2CH2CH2O-, -CH2CH2CH2CH2O-.

[0274] In certain embodiments, n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9.

[0275] In certain embodiments, when n is equal to 0, -(CH2R7)n represents a covalent bond. In certain embodiments, R8 is selected from -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2OCH2CH2-, -CH2CH2OCH2CH2-, -CH2CH2CH2OCH2CH2-, -CH2CH2CH2OCH2CH2-, -CH2CH2CH2OCH2CH2-, -CH2SCH2CH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2-, -CH2CH2SCH2CH2-, -CH2CH2SCH2CH2-, -CH2CH2CH2SCH2CH2-, -CH2CH2CH2SCH2CH2-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, -CH2CH2NHCH2CH In certain embodiments, m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9. In certain embodiments, m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9.

[0276] In certain embodiments, when m represents 0, -(R8) m Represents a covalent bond.

[0277] In certain embodiments, R9 is selected from one or more substituted hydrogen, -F-, -Cl, -Br, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, phenyl.

[0278] In certain embodiments, R 10 Selected from one or more hydrogen, -F-, -Cl, -Br, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, phenyl substituted at any position.

[0279] In certain embodiments, R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、 -NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, homoalanine.

[0280] In certain embodiments, R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, homoalanine.

[0281] In certain embodiments, R 13Selected from hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH2CH2CH2CH3, cyclohexanyl, phenyl, pyridyl, thienyl, imidazolyl, indolyl, quinolinyl, pyridoimidazolyl, pyridoindoleyl, imidazoquinolinyl, imidazoquinoxalinyl, imidazopyridinyl, benzoxazinyl.

[0282] In certain embodiments, R 14 Selected from hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH2CH2CH2CH3, cyclohexanyl, phenyl, pyridyl, thienyl, imidazolyl, indolyl, quinolinyl, pyridoimidazolyl, pyridoindoleyl, imidazoquinolinyl, imidazoquinoxalinyl, imidazopyridinyl, benzoxazinyl.

[0283] In certain embodiments, R 15 Selected from hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH2CH2CH2CH3, cyclohexanyl, phenyl, pyridyl, thienyl, imidazolyl, indolyl, quinolinyl, pyridoimidazolyl, pyridoindoleyl, imidazoquinolinyl, imidazoquinoxalinyl, imidazopyridinyl, benzoxazinyl.

[0284] In yet another aspect, the present disclosure relates to the following compounds, their stereoisomers, cis-trans isomers, or pharmaceutically acceptable salts thereof:

[0285] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)2-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0286] Disodium 4-amino-6-((E)-(4'-(6-(4-((3-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-6-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-tolyloxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0287] Disodium 4-amino-6-((E)-(4'-(6-(4-((6-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0288] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0289] Disodium 4-amino-6-((E)-(4'-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0290] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0291] Disodium 4-amino-6-((E)-(4'-(6-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0292] Trisodium (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-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0293] Disodium 4-amino-6-((E)-(4'-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0294] Disodium 4-amino-6-((E)-(4'-(6-(4-((2-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0295] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0296] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0297] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0298] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0299] Disodium 4-amino-6-((E)-(4'-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0300] Disodium 4-amino-6-((E)-(4'-(6-(4-((2-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0301] Trisodium (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-((((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0302] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(8-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-8-oxooctyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0303] Disodium 4-amino-6-((E)-(4'-(8-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)octanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0304] Disodium 4-amino-6-((E)-(4'-(8-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)octanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0305] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(8-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1'-biphenyl]-4-yl)amino)-8-oxooctyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0306] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(8-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-8-oxooctyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0307] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(2-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxyethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0308] Disodium 4-amino-6-((E)-(4'-(2-(2-(2-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)acetamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0309] Disodium 4-amino-6-((E)-(4'-(2-(2-(2-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)acetamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0310] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(2-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)amino)-2-oxyethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0311] Disodium 4-amino-6-((E)-(4'-(2-(2-(2-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)acetamido)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0312] Disodium 4-amino-6-((E)-(4'-(2-(2-(2-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)acetamido)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0313] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0314] Disodium 4-amino-6-((E)-(4'-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0315] Disodium 4-amino-6-((E)-(4'-(6-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid;

[0316] (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid;

[0317] Sodium 1-amino-7-((E)-(4'-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-8-hydroxy-4-sulfononaphthalene-2-sulfonate;

[0318] (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid trilithium;

[0319] (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid triammonium;

[0320] (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid tripotassium;

[0321] (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid tricesium;

[0322] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-fluorophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0323] Trisodium (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)-2-chloro-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0324] Trisodium (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)-2-bromo-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0325] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0326] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-ethylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0327] Trisodium (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-(1-(((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)ethyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0328] Trisodium (2S,3S,4S,5R,6S)-6-((6-((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)-5-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-[1,1'-biphenyl]-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0329] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0330] Trisodium (2S,3S,4S,5R,6S)-6-(2-amino-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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0331] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-(dimethylamino)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0332] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-fluorophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0333] Trisodium (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)-5-chloro-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0334] Trisodium (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)-5-bromo-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0335] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0336] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0337] Trisodium (2S,3S,4S,5R,6S)-6-((5-((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)-6-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-[1,1'-biphenyl]-3-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0338] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-ethylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0339] Trisodium (2S,3S,4S,5R,6S)-6-(3-amino-5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0340] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(dimethylamino)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0341] Trisodium (2S,3S,4S,5R,6S)-6-(5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-fluorophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0342] Trisodium (2S,3S,4S,5R,6S)-6-(5-((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)-2-chloro-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0343] Trisodium (2S,3S,4S,5R,6S)-6-(5-((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)-2-bromo-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0344] Trisodium (2S,3S,4S,5R,6S)-6-(5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0345] Trisodium (2S,3S,4S,5R,6S)-6-(5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0346] Trisodium (2S,3S,4S,5R,6S)-6-((4-((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)-5-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-[1,1'-biphenyl]-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0347] Trisodium (2S,3S,4S,5R,6S)-6-(5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-ethylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0348] Trisodium (2S,3S,4S,5R,6S)-6-(2-amino-5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0349] Trisodium (2S,3S,4S,5R,6S)-6-(5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-(dimethylamino)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0350] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-6-fluoro-2-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0351] Trisodium (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)-6-chloro-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-fluoro-2-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0352] Trisodium (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)-6-bromo-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0353] Trisodium (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-((((S)-9-ethyl-9-hydroxy-10,13-dioxy-2,3,9,10,13,15-tetrahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0354] Trisodium (2S,3S,4S,5R,6S)-6-(4-((((S)-4-acetoxy-4-ethyl-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-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)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0355] Trisodium (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-((((S)-4-ethyl-3,14-dioxy-4-(propionyloxy)-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0356] Trisodium (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-((((S)-4-ethyl-4-(glycyloxy)-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0357] (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-(((R)-5-ethyl-5-hydroxy-3,15-dioxy-4,5,13,15-tetrahydro-1H,3H-oxa- trisodium 3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0358] Trisodium (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-((((S)-4-ethyl-4-hydroxy-10-(methoxymethyl)-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0359] Trisodium (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-((((S)-4-ethyl-4-hydroxy-10-((isopropylthio)methyl)-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0360] Trisodium (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-((((S)-4-ethyl-4-hydroxy-3-oxy-14-thio-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0361] (2S,3S,4S,5R,6S)-6-(3-((1-(2-((2-((2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)(methyl)amino)-2-oxo trisodium 4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0362] (2S,3S,4S,5R,6S)-6-(3-((1-(2-((2-((2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)- trisodium 1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0363] (2S,3S,4S,5R,6S)-6-(3-((1-(2-(((S)-1-(((S)-1-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14- trisodium dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0364] (2S,3S,4S,5R,6S)-6-(3-((1-(2-(((S)-1-(((S)-1-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino trisodium 4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0365] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(2-(2-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0366] (2S,3S,4S,5R,6S)-6-(3-((1-(2-((2-((2-((2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)amino)ethyl)amino)ethyl)amino)ethyl)- trisodium 1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0367] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(3-(3-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-3-oxopropoxy)propoxy)propyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0368] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(4-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamoyl)phenethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0369] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamoyl)naphthalen-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0370] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(4'-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamoyl)-[1,1'-biphenyl]-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0371] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(4-(4-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-4-oxobutyl)phenethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0372] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(6-(4-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-4-oxobutyl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0373] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(5-(4-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-4-oxobutyl)thiophen-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0374] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3',5,5'-tetramethyl-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0375] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-2,2',3,3',5,5',6,6'-octamethyl-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0376] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-2,2',3,3',5,5',6,6'-octamethoxy-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0377] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3',5,5'-tetrachloro-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0378] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-2,2',3,3',5,5',6,6'-octafluoro-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0379] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3'-chloro-3-methoxy-5,5'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0380] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((6'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1':3',1":3",1"'-tetraphenyl]-4"-yl)-amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0381] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-difluoro-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0382] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dichloro-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0383] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dibromo-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0384] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(5-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-5-oxopentyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0385] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0386] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate;

[0387] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate.

[0388] In another aspect, the present disclosure relates to a method for preparing a compound of formula (I) or its stereoisomers or cis-trans isomers:

[0389] in,

[0390] R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids;

[0391] R2 is selected from hydrogen, C1-C8 hydrocarbon group;

[0392] R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 hydrocarbon group, C1-C8 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group;

[0393] R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8)m, C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides;

[0394] R5 is selected from hydrogen, C1-C8 hydrocarbon group;

[0395] R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkyleneamino (C1-C4 alkyl) 2, C1-C8 alkylenethio C1-C8 alkyl, C1-C9 alkylene-oxy-C1-C9 alkyl;

[0396] R5 and R6 can be connected to form a ring, and when R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring;

[0397] R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene;

[0398] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond;

[0399] R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C8 alkyl or aromatic alkyl group, a C1-C8 alkyleneamino C1-C8 alkylene, a C1-C8 alkylenethio C1-C8 alkylene, or a C1-C8 alkyleneoxy C1-C8 alkylene;

[0400] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond;

[0401] R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0402] R 10 One or more substituted hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0403] R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0404] R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0405] R 13 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0406] R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C18 heteroaromatic groups;

[0407] R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0408] R1, R 11 、R 12 The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine;

[0409] The preparation method comprises:

[0410] (1) reacting the compound of general formula (AI) with the compound of general formula (A-II) to obtain the compound of general formula (A-III),

[0411] Among them, R4', R9', R 10 ' represents the group and the R4, R9, R 10 The same definition as;

[0412] (2) reacting the compound of general formula (A-III) with sodium azide to obtain the compound of general formula (A-IV),

[0413] Among them, R4', R9', R 10 ' represents the group and the R4, R9, R 10 The same definition as;

[0414] (3) Compound of formula (A-IV) and 4-amino-5-hydroxy-1,3-naphthalene disulfonic acid monosodium salt

[0415] The reaction is carried out to obtain a compound of formula (AV),

[0416] Among them, R4', R9', R 10 ' represents the group and the R4, R9, R 10 The same definition as;

[0417] (4) reacting the compound of formula (BI) with carbon tetrabromide to obtain the compound of formula (B-II),

[0418] Wherein, the groups represented by R1', R2', and R3' in the general formula (BI) and the general formula (B-II) are the same as those defined for R1, R2, and R3 in the general formula (I);

[0419] (5) reacting the compound of formula (B-II) with the compound of formula (B-III) to obtain the compound of formula (B-IV)

[0420] Wherein, the groups represented by R1', R2', R3', R5', and R6' in general formula (B-II), general formula (B-III), and general formula (B-IV) are the same as those defined for R1, R2, R3, R5, and R6 in general formula (I);

[0421] (6) The compound of general formula (B-IV) is reacted under alkaline conditions to obtain the compound of general formula (BV)

[0422] Wherein, the groups represented by R1', R2', R3', R5', and R6' in the general formula (B-IV) and the general formula (BV) are the same as those defined for R1, R2, R3, R5, and R6 in the general formula (I);

[0423] (7) reacting the compound of formula (AV) with the compound of formula (BV) to obtain the compound of formula (I), or reacting the compound of formula (AV) with the compound of formula (BV) to obtain a pharmaceutically acceptable salt thereof with a corresponding acid or base.

[0424] Among them, R2', R3', R4', R5', R6', R9', R 10 ' represents the group and R2, R3, R4, R5, R6, R9, R 10 The definition is the same.

[0425] On the other hand, the present disclosure relates to compounds of general formula (I) or their stereoisomers, cis-trans isomers, which can be used to prepare drugs for treating cancer or tumors:

[0426] in,

[0427] R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids;

[0428] R2 is selected from hydrogen, C1-C8 hydrocarbon group;

[0429] R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 hydrocarbon group, C1-C8 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group;

[0430] R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8)m, C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides;

[0431] R5 is selected from hydrogen, C1-C8 hydrocarbon group;

[0432] R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkyleneamino (C1-C4 alkyl) 2, C1-C8 alkylenethio C1-C8 alkyl, C1-C9 alkylene-oxy-C1-C9 alkyl;

[0433] R5 and R6 can be connected to form a ring, and when R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring;

[0434] R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene;

[0435] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond;

[0436] R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C8 alkyl or aromatic alkyl group, a C1-C8 alkyleneamino C1-C8 alkylene, a C1-C8 alkylenethio C1-C8 alkylene, or a C1-C8 alkyleneoxy C1-C8 alkylene;

[0437] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond;

[0438] R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0439] R 10 One or more substituted hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0440] R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0441] R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0442] R 13 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0443] R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C18 heteroaromatic groups;

[0444] R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0445] R1, R 11 、R 12 The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine.

[0446] In certain embodiments, the compound represented by formula (I) and its stereoisomers can be used to prepare drugs for treating cancer or tumors, wherein the cancers include but are not limited to colorectal cancer, lung cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, bladder cancer, liver cancer, gastric cancer, intestinal cancer, head and neck cancer, uterine cancer, urothelial carcinoma, osteosarcoma, sarcoma, kidney cancer, melanoma, prostate cancer, brain glioma, neuroglioma, and leukemia.

[0447] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or its stereoisomers, cis-trans isomers and a pharmaceutically acceptable carrier:

[0448] in,

[0449] R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids;

[0450] R2 is selected from hydrogen, C1-C8 hydrocarbon group;

[0451] R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 hydrocarbon group, C1-C8 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group;

[0452] R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8)m, C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides;

[0453] R5 is selected from hydrogen, C1-C8 hydrocarbon group;

[0454] R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkyleneamino (C1-C4 alkyl) 2, C1-C8 alkylenethio C1-C8 alkyl;

[0455] R5 and R6 can be connected to form a ring. When R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring, or a C1-C9 alkylene-oxy-C1-C9 alkyl group;

[0456] R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene;

[0457] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond;

[0458] R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C8 alkyl or aromatic alkyl group, a C1-C8 alkyleneamino C1-C8 alkylene, a C1-C8 alkylenethio C1-C8 alkylene, or a C1-C8 alkyleneoxy C1-C8 alkylene;

[0459] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond;

[0460] R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0461] R 10 One or more substituted hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0462] R11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0463] R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0464] R 13 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0465] R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0466] R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0467] R1, R 11 、R 12 The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine.

[0468] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), stereoisomers, cis-trans isomers thereof, and pharmaceutically acceptable carriers, solvents, osmotic pressure regulators, pH regulators, solubilizers, cosolvents, antioxidants, bacteriostats, emulsifiers, suspending agents, fillers, complexing agents, and chelating agents:

[0469] in,

[0470] R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids;

[0471] R2 is selected from hydrogen, C1-C8 hydrocarbon group;

[0472] R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 hydrocarbon group, C1-C8 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group;

[0473] R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8)m, C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides;

[0474] R5 is selected from hydrogen, C1-C8 hydrocarbon group;

[0475] R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkyleneamino (C1-C4 alkyl) 2, C1-C8 alkylenethio C1-C8 alkyl;

[0476] R5 and R6 can be connected to form a ring. When R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring, or a C1-C9 alkylene-oxy-C1-C9 alkyl group;

[0477] R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene;

[0478] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond;

[0479] R8 is selected from carbonylamino, wherein the amino group may be substituted simultaneously or separately by C1-C8 hydrocarbon or aromatic hydrocarbon groups, C1-C8 alkyleneamino C1-C8 alkylene, C1-C8 alkylenethio C1-C8 alkylene, C1-C8 alkyleneoxy C1-C8 alkylene;

[0480] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond;

[0481] R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0482] R 10 One or more substituted hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0483] R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0484] R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0485] R13 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0486] R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0487] R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0488] R1, R 11 、R 12 The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine.

[0489] In another aspect, the present disclosure relates to a method for treating a tumor or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof, or administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof, wherein the cancer includes but is not limited to colorectal cancer, lung cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, bladder cancer, liver cancer, gastric cancer, intestinal cancer, head and neck cancer, uterine cancer, urothelial carcinoma, osteosarcoma, sarcoma, renal cancer, melanoma, prostate cancer, glioma, neuroglioma, leukemia:

[0490] in,

[0491] R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids;

[0492] R2 is selected from hydrogen, C1-C8 hydrocarbon group;

[0493] R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 hydrocarbon group, C1-C8 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group;

[0494] R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8)m, C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides;

[0495] R5 is selected from hydrogen, C1-C8 hydrocarbon group;

[0496] R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkyleneamino(C1-C4 alkyl)2, C1-C8 alkylenethioC1-C8 alkyl, C1-C9 alkylene-oxy-C1-C9 alkyl;

[0497] R5 and R6 can be connected to form a ring, and when R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring;

[0498] R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene;

[0499] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond;

[0500] R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C8 alkyl or aromatic alkyl group, a C1-C8 alkyleneamino C1-C8 alkylene, a C1-C8 alkylenethio C1-C8 alkylene, or a C1-C8 alkyleneoxy C1-C8 alkylene;

[0501] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond;

[0502] R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12aromatic groups;

[0503] R 10 One or more substituted hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups;

[0504] R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0505] R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids;

[0506] R 13 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0507] R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0508] R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups;

[0509] R1, R 11 、R 12The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine.

[0510] In certain embodiments, a method of treating a tumor or cancer comprises administering 10 mg to 5 g of a compound of the present disclosure, its stereoisomers, cis-trans isomers, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0511] In certain embodiments, a method of treating a tumor or cancer comprises administering 10 mg to 3000 mg of a compound of the present disclosure, its stereoisomers, cis-trans isomers, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0512] In certain embodiments, a method of treating a tumor or cancer comprises administering 50 mg to 2000 mg of a compound of the present disclosure, its stereoisomers, cis-trans isomers, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0513] In certain embodiments, a method of treating a tumor or cancer comprises administering 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg or 2000 mg of a compound of the present disclosure, a stereoisomer, a cis-trans isomer, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0514] Pharmaceutical composition

[0515] In certain embodiments, a pharmaceutical composition comprises a compound of the present disclosure, a stereoisomer, a cis-trans isomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0516] In certain embodiments, the compound of the present disclosure, its stereoisomers, cis-trans isomers, or pharmaceutically acceptable salts thereof, when administered to a mammal for treating tumors or cancer, may be administered by injection.

[0517] The compounds described herein can be obtained in any suitable form, such as an injectable formulation. Illustrative examples of injectable formulations include, but are not limited to, injectable solutions, sterile powders for injection, and concentrated solutions for injection. Injectable solutions include solutions, emulsions (such as fat emulsion injections), or suspensions (such as some liposome injections and cortisone acetate injections), and can be used for intramuscular injection, intravenous injection, intravenous drip, etc. Large-volume injections (generally not less than 100 ml unless otherwise specified) for intravenous injection are also called intravenous infusions. Ampoules are commonly known as small injections, which are different from large infusions. Sterile powders for injection include lyophilized powder injections and sterile subpackages. Concentrated solutions for injection are sterile concentrated solutions that are diluted before use. Examples of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, any adjuvants, carriers, carrier substances, solvents, osmotic pressure regulators, pH regulators, solubilizers, cosolvents, antioxidants, antibacterial agents, 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), which is incorporated herein by reference in its entirety.

[0518] The pharmaceutical compositions of the present disclosure may be administered by any method that achieves its intended purpose. The pharmaceutical compositions of the present disclosure may 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, as well as on any concurrent treatment, the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.

[0519] Suitable dosage forms include, but are not limited to, injections, sterile powders for injection, and concentrated solutions for injection. Injections include solutions, emulsions (such as fat emulsion injections), or suspensions (such as some liposome injections and cortisone acetate injections), and can be used for intramuscular injection, intravenous injection, intravenous drip, etc. Injections for intravenous injection include intravenous infusions and small water injections. Sterile powders for injection include lyophilized powder injections and sterile packaging. Concentrated solutions for injection are sterile concentrated solutions that are diluted before use. They can be prepared according to methods known in the art.

[0520] The pharmaceutical composition may contain suitable carrier substances, 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.

[0521] 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 depot injections, osmotic pumps, pills, transdermal (including electromigration) patches, etc., at a predetermined rate.

[0522] The pharmaceutical compositions of the present disclosure can be produced according to known methods, for example, by conventional mixing, preparation, filtration, filling, sterilization and other operation methods.

[0523] 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 useful preparation. Suitable formulations depend on the selected route of administration. Any known techniques, carriers, and excipients can be used as is suitable and understood in the art.

[0524] 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.

[0525] In certain embodiments, the pharmaceutical compositions of the present disclosure may contain 0.1%-95% of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0526] In certain embodiments, the pharmaceutical compositions of the present disclosure may comprise 1%-70% of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0527] In any case, the composition or formulation to be administered will contain an amount of a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0528] In any case, the administration contains a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the disease / condition of the subject being treated.

[0529] Dosage

[0530] At least one compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, can be administered to a patient by any method suitable for systemic and / or local delivery of a compound of the present disclosure, a stereoisomer thereof, or a 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.

[0531] 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.

[0532] 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.

[0533] 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.

[0534] 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 certain 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.

[0535] 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 certain 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.

[0536] 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.

[0537] Although the exact dosage can be determined based on a drug-by-drug analysis, in most cases, it is possible to make certain generalizations 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 certain 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 certain 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 certain embodiments, the composition is administered 1 to 4 times daily. Alternatively, the composition described in the present disclosure can be administered by continuous intravenous infusion, in certain embodiments administered at a dosage of up to 2000 mg of each active ingredient per day. As will be appreciated by those skilled in the art, in some cases, 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 certain embodiments, the compounds are administered over a continuous treatment period, such as one or several weeks, or several months or years.

[0538] 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.

[0539] 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 certain embodiments 30-90% of the time, and in certain embodiments 50-90% of the time.

[0540] In cases of local administration or selective uptake, the effective local concentration of the drug is independent of plasma concentration.

[0541] 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.

[0542] The efficacy and toxicity of the compounds described herein 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 certain embodiments, human cell lines. The results of such studies are generally predictive of 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 selecting 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.

[0543] 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 carry instructions for administration. The package or dispensing device can also carry notes associated with the container, which are prescribed 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 notes, for example, can be a label approved for prescription drugs by the State Food and Drug Administration or the U.S. Food and Drug Administration, or an approved product instruction sheet. Compositions comprising a compound of the present disclosure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, can also be prepared in a suitable container and placed in a compatible pharmaceutical carrier and labeled for use in the treatment of a specified disease state.

[0544] 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 certain embodiments of the present application.

[0545] Example

[0546] Abbreviations: aq: aqueous solution ml: milliliter g: gram V: volume / weight eq: equivalent ratio L: liter M: mole / liter mg: milligram μl: microliter EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 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 CuSO4: anhydrous copper sulfate HCl: hydrochloric acid NaOH: sodium hydroxide CBr4: carbon tetrabromide AcOH: glacial ethyl acetate AcidAr: Argon NaN3: Sodium azide NaCl: Sodium chloride AlCl3: Aluminum chloride K2CO3: Potassium carbonate Na2SO4: Sodium sulfate CHCl3: Chloroform NaBH4: Sodium borohydride IPA: Isopropyl alcohol TFA: Trifluoroacetic acid MTBE: Methyl tert-butyl ether HATU: 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate NH4Cl: Ammonium chloride MeONa: Sodium methoxide Ag2O: Silver oxide Boc2O: Di-tert-butyl dicarbonate CDCl3: Deuterated chloroform HPLC: High performance liquid chromatography TLC: Thin layer chromatography DMF: N,N-dimethylformamide EDTA: Ethylenediaminetetraacetic acid mM: mmol / L mm 3 : cubic centimeters 1 HNMR: Nuclear Magnetic Resonance Spectroscopy

[0547] Example 1

[0548] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-6-bromohexanamide

[0549] Add 2.177g of o-toluidine, 2.359g of EDCI, 1.663g of HOBt, and 1.590g of DIEA to 60ml of DCM. Stir under argon until completely dissolved, then cool to 0-5°C. Dissolve 2g of 6-bromohexanoic acid in 40ml of DCM and add dropwise to the reaction system at 0-5°C. After the addition is complete, allow the reaction to proceed overnight at room temperature. Add 20ml of saturated aqueous sodium bicarbonate solution to the system, stir, and filter. Add DCM to the filter cake, stir, filter, and retain the filtrate. Repeat this three times. Combine the DCM phases, dry, filter, and purify by column chromatography after drying. Concentrate to yield 2.047g of the product. MS (m / e): 389.20 [M+H] + .

[0550] Example 2

[0551] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-6-azidohexanamide

[0552] 0.73 g of the compound from Example 1 was added to a reaction flask, followed by 5.1 ml of DMSO and stirring at room temperature until completely dissolved. 0.15 g of NaN3 was added to obtain an orange-red suspension, which was stirred at room temperature overnight. DCM (20 ml) and water (20 ml) were added, and the mixture was extracted and separated. The DCM phase was retained, and the aqueous phase was extracted with DCM (20 ml) and separated. The combined DCM phases were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 0.28 g of the product. MS (m / e): 352.24 [M+H] + .

[0553] Example 3

[0554] Disodium (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0555] Step 1: Add 4 ml of acetonitrile to 0.25 g of the compound from Example 2, cool in an ice-salt bath, and stir under argon to dissolve completely. Cool in an ice-salt bath to 0-5°C, then add dropwise HCl solution (0.18 ml of 12 mol / L hydrochloric acid dissolved in 6 ml of deionized water). Stir for 5 minutes after the addition is complete, then add dropwise sodium nitrite solution (0.1 g of sodium nitrite dissolved in 300 ml of deionized water) for 2-20 minutes. Stir for 30 minutes after the addition is complete.

[0556] Step 2: Add 0.24g of 4-amino-5-hydroxy-1,3-naphthalenedisulfonic acid monosodium salt to a reaction flask, add 5ml of deionized water, cool in an ice-salt bath, and stir under Argon protection to dissolve completely. Cool in an ice-salt bath to 0-5°C, then add sodium bicarbonate solution (0.24g of sodium bicarbonate dissolved in 5ml of deionized water) dropwise for 20 minutes.

[0557] Maintain an ice-salt bath at 0-5°C and slowly add the reaction solution from step 1 to the reaction solution from step 2. Stir in an ice-salt bath for 3 hours. Add 19 mL of 20% NaCl aqueous solution and stir at room temperature overnight. Centrifuge the reaction solution to obtain approximately 1.2 g of a purple solid. Dissolve the solid with H2O:ACN = 10:1 (13.2 mL total) and stir at room temperature overnight. Centrifuge the reaction solution and collect the crude purple solution. Purify the product by medium pressure preparation. Reduce the acetonitrile in the preparation solution and lyophilize to obtain 0.41 g of the product. 1HNMR (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).

[0558] Example 4

[0559] (2S,3R,4S,5S,6S)-2-(4-(bromomethyl)-3-(prop-2-ynyloxy)phenoxy

[0560] 6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0561] 1g (2S,3R,4S,5S,6S)-2-(4-(hydroxymethyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate (prepared according to PCT Int. Appl., 2012153193, 15 Nov 2012) and 1.6g carbon tetrabromide were added to 7mL of DCM and stirred until dissolved. The reaction system was cooled to 6-8°C with stirring in an ice-salt bath. 0.8g of triphenylphosphine was weighed and added portionwise to the reaction flask. The system was stirred in an ice-salt bath for 5 minutes, and the temperature was allowed to cool to approximately 10°C. The ice-salt bath was removed, and the temperature was naturally raised to room temperature with stirring for 2 hours. Silica gel was added directly to the reaction solution, and the sample was mixed. Column chromatography yielded 0.74g of the product.

[0562] 1 HNMR (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). MS (m / e): 579.65 [M+Na]+ .

[0563] Example 5

[0564] (2S,3R,4S,5S,6S)-2-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0565] At room temperature, 0.74 g of (2S,3R,4S,5S,6S)-2-(4-(bromomethyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate and 43.3 g of (S)-4,11-diethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione were placed in a reaction flask, protected from light, and dissolved in 600 mL of DMF. The mixture was cooled in an ice-salt bath and stirred for 2 minutes. 0.04 g of sodium hydride was slowly added in portions under argon protection and stirred for 1 minute. The ice-salt bath was removed, and the solution became clear after 20 minutes. Stir at room temperature for 1 hour. 0.06 mL of AcOH was added to the reaction solution and stirred for 1 minute. Dried DMF was mixed with silica gel and column chromatography was performed to obtain 1.2 g of the product. 12 ml of EA was added, sonicated, and stirred at room temperature for 16 hours. Filtered with suction and washed with EA to obtain 0.73 g of the product. HPLC purity was 96.5%. 1 HNMR (DMSO-d6, 400MHz) δ: 8.076~8.053 (d, 1H), 7.561~7.468 (m, 3H), 7.264 (s, 1H), 6.803 (s, 1H), 6.710~6.689 (d, 1H), 6.492 (s, 1H), 5.731~5.7 11(d, 1H), 5.494~5.446(t, 1H), 5.423(s, 2H), 5.286(s, 2H), 5.234(s, 2H), 5.136~5.050(m, 2H), 4.925(s, 2H), 4.732~4.707(d, 1H), 3.634(s, 3H), 3.586(s, 1H), 3.178~3.160(d, 2H), 2.028(s, 3 H), 2.010(s, 3H), 2.000(s, 3H), 1.883~1.845(m, 2H), 1.297~1.260(t, 3H), 0.895~0.859(t, 3H). MS(m / e):869.98[M+H] + .

[0566] Example 6

[0567] (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0568] At room temperature, 0.72 g of (2S,3R,4S,5S,6S)-2-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate was placed in a reaction flask. 7.2 ml of THF was added and stirred. The mixture was cooled in an ice-cold ethanol bath and stirred for ~30 minutes. 0.2 g of sodium hydroxide was dissolved in 7.2 ml of deionized water and added dropwise until the sample gradually dissolved. The ice-cold ethanol was removed, and the mixture was returned to room temperature and stirred for 1 hour. The ice-cold ethanol was cooled for ~10 minutes, and 5 ml of 1N HCl was added dropwise over ~20 minutes. The THF was then removed. The product was filtered under reduced pressure with a water pump and 0.57 g was obtained by column chromatography.

[0569] 1HNMR (DMSO-d6, 400MHz) δ: 8.050~8.035 (d, 1H), 7.560 (s, 1H), 7.519~7.503 (d, 1H), 7.423 ~7.409(d, 1H), 7.257(s, 1H), 6.863(s, 1H), 6.720~6.707(d, 1H), 6.495(s, 1H), 5.417~5.2 14(m, 9H), 4.997~4.985(d, 1H), 4.893(s, 2H), 3.686(s, 1H), 3.585(s, 1H), 3.310~3.256(m , 3H), 3.164-3.153(d, 2H), 1.905~1.833(m, 2H), 1.301~1.276(t, 3H), 0.890~0.865(t, 3H). MS(m / e):729.74[M+H] + .

[0570] Example 7

[0571] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0572] At room temperature, 0.54 g of the compound from Example 6 and 0.5 g of (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt were placed in a reaction flask. Protected from light, the mixture was dissolved and stirred in 11 ml of THF. 0.02 g of CuSO₄ was then dissolved in 0.3 ml of deionized water, and 0.06 g of VCNa was dissolved in 0.3 ml of deionized water. These were added sequentially to the system, followed by 10 ml of deionized water. Under argon, the mixture was stirred at room temperature for 1 hour. Filtered to obtain a purple filtrate. The solution was concentrated at 38°C to remove the THF. After concentration, the solution was filled with water to 10 ml and stirred for 5-10 minutes. 4 ml of 20% aqueous NaCl solution was added to make the crude product a 5% aqueous NaCl solution. The solution was stirred at room temperature overnight for salting out. The reaction solution was centrifuged to separate the solids, which were then dissolved in 210 ml of deionized water and mechanically stirred at room temperature in the dark for 1 hour. 4 ml of a 20% NaCl aqueous solution was added to convert the crude product to a 3% NaCl aqueous solution, which was stirred at room temperature overnight for salting out. The reaction solution was centrifuged to separate the solids, which were then dissolved in 15 ml of deionized water and stirred at room temperature overnight. The purple filtrate was filtered and purified by medium pressure preparative purification. The acetonitrile in the preparative solution was reduced, lyophilized, and pulverized to yield 0.73 g of the product. 1HNMR (DMSO-d6, 400MHz) δ: 15.907 (s, 1H), 9.638 (s, 1H), 9.378 (s, 1H), 8.413 (s, 1H), 8.281 (s, 1H), 8.029~8.013 (d, 1H), 7.984~7.97 0(d, 1H), 7.816~7.804(d, 1H), 7.580(s, 2H), 7.493~7.432(m, 5H), 7.372~7.358(d, 1H), 7.243(s, 1H), 7.033(s, 1H), 6.979~6.963(d, 1 H), 6.681~6.668(d, 1H), 6.506(s, 1H), 5.424~5.184(m, 10H), 4.980~4.970(d, 1H), 4.348(s, 2H), 3.623(s, 1H), 3.337~3.247(m, 3H), 3 .073(s, 2H), 2.455(s, 3H), 2.315(s, 2H), 2.211(s, 3H), 1.821~1.810(m, 4H), 1.578(s, 2H), 1.233~1.223(m, 5H), 0.884~0.860(t, 3H).

[0573] Example 8

[0574] (2S,3R,4S,5S,6S)-2-(4-Formyl-3-hydroxy-2-methylphenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0575] 1.686g of 2,4-hydroxy-3-methylbenzaldehyde, 4g of (2S,3R,4S,5S,6S)-2-bromo-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate, 1.292g of silver oxide, and 1.6g of 4A molecular sieves were added sequentially to a reaction flask. 80ml of acetonitrile was added, and the mixture was stirred at room temperature in the dark for 1 hour under argon protection. Filtered with suction, padded with celite, and the filter cake was rinsed with dichloromethane. The filtrate was dried. Purification by column chromatography afforded 2.935g of the product. MS (m / e): 491.11 [M+Na] + . 1HNMR (DMSO-d6, 600MHz) δ: 11.348 (s, 1H), 9.895 (s, 1H), 7.674~7.660 (d, 1H), 6.806~6.792 (d, 1H), 5.772~5.759 (d, 1H), 5.531~ 5.499(t, 1H), 5.222~5.193(dd, 1H), 5.120~5.087(t, 1H), 4.796~4.779(d, 1H), 3.649(s, 3H), 2.034~2.020(t, 9H), 1.950(s, 3H).

[0576] Example 9

[0577] (2S,3R,4S,5S,6S)-2-(4-Formyl-2-methyl-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0578] 2.83 g of (2S,3R,4S,5S,6S)-2-(4-formyl-3-hydroxy-2-methylphenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate was weighed and added to 28 ml of dry DMF, and stirred at room temperature until completely dissolved. 2.505 g of potassium carbonate and 1.078 g of propargyl bromide were then slowly added to the reaction system in batches. The reaction was allowed to proceed at room temperature for 4 hours. The system was extracted with ethyl acetate, and the organic phase was washed twice with saturated ammonium chloride solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was filtered to dryness. 2.588 g of the product was purified by column chromatography. MS (m / e): 507.15 [M+H] +. 1HNMR (DMSO-d6, 600MHz) δ: 10.183 (s, 1H), 7.691~7.677 (d, 1H), 7.066~7.051 (d, 1H), 5.782~5.769 (d, 1H), 5.528~5.496 (t, 1H), 5.225~5.1 96(dd, 1H), 5.120~5.087(t, 1H), 4.795~4.779(m, 3H), 3.660~3.652(t , 1H), 3.611(s, 3H), 2.060(s, 3H), 2.047(s, 3H), 2.027~2.021(d, 6H).

[0579] Example 10

[0580] (2S,3R,4S,5S,6S)-2-(4-Hydroxymethyl)-2-methyl-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0581] Weigh 2.367 g of (2S,3R,4S,5S,6S)-2-(4-formyl-2-methyl-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate, add 23.7 ml of chloroform, and stir until completely dissolved. Cool to 0-5°C in an ice-salt bath, then add 11.835 g of silica gel and 4.7 ml of isopropanol. Weigh 442 mg of sodium borohydride and add in batches. Maintain the reaction at 0-5°C for 1 hour. Quench the reaction by adding 1 ml of glacial acetic acid, filter, pad with celite, rinse the filter cake with dichloromethane, and reduce the filtrate to dryness. Purify by column chromatography to yield 2.038 g of the product. MS (m / e): 531.20 [M+Na] + . 1HNMR (DMSO-d6, 600MHz) δ: 7.223~7.209 (d, 1H), 6.868~6.854 (d, 1H), 5.556~5 .543(d, 1H), 5.504~5.472(t, 1H), 5.159~5.130(dd, 1H), 5.091~5.058(t, 1H), 5.027~5.009(t, 1H), 4.727~4.711(d, 1H), 4.569~4.565(d, 2H), 4.501~4.491( d, 2H), 3.652 (s, 3H), 3.571~5.562 (t, 1H), 2.040 (s, 3H), 2.025~2.010 (t, 9H).

[0582] Example 11

[0583] (2S,3R,4S,5S,6S)-2-(4-(Bromomethyl)-2-methyl-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0584] Using the synthesis method of Example 4, 1.99 g of product was synthesized from (2S,3R,4S,5S,6S)-2-(4-hydroxymethyl)-2-methyl-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate. 1HNMR (DMSO-d6, 600MHz) δ: 7.248~7.234 (d, 1H), 6.839~6.825 (d, 1H), 5.375~5.359 (m, 3H), 5.141~5.129 (dd, 1H), 4.676~4.6 59 (m, 3H), 4.614~4.596 (d, 1H), 4.216~4.201 (dd, 1H), 3.756 (s, 3H), 2.585-2.577 (t, 1H), 2.163 (s, 3H), 2.088~2.070 (t, 9H).

[0585] Example 12

[0586] (2S,3R,4S,5S,6S)-2-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0587] Using the synthesis method of Example 5, (2S, 3R, 4S, 5S, 6S) -2- (4- (bromomethyl) -2-methyl-3- (prop-2-ynyloxy) phenoxy) -6- (methoxycarbonyl) tetrahydro -2H- pyran -3,4,5- triacetate and compound (S) -4,11- diethyl -4,9- dihydroxy -1,12- dihydro -14H- pyrano [3 ',4 ':6,7] indolizino [1,2-b] quinoline -3,14 (4H) - dione were prepared. The product (2S,3R,4S,5S,6S)-2-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate was obtained. MS (m / e): 883.49 [M+H]+ .

[0588] 1HNMR (DMSO-d6, 600MHz) δ: 8.086~8.071 (d, 1H), 7.603-7.598 (d, 1H), 7.541~7.521 (dd, 1H), 7.421~7.406 (d, 1H), 7.272 (s, 1H), 6 .937-6.923(d,1H),6.502(s,1H),5.610-5.597(d,1H),5.507-5.460(t,1H),5.432(s,2H),5.350-5.323(d,2H),5.297(s,2H),5.1 79-5.150(q, 1H), 5.097~5.059(t, 1H), 4.745-4.734(d, 1H), 4.700-4.696(d, 2H), 3.652-3.635(s, 3H), 3.609~3.601(t, 1H), 3.196 -3.159(dd, 2H), 2.086(s, 3H), 2.039(s, 3H), 2.013~2.011(d, 6H), 1.915-1.829(m, 2H), 1.294~1.268(t, 3H), 0.896-0.872(t, 3H).

[0589] Example 13

[0590] (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0591] Using the synthesis method of Example 6, 1.5 g of product was synthesized from (2S,3R,4S,5S,6S)-2-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate. MS (m / e): 743.38 [M+H] +. 1HNMR (DMSO-d6, 600MHz) δ: 8.064~8.049 (d, 1H), 7.608 (s, 1H), 7.524~7.509 (d, 1H), 7.344~7.330 ( d, 1H), 7.265 (s, 1H), 6.969-6.955 (d, 1H), 6.497 (s, 1H), 5.454~5.398 (t, 2H), 5.320-5.275 (m, 6H), 5.134(s, 1H), 4.884-4.875(d, 1H), 4.680-4.677(d, 2H), 3.591-3.583(t, 2H), 3.345~3.291(d, 3H), 3.179-3.167(d, 2H), 2.209(s, 3H), 1.913-1.830(m, 2H), 1.315~1.290(t, 3H), 0.897-0.873(t, 3H).

[0592] Example 14

[0593] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)2-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0594] Using the synthetic method of Example 7, 248 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(prop-2-ynyloxy)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. MS (m / e): 1424.70 [M-3Na+4H] + .

[0595] 1HNMR (DMSO-d6, 600MHz) δ: 15.915 (s, 1H), 9.253 (s, 1H), 8.370 (s, 1H), 8.186 ( s, 1H), 8.063-8.032 (t, 2H), 7.887~7.872 (d, 1H), 7.629~7.619 (d, 3H), 7.535- 7.504(m, 2H), 7.469(s, 2H), 7.331~7.317(d, 1H), 7.268(s, 1H), 7.008-6.956( dd, 2H), 6.483 (s, 1H), 5.419~5.414 (d, 2H), 5.292 (s, 2H), 5.253-5.180 (m, 3H) ,5.055-5.016(q,2H),4.979(s,1H),4.817-4.805(d,1H),4.342~4.319(t,2H) ,3.402-3.385(d,1H),3.271-3.255(m,2H),3.171~3.148(t,3H),2.511-2.502 (m, 3H), 2.311-2.288 (t, 2H), 2.243-2.235 (d, 6H), 1.893~1.823 (m, 2H), 1.811 -1.772(m, 2H), 1.588~1.564(m, 2H), 1.264-1.251(m, 5H), 0.885~0.860(t, 3H).

[0596] Example 15

[0597] Disodium 4-amino-6-((E)-(4'-(6-(4-((3-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-6-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methylphenyloxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0598] At room temperature, dissolve 49 mg of the compound from Example 14 in 1 ml of deionized water. Add 0.33 ml of 0.1 M hydrochloric acid with stirring, and stir at room temperature for 1 hour. Purify the purple reaction solution by pressure preparative pressure, deplete the acetonitrile, and lyophilize to obtain 10 mg of the product. MS (m / e): 1424.53 [M-2Na+3H] + .

[0599] Example 16

[0600] (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid methyl ester

[0601] Using the synthetic method of Example 20, 126 mg of the product was obtained from (2S, 3R, 4S, 5S, 6S)-2-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate. MS (m / e): 757.58 [M+H] + .

[0602] Example 17

[0603] Disodium 4-amino-6-((E)-(4'-(6-(4-((6-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0604] Using the synthesis method of Example 7, 24 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid methyl ester 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. MS (m / e): 1438.57 [M-2Na+3H] + .

[0605] Example 18

[0606] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0607] Using the synthetic method of Example 7, 135 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid and (E)-4-amino-6-((4'-(6-azidohexanamide)-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. MS (m / e): 1397.04 [M-3Na+4H] +. 1H NMR (DMSO-d6, 600 MHz) δ: 15.644 (s, 1H), 10.036 (s, 1H), 8.353 (s, 1H), 8.150 (s, 1H), 8.061 - 8.046 (d, 1H), 8.009 - 7.992 (d, 1H), 7.719 - 7.705 (d, 2H), 7.669 - 7.649 (dd, 4H), 7.626 - 7.611 (d, 3H), 7.514 - 7.495 (d, 1H), 7.286 - 7.262 (t, 2H), 6.960 - 6.928 (t, 2H), 6.472 (s, 1H), 5.438 - 5.378 (q, 2H), 5.296 (s, 2H), 5.230 - 5.211 (d, 2H), 5.161 - 5.142 (d, 1H), 5.052 - 5.002 (q, 2H), 4.969 - 4.963 (d, 1H), 4.808 (d, 1H), 4.332 - 4.309 (t, 2H), 3.403 - 3.388 (d, 1H), 3.259 (s, 2H), 3.166 - 3.154 (d, 3H), 2.270 - 2.246 (t, 2H), 2.211 (s, 3H), 1.874 - 1.797 (m, 2H), 1.775 - 1.727 (m, 2H), 1.555 - 1.531 (m, 2H), 1.282 - 1.256 (t, 3H), 1.192 (m, 2H), 0.878 - 0.853 (t, 3H).

[0608] Example 19

[0609] Disodium 4-amino-6-((E)-(4'-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid was obtained by the preparation method of Example 15. Trisodium 2-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate gave 15 mg of the product. MS (m / e): 1410.57 [M-2Na+3H] + .

[0610] Example 20

[0611] (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid methyl ester

[0612] At room temperature, 1 g of (2S,3R,4S,5S,6S)-2-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate was dissolved in 120 ml of methanol and 120 ml of tetrahydrofuran. 180 mg of sodium methoxide was then added and stirred at room temperature for 1 hour. Five drops of glacial acetic acid were added to the reaction mixture, which was then rotary evaporated to dryness. The sample was dissolved in methanol and purified by column chromatography to yield 670 mg of the product. MS (m / e): 743.34 [M+H] + . 1HNMR (DMSO-d6, 600MHz) δ: 8.083~8.068(d, 1H), 7.586~7.584(d, 1H), 7.545~7.525(dd, 1H), 7.443~7.429(d, 1H), 7.276( s, 1H), 6.843~6.839(d, 1H), 6.725~6.707(dd, 1H), 6.482(s, 1H), 5.495~5.487(d, 1H), 5.430~5.421(d, 3H), 5.301(s, 2H), 5.281~5.272(d,1H),5.235(s,2H),5.170~5.158(d,1H),4.918~4.914(d,2H),4.091~4.068(dd,1H),3.661(s,3H),3.572 ~3.564(t, 1H), 3.437~3.305(m, 3H), 3.190~3.165(d, 2H), 1.915~1.832(m, 2H), 1.310~1.284(t, 3H), 0.899~0.848(m, 3H).

[0613] Example 21

[0614] Disodium 4-amino-6-((E)-(4'-(6-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0615] Using the synthetic method of Example 7, 223 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid methyl ester 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. MS (m / e): 1424.91 [M-2Na+3H] + .

[0616] 1HNMR (DMSO-d6, 600MHz) δ: 15.945 (s, 1H), 9.217 (s, 1H), 8.368 (s, 1H), 8.182 (s, 1H) ), 8.065~8.050(d, 1H), 8.040~8.024(d, 1H), 7.881~7.866(d, 1H), 7.625~7.616(d, 2 H), 7.533(s, 3H), 7.465(s, 2H), 7.413~7.398(d, 1H), 7.264(s, 1H), 7.005~6.978(m, 2H), 6.688~6.670(dd, 1H), 6.504(s, 1H), 5.533~5.525(d, 1H), 5.474~5.465(d, 1H), 5.415(s, 2H), 5.329~5.320(d, 1H), 5.292~5.272(t, 3H), 5.225~5.195(t, 4H), 4.35 4~4.330(t, 2H), 4.132~4.116(d, 1H), 3.654(s, 3H), 3.438~3.398(m, 1H), 3.328(s, 2 H), 3.139~3.127(dd, 2H), 2.514~2.505(s, 3H), 2.306~2.284(t, 2H), 2.226(s, 3H), 1 .876~1.792(m, 4H), 1.593~1.569(m, 2H), 1.266~1.219(m, 5H), 0.883~0.858(t, 3H).

[0617] Example 22

[0618] (2S,3R,4S,5S,6S)-2-(4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate

[0619] Using the synthetic method of Example 5, 700 mg of the product was obtained from (2S,3R,4S,5S,6S)-2-(4-(bromomethyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate and (S)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione. MS (m / e): 841.88 [M+H] + .

[0620] Example 23

[0621] (2S,3S,4S,5R,6S)-6-(4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0622] Using the synthetic method of Example 6, 220 mg of the product was synthesized from (2S,3R,4S,5S,6S)-2-(4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate. MS (m / e): 701.51 [M+H] +. 1HNMR (DMSO-d6, 600MHz) δ: 8.551 (s, 1H), 8.075~8.059 (d, 1H), 7.633 (s, 1H), 7.554~7.5 38(d,1H),7.418~7.404(d,1H),7.297(s,1H),6.891(s,1H),6.730-6.717(d,1H),5.450~ 5.394(t,2H),5.273(s,2H),5.182(s,2H),4.889(s,3H),3.596(s,1H),3.446-3.430(d,1 H), 3.296~3.227(m, 2H), 3.185-3.154(t, 1H), 1.917-1.822(m, 2H), 0.802-0.878(t, 3H).

[0623] Example 24

[0624] Trisodium (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-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0625] Using the synthetic method of Example 7, 68 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)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. MS (m / e): 1380.59 [M-3Na+2H] -1HNMR (DMSO-d6, 600MHz) δ: 15.956 (s, 1H), 9.529 (s, 1H), 8.526 (s, 1H), 8.371-8.357 (d, 2 H), 8.062~8.027(t, 2H), 7.889~7.871(d, 1H), 7.631(s, 2H), 7.583~7.57 9(d, 1H), 7.531~7.513(dd, 2H), 7.480~7.446(t, 2H), 7.368~7.355(d, 1H) ), 7.239(s, 1H), 7.041(s, 1H), 7.011~6.991(d, 1H), 6.646(s, 1H), 6.501( s, 1H), 5.441 ~ 5.385 (t, 2H), 5.343 ~ 5.322 (d, 1H), 5.262 (s, 4H), 5.142 (t , 2H), 5.038 (d, 1H), 4.962 (s, 1H), 4.375~4.367 (d, 2H), 3.582 (s, 1H), 3.2 95~3.189(m,3H),2.511~2.502(m,3H),2.352(t,2H),2.234(s,3H),1.89 6~1.815(m, 4H), 1.606(s, 2H), 1.281~1.260(t, 2H), 0.891~0.867(t, 3H).

[0626] Example 25

[0627] 4-amino-6-((E)-(4'-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl

[0628] -[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt

[0629] Using the synthetic method of Example 15, 12 mg of the product was obtained from trisodium (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-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate. MS (m / e): 1382.44 [M-2Na+3H] + .

[0630] Example 26

[0631] (2S,3S,4S,5R,6S)-6-(4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid methyl ester

[0632] Using the synthetic method of Example 20, 108 mg of the product was obtained from (2S,3R,4S,5S,6S)-2-(4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triacetate. MS (m / e): 715.23 [M+H]. + .

[0633] Example 27

[0634] Disodium 4-amino-6-((E)-(4'-(6-(4-((2-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0635] Using the synthetic method of Example 7, 19 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid methyl ester 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. MS (m / e): 1396.37 [M-2Na+3H] + .

[0636] Example 28

[0637] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0638] Using the synthetic method of Example 7, 7 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-methoxy-5-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid and (E)-4-amino-6-((4'-(6-azidohexanamide)-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. MS (m / e): 1412.11 [M-3Na+4H] + .

[0639] Example 29

[0640] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0641] Using the synthetic method of Example 7, 82 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid and (E)-4-amino-6-((4'-(6-azidohexanamide)-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. MS (m / e): 1354.57 [M-3Na+4H] + .

[0642] Example 30

[0643] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0644] Using the synthetic method of Example 7, 5 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-methoxy-5-(prop-2-ynyloxy)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. MS (m / e): 1440.2 [M-3Na+4H]+.

[0645] Example 31

[0646] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0647] Using the synthetic method of Example 7, 82 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid and (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. MS (m / e): 1414.80 [M-3Na+4H]+.

[0648] Example 32

[0649] Disodium 4-amino-6-((E)-(4'-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0650] Using the synthetic method of Example 15, 15 mg of the product was obtained from trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate. MS (m / e): 1414.56 [M-2Na+3H] + .

[0651] Example 33

[0652] Disodium 4-amino-6-((E)-(4'-(6-(4-((2-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0653] Using the synthetic method of Example 7, 11 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid methyl ester and (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. MS (m / e): 1428.33 [M-2Na+3H] + .

[0654] Example 34

[0655] Trisodium (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-((((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0656] Using the synthetic method of Example 7, 5 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)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. MS (m / e): 1439.21 [M-3Na+4H] + .

[0657] Example 35

[0658] tert-Butyl (4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate

[0659]

[0660] Weigh 5g of 3,3'-dimethyl-[1,1'-biphenyl]-4,4'-diamine and add it to 75ml of 1,4-dioxane under argon, stirring at room temperature. Weigh 5.14g of BoC2O, dilute it with 25ml of 1,4-dioxane, and add it dropwise to the reaction mixture. Stir overnight at room temperature. Reduce to dryness and purify by column chromatography to obtain 4.485g of the product.

[0661] Example 36

[0662] tert-Butyl (4'-(8-bromooctanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate

[0663] Weigh 2.4 g of tert-butyl (4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate and 2 g of 8-bromooctanoic acid and dissolve them in 40 ml of dichloromethane. Then, add 2.1 g of EDCI, 1 g of HOBT, and dropwise add 1.3 ml of DIEA. Stir overnight at room temperature under argon. Pump dry and purify by column chromatography to yield 1.247 g of the product. MS (m / e): 517.25 [M+H]. + .

[0664] Example 37

[0665] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-8-bromooctanamide

[0666] Weigh 1.147 g of tert-butyl (4'-(8-bromooctanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate, dissolve in 14 ml of dichloromethane, add 1.4 ml of trifluoroacetic acid dropwise, and react at room temperature for 2 hours. Dried to dryness, and purify by column chromatography to obtain 1.159 g of the product. MS (m / e): 417.24 [M+H] + .

[0667] Example 38

[0668] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-8-azidooctanamide

[0669] Weigh 1.159 g of N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-8-bromooctanamide into a reaction flask, dissolve in 8 ml of dimethyl sulfoxide, and add 271 mg of sodium azide. Move the reaction to an oil bath at 60°C and stir for 6 hours. Quench the reaction with 40 ml of water and stir for 10 minutes. Adjust the pH to 7-8 with saturated sodium bicarbonate solution. Extract the system five times with dichloromethane. Wash the organic phase with saturated sodium chloride, dry over anhydrous sodium sulfate, and filter the filtrate to dryness. Purify by column chromatography to yield 640 mg of the product. MS (m / e): 380.30 [M+H]. + .

[0670] Example 39

[0671] Disodium (E)-4-amino-6-((4'-(8-azidooctanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0672] Using the synthetic method of Example 3, 212 mg of the product was obtained from N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-8-azidooctanamide and 4-amino-5-hydroxy-1,3-naphthalene disulfonic acid monosodium salt. MS (m / e): 710.28 [M-2Na+3H] + . 1HNMR (DMSO-d6, 600MHz) δ: 15.962 (s, 1H), 9.278 (s, 1H), 8.364 (s, 1H), 8.031 (d, 1H), 7.896 (d, 1H), 7.654 (s, 2H), 7.578 (s, 1H), 7.502 ( t, 2H), 7.013 (d, 1H), 3.337 (s, 2H), 2.528-2.508 (s, 3H), 2.376-2.352 (t, 2H), 2.281 (s, 3H), 1.630 (s, 2H), 1.556 (t, 2H), 1.352 (s, 6H).

[0673] Example 40

[0674] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(8-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-8-oxooctyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0675] Using the synthetic method of Example 7, 103 mg of the product was obtained from disodium (E)-4-amino-6-((4'-(8-azidooctanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid and (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid. MS (m / e): 1438.40 [M-3Na+4H] + .

[0676] Example 41

[0677] Disodium 4-amino-6-((E)-(4'-(8-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)octanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0678] Using the synthetic method of Example 15, 18 mg of the product was obtained from trisodium (2S, 3S, 4S, 5R, 6S)-6-(3-((1-(8-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-8-oxooctyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate. MS (m / e): 1438.32 [M-2Na+3H] + .

[0679] Example 42

[0680] Disodium 4-amino-6-((E)-(4'-(8-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)octanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0681] Using the synthetic method of Example 7, 9 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid methyl ester and (E)-4-amino-6-((4'-(8-azidooctanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. MS (m / e): 1452.61 [M-2Na+3H] + .

[0682] Example 43

[0683] tert-Butyl (4'-(8-bromooctanamide)-[1,1'-biphenyl]-4-yl)carbamate

[0684] 942 mg of 8-bromooctanoic acid, 1 g of tert-butyl (4'-amino-[1,1'-biphenyl]-4-yl)carbamate, and 1.605 g of HATU were weighed and dissolved in 20 ml of DMF. 697 μl of DIEA was added dropwise. Stir at room temperature for 1 hour. The reaction mixture was dried and slurried in 20 ml of dichloromethane at room temperature overnight. The solid was filtered and dried to obtain the product (4'-(8-bromooctylamide)-[1,1'-biphenyl]-4-yl)carbamate.

[0685] 1.43 g of tert-butyl (2-(2-methyl-1,2-dextrin)carbamate. MS (m / e): 489.25 [M+H] + .

[0686] Example 44

[0687] N-(4'-amino-[1,1'-biphenyl]-4-yl)-8-bromooctanamide

[0688] Weigh 714 mg of tert-butyl (4'-(8-bromooctanamide)-[1,1'-biphenyl]-4-yl)carbamate and dissolve it in 8.6 ml of dichloromethane. Add 860 μl of trifluoroacetic acid dropwise and stir overnight at room temperature. Drain the reaction mixture and add 10 ml of methyl tert-butyl ether. Incubate overnight at room temperature. Filter the solid and dry to obtain 709 mg of the product. MS (m / e): 389.15 [M+H] + .

[0689] 1HNMR (DMSO-d6, 600MHz) δ: 9.948 (s, 1H), 7.677~7.662 (d, 2H), 7.634~7.620 (d, 2H), 7.581~7.567 (d, 2H), 7.176~7.163 (d, 2H), 3.541~3.518(t, 2H), 2.330~2.306(t, 2H), 1.810~1.786(m, 2H), 1.612~1.588(t, 2H), 1.394~1.381(m, 2H), 1.323~1.312(t, 4H).

[0690] Example 45

[0691] N-(4'-amino-[1,1'-biphenyl]-4-yl)-8-azidooctanamide

[0692] Using the synthesis method of Example 2, 140 mg of N-(4'-amino-[1,1'-biphenyl]-4-yl)-8-azidooctanamide was synthesized from N-(4'-amino-[1,1'-biphenyl]-4-yl)-8-bromooctanamide. MS (m / e): 352.22 [M+H] + .

[0693] Example 46

[0694] Disodium (E)-4-amino-6-((4'-(8-azidooctanamide)-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0695] Using the synthetic method of Example 3, 170 mg of (E)-4-amino-6-((4'-(8-azidooctanamide)-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt was synthesized from N-(4'-amino-[1,1'-biphenyl]-4-yl)-8-azidooctanamide and 4-amino-5-hydroxy-1,3-naphthalene disulfonic acid monosodium salt. MS (m / e): 682.31 [M-2Na+3H].

[0696] 1HNMR (DMSO-d6, 600MHz) δ: 15.656 (s, 1H), 9.966 (s, 1H), 8.351 (s, 1H), 8.015~7.998 (d, 1H), 7.752~7.738 (d, 2H), 7.705~7.656 (m, 6 H), 6.953~6.937(d, 1H), 3.341~3.330(d, 2H), 2.346~2.321(t, 2H), 1.629~1.605(t, 2H), 1.557~1.534(t, 2H), 1.339~1.333(d, 6H).

[0697] Example 47

[0698] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(8-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1'-biphenyl]-4-yl)amino)-8-oxooctyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0699] The synthetic method of Example 7 was used to obtain the product (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from (E)-4-amino-6-((4'-(8-azidooctanamide)-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt and (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid. Trisodium 6-(S,5R,6S)-6-(3-((1-(8-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1'-biphenyl]-4-yl)amino)-8-oxooctyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate 95 mg. MS (m / e): 1410.01 [M-3Na+4H] + .

[0700] Example 48

[0701] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(8-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-8-oxooctyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0702] Using the synthetic method of Example 7, 125 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid and (E)-4-amino-6-((4'-(8-azidooctanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. MS (m / e): 1452.97 [M-3Na+4H] + .

[0703] Example 49

[0704] 2-(2-(2-bromoethoxy)ethoxy)acetic acid

[0705] 400 mg of tert-butyl 2-(2-(2-bromoethoxy)ethoxy)acetate was weighed and placed in a reaction flask. 8 ml of dichloromethane was added to dissolve the mixture. 480 μl of trifluoroacetic acid was added dropwise and stirred at room temperature overnight. The mixture was reduced to dryness. Dissolution in dichloromethane and ethyl acetate was repeated three times, followed by reduction to dryness. 10 ml of methyl tert-butyl ether was added and stirred at room temperature for 3 hours. The reaction mixture was reduced to dryness to obtain the compound. The yield is calculated as 100%.

[0706] Example 50

[0707] tert-Butyl (4'-(2-(2-(2-bromoethoxy)ethoxy)acetylamino)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate

[0708] 321 mg of 2-(2-(2-bromoethoxy)ethoxy)acetic acid, 368 mg of tert-butyl (4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate, and 538 mg of HATU were weighed and dissolved in 6.5 ml of DMF. 40.6 μl of DIEA was added dropwise and stirred at room temperature overnight. 80 ml of water was added to quench the reaction. The system was extracted three times with dichloromethane. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the filtrate was filtered to dryness. Column chromatography was used to purify the product to yield 412 mg. MS (m / e): 521.20 [M+H]. +. 1HNMR (DMSO-d6, 600MHz) δ: 9.073 (s, 1H), 8.553 (s, 1H), 7.636-7.622 (d, 1H), 7.527-7.524 (d, 1H), 7.476-7.439 (m, 2H), 7.425-7.406 (m, 2 H), 4.146 (s, 2H), 3.802-3.783 (t, 2H), 3.748-3.734 (m, 2H), 3.705-3 .688(m, 2H), 3.618-3.599(t, 2H), 2.286-2.266(d, 6H), 1.482(s, 9H).

[0709] Example 51

[0710] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(2-(2-bromoethoxy)ethoxy)acetamide

[0711] Using the synthetic method of Example 37, 389 mg of N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(2-(2-bromoethoxy)ethoxy)acetamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamic acid tert-butyl ester was obtained. MS (m / e): 421.23 [M+H]. + .

[0712] Example 52

[0713] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(2-(2-azidoethoxy)ethoxy)acetamide

[0714] Using the synthetic method of Example 2, 216 mg of N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(2-(2-bromoethoxy)ethoxy)acetamide was synthesized. MS (m / e): 384.24 [M+H] +. 1HNMR (DMSO-d6, 400MHz) δ: 9.001 (s, 1H), 7.530-7.509 (d, 1H), 7.415-7.411 (d, 1H), 7.360-7.335 (dd, 1H), 7.262-7.205 (m, 2H), 6.680- 6.660 (d, 1H), 4.947 (s, 2H), 4.124 (s, 2H), 3.748-3.726 (t, 2H), 3.695-3.645 (m, 4H), 3.429-3.440 (t, 2H), 2.250 (s, 3H), 2.123 (s, 3H).

[0715] Example 53

[0716] Disodium (E)-4-amino-6-((4'-(2-(2-(2-azidoethoxy)ethoxy)acetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0717] Using the synthetic method of Example 3, 137 mg of the product was synthesized from N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(2-(2-azidoethoxy)ethoxy)acetamide and 4-amino-5-hydroxy-1,3-naphthalenedisulfonic acid monosodium salt. MS (m / e): 714.24 [M-2Na+3H] + .

[0718] Example 54

[0719] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(2-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxyethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0720] Using the synthetic method of Example 7, 130 mg of the product was obtained from disodium (E)-4-amino-6-((4'-(2-(2-azidoethoxy)ethoxy)acetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid and (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid. MS (m / e): 1442.45 [M-3Na+4H] + .

[0721] Example 55

[0722] Disodium 4-amino-6-((E)-(4'-(2-(2-(2-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)acetamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0723] Using the synthetic method of Example 15, (2S,3S,4S,5R,6S)-6-(3-((1-(2-(2-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxyethoxy)ethoxy)ethyl)-1H-1,2 The product was obtained by adding trisodium salt of ((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate) to obtain 12 mg of the product. MS (m / e): 1442.39 [M-2Na+3H] + .

[0724] Example 56

[0725] Disodium 4-amino-6-((E)-(4'-(2-(2-(2-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)acetamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0726] Using the synthetic method of Example 7, 20 mg of the product was obtained from disodium (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate and (E)-4-amino-6-((4'-(2-(2-azidoethoxy)ethoxy)acetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid. MS (m / e): 1456.53 [M-2Na+3H] + .

[0727] Example 57

[0728] tert-Butyl (4'-(2-(2-(2-bromoethoxy)ethoxy)acetylamino)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)carbamate

[0729] Using the synthetic method of Example 36, 458 mg of the product was obtained from 2-(2-(2-bromoethoxy)ethoxy)acetic acid and tert-butyl (4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)carbamate. MS (m / e): 553.21 [M+H] +. 1HNMR (DMSO-d6, 600MHz) δ: 9.002 (s, 1H), 8.235 ~ 8.221 (d, 1H), 7.936 (s, 1H), 7.780 ~ 7.767 (d, 1H), 7.323 ~ 7.319 (d, 1H), 7.272 ~ 7.228 (m, 3H), 4.146(s, 2H), 3.980(s, 3H), 3.920(s, 3H), 3.813~3.793(t, 2H), 3.748~ 3.731(m, 2H), 3.706~3.689(m, 2H), 3.627~3.608(t, 2H), 1.479(s, 9H).

[0730] Example 58

[0731] N-(4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)-2-(2-(2-bromoethoxy)ethoxy)acetamide

[0732] Using the synthetic method of Example 37, 432 mg of the product was synthesized from tert-butyl (4'-(2-(2-bromoethoxy)ethoxy)acetylamino)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)carbamate. MS (m / e): 453.20 [M+H] + . 1HNMR (DMSO-d6, 600MHz) δ: 9.000 (s, 1H), 8.227~8.213 (d, 1H), 7.306~7.292 (dd, 2H), 7.257~7.240 (dd, 1H), 7.224~7.207 (dd, 1H), 7.078 ~7.065 (d, 1H), 4.144 (s, 2H), 3.973 ~ 3.934 (d, 6H), 3.811 ~ 3.792 (t, 2H), 3.746 ~ 3.729 (m, 2H), 3.704 ~ 3.687 (m, 2H), 3.607 ~ 3.608 (t, 2H).

[0733] Example 59

[0734] N-(4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)-2-(2-(2-azidoethoxy)ethoxy)acetamide

[0735] Using the synthetic method of Example 2, 252 mg of the product was synthesized from N-(4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)-2-(2-(2-bromoethoxy)ethoxy)acetamide. MS (m / e): 416.27 [M+H] +. 1HNMR (DMSO-d6, 600MHz) δ: 8.951 (s, 1H), 8.169~8.155 (d, 1H), 7.230~7. 226(d, 1H), 7.171~7.154(dd, 1H), 7.102~7.099(d, 1H), 7.057~7.041(dd, 1H), 6.709~6.696(d, 1H), 4.853(s, 2H), 4.126(s, 2H), 3.956(s, 3H), 3.86 5(s, 3H), 3.743~3.729(q, 2H), 3.692~3.662(m, 4H), 3.432~3.416(t, 2H).

[0736] Example 60

[0737] Disodium (E)-4-amino-6-((4'-(2-(2-(2-azidoethoxy)ethoxy)acetamide)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0738] Using the synthetic method of Example 3, 147 mg of (E)-4-amino-6-((4'-(2-(2-(2-azidoethoxy)ethoxy)acetamide)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt was synthesized from N-(4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)-2-(2-(2-azidoethoxy)ethoxy)acetamide and 4-amino-5-hydroxy-1,3-naphthalene disulfonic acid monosodium salt. MS (m / e): 746.40 [M-2Na+3H] + . 1HNMR (DMSO-d6, 600MHz) δ: 15.697 (s, 1H), 9.636 (s, 1H), 9.042 (s, 1H), 8.352 (s, 1H) ), 8.278~8.264(d, 1H), 8.015~7.998(d, 1H), 7.860~7.846(d, 1H), 7.651(s, 1H), 7.4 56~7.411(m, 3H), 7.365~7.348(dd, 1H), 6.979~6.962(d, 1H), 4.153(s, 2H), 4.121(s , 3H), 4.012(s, 3H), 3.757~3.742(q, 2H), 3.702~3.670(m, 4H), 3.441~3.425(t, 2H).

[0739] Example 61

[0740] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(2-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonaphthalen-2-yl)diazenyl)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)amino)-2-oxyethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0741] Using the synthetic method of Example 7, 128 mg of the product was obtained from disodium (E)-4-amino-6-((4'-(2-(2-azidoethoxy)ethoxy)acetamide)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid and (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid. MS (m / e): 1474.63 [M-3Na+4H] +. 1HNMR (DMSO-d6, 600MHz) δ: 15.662 (s, 1H), 9.629 (s, 1H), 8.939 (s, 1H), 8.35 4(s, 1H), 8.319(s, 1H), 8.199~8.185(d, 1H), 8.046~7.998(dd, 2H), 7.801~7. 787(d, 1H), 7.650(s, 1H), 7.530~7.497(q, 2H), 7.393~7.319(m, 4H), 7.277~ 7.253(t, 2H), 7.020(s, 1H), 6.962~6.945(d, 1H), 6.649~6.636(d, 1H), 6.471 (s, 1H), 5.398 (s, 2H), 5.313~5.166 (m, 8H), 4.982 (s, 1H), 4.921~4.909 (d, 1 H), 4.571~4.567(d, 2H), 4.097(s, 3H), 4.017(s, 2H), 3.921(s, 3H), 3.868~3. 851(t, 2H), 3.578~3.571(d, 4H), 3.514(s, 1H), 3.281~3.238(m, 2H), 3.176~3 .116(m, 3H), 1.882~1.801(m, 2H), 1.265~1.239(t, 3H), 0.886~0.861(t, 3H).

[0742] Example 62

[0743] Disodium 4-amino-6-((E)-(4'-(2-(2-(2-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)acetamido)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0744] Using the synthetic method of Example 15, (2S,3S,4S,5R,6S)-6-(3-((1-(2-(2-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)amino)-2-oxyethoxy)ethoxy)ethyl)-1H-1, Trisodium 2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate was used to obtain 20 mg of the product. MS (m / e): 1474.55 [M-2Na+3H] + .

[0745] Example 63

[0746] Disodium 4-amino-6-((E)-(4'-(2-(2-(2-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)acetamido)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0747] Using the synthetic method of Example 7, 16 mg of the product was obtained from disodium (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate and (E)-4-amino-6-((4'-(2-(2-azidoethoxy)ethoxy)acetamide)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid. MS (m / e): 1488.69 [M-2Na+3H] + .

[0748] Example 64

[0749] tert-Butyl (4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)carbamate

[0750] Using the synthesis method of Example 35, 4.879 g of tert-butyl (4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)carbamate was synthesized from 3,3'-dimethoxy-[1,1'-biphenyl]-4,4'-diamine. MS (m / e): 345.19 [M+H] + . 1HNMR (DMSO-d6, 400MHz) δ: 7.835 (s, 1H), 7.688-7.668 (d, 1H), 7.153-7.010 ( m, 4H), 6.706-6.686 (d, 1H), 4.809 (s, 2H), 3.892-3.860 (d, 6H), 1.473 (s, 9H).

[0751] Example 65

[0752] tert-Butyl (4'-(6-bromohexanamide)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)carbamate

[0753] Using the synthetic method of Example 50, 1.735 g of tert-butyl (4'-(6-bromohexanamide)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)carbamate was obtained from tert-butyl (4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)carbamate and 6-bromohexanoic acid. MS (m / e): 521.24 [M+H]. 1HNMR (DMSO-d6, 600MHz) δ: 9.108 (s, 1H), 8.034~8.020 (d, 1H), 7.931 (s, 1H), 7.774~7.761 (d, 1H), 7.272~7.259 (dd, 2H), 7.233~7.204 (m, 2H), 3.939~3.917(d, 6H), 3.566-3.534(t, 2H), 2.434-2.410(t, 2H), 1.859~ 1.823(t, 2H), 1.630~1.592(t, 2H), 1.478(s, 9H), 1.265~1.240(t, 2H).

[0754] Example 66

[0755] N-(4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)-6-bromohexanamide

[0756] Using the synthetic method of Example 37, 1.412 g of N-(4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)-6-bromohexanamide was synthesized from tert-butyl (4'-(6-bromohexanamide)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)carbamate. MS (m / e): 421.23 [M+H] + . 1HNMR (DMSO-d6, 400MHz) δ: 9.090 (s, 1H), 8.022~8.001 (d, 1H), 7.275~7.186 (dd, 4H), 7.075~7.057 (m, 1H), 3.947 ( s, 6H), 3.570~3.537(t, 2H), 2.436~4.400(t, 2H), 1.883~1.812(m, 2H), 1.637~1.581(m, 2H), 1.477~1.402(m, 2H).

[0757] Example 67

[0758] N-(4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)-6-azidohexanamide

[0759] Using the synthetic method of Example 2, 959 mg of the product was synthesized from N-(4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)-6-bromohexanamide. MS (m / e): 384.24 [M+H] + . 1HNMR (DMSO-d6, 600MHz) δ: 9.026 (s, 1H), 7.943-7.929 (d, 1H), 7.179-7.176 (d, 1H), 7.121-7.104 (dd, 1H), 7.089-7.086 (d, 1H), 7.044-7.027(dd, 1H), 6.705-6.692(d, 1H), 4.832(s, 2H), 3.913(s, 3H), 3.862(s, 3H), 3.355-3.332(t, 2H), 2.415-4.390(t, 2H), 1.624-1.566(m, 4H), 1.385-1.360(t, 2H).

[0760] Example 68

[0761] Disodium (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0762] Using the synthetic method of Example 3, 171 mg of the product was synthesized from N-(4'-amino-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)-6-azidohexanamide and 4-amino-5-hydroxy-1,3-naphthalenedisulfonic acid monosodium salt. MS (m / e): 714.25 [M-2Na+3H] + . 1HNMR (DMSO-d6, 600MHz) δ: 15.707 (s, 1H), 9.638 (s, 1H), 9.154 (s, 1H), 8.355 (s, 1H), 8.087 ~8.073(d, 1H), 8.013~7.997(d, 1H), 7.855~7.842(d, 1H), 7.648(s, 1H), 7.444~7.429(d, 2H) ), 7.361~7.358(d, 1H), 7.314~7.297(dd, 1H), 6.982~6.965(d, 1H), 4.118(s, 3H), 3.971(s, 3H), 3.384~3.344(t, 2H), 2.449~2.425(t, 2H), 1.634~1.571(dt, 4H), 1.391~1.366(m, 2H).

[0763] Example 69

[0764] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0765] Using the synthetic method of Example 7, 129 mg of the product was obtained from disodium (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid and (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid. MS (m / e): 1442.04 [M-3Na+4H] + .

[0766] 1HNMR (DMSO-d6, 600MHz) δ: 15.692 (s, 1H), 9.638 (s, 1H), 9.153 (s, 1H), 8.355 (s, 1H), 8.309 (s, 1H), 8.069-8.001 (m, 3H), 7.838~7.824 (d, 1H), 7.646(s, 1H), 7.569~7.565(d, 1H), 7.539~7.520(dd, 1H), 7.423~7.403(m, 2H), 7.379~7.365(d, 1H), 7.321~7.318(d, 1H), 7.270~7. 5.2 44~5.188 (m, 4H), 4.995 (d, 1H), 4.933~4.921 (d, 1H), 4.359~4.336 (t, 2H), 4.111 (s, 3H), 3.934 (s, 3H), 3.528~3.511 (d, 1H), 3.286~3.23 3(m, 2H), 3.168~3.148(m, 3H), 2.392~2.362(t, 2H), 1.894~1.782(m, 4H), 1.560~1.535(t, 2H), 1.279~1.219(m, 5H), 0.887~0.863(t, 3H).

[0767] Example 70

[0768] Disodium 4-amino-6-((E)-(4'-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0769] Using the synthetic method of Example 15, 10 mg of the product was obtained from trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate. MS (m / e): 1442.69 [M-2Na+3H] + .

[0770] Example 71

[0771] Disodium 4-amino-6-((E)-(4'-(6-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0772] Using the synthetic method of Example 7, 12 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid methyl ester and (E)-4-amino-6-((4'-(6-azidohexanamide)-3,3'-dimethoxy-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. MS (m / e): 1456.63 [M-2Na+3H] + .

[0773] Example 72

[0774] 6-Bromohexanoyl chloride

[0775] Weigh 10g of 6-bromohexanoic acid and add 100ml of DCM, stirring to dissolve. Add 1 drop of DMF and 8.75ml of oxalyl chloride dropwise. Stir at room temperature under argon for 1 hour. Reduce to dryness to obtain 11.09g of product. Yield calculated as 100%.

[0776] Example 73

[0777] tert-Butyl (4'-amino-[1,1'-biphenyl]-4-yl)carbamate

[0778] Using the synthesis method of Example 35, 6.5 g of tert-butyl (4'-amino-[1,1'-biphenyl]-4-yl)carbamate was synthesized from p-diaminobenzidine.

[0779] Example 74

[0780] tert-Butyl (4'-(6-bromohexanamide)-[1,1'-biphenyl]-4-yl)carbamate

[0781] Weigh 4.7 g of tert-butyl (4'-amino-[1,1'-biphenyl]-4-yl)carbamate into a reaction flask, dissolve in 50 ml of dichloromethane, add 4.7 g of DIEA, and stir at room temperature. Cool to 0°C with glacial ethanol. Dissolve 4.587 g of 6-bromohexanoyl chloride in 10 ml of dichloromethane and add to the reaction flask. The reaction will turn into a white suspension. Remove the glacial ethanol and return the reaction to room temperature with stirring for 2 hours. Quench the reaction by adding 20 ml of water and stir for 10 minutes, filter, and dry. 5.524 g of product is obtained. MS (m / e): 461.23 [M+H] +. 1HNMR (DMSO-d6, 600MHz) δ: 9.936 (s, 1H), 9.406 (s, 1H), 7.662~7.847 (d, 2H), 7.568~7.511 (m, 6H), 3.565~3 .542(t, 2H), 2.346-2.321(t, 2H), 1.868~1.820(t, 2H), 1.658-1.608(t, 2H), 1.493(s, 9H), 1.451~1.426(t, 2H).

[0782] Example 75

[0783] N-(4'-amino-[1,1'-biphenyl]-4-yl)-6-bromohexanamide

[0784] Weigh 5.5 g of tert-butyl (4'-(6-bromohexanamide)-[1,1'-biphenyl]-4-yl)carbamate into a reaction flask, dissolve in 66 ml of dichloromethane, and add 6.6 ml of trifluoroacetic acid, stirring at room temperature for 6 hours. Drain, dissolve in dichloromethane three times, and dissolve in ethyl acetate twice, stirring at room temperature overnight. Add 30 ml of methyl tert-butyl ether, stir at room temperature, filter, and rinse with methyl tert-butyl ether to obtain a white cake. Dry to yield 5.624 g of product. 1HNMR (DMSO-d6, 600MHz) δ: 9.991 (s, 1H), 7.686~7.672 (d, 2H), 7.631~7.617 (d, 2H), 7.586~7.572 (d, 2H), 7.174~7.1 60(d, 2H), 3.562~3.539(t, 2H), 2.352~2.328(t, 2H), 1.854~1.829(t, 2H), 1.646~1.621(t, 2H), 1.450~1.425(t, 2H).

[0785] Example 76

[0786] N-(4'-amino-[1,1'-biphenyl]-4-yl)-6-azidohexanamide

[0787] Using the synthetic method of Example 2, 1.352 g of the product was synthesized from N-(4'-amino-[1,1'-biphenyl]-4-yl)-6-bromohexanamide. MS (m / e): 324.22 [M+H] + .

[0788] 1HNMR (DMSO-d6, 600MHz) δ: 9.853 (s, 1H), 7.597-7.582 (d, 2H), 7.463-7.449 (d, 2H), 7.324-7.310 (d, 2H), 6.626-6.612 (d, 2 H), 5.158(s, 2H), 3.357-3.334(t, 2H), 2.330-2.306(t, 2H), 1.637-1.612(t, 2H), 1.587-1.562(t, 2H), 1.386-1.357(t, 2H).

[0789] Example 77

[0790] Disodium (E)-4-amino-6-((4'-(6-azidohexanamido)-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0791] Using the synthetic method of Example 3, 206 mg of the product was synthesized from N-(4'-amino-[1,1'-biphenyl]-4-yl)-6-azidohexanamide and 4-amino-5-hydroxy-1,3-naphthalenedisulfonic acid monosodium salt. MS (m / e): 654.25 [M-2Na+3H] + . 1HNMR (DMSO-d6, 600MHz) δ: 15.658 (s, 1H), 9.986 (s, 1H), 8.354 (s, 1H), 8.014-7.998 (d, 1H), 7.754-7.739(d, 2H), 7.708-7.659(m, 6H), 6.957-6.940(d, 1H), 3.365-3.342(t, 2H), 2.362-2.337(t, 2H), 1.655-1.630(t, 2H), 1.597-1.572(t, 2H), 1.385-1.370(t, 2H).

[0792] Example 78

[0793] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0794] Using the synthetic method of Example 7, 150 mg of the product was obtained from disodium (E)-4-amino-6-((4'-(6-azidohexanamide)-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid and (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid. MS (m / e): 1382.48 [M-3Na+4H] + .

[0795] 1HNMR (DMSO-d6, 600MHz) δ: 15.664 (s, 1H), 10.332 (s, 1H), 8.361 (s, 2H), 8.065~8.050 (d, 1H), 8.008~7.994 (d, 1H), 7.733-7.718 (d, 2H), 7.690~7.662 (t, 4H),, 7.626~7.61 2(d, 2H), 7.564~7.560(d, 1H), 7.531~7.511(dd, 1H), 7.366~7.352(d, 1H), 7.272(s, 1 H), 7.048 (s, 1H), 6.962~6.944 (d, 1H), 6.644~6.632 (d, 1H), 6.485 (s, 1H), 5.415~5.40 8(d, 2H), 5.381~5.343(d, 1H), 5.289(s, 2H), 5.264~5.256(d, 2H), 5.234~5.228(d, 1H) ), 5.209~5.175(t, 2H), 5.033~5.025(d, 1H), 4.966~4.956(d, 1H), 4.381~4.314(m, 2H) , 3.617~3.600(d, 1H), 3.290~3.203(s, 3H), 3.158~3.145(m, 2H), 2.355~2.279(m, 2H) , 1.897~1.774(m, 4H), 1.599~1.566(m, 2H), 1.279~1.231(m, 5H), 0.890~0.865(t, 3H).

[0796] Example 79

[0797] Disodium 4-amino-6-((E)-(4'-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0798] Using the synthetic method of Example 15, 18 mg of the product was obtained from trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1'-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate. MS (m / e): 1382.42 [M-2Na+3H] + .

[0799] Example 80

[0800] Disodium 4-amino-6-((E)-(4'-(6-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0801] Using the synthetic method of Example 7, 19 mg of the product was obtained from (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid methyl ester and (E)-4-amino-6-((4'-(6-azidohexanamide)-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt. MS (m / e): 1396.10 [M-2Na+3H] + .

[0802] Example 81

[0803] tert-Butyl (4'-(5-bromopentanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate

[0804]

[0805] Using the synthetic method of Example 74, tert-butyl (4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate and 5-bromovaleryl chloride were synthesized to obtain tert-butyl (4'-(5-bromopentanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate as a white solid (763 mg). MS (m / e): 475.52 [M+H].

[0806] Example 82

[0807] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-5-bromopentanamide

[0808] Using the synthetic method of Example 75, 665 mg of N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-5-bromopentanamide was synthesized from tert-butyl (4'-(5-bromopentanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate. MS (m / e): 375.20 [M+H].

[0809] Example 83

[0810] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-5-azidopentanamide

[0811] Using the synthetic method of Example 2, N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-5-bromopentanamide was synthesized to obtain 347 mg of N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-5-azidopentanamide as a yellow solid. MS (m / e): 338.31 [M+H].

[0812] Example 84

[0813] Disodium (E)-4-amino-6-((4'-(5-azidopentanamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0814] The title compound (E)-4-amino-6-((4'-(5-azidopentanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt was synthesized from N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-5-azidopentanamide and 4-amino-5-hydroxy-1,3-naphthalene disulfonic acid monosodium salt using the synthetic method of Example 3 as a purple solid (233 mg). MS (m / e): 668.46 [M-2Na+3H].

[0815] Example 85

[0816] (2S,3S,4S,5R,6S)-6-(3-((1-(5-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-5-oxopentyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[ Trisodium 3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate was synthesized by the method of Example 7 from compound (E)-4-amino-6-((4'-(5-azidopentanamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium and compound (2S,3S,4S,5R,6S)-6-(4-((((S )-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid to obtain the product (2S,3S,4S,5R,6S)-6-(3-((1-(5-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonic acid) (((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)-1H-1,2,3-triazol-4-yl)-1,2,3-triazol-4-yl)-2,3-naphthalenyl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-5-oxopentyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)

[0817] 70 mg of trisodium carboxylate. MS (m / e): 1396.84 [M-3Na+4H]+.

[0818] Example 86

[0819] tert-Butyl (4'-(2-bromoacetamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate

[0820] Using the method of Example 74, tert-butyl 4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate and 2-bromoacetyl chloride were synthesized to obtain tert-butyl (4'-(2-bromoacetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate as a white solid (390 mg). MS (m / e): 433.10 [M+H].

[0821] Example 87

[0822] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-bromoacetamide

[0823] Using the method of Example 75, N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-bromoacetamide was synthesized from tert-butyl (4'-(2-bromoacetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate as a yellow solid (263 mg). MS (m / e): 333.18 [M+H].

[0824] Example 88

[0825] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-azidoacetamide

[0826] Using the synthetic method of Example 2, N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-azidoacetamide was synthesized from N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-bromoacetamide to obtain 180 mg of N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-azidoacetamide as a yellow solid. MS (m / e): 296.24 [M+H].

[0827] Example 89

[0828] Disodium (E)-4-amino-6-((4'-(2-azidoacetamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0829] The title compound (E)-4-amino-6-((4'-(2-azidoacetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt was synthesized from N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-azidoacetamide and 4-amino-5-hydroxy-1,3-naphthalene disulfonic acid monosodium salt using the synthetic method of Example 3 as a purple solid (271 mg). MS (m / e): 626.57 [M = 2Na + 3H].

[0830] Example 90

[0831] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0832] The synthetic method of Example 7 was used to obtain the product (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from the compound (E)-4-amino-6-((4'-(2-azidoacetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt and the compound (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid. Trisodium S,4S,5R,6S)-6-(3-((1-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate 61 mg. MS(m / e): 1354.73[M-3Na+4H]+.

[0833] Example 91

[0834] 2-(3-chloropropoxy)acetic acid

[0835] At room temperature, ethyl 2-(3-chloropropoxy)acetate (1.0 g) was dissolved in tetrahydrofuran (10.0 ml) and stirred. Sodium hydroxide (266 mg) was dissolved in water (10.0 ml) and added dropwise, stirring at room temperature for 1.5 hours. The tetrahydrofuran was dried, and 1 mol / L hydrochloric acid (6.64 ml) was added dropwise to adjust the pH. The system was extracted three times with ethyl acetate, and the organic phase was washed with saturated sodium chloride water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. The product, 2-(3-chloropropoxy)acetic acid, was obtained as a yellow oil (723 mg). MS (m / e): 153.75 [M+H]+.

[0836] Example 92

[0837] tert-Butyl (4'-(2-(3-chloropropoxy)acetamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate

[0838] Using the synthetic method of Example 50, tert-butyl 4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate and 2-(3-chloropropoxy)acetic acid were synthesized to obtain tert-butyl (4'-(2-(3-chloropropoxy)acetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate as a white solid (1.61 g). MS (m / e): 447.40 [M+H].

[0839] Example 93

[0840] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(3-chloropropoxy)acetamide was synthesized from tert-butyl (4'-(2-(3-chloropropoxy)acetamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate using the method of Example 37 to obtain N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(3-chloropropoxy)acetamide as a yellow solid (1.315 g). MS (m / e): 347.32 [M+H].

[0841] Example 94

[0842] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(3-azidopropoxy)acetamide

[0843] To the starting material, N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-2-(3-chloropropoxy)acetamide (1.315 g) was added dimethyl sulfoxide (10 ml) and stirred at room temperature until completely dissolved. Sodium azide (287 mg) and sodium iodide (441 mg) were added and the mixture was allowed to react at 80°C for 17 hours. The reaction was quenched by adding water and the mixture was extracted with dichloromethane (200 ml). The aqueous phase was extracted again with dichloromethane (200 ml) and separated. The combined dichloromethane phases were washed four times with saturated sodium chloride (100 ml) aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. Column chromatography (eluent: dichloromethane:ethyl acetate = 10:1) afforded 914 mg of a yellow oil. MS (m / e): 354.32 [M+H]+.

[0844] Example 95

[0845] Disodium (E)-4-amino-6-((4'-(2-(3-azidopropoxy)acetamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0846] Using the synthetic method of Example 3, 345 mg of the product was synthesized 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): 684.39 [M-2Na+3H]+.

[0847] Example 96

[0848] Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(3-(2-((4'-((E)-(8-amino-1-hydroxy-5,7-disulfonaphthalen-2-yl)diazenyl)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)amino)-2-oxoethoxy)propyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0849] Using the synthetic method of Example 7, 234 mg of the product was obtained from the compound (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 and the compound (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid. MS(m / e): 1412.27[M-3Na+4H]+.

[0850] Example 97

[0851] tert-Butyl (4'-(3-(2-bromoethoxy)propionamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate

[0852] Using the synthetic method of Example 50, 1.6 g of the product was synthesized from tert-butyl 4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate and 3-(2-bromoethoxy)propionic acid. MS (m / e): 491.35 [M+H]+.

[0853] Example 98

[0854] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-3-(2-bromoethoxy)propionamide

[0855] Using the synthetic method of Example 37, 1.2 g of the product was synthesized from tert-butyl (4'-(3-(2-bromoethoxy)propionamide)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)carbamate. MS (m / e): 391.30 [M+H]+.

[0856] Example 99

[0857] N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-3-(2-azidoethoxy)propionamide

[0858] 770 mg of the product was synthesized from N-(4'-amino-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)-3-(2-bromoethoxy)propionamide using the synthetic method of Example 2. MS (m / e): 354.32 [M+H]+.

[0859] Example 100

[0860] Disodium (E)-4-amino-6-((4'-(3-(2-azidoethoxy)propionamido)-3,3'-dimethyl-[1,1'-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid

[0861] Using the synthetic method of Example 3, 379 mg of the product was synthesized 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].

[0862] Example 101

[0863] Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate

[0864] Using the synthetic method of Example 7, 129 mg of the product was obtained from the compound (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 and the compound (2S,3S,4S,5R,6S)-6-(4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3-(prop-2-ynyloxy)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid. MS(m / e): 1412.55[M-3Na+4H]+.

[0865] Biological Examples

[0866] Biological Example 1

[0867] In vitro inhibitory effect study on human tumor cells

[0868] 1.1 Test method

[0869] 1.1.1 The cell culture medium formula (complete culture medium) is generally based on the formula provided by the Cell Bank of the Chinese Academy of Sciences and ATCC (American Type Culture Collection), and the additives are adjusted in combination with the formula of the basal culture medium.

[0870] 1.1.2 Cell culture method: Culture cells in complete medium at 37°C, 5% CO2, and saturated humidity until the logarithmic growth phase (adherent cells are generally close to complete confluence) and collect cells for subsequent experiments (adherent cells are first digested with trypsin / ethylenediaminetetraacetic acid (EDTA) to remove adhesion).

[0871] 1.1.3 A certain number of cells (see Table 1 for details) were seeded into a 96-well cell culture plate (hereinafter referred to as a 96-well plate) and cultured overnight to allow the cells to adhere. Different concentrations of compounds were added and co-cultured for a period of time (generally 3 days). Finally, the total amount of cellular protein in the test wells was determined by the SRB assay, or the cell viability was measured by the MTT assay:

[0872] 1.1.3.1 Determination of total cellular protein by SRB method: Aspirate the culture medium from the wells and add 10% trichloroacetic acid to fix the cells 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 the protein-bound SRB and detect at a wavelength of 570 nm.

[0873] 1.1.3.2 MTT assay for cell viability:

[0874] For firmly adherent cells: Aspirate the culture medium and add 100 μl / well of basal medium (generally refers to medium without fetal bovine serum (FBS) and other additives) containing 0.5 mg / ml MTT. Continue culturing for 3 hours. Aspirate the basal medium containing MTT and add 100 μl / well of DMSO to dissolve the formazan. Detect at a wavelength of 490 nm.

[0875] 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 an equal volume of Triple Dissolution Solution to dissolve the formazan, and detect at a wavelength of 570 nm.

[0876] 1.1.3.3 Basis for choosing between SRB and MTT: The SRB and MTT methods reflect the number of cells in the test well from different perspectives and generally provide a good indicator of the inhibitory activity of a compound on cells. The SRB method has higher sensitivity and requires fewer cells, while the MTT method is simpler, but the MTT reduction capacity of different cells varies significantly. The key principle for choosing between the SRB and MTT methods is that if the cells have sufficient MTT reduction capacity, for example, if the OD value (optical density) of the positive solvent control group reaches 0.4 or above after the co-culture, the MTT method is preferred.

[0877] 1.1.4 Dilute and add β-glucuronidase: Weigh 1-2 mg of β-glucuronidase and dissolve it in PBS to a 2 mg / ml stock solution. Dilute it with complete culture medium to a 12.5 μg / ml working solution. Add 80 μl of the working solution to the wells containing the enzyme, at a dosage of 1 μg / well. Add 80 μl of complete culture medium to the wells not containing the enzyme.

[0878] 1.1.5 Dilution and Compound Addition: Weigh 1-3 mg of the test compound and dissolve it in DMSO to a 20 mM stock solution. Adjust the starting concentration according to experimental needs. Perform a 3-fold serial dilution with DMSO and then dilute 100-fold with RPMI1640 basal medium to obtain a 10× working solution, for a total of 8 concentrations. Add 20 μl of the 10× working solution to the test wells, for a final volume of 200 μl per well. The DMSO concentration is 0.1%.

[0879] 1.1.6 Calculation of Compound Inhibitory Activity: The assay consists of a compound test group, a positive solvent control group (PC) without compound, and a negative solvent control group (NC) without cells or compound. Inhibition rate = [1 - (test value - NC mean) / (PC mean - NC mean)] × 100%. The mean and standard deviation (SD) of the inhibition rate were calculated from replicate wells. The plot was plotted logarithmically with compound concentration as the abscissa and the mean inhibition rate as the ordinate. A four-parameter logistic equation was used to fit the curve. The compound concentration corresponding to 50% inhibition on the curve was the IC50 value. The assay was generally repeated three times to obtain valid results.

[0880] Table 1: Culture medium formulations and cell seeding concentrations for human tumor cell lines

[0881] 1.2 Test results

[0882] Inhibitory IC against various tumor cell lines 50 Value (see Table 2-4)

[0883] Table 2: Inhibitory activity of compounds against various tumor cells (IC50 :nM,)

[0884] Note:

[0885] βGU:β-glucuronidase

[0886] No βGU: Compounds act directly on cells

[0887] Effects of adding βGU compounds and β-glucuronidase on cells

[0888] Table 3: Inhibitory activity of compounds against human tumor cells (IC50: nM)

[0889] Table 4: Inhibitory activity of compounds against human tumor cells (IC 50 :nM)

[0890] Biological Example 2

[0891] Effect of drug efficacy evaluation on the growth of human colon cancer LoVo xenograft model

[0892] 2.1 Test method

[0893] The human colon cancer LoVo xenograft model was established subcutaneously in nude mice using tumor block inoculation. 3 When tumors reached approximately 100 μg / cm2 and maintained stable growth, animals were randomly divided into groups (day 0) using the remainder method according to tumor volume. Dosing was then initiated, and tumor volume was measured 2-3 times per week. After the dosing period, animals were sacrificed, and subcutaneous tumors were removed and weighed. Tumor volume and weight were used to evaluate the antitumor activity of the drug in this model.

[0894] 2.1.1 Grouping and Dosage Regimen

[0895] Table 5 Effects of LoVo xenograft model on the growth of human colon cancer

[0896] Experimental animal grouping and dosing schedule

[0897] Note: “—” means no entry or no valid data.

[0898] 2.2 Evaluation indicators and statistical methods

[0899] The formula for calculating tumor volume is: volume = 0.5 × long diameter × short diameter 2 .

[0900] Relative tumor volume (RTV): RTV = Vt / V0.

[0901] V0 is the tumor volume measured at the time of group administration (i.e., d0), and Vt is the tumor volume at each measurement.

[0902] Relative tumor proliferation rate T / C: T / C = TRTV / CRTV × 100%.

[0903] T is the test substance, and C is the model control group.

[0904] TRTV is the mean RTV of the test substance, and CRTV is the mean RTV of the model control group.

[0905] Tumor inhibition rate (%) = (average tumor weight of model control group - average tumor weight of drug-treated group) / average tumor weight of model control group × 100%.

[0906] Percentage change in body weight = Wn / W0×100%.

[0907] Wn: average body weight of experimental animals in each group on day n, W0: average body weight of experimental animals in each group on day 0.

[0908] 2.3 Experimental Results

[0909] Table 6 Effects of compounds on the growth of human colon cancer LoVo xenograft model

[0910] Note:

[0911] “—” means no valid data or no entry

[0912] Biological Example 3

[0913] Effect of drug efficacy evaluation on the growth of human colon cancer SW620 xenograft model

[0914] 3.1 Test method

[0915] The human colon cancer SW620 xenograft model was established in nude mice using the tumor block inoculation method. 3 When tumors reached approximately 100 μg / cm2 and maintained stable growth, animals were randomly divided into groups (day 0) using the remainder method according to tumor volume. Dosing was then initiated, and tumor volume was measured 2-3 times per week. After the dosing period, animals were sacrificed, and subcutaneous tumors were removed and weighed. Tumor volume and weight were used to evaluate the antitumor activity of the drug in this model.

[0916] 3.1.1 Grouping and Dosage Regimen

[0917] Table 7 Effects on the growth of human colon cancer SW620 xenograft model

[0918] Experimental animal grouping and dosing schedule

[0919] Note: “—” means no entry or no valid data.

[0920] 3.2 Evaluation indicators and statistical methods

[0921] The formula for calculating tumor volume is: volume = 0.5 × long diameter × short diameter 2 .

[0922] Relative tumor volume (RTV): RTV = Vt / V0.

[0923] V0 is the tumor volume measured at the time of group administration (i.e., d0), and Vt is the tumor volume at each measurement.

[0924] Relative tumor proliferation rate T / C: T / C = TRTV / CRTV × 100%.

[0925] T is the test substance, and C is the model control group.

[0926] TRTV is the mean RTV of the test substance, CRTV 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-administered group) / mean tumor weight of the model control group × 100%.

[0927] Percentage change in body weight = Wn / W0×100%.

[0928] Wn: average body weight of experimental animals in each group on day n, W0: average body weight of experimental animals in each group on day 0.

[0929] 3.3 Experimental Results

[0930] Table 8 Effects of compounds on the growth of human colon cancer SW620 xenograft model

[0931] Biological Example 4

[0932] Effect of drug efficacy evaluation on the growth of human colon cancer HCT116 xenograft model

[0933] 4.1 Test method

[0934] The human colon cancer HCT116 xenograft model was established in nude mice using the tumor block inoculation method. 3When tumors reached approximately 100 μg / cm2 and maintained stable growth, animals were randomly divided into groups (day 0) using the remainder method according to tumor volume. Dosing was then initiated, and tumor volume was measured 2-3 times per week. After the dosing period, animals were sacrificed, and subcutaneous tumors were removed and weighed. Tumor volume and weight were used to evaluate the antitumor activity of the drug in this model.

[0935] 4.1.1 Grouping and Dosage Regimen

[0936] Table 9 Effects on the growth of human colon cancer HCT116 xenograft model

[0937] Experimental animal grouping and dosing schedule

[0938] Note: “—” means no entry or no valid data.

[0939] 4.2 Evaluation indicators and statistical methods

[0940] The formula for calculating tumor volume is: volume = 0.5 × long diameter × short diameter 2 .

[0941] Relative tumor volume (RTV): RTV = Vt / V0.

[0942] V0 is the tumor volume measured at the time of group administration (i.e., d0), and Vt is the tumor volume at each measurement.

[0943] Relative tumor proliferation rate T / C: T / C = TRTV / CRTV × 100%.

[0944] T is the test substance, and C is the model control group.

[0945] TRTV is the mean RTV of the test substance, CRTV 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-administered group) / mean tumor weight of the model control group × 100%.

[0946] Percentage change in body weight = Wn / W0×100%.

[0947] Wn: average body weight of experimental animals in each group on day n, W0: average body weight of experimental animals in each group on day 0.

[0948] 4.3 Experimental Results

[0949] Table 10 Effects of compounds on the growth of human colon cancer HCT116 xenograft model

[0950] Biological Example 5

[0951] Effect of drug efficacy evaluation on the growth of human pancreatic cancer BxPC-3 xenograft model

[0952] 5.1 Test method

[0953] The human pancreatic cancer BxPC-3 xenograft model was established in nude mice subcutaneously using the tumor block inoculation method. 3 When tumors reached approximately 100 μg / cm2 and maintained stable growth, animals were randomly divided into groups (day 0) using the remainder method according to tumor volume. Dosing was then initiated, and tumor volume was measured 2-3 times per week. After the dosing period, animals were sacrificed, and subcutaneous tumors were removed and weighed. Tumor volume and weight were used to evaluate the antitumor activity of the drug in this model.

[0954] 5.1.1 Grouping and Dosage Regimen

[0955] Table 11 Effects on the growth of human pancreatic cancer BxPC-3 xenograft model

[0956] Experimental animal grouping and dosing schedule

[0957] Note: “—” means no entry or no valid data.

[0958] After the animals in group G5 completed two doses of medication, the tumor volume of the animals in this group continued to grow until the average tumor volume exceeded 600 mm 3 After eliminating the smaller experimental animals 8# and 18#, the animals were redivided into 4 groups, namely the model control group (G6.1) and 3 experimental groups (G6.2, G6.3, and G6.4), to continue investigating the inhibitory effect of the compound of the present application on the growth of large tumors after irinotecan treatment.

[0959] 5.2 Evaluation indicators and statistical methods

[0960] The formula for calculating tumor volume is: volume = 0.5 × long diameter × short diameter 2 .

[0961] Relative tumor volume (RTV): RTV = Vt / V0.

[0962] V0 is the tumor volume measured at the time of group administration (i.e., d0), and Vt is the tumor volume at each measurement.

[0963] Relative tumor proliferation rate T / C: T / C = TRTV / CRTV × 100%.

[0964] T is the test substance, and C is the model control group.

[0965] TRTV is the mean RTV of the test substance, CRTV 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-administered group) / mean tumor weight of the model control group × 100%.

[0966] Percentage change in body weight = Wn / W0×100%.

[0967] Wn: average body weight of experimental animals in each group on day n, W0: average body weight of experimental animals in each group on day 0.

[0968] On day 17 (day 17), the G5 group underwent a secondary subgrouping and dosing. Therefore, the end-of-experiment data for the G5 group in the main study were from day 17. Tumors were not removed from this group, so no tumor inhibition rate data were available. In the large tumor efficacy study after the G5 group underwent secondary subgrouping, since the G6.1 and G6.4 groups had fewer than three samples each, the relevant data from the large tumor efficacy study were statistically analyzed between groups using the T-test method.

[0969] 5.3 Experimental Results

[0970] Table 12 Effects on the growth of human pancreatic cancer BxPC-3 xenograft model

[0971] a: Because the G5 group was given a second dose of drugs on d17, the end-of-experiment data of the G5 group in the main experiment were d17 data. Tumors were not removed from this group, so there is no data on tumor weight and tumor inhibition rate;

[0972] Table 13 Effect of irinotecan treatment on the growth of a large human pancreatic cancer BxPC-3 xenograft model

[0973] Biological Example 6

[0974] Effect of drug efficacy evaluation on the growth of human small cell lung cancer NCI-H446 xenograft model

[0975] 6.1 Test method

[0976] The human small cell lung cancer NCI-H446 xenograft model was established subcutaneously in nude mice using tumor block inoculation. 3 When tumors reached approximately 300 μg / cm2 and maintained stable growth, animals were randomly divided into groups (day 0, d0) using the remainder method and dosed. Tumor volumes were measured 2-3 times per week. After the dosing period, animals were sacrificed, and subcutaneous tumors were removed and weighed. Tumor volume and weight were used to evaluate the antitumor activity of the drug in this model.

[0977] 6.1.1 Grouping and Dosage Regimen

[0978] Table 14 Effects on the growth of human small cell lung cancer NCI-H446 xenograft model

[0979] Experimental animal grouping and dosing schedule

[0980] Note: “—” means no entry or no valid data.

[0981] 6.2 Evaluation indicators and statistical methods

[0982] The formula for calculating tumor volume is: volume = 0.5 × long diameter × short diameter 2 .

[0983] Relative tumor volume (RTV): RTV = Vt / V0.

[0984] V0 is the tumor volume measured at the time of group administration (i.e., d0), and Vt is the tumor volume at each measurement.

[0985] Relative tumor proliferation rate T / C: T / C = TRTV / CRTV × 100%.

[0986] T is the test substance, and C is the model control group.

[0987] TRTV is the mean RTV of the test substance, CRTV 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-administered group) / mean tumor weight of the model control group × 100%.

[0988] Percentage change in body weight = Wn / W0×100%.

[0989] Wn: average body weight of experimental animals in each group on day n, W0: average body weight of experimental animals in each group on day 0.

[0990] 6.3 Experimental Results

[0991] Table 15 Effects on the growth of human small cell lung cancer NCI-H446 xenograft model

[0992] Biological Example 7

[0993] Effect of drug efficacy evaluation experiment on the growth of human gastric cancer NCI-N87 xenograft model

[0994] 7.1 Test method

[0995] The human gastric cancer NCI-N87 xenograft model was established subcutaneously in nude mice using the tumor block inoculation method. 3When tumors reached approximately 300 μg / cm2 and maintained stable growth, animals were randomly divided into groups (day 0, d0) using the remainder method and dosed. Tumor volumes were measured 2-3 times per week. After the dosing period, animals were sacrificed, and subcutaneous tumors were removed and weighed. Tumor volume and weight were used to evaluate the antitumor activity of the drug in this model.

[0996] 7.1.1 Grouping and Dosage Regimen

[0997] Table 16 Effects on the growth of human gastric cancer NCI-N87 xenograft model

[0998] Experimental animal grouping and dosing schedule

[0999] Note: “—” means no entry or no valid data.

[1000] 7.2 Evaluation indicators and statistical methods

[1001] The formula for calculating tumor volume is: volume = 0.5 × long diameter × short diameter 2 .

[1002] Relative tumor volume (RTV): RTV = Vt / V0.

[1003] V0 is the tumor volume measured at the time of group administration (i.e., d0), and Vt is the tumor volume at each measurement.

[1004] Relative tumor proliferation rate T / C: T / C = TRTV / CRTV × 100%.

[1005] T is the test substance, and C is the model control group.

[1006] TRTV is the mean RTV of the test substance, CRTV 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-administered group) / mean tumor weight of the model control group × 100%.

[1007] Percentage change in body weight = Wn / W0×100%.

[1008] Wn: average body weight of experimental animals in each group on day n, W0: average body weight of experimental animals in each group on day 0.

[1009] 7.3 Experimental Results

[1010] Table 17 Effects on the growth of human gastric cancer NCI-N87 xenograft model

[1011] Biological Example 8

[1012] Effect of irinotecan treatment on the growth of large human colon cancer HCT116 xenograft model

[1013] 8.1 Test method

[1014] First, a human colon cancer HCT116 xenograft model was established subcutaneously in nude mice using tumor block inoculation. After the xenograft tumor grew to a volume of 100-300 mm 3 When the tumor volume grew to 600 mm, 15 experimental animals were selected and given irinotecan (100 mg / kg qw×2). 3 When the tumor volume exceeds 500 μg / mL and maintains stable growth, the animals are randomly divided into groups using the remainder method according to tumor volume and dosed. Tumor volume is measured 2-3 times per week. After the dosing period, the animals are sacrificed, and the subcutaneous tumor is removed and weighed. Tumor volume and weight data are used to evaluate the antitumor activity of the drug against large tumors in this model treated with irinotecan.

[1015] 8.1.1 Grouping and Dosage Regimen

[1016] Table 18 Effect of irinotecan treatment on the growth of human colon cancer HCT116 large tumor xenograft model Experimental animal grouping and dosing regimen

[1017] Note: “—” means no entry or no valid data.

[1018] 8.2 Evaluation indicators and statistical methods

[1019] The formula for calculating tumor volume is: volume = 0.5 × long diameter × short diameter 2 .

[1020] Relative tumor volume (RTV): RTV = Vt / V0.

[1021] V0 is the tumor volume measured at the time of group administration (i.e., d0), and Vt is the tumor volume at each measurement.

[1022] Relative tumor proliferation rate T / C: T / C = TRTV / CRTV × 100%.

[1023] T is the test substance, and C is the model control group.

[1024] TRTV is the mean RTV of the test substance, CRTV 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-administered group) / mean tumor weight of the model control group × 100%.

[1025] Percentage change in body weight = Wn / W0×100%.

[1026] Wn: average body weight of experimental animals in each group on day n, W0: average body weight of experimental animals in each group on day 0.

[1027] 8.3 Experimental Results

[1028] 8.3.1 Model Tumor Growth Curve Before Grouping

[1029] On day 18 after modeling, the tumor volume was measured and the tumor volume range was selected as 90.36 mm 3 -187.06mm 3 (The average value is 142.55mm 3 Fifteen experimental animals (with a mean ± SD of 31.36) were treated with irinotecan (100 mg / kg qw x 2). Tumor growth was observed regularly after administration. The tumor growth curve is shown in Figure 1. On day 53 after modeling, the tumor volume of the model treated with irinotecan rebounded significantly, reaching a mean of 689.82 mm. 3 Therefore, the patients were divided into groups and given the compound of the present application for continued treatment.

[1030] 8.3.2 Effect of Irinotecan Treatment on the Growth of the Human Colon Cancer HCT116 Large Tumor Xenograft Model

[1031] Table 19 Effect of irinotecan treatment on the growth of human colon cancer HCT116 large tumor xenograft model

[1032] Biological Example 9

[1033] Multiple-dose toxicity evaluation experiment in mice

[1034] 9.1 Test method

[1035] Experimental animals were randomly divided into groups based on weight. Each group received the corresponding dose of compound via tail vein injection (iv). Grouping and dosing schedules are detailed in Table 2. Dosing schedules were adjusted as appropriate based on animal toxicity. Following dosing, the animals were regularly observed, and their weights and autopsies were recorded. At the end of the observation period, the animals were sacrificed and dissected to observe changes in major organs and assess the compound's toxic effects and recovery from toxicity.

[1036] 9.1.1 Grouping and Dosage Regimen

[1037] Table 20 Multiple-dose toxicity test protocol for mice

[1038] Note: “—” means no entry or no valid data

[1039] 9.2 Evaluation indicators and statistical methods

[1040] Percent change in body weight = Wn / W0×100%

[1041] (Wn: average weight of experimental animals in each group on day n, W0: average weight of experimental animals in each group on day 0)

[1042] Animal 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-measurement data 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-measurement data were considered to be correlated, and multivariate analysis of variance was used for inter-group statistical analysis.

[1043] 9.3 Experimental Results

[1044] By the end of the trial, no animals in any dosing group had died or were near death. The maximum tolerated dose (MTD) of the compound of the present invention for a single dose was greater than 150 mg / kg, and the maximum tolerated dose (MTD) for the total dose was greater than 300 mg / kg. This suggests that the compound of the present invention has good safety and is well tolerated.

[1045] In this disclosure, relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any actual relationship or order between these entities or operations.

[1046] It will be appreciated from the foregoing that, although specific embodiments of the present disclosure have been described for illustrative purposes, various modifications or variations may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. Such modifications or variations are intended to fall within the scope of the appended claims of the present disclosure.

Claims

1. Compounds of general formula (I), their stereoisomers, and cis-trans isomers: in, R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids; R2 is selected from hydrogen, C1-C8 hydrocarbon group; R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 hydrocarbon group, C1-C8 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group; R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8) m , C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides; R5 is selected from hydrogen, C1-C8 hydrocarbon group; R6 is selected from hydrogen, C1-C8 hydrocarbon, C1-C8 alkylene amino (C1-C4 hydrocarbon) 2, C1-C8 Alkylidenethio C1-C8 alkyl, C1-C9 alkylene-oxy-C1-C9 alkyl; R5 and R6 can be connected to form a ring, and when R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring; R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene; n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond; R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C8 alkyl or aromatic alkyl group, a C1-C8 alkyleneamino C1-C8 alkylene, a C1-C8 alkylenethio C1-C8 alkylene, or a C1-C8 alkyleneoxy C1-C8 alkylene; m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond; R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups; R 10 Selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups; R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids; R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids; R 13 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups; R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups; R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups; R1, R 11 、R 12 The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine.

2. The compound of general formula (I) according to claim 1, its stereoisomers, and cis-trans isomers: in, R1 is selected from hydrogen, C1-C4 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids; R2 is selected from hydrogen, C1-C4 hydrocarbon group; R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C4 hydrocarbon group, C1-C4 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group; R4 is selected from C1-C6 alkylene, C1-C6 alkyleneoxy, C1-C6 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8)m, C1-C4 alkylene-aromatic subunit, C1-C4 alkylene-aromatic subunit-C1-C4 alkylene, C1-C4 alkylene-aromatic subunit-aromatic subunit, C1-C4 alkylene-heteroaromatic subunit-C1-C4 alkylene, amino acid peptide chain; wherein the amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides; R5 is selected from hydrogen, C1-C4 hydrocarbon group; R6 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkyleneamino (C1-C4 alkyl) 2, C1-C4 alkylenethio C1-C4 alkyl, C1-C4 alkylene-oxy-C1-C4 alkyl; R5 and R6 can be connected to form a ring. When R5 and R6 are connected to form a ring, the whole ring can be five a 1-membered ring or a 6-membered ring; R7 is selected from hydrogen, C1-C4 alkyleneoxy, amino C1-C4 alkylene, thio C1-C4 alkylene, oxy C1-C4 alkylene; n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when n is equal to 0, -(CH2R7)n represents a covalent bond; R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C4 alkyl or aromatic alkyl group, a C1-C4 alkyleneamino C1-C4 alkylene, a C1-C4 alkylenethio C1-C4 alkylene, or a C1-C4 alkyleneoxy C1-C4 alkylene; m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; when m represents 0, -(R8) m represents a covalent bond; R9 is selected from one or more hydrogen, halogen, cyano, C1-C4 hydrocarbon, C1-C4 alkoxy, C5-C 12 aromatic groups; R 10 Selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups; R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids; R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids; R 13 Selected from hydrogen, C1-C4 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups; R 14 Selected from hydrogen, C1-C4 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups; R 15 Selected from hydrogen, C1-C4 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups; R1, R 11 、R 12 The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, and homoalanine.

3. The compound of general formula (I) according to claim 1 or 2, its stereoisomers, cis-trans isomers, R1 is selected from hydrogen, -CH3, -CH2CH3, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids; R2 is selected from hydrogen, -CH3, -CH2CH3; R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, -F-, -Cl, -Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH2CH2CH3, phenyl, benzyl, -NO2, -NH2, -N(CH3)2; R4 is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2OCH2-, -CH2OCH2CH2-, -CH2OCH2CH2OCH2-, -CH2OCH2CH2OCH2CH2OCH2-, -CH2OCH2CH2OCH2CH2OCH2CH2OCH2-, -CH2CH2OCH2CH2CH2OCH2 -, -CH2CH2OCH2CH2CH2OCH2CH2CH2OCH2-, -CH2CH2OCH2CH2CH2OCH2CH2CH2OCH2CH2CH2OCH2-, -CH2CH2OCH2-, -CH2CH2OCH2CH2CH2OCH2CH2-, -CH2CH2OCH2CH2CH2OCH2-、-CH2NHCH2CH2NHCH2CH2NHCH2-、 A polypeptide composed of a combination of natural or unnatural amino acids, such as glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, homoalanine, or any combination thereof; the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides; R5 is selected from hydrogen, -CH3, -CH2CH3; R6 is selected from hydrogen, -CH3, -CH2OCH3, -CH2N(CH3)2, -CH2SCH(CH3)2; When R5 and R6 form a ring, the entire ring can be selected from a five-membered ring or a six-membered ring; R7 is selected from -H, -OCH2-, -OCH2CH2-, -OCH2CH2CH2-, -OCH2CH2CH2CH2-, -NHCH2-, -NHCH2CH2-, -NHCH2CH2CH2-, -NHCH2CH2CH 2CH2-, -SCH2-, -SCH2CH2-, -SCH2CH2CH2-, -SCH2CH2CH2CH2-, -CH2O-, -CH2CH2O-, -CH2CH2CH2O-, -CH2CH2CH2CH2O-; n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; When n is equal to 0, -(CH2R7)n represents a covalent bond; R8 is selected from -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2OCH2CH2-, -CH2CH2OCH2CH2CH2-, -CH2CH2CH2OCH2CH2-, -CH2CH2CH2OCH2CH2CH2-, -CH2SCH2CH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2-, -CH2CH2SCH2CH2CH2-, -CH2CH2CH2SCH2CH2-, -CH2CH2CH2SCH2CH2CH2-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, -C H2CH2NHCH2CH2-, -CH2CH2NHCH2CH2CH2-, -CH2CH2CH2NHCH2CH2-, -CH2CH2CH2NHCH2CH2CH2-, -CONHCH2-, -CONHCH2CH2-, -CONHCH2CH2CH2-, -C ON(CH3)CH2-, -CON(CH3)CH2CH2-, -CON(CH3)CH2CH2CH2-, -CONHCH(CH3)-, -CONHCH(CH3)CH2-, -CONHCH(CH3)CH2CH2-, -CONHCH2CH(CH3)CH2-, -CONHCH(CH3)CONHCH(CH3)CH2C6H5-,; m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9. When m represents 0, -(R8) m represents a covalent bond; R9 is selected from one or more arbitrarily substituted hydrogen, -F-, -Cl, -Br, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, phenyl; R 10 Selected from one or more hydrogen, -F-, -Cl, -Br, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, phenyl group substituted at any position; R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, homoalanine; R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NHR 13 R 14 R 15 、-NH3 + R 13 , glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, homoalanine; R 13 Selected from hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH2CH2CH2CH3, cyclohexanyl, phenyl, pyridyl, thienyl, imidazolyl, indolyl, quinolinyl, pyridoimidazolyl, pyridoindoleyl, imidazoquinolinyl, imidazoquinoxalinyl, imidazopyridinyl, benzoxazinyl; R 14 Selected from hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH2CH2CH2CH3, cyclohexanyl, phenyl, pyridyl, thienyl, imidazolyl, indolyl, quinolinyl, pyridoimidazolyl, pyridoindoleyl, imidazoquinolinyl, imidazoquinoxalinyl, imidazopyridinyl, benzoxazinyl; R 15 Selected from hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH2CH2CH2CH3, cyclohexanyl, phenyl, pyridyl, thienyl, imidazolyl, indolyl, quinolinyl, pyridoimidazolyl, pyridoindoleyl, imidazoquinolinyl, imidazoquinoxalinyl, imidazopyridinyl, benzoxazinyl.

4. The following compounds, their stereoisomers, and cis-trans isomers: (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-oxo- trisodium 3-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Disodium 4-amino-6-((E)-(4′-(6-(4-((3-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-6-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-tolyloxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Disodium 4-amino-6-((E)-(4′-(6-(4-((6-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methyl-3-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Disodium 4-amino-6-((E)-(4′-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Disodium 4-amino-6-((E)-(4′-(6-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Trisodium (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-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Disodium 4-amino-6-((E)-(4′-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Disodium 4-amino-6-((E)-(4′-(6-(4-((2-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Disodium 4-amino-6-((E)-(4′-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Disodium 4-amino-6-((E)-(4′-(6-(4-((2-((((S)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Trisodium (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-((((S)-10-((dimethylamino)methyl)-4-ethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (2S,3S,4S,5R,6S)-6-(3-((1-(8-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-8-oxooctyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-(((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline) trisodium 3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Disodium 4-amino-6-((E)-(4′-(8-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)octanamido)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Disodium 4-amino-6-((E)-(4′-(8-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)octanamido)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(8-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1′-biphenyl]-4-yl)amino)-8-oxooctyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(8-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-8-oxooctyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(2-(2-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-2-oxyethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; 4-amino-6-((E)-(4′-(2-(2-(2-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy (3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)acetamido)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid disodium salt; Disodium 4-amino-6-((E)-(4′-(2-(2-(2-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)acetamido)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(2-(2-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)amino)-2-oxyethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Disodium 4-amino-6-((E)-(4′-(2-(2-(2-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)acetamido)-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Disodium 4-amino-6-((E)-(4′-(2-(2-(2-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)acetamido)-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-(((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]) trisodium quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Disodium 4-amino-6-((E)-(4′-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; Disodium 4-amino-6-((E)-(4′-(6-(4-((2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(((2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)diazenyl)-5-hydroxynaphthalene-1,3-disulfonic acid; (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; Sodium 1-amino-7-((E)-(4′-(6-(4-((5-(((2S,3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)-2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)diazenyl)-8-hydroxy-4-sulfononaphthalene-2-sulfonate; (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid trilithium; (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-(((S)-4,11-diethyl-4-hydroxy -3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid triammonium; (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid tripotassium phosphate; (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid tricesium; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-fluorophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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)-2-chloro-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (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)-2-bromo-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl) trisodium carboxylate; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-ethylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-(1-(((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)ethyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-((6-((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)-5-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-[1,1′-biphenyl]-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (2S,3S,4S,5R,6S)-6-(2-amino-3-((1-(6-((4′-((E)-(8-amino-1-hydroxy trisodium trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-(dimethylamino)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-fluorophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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)-5-chloro-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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)-5-bromo-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (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-(((S)-4,11-diethyl-4-hydroxy trisodium 3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-((5-((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)-6-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-[1,1′-biphenyl]-3-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-ethylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-amino-5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(dimethylamino)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-(dimethylamino)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-3,4,5-trihydroxytetrahydro-2H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl) Trisodium furan-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-fluorophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(5-((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)-2-chloro-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(5-((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)-2-bromo-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-nitrophenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (2S,3S,4S,5R,6S)-6-((4-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonic trisodium 3-(((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-[1,1′-biphenyl]-2-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-ethylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(2-amino-5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(5-((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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-(dimethylamino)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-6-fluoro-2-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (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)-6-chloro-4-((((S)-4,11-diethyl-4- Trisodium hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-5-fluoro-2-methylphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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)-6-bromo-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-2-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-9-ethyl-9-hydroxy-10,13-dioxy-2,3,9,10,13,15-tetrahydro-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(4-((((S)-4-acetoxy-4-ethyl-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)-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)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4-ethyl-3,14-dioxy-4-(propionyloxy)-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (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-((((S)-4-ethyl-4-(glycyloxy)-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid tris(II) sodium; (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-(((R)-5-ethyl-5-hydroxy-3,15-dioxy-4,5,13,15-tetrahydro-1H,3H-oxazoline)- trisodium 3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4-ethyl-4-hydroxy-10-(methoxymethyl)-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4-ethyl-4-hydroxy-10-((isopropylthio)methyl)-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4-ethyl-4-hydroxy-3-oxy-14-thio-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (2S,3S,4S,5R,6S)-6-(3-((1-(2-((2-((2-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl)(methyl)amino)-2-oxoethyl trisodium trihydroxytetrahydro-2H-pyran-2-carboxylate; (2S,3S,4S,5R,6S)-6-(3-((1-(2-((2-((2-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino trisodium ((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate); (2S,3S,4S,5R,6S)-6-(3-((1-(2-(((S)-1-(((S)-1-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)amino)- trisodium 2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (2S,3S,4S,5R,6S)-6-(3-((1-(2-(((S)-1-(((S)-1-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino) trisodium 3-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (2S,3S,4S,5R,6S)-6-(3-((1-(2-(2-(2-(2-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-2-oxoethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid trisodium; (2S,3S,4S,5R,6S)-6-(3-((1-(2-((2-((2-((2-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-2-oxoethyl)amino)ethyl)amino)ethyl)amino)ethyl)- trisodium 1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (2S,3S,4S,5R,6S)-6-(3-((1-(3-(3-(3-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-3-oxopropoxy)propoxy)propyl)-1H-1,2,3-triazol-4-yl)methoxy trisodium 4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(4-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)carbamoyl)phenethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)carbamoyl)naphthalen-2-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-(4′-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)carbamoyl)-[1,1′-biphenyl]-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(4-(4-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-4-oxobutyl)phenethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (2S,3S,4S,5R,6S)-6-(3-((1-(2-(6-(4-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-4-oxobutyl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5- Trisodium trihydroxytetrahydro-2H-pyran-2-carboxylate; (2S,3S,4S,5R,6S)-6-(3-((1-(2-(5-(4-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-4-oxobutyl)thiophen-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid trisodium; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′,5,5′-tetramethyl-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-2,2′,3,3′,5,5′,6,6′-octamethyl-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-2,2′,3,3′,5,5′,6,6′-octamethoxy-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′,5,5′-tetrachloro-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonic trisodium trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3′-chloro-3-methoxy-5,5′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((6′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-[1,1′:3′,1″:3″,1″′-tetraphenyl]-4″-yl)-amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-difluoro-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dichloro-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; (2S,3S,4S,5R,6S)-6-(3-((1-(6-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dibromo-[1,1′-biphenyl]-4-yl)amino)-6-oxohexyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-(((S)-4,11-diethyl-4-hydroxy trisodium 3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(5-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-5-oxopentyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (2S,3S,4S,5R,6S)-6-(3-((1-(2-((4′-((E)-(8-amino-1-hydroxy-5,7-disulfonatonaphthalen-2-yl)diazenyl)-3,3′-dimethyl-[1,1′-biphenyl]-4-yl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate; Trisodium (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-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate.

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or its stereoisomers, cis-trans isomers and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 5 , which is prepared as an injection preparation.

7. The pharmaceutical composition according to claim 6, wherein the injection preparation is an injection solution, sterile powder for injection and concentrated solution for injection.

8. A method for treating tumors or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 4 or its stereoisomers, cis-trans isomers, or the pharmaceutical composition according to any one of claims 5 to 7.

9. The method of claim 8, wherein the tumor or cancer is selected from colorectal cancer, lung cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, bladder cancer, liver cancer, stomach cancer, intestinal cancer, head and neck cancer, uterine cancer, urothelial carcinoma, osteosarcoma, sarcoma, kidney cancer, melanoma, prostate cancer, glioma, neuroglioma, leukemia.

10. A method for preparing a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof of its stereoisomers or cis-trans isomers: R1 is selected from hydrogen, C1-C8 hydrocarbon, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH + 3R 13 , natural or unnatural amino acids; R2 is selected from hydrogen, C1-C8 hydrocarbon group; R3 is selected from one or more substituents substituted at any position, the substituents being selected from hydrogen, halogen, C1-C8 hydrocarbon group, C1-C8 hydrocarbon oxy group, cyano group, nitro group, amino group, aromatic group, aromatic hydrocarbon group, and amino group substituted with C1-C4 hydrocarbon group; R4 is selected from C1-C9 alkylene, C1-C8 alkyleneoxy, C1-C8 hydrocarbon substituted or unsubstituted C3-C8 heteroaromatic ring group, C1-C8 hydrocarbon substituted or unsubstituted C3-C 15 Aromatic ring group, -(CH2R7)n, -(R8) m , C1-C9 alkylene-aromatic subunit, C1-C9 alkylene-aromatic subunit-C1-C9 alkylene, C1-C9 alkylene-aromatic subunit-aromatic subunit, C1-C9 alkylene-heteroaromatic subunit-C1-C9 alkylene, amino acid peptide chain; wherein, The amino acid peptide chain is composed of natural or non-natural amino acids, and the polypeptide chain length is 1-100 peptides, preferably 1-50 peptides, and more preferably 1-20 peptides; R5 is selected from hydrogen, C1-C8 hydrocarbon group; R6 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkyleneamino (C1-C4 alkyl) 2, C1-C8 alkylenethio C1-C8 alkyl, C1-C9 alkylene-oxy-C1-C9 alkyl; R5 and R6 can be connected to form a ring, and when R5 and R6 are connected to form a ring, the entire ring can be a five-membered ring or a six-membered ring; R7 is selected from hydrogen, C1-C8 alkyleneoxy, amino C1-C8 alkylene, thio C1-C8 alkylene, oxy C1-C8 alkylene; n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; When n is equal to 0, -(CH2R7)n represents a covalent bond; R8 is selected from carbonylamino, wherein the amino group may be substituted by a C1-C8 alkyl or aromatic alkyl group, a C1-C8 alkyleneamino C1-C8 alkylene, a C1-C8 alkylenethio C1-C8 alkylene, or a C1-C8 alkyleneoxy C1-C8 alkylene; m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9; When m represents 0, -(R8) m represents a covalent bond; R9 is selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups; R 10 Selected from one or more hydrogen, halogen, cyano, C1-C8 hydrocarbon, C1-C8 alkoxy, C5-C 12 aromatic groups; R 11 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids; R 12 Selected from hydrogen, -Na, -Li, -K, -Cs, -NH4 + 、-NH2 + R 13 R 14 、-NH + R 13 R 14 R 15 、-NH3 + R 13 , natural or unnatural amino acids; R 13 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups; R 14 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups; R 15 Selected from hydrogen, C1-C8 hydrocarbon group, C1-C8 cycloalkyl group, C5-C 18 Aromatic, C5-C 18 heteroaromatic groups; R1, R 11 、R 12 The natural or unnatural amino acid is selected from glycine, alanine, valine, leucine, isoleucine, methionine (methionine), proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, sarcosine, pyrrolysine, homoalanine: The preparation method comprises: (1) reacting the compound of general formula (AI) with the compound of general formula (A-II) to obtain the compound of general formula (A-III), Among them, R4', R9', R 10 ' represents the group and the R4, R9, R 10 The same definition as; (2) reacting the compound of general formula (A-III) with sodium azide to obtain the compound of general formula (A-IV), Among them, R4', R9', R 10 ' represents the group and the R4, R9, R 10 The same definition as; (3) Compound of general formula (A-IV) and 4-amino-5-hydroxy-1,3-naphthalene disulfonic acid monosodium salt The reaction is carried out to obtain a compound of formula (AV), Among them, R4', R9', R 10 ' represents the group and the R4, R9, R 10 The same definition as; (4) reacting the compound of formula (BI) with carbon tetrabromide to obtain the compound of formula (B-II), Wherein, the groups represented by R1', R2', and R3' in the general formula (BI) and the general formula (B-II) have the same definitions as R1, R2, and R3 in the general formula (I); (5) reacting the compound of formula (B-II) with the compound of formula (B-III) to obtain the compound of formula (B-IV) Wherein, the groups represented by R1', R2', R3', R5', and R6' in general formula (B-II), general formula (B-III), and general formula (B-IV) are the same as those defined for R1, R2, R3, R5, and R6 in general formula (I); (6) The compound of formula (B-IV) is reacted under alkaline conditions to obtain the compound of formula (BV) Wherein, the groups represented by R1', R2', R3', R5', and R6' in the general formula (B-IV) and the general formula (BV) are the same as those defined for R1, R2, R3, R5, and R6 in the general formula (I); (7) reacting the compound of formula (AV) with the compound of formula (BV) to obtain the compound of formula (I), or reacting the compound of formula (AV) with the compound of formula (BV) to obtain a product and forming a pharmaceutically acceptable salt thereof with a corresponding acid or base. Among them, R2', R3', R4', R5', R6', R9', R 10 ' represents the group and the R2, R3, R4, R5, R6, R9, R 10 , have the same definition.

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