Triptolide conjugates and their use

Abstract

This disclosure provides triptolide conjugates, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, as well as methods of using such compounds in the treatment of conditions / diseases such as those associated with cancer, immunomodulation and / or inflammation.

Description

[Technical Field]

[0001] Related applications This application claims the benefit of priority from U.S. Provisional Application 63 / 068,898, filed on 21 August 2020, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Triptolide, a bioactive compound isolated from the plant Tripterygium wilfordii Hook F, has been widely used in traditional Chinese medicine to treat diseases or disorders associated with immunomodulation and anti-inflammatory effects. Triptolide has attracted the attention of research in recent decades due to its potential therapeutic uses for immunosuppression, anti-inflammatory effects, cancer treatment, and neuroprotection. [Ziaei S., Halaby R. Immunosuppressive, anti-inflammatory and anti-cancer properties of triptolide: A mini review. Avicenna, J. Phytomed. Avicenna, J. Phytomed. 2016, 6(2), 149~64; Yuan K., Li X., Lu Q. et al. Application and mechanisms of triptolide in the treatment of inflammatory diseases - a review. Front. Pharmacol. 2019, 10, 1469; Noel P., Von Hoff DD, Saluja AK et al. Triptolide and its derivatives as cancer therapies.] Trends in Pharmacol.Sci. 2019, 40(5), 327~41;Zhang B., Song C., Feng B., Fan W.Neuroprotection by triptolide against cerebral ischemia / reperfusion injury through the inhibition of NF-κB / PUMA signal in rats. Ther.Clin.Risk Manag.2106, 12, 817~824.]

[0003] However, there are several drawbacks associated with the use of triptolide, including poor water solubility, a narrow therapeutic index, and a very short in vivo half-life, which limit preclinical development and clinical application. [Patil S., Lis LG, Schumacher RJ et al., Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts. J. Med. Chem. 2015, 58, 9334~44; and Zhao Y., Miao D., Hou S., Huang Q. Compositions of Schisandra Extracts and Methods Thereof. [WO2018 / 200143A2, 2018.] To address the poor water solubility of triptolides, several prodrugs have been developed using the chemical components: carboxylic acids [Dai, D., Yuan, H., Musser, J.H. Preparation of triptolide prodrugs having high aqueous solubility. WO02070472, 2002], amino acids [Musser, J.H. Synthesis of triptolide prodrugs having high aqueous solubility for immunosuppressive and anti-inflammatory treatment. WO0012483, 2000], and phosphonooxymethyl esters [Georg EG, Patil SP, Saluja AK, Chugh R., Vickers SMT Triptolide Prodrugs. [WO2010129918A1, 2010] Hydroquinone-derived carboxylic acid ester [Peng Z., Liu M., Du Q., Yang Y., Song W., Chen Y. Preparation of water-soluble triptolide derivatives useful as anticancer agents.[CN110003304A, 2019], polyethylene glycol [Lin Y., Huang X., Yan.D. A water-soluble triptolide prodrug using polyethylene glycol as carrier, its preparation method and application. CN104629036A, 2015], or carboxylated chitosan [Zeng H., Zhang Z., Yan M. et al. Preparation method and application of triptolide-carboxylated chitosan conjugate in preparing drug for treating rheumatic arthritis, cancer and Alzheimer's disease. CN 109464675A, 2019.]. These prodrugs have better water solubility; however, their therapeutic index and / or half-life times do not change significantly compared to triptolide due to the lack of a targeted prodrug and the rapid release of triptolide into the bloodstream. To increase the therapeutic targeting of cancer treatments, triptolides have recently been conjugated with glucose, and their transport by tumors overexpressing glucose transporters has been investigated [He Q., Minn L., Wang Q. et al., Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation. Angew. Chem. Int. Ed. Engl. 2016, 55(39), 12035~9; and Liu J., He Q., Minn L., Yu B., Wang Q., Glucose Conjugate of Triptolide, Analogs and Uses Thereof.].[WO2017 / 136739A1, 2017] or clinically available anti-EGFR monoclonal antibodies for forming antibody-drug conjugates [Zhang K., Ma Y., Guo Y. et al., Cetuximab-triptolide conjugate suppresses the growth of EGFR-overexpressing lung cancers through targeting RNA polymerase II. Mol.Ther.Oncolytics. 2020, 18, 304-316.] have been enabled, and both of these have shown higher therapeutic indices in preclinical models. Therefore, there is still a need to develop triptolide conjugates with good water solubility, higher therapeutic indices and / or longer half-lives. [Overview of the Initiative]

[0004] This disclosure addresses this need by providing triptolide conjugates having good water solubility, a higher therapeutic index and / or a longer half-life; methods for producing such compounds; pharmaceutical compositions and pharmaceuticals containing such compounds; and similarly, methods for using such compounds in the treatment of a condition / disease.

[0005] A compound of formula (I), or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof is provided in one embodiment:

[0006] [ka] During the ceremony, m1, m2, n1, and n2 are each independently between 0 and 15; R1, R2, and R3 are each independently OH, H, halo, unsubstituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C10 a carboxyl ester, an unsubstituted or substituted C1-C 10 alkyl ketone, or an unsubstituted or substituted C1-C 10 alkyl ether; M1 is selected from a bond, -C=O-, -OPO2-, -SO2-, -NH(CO)-, -(CO)NH-, -CH2OPO2-, -CH2OCO-, and -CH2O-; M2 is selected from C and Si; X1, X2, X3, X4 and X5 are each independently a bond, C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, O, S, S-S, Se-Se-, NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, L2-(CO)NH, -(CO)NH-L2, (CO)NH-L2-NH(CO), NR-L2-NR, L2-O, O-L2, an unsubstituted or substituted C1-C 10 alkylene, an unsubstituted or substituted C3-C 10 cycloalkylene, an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, an unsubstituted or substituted C1-C 10 heterocyclylene, or an unsubstituted or substituted peptide containing from 1 to 10 natural amino acids; each L1 is each independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, an unsubstituted or substituted C1-C 10 heterocyclylene; each L2 is each independently an unsubstituted or substituted C1-C 10 alkylene; each R is independently an unsubstituted or substituted C1-C 10 alkyl, an unsubstituted or substituted C3-C 10 cycloalkyl, an unsubstituted or substituted C1-C 10 acyl, an unsubstituted or substituted C1-C 10 carboxyl ester, an unsubstituted or substituted C1-C 10 alkyl ketone, or an unsubstituted or substituted C1-C 10Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, or unsubstituted or substituted C1-C 10 It is a heterocycline; X5 is attached to one of R4, R5, R6, R7, and R8; the remaining R4, R5, R6, R7, and R8 not attached to X5 are each independently H, OH, O(CO)NH2, halo, NH(C1~C) 10 O(C1~C) is either acyl, unsubstituted, or substituted. 10 Alkyl), unsubstituted or substituted O(C3~C 10 O(C1~C) (cycloalkyl), unsubstituted or substituted O(C1~C) 10 C1-C (acyl), non-substituted or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, unsubstituted or substituted C1-C 10 Heterocyclines are unsubstituted or substituted peptides containing 1 to 10 amino acids, or they form glycosidic bonds with native monosaccharides.

[0007] A compound of formula (II), or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof is provided in one embodiment:

[0008] [ka] During the ceremony, n1 and n2 are each independently between 0 and 15; R1 and R2 are, independently, OH, H, halo, unsubstituted or substituted C1-C. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C10 Alkyl ketones, or unsubstituted or substituted C1-C 10 It is an alkyl ether; X1, X2, and X3 are each independently bonded, C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, L2-(CO)O, O(CO)-L2, O, S, SS, Se-Se-, NH, NR, NH(CO), (CO)NH, L2-(CO)NH, (CO)NH-L2, L2-NH(CO), NH(CO)-L2, NH(CO)-L2-NH(CO), -NR-L2-NR, L2-O, O-L2, L2-NR, NR-L2, unsubstituted or substituted C1~C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes, unsubstituted or substituted arylenes, unsubstituted or substituted heteroarylenes, unsubstituted or substituted C1-C 10 Heterocyclylene, or unsubstituted or substituted peptides containing 1 to 10 native amino acids; Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C 10 It is a heterocycline; Each L2 independently determines whether C1-C is non-substitutive or substituted. 10 It is alkylene; Each R is independently either non-substituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, or unsubstituted or substituted C1-C 10 It is a heterocycline; X3 is attached to one of R3, R4, R5, R6, and R7, and the remaining R3, R4, R5, R6, and R7 not attached to X3 are, independently, H, OH, O(CO)NH2, halo, an unsubstituted or substituted amino group, and an unsubstituted or substituted C1-C. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, unsubstituted or substituted C1-C 10 Heterocyclines are unsubstituted or substituted peptides containing 1 to 10 amino acids, or they form glycosidic bonds with native monosaccharides.

[0009] A compound of formula (III), or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof is provided in one embodiment:

[0010] [ka] During the ceremony, m1, m2, and m3 are each independently between 0 and 15; M1 is selected from -CO-, -OPO2-, -SO2-, -CH2OPO2, -CH2OCO-, and -CH2O-; R1, R2, and R3 are each independently OH, H, halo, unsubstituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C10 It is an alkyl ether; X1, X2, and X3 are each independently bonded, C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, O, S, SS, Se-Se-, NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2, unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes, unsubstituted or substituted arylenes, unsubstituted or substituted heteroarylenes, unsubstituted or substituted C1-C 10 Heterocyclylene, or unsubstituted or substituted peptides containing 1 to 10 native amino acids; Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C 10 It is a heterocycline; Each L2 independently determines whether C1-C is non-substitutive or substituted. 10 It is alkylene; Each R is independently either non-substituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, or unsubstituted or substituted C1-C 10 It is a heterocycline; R4 is NHR', NHCOR', NHCOOR', CONHR', or COOR'; Each R' is C1-C of H, unsubstituted or substituted. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C3-C 10 Cycloalkyl (C1~C 10C1-C (alkyl), unsubstituted or substituted 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, unsubstituted or substituted C1-C 10 Heterocyclines, or unsubstituted or substituted C1-C 10 Heterocycline (C1~C 10 Alkyl) is; R5 is either non-substituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted C1-C 10 It is a heterocycline.

[0011] A compound of formula (IV), or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof is provided in one embodiment:

[0012] [ka] During the ceremony, n1 and n2 are each independently between 0 and 15; R1 and R2 are, independently, OH, H, halo, unsubstituted or substituted C1-C. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 It is an alkyl ether; X1, X2, and X3 are each independently a bond, C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, O, S, S-S, Se-Se-, NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2, L2-NH, NH-L2, an unsubstituted or substituted C1-C 10 alkylene, an unsubstituted or substituted C3-C 10 cycloalkylene, an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, an unsubstituted or substituted C1-C 10 heterocyclylene, or an unsubstituted or substituted peptide containing 1 to 10 natural amino acids; Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, an unsubstituted or substituted C1-C 10 heterocyclylene;[[ID=...]] Each L2 is independently an unsubstituted or substituted C1-C 10 alkylene; Each R is independently an unsubstituted or substituted C1-C 10 alkyl, an unsubstituted or substituted C3-C 10 cycloalkyl, an unsubstituted or substituted C1-C 10 acyl, an unsubstituted or substituted C1-C 10 carboxyl ester, an unsubstituted or substituted C1-C 10 alkyl ketone, or an unsubstituted or substituted C1-C 10 alkyl ether, an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, or an unsubstituted or substituted C1-C 10 heterocyclyl; A is an unsubstituted or substituted C3-C 15 cycloalkyl, an unsubstituted or substituted C1-C 15 heterocyclyl, an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, or an oligosaccharide containing 3 to 15 same or different monosaccharides.

[0013] It should be noted that the original text seems to be incomplete in some parts where the carbon atom number range is not fully specified. The translation is based on the existing text as accurately as possible while maintaining the specific tags and structures.A pharmaceutical composition comprising one of the compounds disclosed herein or their enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, or pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient is also provided herein in one embodiment.

[0014] Methods for treating cancer in a subject requiring such treatment are also provided herein, comprising administering a therapeutically effective amount of the compound, or one of its enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, or pharmaceutically acceptable salts thereof, to the subject. In some embodiments, the cancer is hepatocellular carcinoma (HCC), lung cancer, breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, or glioblastoma.

[0015] Methods for treating immunomodulatory and / or inflammation-related diseases or disorders in subjects requiring such treatment are also provided herein, comprising administering a therapeutically effective amount of the compound, or one of its enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, or pharmaceutically acceptable salts thereof, to a subject. In some embodiments, the disease or disorder is related to an inflammatory and / or autoimmune disease. In some embodiments, the inflammatory and / or inflammation-related disease or disorder is membranous nephropathy (MN), lupus nephritis, systemic lupus erythematosus, kidney transplantation, renal fibrosis, inflammatory bowel disease, Crohn's disease, intestinal fibrosis, hepatic fibrosis, asthma, acute lung injury, pulmonary arterial hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis, or psoriasis. [Brief explanation of the drawing]

[0016] [Figure 1]This figure shows the tumor growth-time treatment curves for mice treated over a 3-week period: Group 1 (control group; ip 0.5% CMC-Na / carboxymethylcellulose sodium; once daily); Group 2 (compound 1; 2.0 mg / kg, ip; once daily); Group 3 (compound 2; 2.0 mg / kg, ip; once daily); and Group 4 (lenvatinib; 5.0 mg / kg, oral; once daily). [Figure 2] This figure shows the average tumor weight for each mouse group 21 days after treatment: Group 1 (control group; ip 0.5% CMC-Na; once daily); Group 2 (compound 1; 2.0 mg / kg, ip; once daily); Group 3 (compound 2; 2.0 mg / kg, ip; once daily); and Group 4 (lenvatinib; 5.0 mg / kg, oral; once daily). [Figure 3] This figure shows the tumor growth-time treatment curves for mice treated over a 4-week period: Group 1 (control group; ip brine; once daily); Group 2 (conjugate 4; 2.0 mg / kg, ip; once daily); Group 3 (conjugate 8; 6.0 mg / kg, ip; once daily); Group 4 (conjugate 9; 6.0 mg / kg, ip; once daily); and Group 5 (conjugate 10; 6.0 mg / kg, ip; once daily). [Figure 4] This figure shows the average tumor weight for each mouse group 28 days after treatment: Group 1 (control group; ip brine; once daily); Group 2 (conjugate 4; 2.0 mg / kg, ip; once daily); Group 3 (conjugate 8; 6.0 mg / kg, ip; once daily); Group 4 (conjugate 9; 6.0 mg / kg, ip; once daily); and Group 5 (conjugate 10; 6.0 mg / kg, ip; once daily). [Modes for carrying out the invention]

[0017] This disclosure provides triptolide conjugates that may have any one of the following desirable properties for preclinical development and clinical use, e.g., good water solubility, a higher therapeutic index, and / or a longer half-life. Such compounds, pharmaceutical compositions comprising such compounds, methods for preparing pharmaceuticals, as well as methods for using such compounds in the treatment of conditions / diseases such as cancer, immunomodulation, and / or inflammation-related conditions.

[0018] compound A compound of formula (I), or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof is provided in one embodiment:

[0019] [ka] During the ceremony, m1, m2, n1, and n2 are each independently between 0 and 15; R1, R2, and R3 are each independently OH, H, halo, unsubstituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 It is an alkyl ether; M1 is selected from the bonds -C=O-, -OPO2-, -SO2-, -NH(CO)-, -(CO)NH-, -CH2OPO2-, -CH2OCO-, and -CH2O-; M2 is selected from C and Si; X1, X2, X3, X4, and X5 are each independently bonded, C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, O, S, SS, Se-Se-, NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, L2-(CO)NH, -(CO)NH-L2, (CO)NH-L2-NH(CO), NR-L2-NR, L2-O, O-L2, unsubstituted or substituted C1~C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes, unsubstituted or substituted arylenes, unsubstituted or substituted heteroarylenes, unsubstituted or substituted C1-C 10 Heterocyclylene, or unsubstituted or substituted peptides containing 1 to 10 native amino acids; Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C 10 It is a heterocycline; Each L2 independently determines whether C1-C is non-substitutive or substituted. 10 It is alkylene; Each R is independently either non-substituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, or unsubstituted or substituted C1-C 10 It is a heterocycline; X5 is attached to one of R4, R5, R6, R7, and R8; the remaining R4, R5, R6, R7, and R8 not attached to X5 are each independently H, OH, O(CO)NH2, halo, NH(C1~C) 10 O(C1~C) is either acyl, unsubstituted, or substituted. 10 Alkyl), unsubstituted or substituted O(C3~C10 O(C1~C) (cycloalkyl), unsubstituted or substituted O(C1~C) 10 C1-C (acyl), non-substituted or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, unsubstituted or substituted C1-C 10 Heterocyclines are unsubstituted or substituted peptides containing 1 to 10 amino acids, or they form glycosidic bonds with native monosaccharides.

[0020] In some embodiments, m1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, m1 is 0. In some embodiments, m1 is 1. In some embodiments, m1 is 2. In some embodiments, m1 is 3. In some embodiments, m1 is 4. In some embodiments, m1 is 5. In some embodiments, m1 is 6. In some embodiments, m1 is 7. In some embodiments, m1 is 8. In some embodiments, m1 is 9. In some embodiments, m1 is 10. In some embodiments, m1 is 11. In some embodiments, m1 is 12. In some embodiments, m1 is 13. In some embodiments, m1 is 14. In some embodiments, m1 is 15.

[0021] In some embodiments, m2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, m2 is 0. In some embodiments, m2 is 1. In some embodiments, m2 is 2. In some embodiments, m2 is 3. In some embodiments, m2 is 4. In some embodiments, m2 is 5. In some embodiments, m2 is 6. In some embodiments, m2 is 7. In some embodiments, m2 is 8. In some embodiments, m2 is 9. In some embodiments, m2 is 10. In some embodiments, m2 is 11. In some embodiments, m2 is 12. In some embodiments, m2 is 13. In some embodiments, m2 is 14. In some embodiments, m2 is 15.

[0022] In some embodiments, n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, n1 is 0. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3. In some embodiments, n1 is 4. In some embodiments, n1 is 5. In some embodiments, n1 is 6. In some embodiments, n1 is 7. In some embodiments, n1 is 8. In some embodiments, n1 is 9. In some embodiments, n1 is 10. In some embodiments, n1 is 11. In some embodiments, n1 is 12. In some embodiments, n1 is 13. In some embodiments, n1 is 14. In some embodiments, n1 is 15.

[0023] In some embodiments, n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, n2 is 0. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4. In some embodiments, n2 is 5. In some embodiments, n2 is 6. In some embodiments, n2 is 7. In some embodiments, n2 is 8. In some embodiments, n2 is 9. In some embodiments, n2 is 10. In some embodiments, n2 is 11. In some embodiments, n2 is 12. In some embodiments, n2 is 13. In some embodiments, n2 is 14. In some embodiments, n2 is 15.

[0024] In some embodiments, R1 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, R1 is an OH group. In some embodiments, R1 is hydrogen. In some embodiments, R1 is a halo. In some embodiments, R1 is an unsubstituted or substituted C1-C group. 10 It is alkyl. In some embodiments, R1 is unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, R1 is an unsubstituted or substituted C1-C 10It is an alkyl ketone. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0025] In some embodiments, R2 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, R2 is an OH group. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halo. In some embodiments, R2 is an unsubstituted or substituted C1-C group. 10 It is alkyl. In some embodiments, R2 is unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0026] In some embodiments, R3 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10It is an alkyl ether. In some embodiments, R3 is an OH group. In some embodiments, R3 is hydrogen. In some embodiments, R3 is a halo. In some embodiments, R3 is an unsubstituted or substituted C1-C group. 10 It is alkyl. In some embodiments, R3 is unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, R3 is an unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, R3 is unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, R3 is an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, R3 is an unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0027] In some embodiments, M1 is one of the following: a bond; -C=O-; -OPO2-; -SO2-; -NH(CO)- or -(CO)NH-; and -CH2OPO2-, -CH2OCO-, or -CH2O-. In some embodiments, M1 is a bond. In some embodiments, M1 is -C=O-. In some embodiments, M1 is -OPO2-. In some embodiments, M1 is -SO2-. In some embodiments, M1 is NH(CO)- or -(CO)NH-. In some embodiments, M1 is -CH2OPO2-, -CH2OCO-, or -CH2O-. In some embodiments, M1 is -CH2OPO2. In some embodiments, M1 is -CH2OCO-. In some embodiments, M1 is -CH2O-.

[0028] In some embodiments, M2 is one of the following: C; and Si. In some embodiments, M2 is C. In some embodiments, M2 is Si.

[0029] In some embodiments, X1 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, L2-(CO)NH, -(CO)NH-L2, (CO)NH-L2-NH(CO), -NR-L2-NR, L2-O, or O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X1 is a bond. In some embodiments, X1 is C=O. In some embodiments, X1 is (C=O)-L1-(C=O). In some embodiments, X1 is (C=O)-L1. In some embodiments, X1 is L1-(C=O). In some embodiments, X1 is O(CO). In some embodiments, X1 is (CO)O. In some embodiments, X1 is O. In some embodiments, X1 is S. In some embodiments, X1 is SS. In some embodiments, X1 is Se-Se-. In some embodiments, X1 is NH. In some embodiments, X1 is NR. In some embodiments, X1 is NH(CO). In some embodiments, X1 is (CO)NH. In some embodiments, X1 is L2-NH(CO). In some embodiments, X1 is NH(CO)-L2. In some embodiments, X1 is L2-(CO)NH. In some embodiments, X1 is -(CO)NH-L2. In some embodiments, X1 is (CO)NH-L2-NH(CO). In some embodiments, X1 is -NR-L2-NR. In some embodiments, X1 is L2-O. In some embodiments, X1 is O-L2. In some embodiments, X1 is unsubstituted or substituted C1~C 10It is an alkylene. In some embodiments, X1 is unsubstituted or substituted C3-C 10 It is a cycloalkylene. In some embodiments, X1 is an unsubstituted or substituted arylene. In some embodiments, X1 is an unsubstituted or substituted heteroarylene. In some embodiments, X1 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X1 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0030] In some embodiments, X2 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, L2-(CO)NH, -(CO)NH-L2, (CO)NH-L2-NH(CO), -NR-L2-NR, L2-O, or O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X2 is a bond. In some embodiments, X2 is C=O. In some embodiments, X2 is (C=O)-L1-(C=O). In some embodiments, X2 is (C=O)-L1. In some embodiments, X2 is L1-(C=O). In some embodiments, X2 is O(CO). In some embodiments, X2 is (CO)O. In some embodiments, X2 is O. In some embodiments, X2 is S. In some embodiments, X2 is SS. In some embodiments, X2 is Se-Se-. In some embodiments, X2 is NH. In some embodiments, X2 is NR. In some embodiments, X2 is NH(CO). In some embodiments, X2 is (CO)NH. In some embodiments, X2 is L2-NH(CO). In some embodiments, X2 is NH(CO)-L2. In some embodiments, X2 is L2-(CO)NH. In some embodiments, X2 is -(CO)NH-L2. In some embodiments, X2 is (CO)NH-L2-NH(CO). In some embodiments, X2 is -NR-L2-NR. In some embodiments, X2 is L2-O. In some embodiments, X2 is O-L2. In some embodiments, X2 is unsubstituted or substituted C1-C 10 It is an alkylene. In some embodiments, X2 is unsubstituted or substituted C3~C 10 It is a cycloalkylene. In some embodiments, X2 is an unsubstituted or substituted arylene. In some embodiments, X2 is an unsubstituted or substituted heteroarylene. In some embodiments, X2 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X2 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0031] In some embodiments, X3 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, L2-(CO)NH, -(CO)NH-L2, (CO)NH-L2-NH(CO), -NR-L2-NR, L2-O, or O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X3 is a bond. In some embodiments, X3 is C=O. In some embodiments, X3 is (C=O)-L1-(C=O). In some embodiments, X3 is (C=O)-L1. In some embodiments, X3 is L1-(C=O). In some embodiments, X3 is O(CO). In some embodiments, X3 is (CO)O. In some embodiments, X3 is O. In some embodiments, X3 is S. In some embodiments, X3 is SS. In some embodiments, X3 is Se-Se-. In some embodiments, X3 is NH. In some embodiments, X3 is NR. In some embodiments, X3 is NH(CO). In some embodiments, X3 is (CO)NH. In some embodiments, X3 is L2-NH(CO). In some embodiments, X3 is NH(CO)-L2. In some embodiments, X3 is L2-(CO)NH. In some embodiments, X3 is -(CO)NH-L2. In some embodiments, X3 is (CO)NH-L2-NH(CO). In some embodiments, X3 is -NR-L2-NR. In some embodiments, X3 is L2-O. In some embodiments, X3 is O-L2. In some embodiments, X3 is unsubstituted or substituted C1-C 10It is an alkylene. In some embodiments, X3 is unsubstituted or substituted C3-C 10 It is a cycloalkylene. In some embodiments, X3 is an unsubstituted or substituted arylene. In some embodiments, X3 is an unsubstituted or substituted heteroarylene. In some embodiments, X3 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X3 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0032] In some embodiments, X4 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, L2-(CO)NH, -(CO)NH-L2, (CO)NH-L2-NH(CO), -NR-L2-NR, L2-O, or O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X4 is a bond. In some embodiments, X4 is C=O. In some embodiments, X4 is (C=O)-L1-(C=O). In some embodiments, X4 is (C=O)-L1. In some embodiments, X4 is L1-(C=O). In some embodiments, X4 is O(CO). In some embodiments, X4 is (CO)O. In some embodiments, X5 is O. In some embodiments, X4 is S. In some embodiments, X4 is SS. In some embodiments, X4 is Se-Se-. In some embodiments, X4 is NH. In some embodiments, X4 is NR. In some embodiments, X4 is NH(CO). In some embodiments, X4 is (CO)NH. In some embodiments, X4 is L2-NH(CO). In some embodiments, X4 is NH(CO)-L2. In some embodiments, X4 is L2-(CO)NH. In some embodiments, X4 is -(CO)NH-L2. In some embodiments, X4 is (CO)NH-L2-NH(CO). In some embodiments, X4 is -NR-L2-NR. In some embodiments, X4 is L2-O. In some embodiments, X4 is O-L2. In some embodiments, X4 is unsubstituted or substituted C1-C 10 It is an alkylene. In some embodiments, X4 is unsubstituted or substituted C3-C 10 It is a cycloalkylene. In some embodiments, X4 is an unsubstituted or substituted arylene. In some embodiments, X4 is an unsubstituted or substituted heteroarylene. In some embodiments, X4 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X4 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0033] In some embodiments, X5 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, L2-(CO)NH, -(CO)NH-L2, (CO)NH-L2-NH(CO), -NR-L2-NR, L2-O, or O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X5 is a bond. In some embodiments, X5 is C=O. In some embodiments, X5 is (C=O)-L1-(C=O). In some embodiments, X5 is (C=O)-L1. In some embodiments, X5 is L1-(C=O). In some embodiments, X5 is O(CO). In some embodiments, X5 is (CO)O. In some embodiments, X5 is O. In some embodiments, X5 is S. In some embodiments, X5 is SS. In some embodiments, X5 is Se-Se-. In some embodiments, X5 is NH. In some embodiments, X5 is NR. In some embodiments, X5 is NH(CO). In some embodiments, X5 is (CO)NH. In some embodiments, X5 is L2-NH(CO). In some embodiments, X5 is NH(CO)-L2. In some embodiments, X5 is L2-(CO)NH. In some embodiments, X5 is -(CO)NH-L2. In some embodiments, X5 is (CO)NH-L2-NH(CO). In some embodiments, X5 is -NR-L2-NR. In some embodiments, X5 is L2-O. In some embodiments, X5 is O-L2. In some embodiments, X5 is unsubstituted or substituted C1-C 10It is an alkylene. In some embodiments, X5 is unsubstituted or substituted C3-C 10 It is a cycloalkylene. In some embodiments, X5 is an unsubstituted or substituted arylene. In some embodiments, X5 is an unsubstituted or substituted heteroarylene. In some embodiments, X5 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X5 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0034] In some embodiments, each L1 is independently an unsubstituted or substituted arylene; an unsubstituted or substituted heteroarylene; or an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, each L1 is independently an unsubstituted or substituted arylene. In some embodiments, each L1 is independently an unsubstituted or substituted heteroarylene. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0035] In some embodiments, each R is independently either unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryls; unsubstituted or substituted heteroaryls; or unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, each R is independently unsubstituted or substituted C1-C 10 It is alkyl. In some embodiments, each R is independently unsubstituted or substituted C3-C 10It is a cycloalkyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C1. 10 It is an acyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0036] In some embodiments, X5 is attached to R4; R5, R6, R7, and R8 are each independently: H; OH; O(CO)NH2; Halogen; NH(C1~C 10 Acyl; non-substituted or substituted O(C1~C 10 Alkyl); unsubstituted or substituted O(C3~C) 10 Cycloalkyl; unsubstituted or substituted O(C1~C) 10 Acyl; non-substitutional or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10Heterocyclyl; one of either unsubstituted or substituted peptides containing 1 to 10 amino acids; forming glycosidic bonds with native monosaccharides. In some embodiments, X5 is attached to R4; R5, R6, R7, and R8 are each independently H. In some embodiments, X5 is attached to R4; R5, R6, R7, and R8 are each independently OH. In some embodiments, X5 is attached to R4; R5, R6, R7, and R8 are each independently O(CO)NH2. In some embodiments, X5 is attached to R4; R5, R6, R7, and R8 are each independently halo. In some embodiments, X5 is attached to R4; R5, R6, R7, and R8 are each independently NH(C1~C 10 It is an acyl. In some embodiments, X5 is attached to R4; R5, R6, R7 and R8 are each independently unsubstituted or substituted O(C1~C 10 It is alkyl. In some embodiments, X5 is attached to R4; R5, R6, R7 and R8 are each independently unsubstituted or substituted O(C3~C 10 It is a cycloalkyl group. In some embodiments, X5 is attached to R4; R5, R6, R7 and R8 are each independently unsubstituted or substituted O(C1~C 10 It is an acyl. In some embodiments, X5 is attached to R4; R5, R6, R7 and R8 are each independently unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, X5 is attached to R4; R5, R6, R7 and R8 are each independently unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, X5 is attached to R4; R5, R6, R7 and R8 are each independently unsubstituted or substituted C1-C 10It is an alkyl ether. In some embodiments, X5 is attached to R4; R5, R6, R7 and R8 are each independently unsubstituted or substituted aryls. In some embodiments, X5 is attached to R4; R5, R6, R7 and R8 are each independently unsubstituted or substituted heteroaryls. In some embodiments, X5 is attached to R4; R5, R6, R7 and R8 are each independently unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, X5 is attached to R4; R5, R6, R7, and R8 are each independently unsubstituted or substituted peptides containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X5 is attached to R4; R5, R6, R7, and R8 each independently form glycosidic bonds with native monosaccharides.

[0037] In some embodiments, X5 is attached to R6; R4, R5, R7, and R8 are each independently: H; OH; O(CO)NH2; Halogen; NH(C1~C 10 Acyl; non-substituted or substituted O(C1~C 10 Alkyl); unsubstituted or substituted O(C3~C) 10 Cycloalkyl; unsubstituted or substituted O(C1~C) 10 Acyl; non-substitutional or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10Heterocyclyl; one of either unsubstituted or substituted peptides containing 1 to 10 amino acids; forming glycosidic bonds with native monosaccharides. In some embodiments, X5 is attached to R6; R4, R5, R7, and R8 are each independently H. In some embodiments, X5 is attached to R6; R4, R5, R7, and R8 are each independently OH. In some embodiments, X5 is attached to R6; R4, R5, R7, and R8 are each independently O(CO)NH2. In some embodiments, X5 is attached to R6; R4, R5, R7, and R8 are each independently halo. In some embodiments, X5 is attached to R6; R4, R5, R7, and R8 are each independently NH(C1~C 10 It is an acyl. In some embodiments, X5 is attached to R6; R4, R5, R7 and R8 are each independently unsubstituted or substituted O(C1~C 10 It is alkyl. In some embodiments, X5 is attached to R6; R4, R5, R7 and R8 are each independently unsubstituted or substituted O(C3~C 10 It is a cycloalkyl group. In some embodiments, X5 is attached to R6; R4, R5, R7 and R8 are each independently unsubstituted or substituted O(C1~C 10 It is an acyl. In some embodiments, X5 is attached to R6; R4, R5, R7 and R8 are each independently unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, X5 is attached to R6; R4, R5, R7 and R8 are each independently unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, X5 is attached to R6; R4, R5, R7 and R8 are each independently unsubstituted or substituted C1-C 10It is an alkyl ether. In some embodiments, X5 is attached to R6; R4, R5, R7 and R8 are each independently unsubstituted or substituted aryls. In some embodiments, X5 is attached to R6; R4, R5, R7 and R8 are each independently unsubstituted or substituted heteroaryls. In some embodiments, X5 is attached to R6; R4, R5, R7 and R8 are each independently unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, X5 is attached to R6; R4, R5, R7, and R8 are each independently unsubstituted or substituted peptides containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X5 is attached to R6; R4, R5, R7, and R8 each independently form glycosidic bonds with native monosaccharides.

[0038] In some embodiments, X5 is attached to R7; R4, R5, R6 and R8 are each independently: H; OH; O(CO)NH2; Halogen; NH(C1~C 10 Acyl; non-substituted or substituted O(C1~C 10 Alkyl); unsubstituted or substituted O(C3~C) 10 Cycloalkyl; unsubstituted or substituted O(C1~C) 10 Acyl; non-substitutional or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10Heterocyclyl; one of either unsubstituted or substituted peptides containing 1 to 10 amino acids; forming glycosidic bonds with native monosaccharides. In some embodiments, X5 is attached to R7; R4, R5, R6, and R8 are each independently H. In some embodiments, X5 is attached to R7; R4, R5, R6, and R8 are each independently OH. In some embodiments, X5 is attached to R7; R4, R5, R6, and R8 are each independently O(CO)NH2. In some embodiments, X5 is attached to R7; R4, R5, R6, and R8 are each independently halo. In some embodiments, X5 is attached to R7; R4, R5, R6, and R8 are each independently NH(C1~C 10 It is an acyl. In some embodiments, X5 is attached to R7; R4, R5, R6 and R8 are each independently unsubstituted or substituted O(C1~C 10 It is alkyl. In some embodiments, X5 is attached to R7; R4, R5, R6 and R8 are each independently unsubstituted or substituted O(C3~C 10 It is a cycloalkyl group. In some embodiments, X5 is attached to R7; R4, R5, R6 and R8 are each independently unsubstituted or substituted O(C1~C 10 It is an acyl. In some embodiments, X5 is attached to R7; R4, R5, R6 and R8 are each independently unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, X5 is attached to R7; R4, R5, R6 and R8 are each independently unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, X5 is attached to R7; R4, R5, R6 and R8 are each independently unsubstituted or substituted C1-C 10It is an alkyl ether. In some embodiments, X5 is attached to R7; R4, R5, R6 and R8 are each independently unsubstituted or substituted aryls. In some embodiments, X5 is attached to R7; R4, R5, R6 and R8 are each independently unsubstituted or substituted heteroaryls. In some embodiments, X5 is attached to R7; R4, R5, R6 and R8 are each independently unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, X5 is attached to R7; R4, R5, R6, and R8 are each independently unsubstituted or substituted peptides containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X5 is attached to R7; R4, R5, R6, and R8 each independently form glycosidic bonds with native monosaccharides.

[0039] In some embodiments, X5 is attached to R8; R4, R5, R6, and R7 are each independently: H; OH; O(CO)NH2; Halogen; NH(C1~C 10 Acyl; non-substituted or substituted O(C1~C 10 Alkyl); unsubstituted or substituted O(C3~C) 10 Cycloalkyl; unsubstituted or substituted O(C1~C) 10 Acyl; non-substitutional or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10Heterocyclyl; one of either unsubstituted or substituted peptides containing 1 to 10 amino acids; forming glycosidic bonds with native monosaccharides. In some embodiments, X5 is attached to R8; R4, R5, R6, and R7 are each independently H. In some embodiments, X5 is attached to R8; R4, R5, R6, and R7 are each independently OH. In some embodiments, X5 is attached to R8; R4, R5, R6, and R7 are each independently O(CO)NH2. In some embodiments, X5 is attached to R8; R4, R5, R6, and R7 are each independently halo. In some embodiments, X5 is attached to R8; R4, R5, R6, and R7 are each independently NH(C1~C 10 It is an acyl. In some embodiments, X5 is attached to R8; R4, R5, R6 and R7 are each independently unsubstituted or substituted O(C1~C 10 It is alkyl. In some embodiments, X5 is attached to R8; R4, R5, R6 and R7 are each independently unsubstituted or substituted O(C3~C 10 It is a cycloalkyl group. In some embodiments, X5 is attached to R8; R4, R5, R6 and R7 are each independently unsubstituted or substituted O(C1~C 10 It is an acyl. In some embodiments, X5 is attached to R8; R4, R5, R6 and R7 are each independently unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, X5 is attached to R8; R4, R5, R6 and R7 are each independently unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, X5 is attached to R8; R4, R5, R6 and R7 are each independently unsubstituted or substituted C1-C 10It is an alkyl ether. In some embodiments, X5 is attached to R8; R4, R5, R6 and R7 are each independently unsubstituted or substituted aryls. In some embodiments, X5 is attached to R8; R4, R5, R6 and R7 are each independently unsubstituted or substituted heteroaryls. In some embodiments, X5 is attached to R8; R4, R5, R6 and R7 are each independently unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, X5 is attached to R8; R4, R5, R6, and R7 are each independently unsubstituted or substituted peptides containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X5 is attached to R8; R4, R5, R6, and R7 each independently form glycosidic bonds with native monosaccharides.

[0040] In some embodiments of formula I, m1 and m2 are independently 0, 1, 2, 3, or 4. In some embodiments, n1 and n2 are independently 0, 1, 2, 3, or 4. In some embodiments, R1, R2, and R3 are each H. In some embodiments, M1 is -C=O-, -NH(CO)-, or -(CO)NH-; M2 is C. In some embodiments, X1 is a bond, and X2 is NH(CO) or (CO)NH. In some embodiments, X3 is O; X4 is (CO)NH-L2-NH(CO); X5 is NH(CO)-L2, L2-(CO)NH, L2-O, or O-L2. In some embodiments, X5 is attached to R4; R5, R6, R7, and R8 are independently OH or NH(C1~C 10 It is an acyl. In some embodiments, X5 is attached to R5; R4, R6, R7 and R8 are each independently OH or NH(C1~C 10 It is an acyl. In some embodiments, X5 is attached to R8; R4, R5, R6 and R7 are each independently OH or NH(C1~C 10 It is Ashiru.

[0041] A compound of formula (II), or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof is provided in one embodiment:

[0042] [ka] During the ceremony, n1 and n2 are each independently between 0 and 15; R1 and R2 are, independently, OH, H, halo, unsubstituted or substituted C1-C. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 It is an alkyl ether; X1, X2, and X3 are each independently bonded, C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, L2-(CO)O, O(CO)-L2, O, S, SS, Se-Se-, NH, NR, NH(CO), (CO)NH, L2-(CO)NH, (CO)NH-L2, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2, unsubstituted or substituted C1~C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes, unsubstituted or substituted arylenes, unsubstituted or substituted heteroarylenes, unsubstituted or substituted C1-C 10 Heterocyclylene, or unsubstituted or substituted peptides containing 1 to 10 native amino acids; Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C 10 It is a heterocycline; Each L2 independently determines whether C1-C is non-substitutive or substituted.10 It is alkylene; Each R is independently either non-substituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, or unsubstituted or substituted C1-C 10 It is a heterocycline; X3 is attached to one of R3, R4, R5, R6, and R7, and the remaining R3, R4, R5, R6, and R7 not attached to X3 are, independently, H, OH, O(CO)NH2, halo, an unsubstituted or substituted amino group, and an unsubstituted or substituted C1-C. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, unsubstituted or substituted C1-C 10 Heterocyclines are unsubstituted or substituted peptides containing 1 to 10 amino acids, or they form glycosidic bonds with native monosaccharides.

[0043] In some embodiments, n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, n1 is 0. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3. In some embodiments, n1 is 4. In some embodiments, n1 is 5. In some embodiments, n1 is 6. In some embodiments, n1 is 7. In some embodiments, n1 is 8. In some embodiments, n1 is 9. In some embodiments, n1 is 10. In some embodiments, n1 is 11. In some embodiments, n1 is 12. In some embodiments, n1 is 13. In some embodiments, n1 is 14. In some embodiments, n1 is 15.

[0044] In some embodiments, n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, n2 is 0. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4. In some embodiments, n2 is 5. In some embodiments, n2 is 6. In some embodiments, n2 is 7. In some embodiments, n2 is 8. In some embodiments, n2 is 9. In some embodiments, n2 is 10. In some embodiments, n2 is 11. In some embodiments, n2 is 12. In some embodiments, n2 is 13. In some embodiments, n2 is 14. In some embodiments, n2 is 15.

[0045] In some embodiments, R1 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, R1 is an OH group. In some embodiments, R1 is hydrogen. In some embodiments, R1 is a halo. In some embodiments, R1 is an unsubstituted or substituted C1-C group. 10 It is alkyl. In some embodiments, R1 is unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0046] In some embodiments, R2 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, R2 is an OH group. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halo. In some embodiments, R2 is an unsubstituted or substituted C1-C group. 10 It is alkyl. In some embodiments, R2 is unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, R2 is an unsubstituted or substituted C1-C 10It is a carboxyl ester. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0047] In some embodiments, X1 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, L2-(CO)O, or O(CO)-L2; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-(CO)NH, (CO)NH-L2, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X1 is a bond. In some embodiments, X1 is C=O. In some embodiments, X1 is (C=O)-L1-(C=O). In some embodiments, X1 is (C=O)-L1. In some embodiments, X1 is L1-(C=O). In some embodiments, X1 is O(CO). In some embodiments, X1 is (CO)O. In some embodiments, X1 is L2-(CO)O. In some embodiments, X1 is O(CO)-L2. In some embodiments, X1 is O. In some embodiments, X1 is S. In some embodiments, X1 is SS. In some embodiments, X1 is Se-Se-. In some embodiments, X1 is NH. In some embodiments, X1 is NR. In some embodiments, X1 is NH(CO). In some embodiments, X1 is (CO)NH. In some embodiments, X1 is L2-(CO)NH. In some embodiments, X1 is (CO)NH-L2. In some embodiments, X1 is L2-NH(CO). In some embodiments, X1 is NH(CO)-L2. In some embodiments, X1 is -NR-L2-NR. In some embodiments, X1 is L2-O. In some embodiments, X1 is O-L2. In some embodiments, X1 is unsubstituted or substituted C1~C 10 It is an alkylene. In some embodiments, X1 is unsubstituted or substituted C3-C 10 It is a cycloalkylene. In some embodiments, X1 is an unsubstituted or substituted arylene. In some embodiments, X1 is an unsubstituted or substituted heteroarylene. In some embodiments, X1 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X1 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0048] In some embodiments, X2 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, L2-(CO)O, or O(CO)-L2; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-(CO)NH, (CO)NH-L2, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X2 is a bond. In some embodiments, X2 is C=O. In some embodiments, X2 is (C=O)-L1-(C=O). In some embodiments, X2 is (C=O)-L1. In some embodiments, X2 is L1-(C=O). In some embodiments, X2 is O(CO). In some embodiments, X2 is (CO)O. In some embodiments, X2 is L2-(CO)O. In some embodiments, X2 is O(CO)-L2. In some embodiments, X2 is O. In some embodiments, X2 is S. In some embodiments, X2 is SS. In some embodiments, X2 is Se-Se-. In some embodiments, X2 is NH. In some embodiments, X2 is NR. In some embodiments, X2 is NH(CO). In some embodiments, X2 is (CO)NH. In some embodiments, X2 is L2-(CO)NH. In some embodiments, X2 is (CO)NH-L2. In some embodiments, X2 is L2-NH(CO). In some embodiments, X2 is NH(CO)-L2. In some embodiments, X2 is -NR-L2-NR. In some embodiments, X2 is L2-O. In some embodiments, X2 is O-L2. In some embodiments, X2 is unsubstituted or substituted C1-C10 It is an alkylene. In some embodiments, X2 is unsubstituted or substituted C3~C 10 It is a cycloalkylene. In some embodiments, X2 is an unsubstituted or substituted arylene. In some embodiments, X2 is an unsubstituted or substituted heteroarylene. In some embodiments, X2 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X2 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0049] In some embodiments, X3 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, L2-(CO)O, or O(CO)-L2; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-(CO)NH, (CO)NH-L2, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X3 is a bond. In some embodiments, X3 is C=O. In some embodiments, X3 is (C=O)-L1-(C=O). In some embodiments, X3 is (C=O)-L1. In some embodiments, X3 is L1-(C=O). In some embodiments, X3 is O(CO). In some embodiments, X3 is (CO)O. In some embodiments, X3 is L2-(CO)O. In some embodiments, X3 is O(CO)-L2. In some embodiments, X3 is O. In some embodiments, X3 is S. In some embodiments, X3 is SS. In some embodiments, X3 is Se-Se-. In some embodiments, X3 is NH. In some embodiments, X3 is NR. In some embodiments, X3 is NH(CO). In some embodiments, X3 is (CO)NH. In some embodiments, X3 is L2-(CO)NH. In some embodiments, X3 is (CO)NH-L2. In some embodiments, X3 is L2-NH(CO). In some embodiments, X3 is NH(CO)-L2. In some embodiments, X3 is -NR-L2-NR. In some embodiments, X3 is L2-O. In some embodiments, X3 is O-L2. In some embodiments, X3 is unsubstituted or substituted C1-C 10 It is an alkylene. In some embodiments, X3 is unsubstituted or substituted C3-C 10 It is a cycloalkylene. In some embodiments, X3 is an unsubstituted or substituted arylene. In some embodiments, X3 is an unsubstituted or substituted heteroarylene. In some embodiments, X3 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X3 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0050] In some embodiments, each L1 is independently an unsubstituted or substituted arylene; an unsubstituted or substituted heteroarylene; or an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, each L1 is independently an unsubstituted or substituted arylene. In some embodiments, each L1 is independently an unsubstituted or substituted heteroarylene. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0051] In some embodiments, each R is independently either unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryls; unsubstituted or substituted heteroaryls; or unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, each R is independently unsubstituted or substituted C1-C 10 It is alkyl. In some embodiments, each R is independently unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C1. 10 It is an acyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10It is an alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0052] In some embodiments, X3 is attached to R3; R4, R5, R6 and R7 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclyl; one of either unsubstituted or substituted peptides containing 1 to 10 amino acids; forming glycosidic bonds with native monosaccharides. In some embodiments, X3 is attached to R3; R4, R5, R6, and R7 are each independently H. In some embodiments, X3 is attached to R3; R4, R5, R6, and R7 are each independently OH. In some embodiments, X3 is attached to R3; R4, R5, R6, and R7 are each independently O(CO)NH2. In some embodiments, X3 is attached to R3; R4, R5, R6, and R7 are each independently halo. In some embodiments, X3 is attached to R3; R4, R5, R6, and R7 are each independently amino groups. In some embodiments, X3 is attached to R3; R4, R5, R6, and R7 are each independently unsubstituted or substituted C1-C 10It is alkyl. In some embodiments, X3 is attached to R3; R4, R5, R6, and R7 are each independently unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, X3 is attached to R3; R4, R5, R6, and R7 are each independently unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, X3 is attached to R3; R4, R5, R6 and R7 are each independently unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, X3 is attached to R3; R4, R5, R6, and R7 are each independently unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, X3 is attached to R3; R4, R5, R6, and R7 are each independently unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, X3 is attached to R3; R4, R5, R6 and R7 are each independently unsubstituted or substituted aryls. In some embodiments, X3 is attached to R3; R4, R5, R6 and R7 are each independently unsubstituted or substituted heteroaryls. In some embodiments, X3 is attached to R3; R4, R5, R6 and R7 are each independently unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, X3 is attached to R3; R4, R5, R6, and R7 are each independently unsubstituted or substituted peptides containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X3 is attached to R3; R4, R5, R6, and R7 each independently form glycosidic bonds with native monosaccharides.

[0053] In some embodiments, X3 is attached to R4; R3, R5, R6 and R7 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclyl; one of either an unsubstituted or substituted peptide containing 1 to 10 amino acids; forming a glycosidic bond with a native monosaccharide. In some embodiments, X3 is attached to R4; R3, R5, R6, and R7 are each independently H. In some embodiments, X3 is attached to R4; R3, R5, R6, and R7 are each independently OH. In some embodiments, X3 is attached to R4; R3, R5, R6, and R7 are each independently O(CO)NH2. In some embodiments, X3 is attached to R4; R3, R5, R6, and R7 are each independently halo. In some embodiments, X3 is attached to R4; R3, R5, R6, and R7 are each independently amino groups. In some embodiments, X3 is attached to R4; R3, R5, R6, and R7 are each independently unsubstituted or substituted C1-C 10 It is alkyl. In some embodiments, X3 is attached to R4; R3, R5, R6 and R7 are each independently unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, X3 is attached to R4; R3, R5, R6 and R7 are each independently unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, X3 is attached to R4; R3, R5, R6 and R7 are each independently unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, X3 is attached to R4; R3, R5, R6 and R7 are each independently unsubstituted or substituted C1-C 10It is an alkyl ketone. In some embodiments, X3 is attached to R4; R3, R5, R6 and R7 are each independently unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, X3 is attached to R4; R3, R5, R6 and R7 are each independently unsubstituted or substituted aryls. In some embodiments, X3 is attached to R4; R3, R5, R6 and R7 are each independently unsubstituted or substituted heteroaryls. In some embodiments, X3 is attached to R4; R3, R5, R6 and R7 are each independently unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, X3 is attached to R4; R3, R5, R6, and R7 are each independently unsubstituted or substituted peptides containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X3 is attached to R4; R3, R5, R6, and R7 each independently form glycosidic bonds with native monosaccharides.

[0054] In some embodiments, X3 is attached to R5; R3, R4, R6 and R7 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10Heterocyclyl; one of either an unsubstituted or substituted peptide containing 1 to 10 amino acids; forming a glycosidic bond with a native monosaccharide. In some embodiments, X3 is attached to R5; R3, R4, R6, and R7 are each independently H. In some embodiments, X3 is attached to R5; R3, R4, R6, and R7 are each independently OH. In some embodiments, X3 is attached to R5; R3, R4, R6, and R7 are each independently O(CO)NH2. In some embodiments, X3 is attached to R5; R3, R4, R6, and R7 are each independently halo. In some embodiments, X3 is attached to R5; R3, R4, R6, and R7 are each independently amino groups. In some embodiments, X3 is attached to R5; R3, R4, R6, and R7 are each independently unsubstituted or substituted C1-C 10 It is alkyl. In some embodiments, X3 is attached to R5; R3, R4, R6 and R7 are each independently unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, X3 is attached to R5; R3, R4, R6, and R7 are each independently unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, X3 is attached to R5; R3, R4, R6 and R7 are each independently unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, X3 is attached to R5; R3, R4, R6 and R7 are each independently unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, X3 is attached to R5; R3, R4, R6 and R7 are each independently unsubstituted or substituted C1-C 10It is an alkyl ether. In some embodiments, X3 is attached to R5; R3, R4, R6 and R7 are each independently unsubstituted or substituted aryls. In some embodiments, X3 is attached to R5; R3, R4, R6 and R7 are each independently unsubstituted or substituted heteroaryls. In some embodiments, X3 is attached to R5; R3, R4, R6 and R7 are each independently unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, X3 is attached to R5; R3, R4, R6, and R7 are each independently unsubstituted or substituted peptides containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X3 is attached to R5; R3, R4, R6, and R7 each independently form glycosidic bonds with native monosaccharides.

[0055] In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10Heterocyclyl; one of either an unsubstituted or substituted peptide containing 1 to 10 amino acids; forming a glycosidic bond with a native monosaccharide. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently H. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently OH. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently O(CO)NH2. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently halo. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently amino groups. In some embodiments, X3 is attached to R6; R3, R4, R5, and R7 are each independently unsubstituted or substituted C1-C 10 It is alkyl. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently unsubstituted or substituted C1-C 10It is an alkyl ether. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently unsubstituted or substituted aryls. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently unsubstituted or substituted heteroaryls. In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, X3 is attached to R6; R3, R4, R5, and R7 are each independently unsubstituted or substituted peptides containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X3 is attached to R6; R3, R4, R5, and R7 each independently form glycosidic bonds with native monosaccharides.

[0056] In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10Heterocyclyl; one of either an unsubstituted or substituted peptide containing 1 to 10 amino acids; forming a glycosidic bond with a native monosaccharide. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently H. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently OH. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently O(CO)NH2. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently halo. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently amino groups. In some embodiments, X3 is attached to R7; R3, R4, R5, and R6 are each independently unsubstituted or substituted C1-C 10 It is alkyl. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently unsubstituted or substituted C1-C 10 It is acyl. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently unsubstituted or substituted C1-C 10It is an alkyl ether. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently unsubstituted or substituted aryls. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently unsubstituted or substituted heteroaryls. In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, X3 is attached to R7; R3, R4, R5, and R6 are each independently unsubstituted or substituted peptides containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X3 is attached to R7; R3, R4, R5, and R6 each independently form glycosidic bonds with native monosaccharides.

[0057] In some embodiments of Formula II, n1 and n2 are independently 0, 1, 2, 3, or 4. In some embodiments, R1 and R2 are each H. In some embodiments, X1 is bonded, NH(CO), (CO)NH, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), and O; L1 is unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X2 is a bond, C=O, NH(CO), (CO)NH, L2-NH(CO), and NH(CO)-L2. In some embodiments, X3 is a bond, O(CO), (CO)O, L2-(CO)O, O(CO)-L2, O, S, L2-NH(CO), or NH(CO)-L2. In some embodiments, X3 is attached to R4; R3, R5, R6, and R7 are each independently OH or halo. In some embodiments, X3 is attached to R7; R3, R4, R5, and R6 are each independently OH or halo.

[0058] A compound of formula (III), or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof is provided in one embodiment:

[0059] [ka] During the ceremony, m1, m2, and m3 are each independently between 0 and 15; M1 is selected from -CO-, -OPO2-, -SO2-, -CH2OPO2, -CH2OCO-, and -CH2O-; R1, R2, and R3 are each independently OH, H, halo, unsubstituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 It is an alkyl ether; X1, X2, and X3 are each independently bonded, C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, O, S, SS, Se-Se-, NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2, unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes, unsubstituted or substituted arylenes, unsubstituted or substituted heteroarylenes, unsubstituted or substituted C1-C 10 Heterocyclylene, or unsubstituted or substituted peptides containing 1 to 10 native amino acids; Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C 10 It is a heterocycline; Each L2 independently determines whether C1-C is non-substitutive or substituted. 10 It is alkylene; Each R is independently either non-substituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, or unsubstituted or substituted C1-C 10 It is a heterocycline; R4 is NHR', NHCOR', NHCOOR', CONHR', or COOR'; Each R' is C1-C of H, unsubstituted or substituted. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C3-C 10 Cycloalkyl (C1~C 10 C1-C (alkyl), unsubstituted or substituted 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, unsubstituted or substituted C1-C 10 Heterocyclines, or unsubstituted or substituted C1-C 10 Heterocycline (C1~C 10 Alkyl) is; R5 is either non-substituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted C1-C 10 It is a heterocycline.

[0060] In some embodiments, m1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, m1 is 0. In some embodiments, m1 is 1. In some embodiments, m1 is 2. In some embodiments, m1 is 3. In some embodiments, m1 is 4. In some embodiments, m1 is 5. In some embodiments, m1 is 6. In some embodiments, m1 is 7. In some embodiments, m1 is 8. In some embodiments, m1 is 9. In some embodiments, m1 is 10. In some embodiments, m1 is 11. In some embodiments, m1 is 12. In some embodiments, m1 is 13. In some embodiments, m1 is 14. In some embodiments, m1 is 15.

[0061] In some embodiments, m2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, m2 is 0. In some embodiments, m2 is 1. In some embodiments, m2 is 2. In some embodiments, m2 is 3. In some embodiments, m2 is 4. In some embodiments, m2 is 5. In some embodiments, m2 is 6. In some embodiments, m2 is 7. In some embodiments, m2 is 8. In some embodiments, m2 is 9. In some embodiments, m2 is 10. In some embodiments, m2 is 11. In some embodiments, m2 is 12. In some embodiments, m2 is 13. In some embodiments, m2 is 14. In some embodiments, m2 is 15.

[0062] In some embodiments, m3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, m3 is 0. In some embodiments, m3 is 1. In some embodiments, m3 is 2. In some embodiments, m3 is 3. In some embodiments, m3 is 4. In some embodiments, m3 is 5. In some embodiments, m3 is 6. In some embodiments, m3 is 7. In some embodiments, m3 is 8. In some embodiments, m3 is 9. In some embodiments, m3 is 10. In some embodiments, m3 is 11. In some embodiments, m3 is 12. In some embodiments, m3 is 13. In some embodiments, m3 is 14. In some embodiments, m3 is 15.

[0063] In some embodiments, M1 is one of the following: bond; -C=O-; -OPO2-; -SO2-; -CH2OPO2, -CH2OCO-, and -CH2O-. In some embodiments, M1 is a bond. In some embodiments, M1 is -C=O-. In some embodiments, M1 is -OPO2-. In some embodiments, M1 is -SO2-. In some embodiments, M1 is -CH2OPO2. In some embodiments, M1 is -CH2OCO-. In some embodiments, M1 is -CH2O-.

[0064] In some embodiments, R1 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10It is an alkyl ether. In some embodiments, R1 is an OH group. In some embodiments, R1 is hydrogen. In some embodiments, R1 is a halo. In some embodiments, R1 is an unsubstituted or substituted C1-C group. 10 It is alkyl. In some embodiments, R1 is unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0065] In some embodiments, R2 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, R2 is an OH group. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halo. In some embodiments, R2 is an unsubstituted or substituted C1-C group. 10 It is alkyl. In some embodiments, R2 is unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, R2 is an unsubstituted or substituted C1-C 10It is an alkyl ketone. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0066] In some embodiments, R3 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, R3 is an OH group. In some embodiments, R3 is hydrogen. In some embodiments, R3 is a halo. In some embodiments, R3 is an unsubstituted or substituted C1-C group. 10 It is alkyl. In some embodiments, R3 is unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, R3 is an unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, R3 is unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, R3 is an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, R3 is an unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0067] In some embodiments, X1 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X1 is a bond. In some embodiments, X1 is C=O. In some embodiments, X1 is (C=O)-L1-(C=O). In some embodiments, X1 is (C=O)-L1. In some embodiments, X1 is L1-(C=O). In some embodiments, X1 is O(CO). In some embodiments, X1 is (CO)O. In some embodiments, X1 is O. In some embodiments, X1 is S. In some embodiments, X1 is SS. In some embodiments, X1 is Se-Se-. In some embodiments, X1 is NH. In some embodiments, X1 is NR. In some embodiments, X1 is NH(CO). In some embodiments, X1 is (CO)NH. In some embodiments, X1 is L2-NH(CO). In some embodiments, X1 is NH(CO)-L2. In some embodiments, X1 is -NR-L2-NR. In some embodiments, X1 is L2-O. In some embodiments, X1 is O-L2. In some embodiments, X1 is unsubstituted or substituted C1-C 10 It is an alkylene. In some embodiments, X1 is unsubstituted or substituted C3-C 10 It is a cycloalkylene. In some embodiments, X1 is an unsubstituted or substituted arylene. In some embodiments, X1 is an unsubstituted or substituted heteroarylene. In some embodiments, X1 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X1 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0068] In some embodiments, X2 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X2 is a bond. In some embodiments, X2 is C=O. In some embodiments, X2 is (C=O)-L1-(C=O). In some embodiments, X2 is (C=O)-L1. In some embodiments, X2 is L1-(C=O). In some embodiments, X2 is O(CO). In some embodiments, X2 is (CO)O. In some embodiments, X2 is O. In some embodiments, X2 is S. In some embodiments, X2 is SS. In some embodiments, X2 is Se-Se-. In some embodiments, X2 is NH. In some embodiments, X2 is NR. In some embodiments, X2 is NH(CO). In some embodiments, X2 is (CO)NH. In some embodiments, X2 is L2-NH(CO). In some embodiments, X2 is NH(CO)-L2. In some embodiments, X2 is -NR-L2-NR. In some embodiments, X2 is L2-O. In some embodiments, X2 is O-L2. In some embodiments, X2 is unsubstituted or substituted C1-C 10 It is an alkylene. In some embodiments, X2 is unsubstituted or substituted C3~C 10It is a cycloalkylene. In some embodiments, X2 is an unsubstituted or substituted arylene. In some embodiments, X2 is an unsubstituted or substituted heteroarylene. In some embodiments, X2 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X2 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0069] In some embodiments, X3 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X3 is a bond. In some embodiments, X3 is C=O. In some embodiments, X3 is (C=O)-L1-(C=O). In some embodiments, X3 is (C=O)-L1. In some embodiments, X3 is L1-(C=O). In some embodiments, X3 is O(CO). In some embodiments, X3 is (CO)O. In some embodiments, X3 is O. In some embodiments, X3 is S. In some embodiments, X3 is SS. In some embodiments, X3 is Se-Se-. In some embodiments, X3 is NH. In some embodiments, X3 is NR. In some embodiments, X3 is NH(CO). In some embodiments, X3 is (CO)NH. In some embodiments, X3 is L2-NH(CO). In some embodiments, X3 is NH(CO)-L2. In some embodiments, X3 is -NR-L2-NR. In some embodiments, X3 is L2-O. In some embodiments, X3 is O-L2. In some embodiments, X3 is unsubstituted or substituted C1-C 10 It is an alkylene. In some embodiments, X3 is unsubstituted or substituted C3-C 10 It is a cycloalkylene. In some embodiments, X3 is an unsubstituted or substituted arylene. In some embodiments, X3 is an unsubstituted or substituted heteroarylene. In some embodiments, X3 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X3 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0070] In some embodiments, each L1 is independently an unsubstituted or substituted arylene; an unsubstituted or substituted heteroarylene; or an unsubstituted or substituted C1-C 10It is a heterocyclylene. In some embodiments, each L1 is independently an unsubstituted or substituted arylene. In some embodiments, each L1 is independently an unsubstituted or substituted heteroarylene. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0071] In some embodiments, each R is independently either unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryls; unsubstituted or substituted heteroaryls; or unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, each R is independently unsubstituted or substituted C1-C 10 It is alkyl. In some embodiments, each R is independently unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C1. 10 It is an acyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0072] In some embodiments, R4 is one of the following: NHR'; NHCOR'; NHCOOR'; CONHR'; and COOR'. In some embodiments, R4 is NHR'. In some embodiments, R4 is NHCOR'. In some embodiments, R4 is NHCOOR'. In some embodiments, R4 is CONHR'. In some embodiments, R4 is COOR'.

[0073] In some embodiments, each R' is independently either unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C3-C 10 Cycloalkyl (C1~C 10 Alkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclines; or unsubstituted or substituted C1-C 10 Heterocycline (C1~C 10 It is alkyl. In some embodiments, each R' is independently unsubstituted or substituted C1-C 10 It is alkyl. In some embodiments, each R' is independently unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, each R' is independently an unsubstituted or substituted C3-C3 group. 10 Cycloalkyl (C1~C 10 It is alkyl. In some embodiments, each R' is independently unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, each R' is independently an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, each R' is independently an unsubstituted or substituted C1-C10 It is an alkyl ketone. In some embodiments, each R' is independently an unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, each R' is independently an unsubstituted or substituted aryl. In some embodiments, each R' is independently an unsubstituted or substituted heteroaryl. In some embodiments, each R' is independently an unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, each R' is independently an unsubstituted or substituted C1-C 10 Heterocycline (C1~C 10 It is alkyl.

[0074] In some embodiments, R5 is either unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted aryl; unsubstituted or substituted heteroaryl; or unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, R5 is an unsubstituted or substituted C1-C 10 It is alkyl. In some embodiments, R5 is unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, each R5 is independently an unsubstituted or substituted aryl group. In some embodiments, each R5 is independently an unsubstituted or substituted heteroaryl group. In some embodiments, each R5 is independently an unsubstituted or substituted C1-C1 10 It is a heterocycline.

[0075] In some embodiments of Formula III, m1, m2, and m3 are each independently 0, 1, 2, 3, or 4. In some embodiments, M1 is -C=O-. In some embodiments, R1, R2, and R3 are each H. In some embodiments, X1 is bonded. In some embodiments, X2 is NH(CO) or (CO)NH. In some embodiments, X3 is NH or NR. In some embodiments, R4 is NHCOR' or NHCOOR'; R' is unsubstituted or substituted C1~C 10 Alkyl, unsubstituted, or substituted C3-C 10 It is cycloalkyl. In some embodiments, R5 is unsubstituted or substituted C1-C 10 It is alkyl.

[0076] A compound of formula (IV), or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof is provided in one embodiment:

[0077] [ka] During the ceremony, n1 and n2 are each independently between 0 and 15; R1 and R2 are, independently, OH, H, halo, unsubstituted or substituted C1-C. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 It is an alkyl ether; X1, X2, and X3 are each independently bonded, C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, O, S, SS, Se-Se-, NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2, L2-NH, NH-L2, unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes, unsubstituted or substituted arylenes, unsubstituted or substituted heteroarylenes, unsubstituted or substituted C1-C 10 Heterocyclylene, or unsubstituted or substituted peptides containing 1 to 10 native amino acids; Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C 10 It is a heterocycline; Each L2 independently determines whether C1-C is non-substitutive or substituted. 10 It is alkylene; Each R is independently either non-substituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, or unsubstituted or substituted C1-C 10 It is a heterocycline; A is either non-substituted or substituted C3~C 15 Cycloalkyl, unsubstituted or substituted C1-C 15 These are heterocyclines, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, or oligosaccharides containing 3 to 15 identical or different monosaccharides.

[0078] In some embodiments, n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, n1 is 0. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3. In some embodiments, n1 is 4. In some embodiments, n1 is 5. In some embodiments, n1 is 6. In some embodiments, n1 is 7. In some embodiments, n1 is 8. In some embodiments, n1 is 9. In some embodiments, n1 is 10. In some embodiments, n1 is 11. In some embodiments, n1 is 12. In some embodiments, n1 is 13. In some embodiments, n1 is 14. In some embodiments, n1 is 15.

[0079] In some embodiments, n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, n2 is 0. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4. In some embodiments, n2 is 5. In some embodiments, n2 is 6. In some embodiments, n2 is 7. In some embodiments, n2 is 8. In some embodiments, n2 is 9. In some embodiments, n2 is 10. In some embodiments, n2 is 11. In some embodiments, n2 is 12. In some embodiments, n2 is 13. In some embodiments, n2 is 14. In some embodiments, n2 is 15.

[0080] In some embodiments, R1 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, R1 is an OH group. In some embodiments, R1 is hydrogen. In some embodiments, R1 is a halo. In some embodiments, R1 is an unsubstituted or substituted C1-C group. 10 It is alkyl. In some embodiments, R1 is unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, R1 is an unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0081] In some embodiments, R2 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, R2 is an OH group. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halo. In some embodiments, R2 is an unsubstituted or substituted C1-C group. 10 It is alkyl. In some embodiments, R2 is unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is an acyl. In some embodiments, R2 is an unsubstituted or substituted C1-C 10It is a carboxyl ester. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, R2 is an unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0082] In some embodiments, X1 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2, L2-NH, or NH-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X1 is a bond. In some embodiments, X1 is C=O. In some embodiments, X1 is (C=O)-L1-(C=O). In some embodiments, X1 is (C=O)-L1. In some embodiments, X1 is L1-(C=O). In some embodiments, X1 is O(CO). In some embodiments, X1 is (CO)O. In some embodiments, X1 is O. In some embodiments, X1 is S. In some embodiments, X1 is SS. In some embodiments, X1 is Se-Se-. In some embodiments, X1 is NH. In some embodiments, X1 is NR. In some embodiments, X1 is NH(CO). In some embodiments, X1 is (CO)NH. In some embodiments, X1 is L2-NH(CO). In some embodiments, X1 is NH(CO)-L2. In some embodiments, X1 is -NR-L2-NR. In some embodiments, X1 is L2-O. In some embodiments, X1 is O-L2. In some embodiments, X1 is L2-NH. In some embodiments, X1 is NH-L2. In some embodiments, X1 is unsubstituted or substituted C1-C 10 It is an alkylene. In some embodiments, X1 is unsubstituted or substituted C3-C 10 It is a cycloalkylene. In some embodiments, X1 is an unsubstituted or substituted arylene. In some embodiments, X1 is an unsubstituted or substituted heteroarylene. In some embodiments, X1 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X1 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0083] In some embodiments, X2 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2, L2-NH, or NH-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X2 is a bond. In some embodiments, X2 is C=O. In some embodiments, X2 is (C=O)-L1-(C=O). In some embodiments, X2 is (C=O)-L1. In some embodiments, X2 is L1-(C=O). In some embodiments, X2 is O(CO). In some embodiments, X2 is (CO)O. In some embodiments, X2 is O. In some embodiments, X2 is S. In some embodiments, X2 is SS. In some embodiments, X2 is Se-Se-. In some embodiments, X2 is NH. In some embodiments, X2 is NR. In some embodiments, X2 is NH(CO). In some embodiments, X2 is (CO)NH. In some embodiments, X2 is L2-NH(CO). In some embodiments, X2 is NH(CO)-L2. In some embodiments, X2 is -NR-L2-NR. In some embodiments, X2 is L2-O. In some embodiments, X2 is O-L2. In some embodiments, X2 is L2-NH. In some embodiments, X2 is NH-L2. In some embodiments, X2 is unsubstituted or substituted C1-C 10 It is an alkylene. In some embodiments, X2 is unsubstituted or substituted C3~C 10It is a cycloalkylene. In some embodiments, X2 is an unsubstituted or substituted arylene. In some embodiments, X2 is an unsubstituted or substituted heteroarylene. In some embodiments, X2 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X2 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0084] In some embodiments, X3 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2, L2-NH, or NH-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10Heterocyclylene; and unsubstituted or substituted peptides containing 1 to 10 native amino acids. In some embodiments, X3 is a bond. In some embodiments, X3 is C=O. In some embodiments, X3 is (C=O)-L1-(C=O). In some embodiments, X3 is (C=O)-L1. In some embodiments, X3 is L1-(C=O). In some embodiments, X3 is O(CO). In some embodiments, X3 is (CO)O. In some embodiments, X3 is O. In some embodiments, X3 is S. In some embodiments, X3 is SS. In some embodiments, X3 is Se-Se-. In some embodiments, X3 is NH. In some embodiments, X3 is NR. In some embodiments, X3 is NH(CO). In some embodiments, X3 is (CO)NH. In some embodiments, X3 is L2-NH(CO). In some embodiments, X3 is NH(CO)-L2. In some embodiments, X3 is -NR-L2-NR. In some embodiments, X3 is L2-O. In some embodiments, X3 is O-L2. In some embodiments, X3 is L2-NH. In some embodiments, X3 is NH-L2. In some embodiments, X3 is unsubstituted or substituted C1-C 10 It is an alkylene. In some embodiments, X3 is unsubstituted or substituted C3-C 10 It is a cycloalkylene. In some embodiments, X3 is an unsubstituted or substituted arylene. In some embodiments, X3 is an unsubstituted or substituted heteroarylene. In some embodiments, X3 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X3 is an unsubstituted or substituted peptide containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 native amino acids.

[0085] In some embodiments, each L1 is independently an unsubstituted or substituted arylene; an unsubstituted or substituted heteroarylene; or an unsubstituted or substituted C1-C 10It is a heterocyclylene. In some embodiments, each L1 is independently an unsubstituted or substituted arylene. In some embodiments, each L1 is independently an unsubstituted or substituted heteroarylene. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0086] In some embodiments, each R is independently either unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryls; unsubstituted or substituted heteroaryls; or unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, each R is independently unsubstituted or substituted C1-C 10 It is alkyl. In some embodiments, each R is independently unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C1. 10 It is an acyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0087] In some embodiments, A is either unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 15 The oligosaccharide comprises heterocyclyls; unsubstituted or substituted aryls; unsubstituted or substituted heteroaryls; and 3-15 identical or different monosaccharides. In some embodiments, A is unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, A is an unsubstituted or substituted C1-C 15 It is a heterocyclyl. In some embodiments, A is an unsubstituted or substituted aryl. In some embodiments, A is an unsubstituted or substituted heteroaryl. In some embodiments, the unsubstituted or substituted heteroaryl is an unsubstituted or substituted quinolinyl or an unsubstituted or substituted acridinyl. In some embodiments, A is an oligosaccharide comprising the same or different monosaccharides 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0088] In some embodiments of formula IV, n1 and n2 are independently 0, 1, 2, 3, or 4. In some embodiments, R1 and R2 are hydrogen. In some embodiments, X1 is a bond, (C=O)-L1, L1-(C=O), and O; L1 is an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, X2 is a bond. In some embodiments, X3 is a bond, O, L2-NH, or NH-L2. In some embodiments, A is an unsubstituted or substituted heteroaryl.

[0089] A compound of formula (V), or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof is provided in one embodiment:

[0090] [ka] During the ceremony, n, n1, and n2 are each independently between 0 and 15; R1 and R2 are, independently, OH, H, halo, unsubstituted or substituted C1-C. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 It is an alkyl ether; X1, X2, and X4 are each independently bonded, C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, O, S, SS, Se-Se-, NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2, unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes, unsubstituted or substituted arylenes, unsubstituted or substituted heteroarylenes, unsubstituted or substituted C1-C 10 Heterocyclylene, or unsubstituted or substituted peptides containing 1 to 10 native amino acids; Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C 10 It is a heterocycline; Each L2 independently determines whether C1-C is non-substitutive or substituted. 10 It is alkylene; Each R is independently either non-substituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, or unsubstituted or substituted C1-C 10 It is a heterocycline; X4 is attached to one of R3, R4, R5, R6, and R7, and the remaining R3, R4, R5, R6, and R7 not attached to X4 are, independently, H, OH, O(CO)NH2, halo, unsubstituted or substituted amino group, and unsubstituted or substituted C1-C. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, unsubstituted or substituted C1-C 10 Heterocyclines are unsubstituted or substituted peptides containing 1 to 10 amino acids, or they form glycosidic bonds with native monosaccharides; R8 is OR 10 , or oligopeptide bonds formed from natural amino acids; R 10 C1-C are either non-substitutive or substituted. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, or unsubstituted or substituted C1-C 10 It is a heterocycline; R9 is H, or the side chain of a natural amino acid.

[0091] In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0092] In some embodiments, R1 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0093] In some embodiments, R2 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0094] In some embodiments, X1 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylenes; and unsubstituted or substituted peptides containing 1 to 10 native amino acids.

[0095] In some embodiments, X2 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylenes; and unsubstituted or substituted peptides containing 1 to 10 native amino acids.

[0096] In some embodiments, X4 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylenes; and unsubstituted or substituted peptides containing 1 to 10 native amino acids.

[0097] In some embodiments, each L1 is independently an unsubstituted or substituted arylene; an unsubstituted or substituted heteroarylene; or an unsubstituted or substituted C1-C 10It is a heterocyclylene. In some embodiments, each L1 is independently an unsubstituted or substituted arylene. In some embodiments, each L1 is independently an unsubstituted or substituted heteroarylene. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0098] In some embodiments, each R is independently either unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryls; unsubstituted or substituted heteroaryls; or unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, each R is independently unsubstituted or substituted C1-C 10 It is alkyl. In some embodiments, each R is independently unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C1. 10 It is an acyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0099] In some embodiments, X4 is attached to R3; R4, R5, R6 and R7 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclyl; a peptide consisting of either 1 to 10 amino acids, either unsubstituted or substituted; which forms glycosidic bonds with native monosaccharides.

[0100] In some embodiments, X4 is attached to R4; R3, R5, R6 and R7 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclyl; a peptide consisting of either 1 to 10 amino acids, either unsubstituted or substituted; which forms glycosidic bonds with native monosaccharides.

[0101] In some embodiments, X4 is attached to R5; R3, R4, R6 and R7 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclyl; a peptide consisting of either 1 to 10 amino acids, either unsubstituted or substituted; which forms glycosidic bonds with native monosaccharides.

[0102] In some embodiments, X4 is attached to R6; R3, R4, R5 and R7 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclyl; a peptide consisting of either 1 to 10 amino acids, either unsubstituted or substituted; which forms glycosidic bonds with native monosaccharides.

[0103] In some embodiments, X4 is attached to R7; R3, R4, R5 and R6 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclyl; a peptide consisting of either 1 to 10 amino acids, either unsubstituted or substituted; which forms glycosidic bonds with native monosaccharides.

[0104] In some embodiments, R8 is OR 10 or an oligopeptide bond formed by natural amino acids. In some embodiments, R8 is OR 10 In some embodiments, R8 is an oligopeptide bond formed from natural amino acids.

[0105] In some embodiments, R 10 C1-C are either non-substitutive or substituted. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryls; unsubstituted or substituted heteroaryls; or unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, R 10 C1-C are either non-substitutive or substituted. 10 It is alkyl. In some embodiments, R 10 C3~C is either non-substitutive or substituted. 10 It is cycloalkyl. In some embodiments, R 10 C1-C are either non-substitutive or substituted. 10 It is an acyl. In some embodiments, R 10 C1-C are either non-substitutive or substituted. 10 It is a carboxyl ester. In some embodiments, R 10 C1-C are either non-substitutive or substituted. 10It is an alkyl ketone. In some embodiments, R 10 C1-C are either non-substitutive or substituted. 10 It is an alkyl ether. In some embodiments, R 10 R is an aryl that is either unsubstituted or substituted. In some embodiments, R 10 is an unsubstituted or substituted heteroaryl. In some embodiments, R 10 C1-C are either non-substitutive or substituted. 10 It is a heterocycline.

[0106] In some embodiments, R9 is H; or a side chain of a natural amino acid. In some embodiments, R9 is H. In some embodiments, R9 is a side chain of a natural amino acid.

[0107] A compound of formula (VI), or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof is provided in one embodiment:

[0108] [ka] During the ceremony, n1 and n2 are each independently between 0 and 15; R1 and R2 are, independently, OH, H, halo, unsubstituted or substituted C1-C. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 It is an alkyl ether; X1, X2, and X3 are each independently bonded, C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, O, S, SS, Se-Se-, NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2, unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes, unsubstituted or substituted arylenes, unsubstituted or substituted heteroarylenes, unsubstituted or substituted C1-C 10 Heterocyclylene, or unsubstituted or substituted peptides containing 1 to 10 native amino acids; Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C 10 It is a heterocycline; Each L2 independently determines whether C1-C is non-substitutive or substituted. 10 It is alkylene; Each R is independently either non-substituted or substituted C1-C 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, or unsubstituted or substituted C1-C 10 It is a heterocycline; X3 is attached to one of R3, R4, R5, R6, and R7, and the remaining R3, R4, R5, R6, and R7 not attached to X3 are, independently, H, OH, O(CO)NH2, halo, an unsubstituted or substituted amino group, and an unsubstituted or substituted C1-C. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryls, unsubstituted or substituted heteroaryls, unsubstituted or substituted C1-C 10 Heterocyclines are unsubstituted or substituted peptides containing 1 to 10 amino acids, or they form glycosidic bonds with native monosaccharides; A1 is either non-substituted or substituted C3~C 15 Cycloalkyl, unsubstituted or substituted C1-C 15 Heterocyclines, unsubstituted or substituted aryls, or unsubstituted or substituted heteroaryls,

[0109] [ka] That is the case.

[0110] In some embodiments, n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0111] In some embodiments, R1 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0112] In some embodiments, R2 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0113] In some embodiments, X1 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylenes; and unsubstituted or substituted peptides containing 1 to 10 native amino acids.

[0114] In some embodiments, X2 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylenes; and unsubstituted or substituted peptides containing 1 to 10 native amino acids.

[0115] In some embodiments, X3 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylenes; and unsubstituted or substituted peptides containing 1 to 10 native amino acids.

[0116] In some embodiments, each L1 is independently an unsubstituted or substituted arylene; an unsubstituted or substituted heteroarylene; or an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, each L1 is independently an unsubstituted or substituted arylene. In some embodiments, each L1 is independently an unsubstituted or substituted heteroarylene. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0117] In some embodiments, each R is independently either unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryls; unsubstituted or substituted heteroaryls; or unsubstituted or substituted C1-C 10 It is a heterocycline. In some embodiments, each R is independently unsubstituted or substituted C1-C 10It is alkyl. In some embodiments, each R is independently unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C1. 10 It is an acyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0118] In some embodiments, X3 is attached to R3; R4, R5, R6 and R7 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclyl; a peptide consisting of either 1 to 10 amino acids, either unsubstituted or substituted; which forms glycosidic bonds with native monosaccharides.

[0119] In some embodiments, X3 is attached to R4; R3, R5, R6 and R7 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclyl; a peptide consisting of either 1 to 10 amino acids, either unsubstituted or substituted; which forms glycosidic bonds with native monosaccharides.

[0120] In some embodiments, X3 is attached to R5; R3, R4, R6 and R7 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclyl; a peptide consisting of either 1 to 10 amino acids, either unsubstituted or substituted; which forms glycosidic bonds with native monosaccharides.

[0121] In some embodiments, X3 is attached to R6; R3, R4, R5 and R7 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclyl; a peptide consisting of either 1 to 10 amino acids, either unsubstituted or substituted; which forms glycosidic bonds with native monosaccharides.

[0122] In some embodiments, X3 is attached to R7; R3, R4, R5 and R6 are each independently: H; OH; O(CO)NH2; halo; amino group; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl ethers; unsubstituted or substituted heteroaryl ethers; unsubstituted or substituted C1-C ethers 10 Heterocyclyl; a peptide consisting of either 1 to 10 amino acids, either unsubstituted or substituted; which forms glycosidic bonds with native monosaccharides.

[0123] In some embodiments, A1 is either unsubstituted or substituted C3-C 15 Cycloalkyl; unsubstituted or substituted C1-C 15 Heterocyclyl; unsubstituted or substituted aryl; unsubstituted or substituted heteroaryl; or

[0124] [ka] In some embodiments, A1 is either unsubstituted or substituted C3-C 15 It is a cycloalkyl group. In some embodiments, A1 is an unsubstituted or substituted C1-C 15It is a heterocyclyl. In some embodiments, A1 is an unsubstituted or substituted aryl. In some embodiments, A1 is an unsubstituted or substituted heteroaryl. In some embodiments, A1 is

[0125] [ka] That is the case.

[0126] A compound of formula (VII), or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof is provided in one embodiment:

[0127] [ka] During the ceremony, n1 and n2 are each independently between 0 and 15; R1 and R2 are, independently, OH, H, halo, unsubstituted or substituted C1-C. 10 Alkyl, unsubstituted, or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted, or substituted C1-C 10 Carboxyl esters, unsubstituted or substituted C1-C 10 Alkyl ketones, or unsubstituted or substituted C1-C 10 It is an alkyl ether; X1, X2, and X3 are each independently bonded, C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), (CO)O, O, S, SS, Se-Se-, NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2, unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes, unsubstituted or substituted arylenes, unsubstituted or substituted heteroarylenes, unsubstituted or substituted C1-C10 A heterocyclylene, or an unsubstituted or substituted peptide containing 1 to 10 natural amino acids; Each L1 is, independently of one another, an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, an unsubstituted or substituted C1-C 10 heterocyclylene; Each L2 is, independently of one another, an unsubstituted or substituted C1-C 10 alkylene; Each R is independently an unsubstituted or substituted C1-C 10 alkyl, an unsubstituted or substituted C3-C 10 cycloalkyl, an unsubstituted or substituted C1-C 10 acyl, an unsubstituted or substituted C1-C 10 carboxyl ester, an unsubstituted or substituted C1-C 10 alkyl ketone, or an unsubstituted or substituted C1-C 10 alkyl ether, an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, or an unsubstituted or substituted C1-C 10 heterocyclyl; A2 is a linear or star-shaped poly(d-glutamic acid), poly(l-glutamic acid), or poly(dl-glutamic acid).

[0128] In some embodiments, n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In some embodiments, n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0129] In some embodiments, R1 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 alkyl; unsubstituted or substituted C3-C 10 cycloalkyl; unsubstituted or substituted C1-C 10 acyl; unsubstituted or substituted C1-C 10 carboxyl ester; unsubstituted or substituted C1-C 10 \nalkyl ketone; or unsubstituted or substituted C1-C 10It is an alkyl ether.

[0130] In some embodiments, R2 is OH; hydrogen; halo; unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 It is an alkyl ether.

[0131] In some embodiments, X1 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylenes; and unsubstituted or substituted peptides containing 1 to 10 native amino acids.

[0132] In some embodiments, X2 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10Heterocyclylenes; and unsubstituted or substituted peptides containing 1 to 10 native amino acids.

[0133] In some embodiments, X3 is one of the following: bonded; C=O, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), O(CO), or (CO)O; O, S, SS, or Se-Se-; NH, NR, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, -NR-L2-NR, L2-O, O-L2; unsubstituted or substituted C1-C 10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylenes; unsubstituted or substituted arylenes; unsubstituted or substituted heteroarylenes; unsubstituted or substituted C1-C 10 Heterocyclylenes; and unsubstituted or substituted peptides containing 1 to 10 native amino acids.

[0134] In some embodiments, each L1 is independently an unsubstituted or substituted arylene; an unsubstituted or substituted heteroarylene; or an unsubstituted or substituted C1-C 10 It is a heterocyclylene. In some embodiments, each L1 is independently an unsubstituted or substituted arylene. In some embodiments, each L1 is independently an unsubstituted or substituted heteroarylene. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0135] In some embodiments, each R is independently either unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl; non-substitutive or substituted C1-C 10 Carboxyl esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryls; unsubstituted or substituted heteroaryls; or unsubstituted or substituted C1-C10 It is a heterocycline. In some embodiments, each R is independently unsubstituted or substituted C1-C 10 It is alkyl. In some embodiments, each R is independently unsubstituted or substituted C3-C 10 It is a cycloalkyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C1. 10 It is an acyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a carboxyl ester. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ketone. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is an alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl. In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 It is a heterocycline.

[0136] In some embodiments, A2 is linear or star-shaped poly(d-glutamic acid); linear or star-shaped poly(1-glutamic acid); or linear or star-shaped poly(dl-glutamic acid). In some embodiments, A2 is linear or star-shaped poly(d-glutamic acid). In some embodiments, A2 is linear or star-shaped poly(1-glutamic acid). In some embodiments, A2 is linear or star-shaped poly(dl-glutamic acid).

[0137] In any embodiment disclosed herein, the compound is one of the compounds disclosed in any of the following tables.

[0138] [Table 1] JPEG0007846090000016.jpg232169JPEG0007846090000017.jpg207168JPEG0007846090000018.jpg68167

[0139] [Table 2] JPEG0007846090000020.jpg202144JPEG0007846090000021.jpg190144

[0140] [Table 3] JPEG0007846090000023.jpg63156

[0141] [Table 4]

[0142] [Table 5] JPEG0007846090000026.jpg79156

[0143] [Table 6] JPEG0007846090000028.jpg179168

[0144] In some embodiments, enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, or pharmaceutically acceptable salts of compounds listed in any one of the tables disclosed herein are provided herein.

[0145] In one embodiment, the compounds described herein are in the form of pharmaceutically acceptable salts. Similarly, active metabolites of these compounds having the same type of activity are included within the scope of this disclosure.

[0146] In some embodiments, the compounds described herein have one or more stereocenters, each stereocenter independently existing in either an R or S configuration. The compounds represented herein include all diastereomers, enantiomers, atropisomers, and epimers, as well as suitable mixtures thereof.

[0147] Compound Synthesis The compounds described herein are synthesized using standard synthesis techniques or by methods known in the art in combination with the methods described herein.

[0148] Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used.

[0149] The compounds are prepared using standard organic chemistry techniques known to those skilled in the art. Alternative reaction conditions may be used for the synthetic transformations described herein, including variations in solvent, reaction temperature, reaction time, and different chemical reagents and other reaction conditions. Starting materials are available from commercially available sources or are readily prepared.

[0150] The compounds described herein can be prepared by the general synthetic routes shown in the following schemes. Schemes A1 to A4 each represent a non-limiting general synthetic route for the preparation of the compounds described herein.

[0151] Scheme A1 [ka]

[0152] Scheme A2 [ka]

[0153] Scheme A3 [ka]

[0154] Scheme A4 [ka]

[0155] Pharmaceutical composition In one embodiment, the herein describes a pharmaceutical composition comprising a compound described herein, or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and / or carrier. Examples of pharmaceutically acceptable excipients include, but are not limited to, binders, flavoring agents, lubricants, disintegrants, retarders, organic solvents, suspending agents, isotonic agents, buffers, emulsifiers, stabilizers, and preservatives.

[0156] In some embodiments, the pharmaceutical composition is formulated for administration to mammals by intravenous, subcutaneous, oral, inhalation, nasal, transdermal, or ophthalmic administration.

[0157] In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

[0158] Treatment method Methods for treating cancer in a subject requiring such treatment are also provided herein, comprising administering a therapeutically effective amount of any one of the compounds, enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, or pharmaceutically acceptable salts disclosed herein to the subject.

[0159] In some embodiments, the cancer is hepatocellular carcinoma (HCC), lung cancer, breast cancer, pancreatic cancer, bile duct cancer, colorectal cancer, or glioblastoma.

[0160] The term "cancer" refers to the proliferation of tumor cells that have distinctive characteristics of loss of normal control, resulting in dysregulation of growth, lack of differentiation, local tissue invasion, and / or metastasis. As used herein, neoplasm includes, without limitation, morphological irregularities in cells in the tissue of the subject or host, as well as pathological proliferation of cells in the tissue of the subject compared to normal proliferation in the same type of tissue. In addition, neoplasm includes benign and malignant tumors (e.g., colon tumors) that are either invasive or non-invasive. Malignant neoplasms and benign neoplasms are distinguished in that the former exhibit a greater degree of dysplasia, or loss of differentiation and cell orientation, as well as the characteristics of invasion and metastasis. Furthermore, the term cancer in this context includes drug-resistant cancers, including multiple drug-resistant cancers.Examples of neoplasms (singular or plural) in which the target cells of the present invention can induce include, but are not limited to, carcinomas (e.g., squamous cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma), particularly those of the bladder, bones, intestines, breasts, neck, colon (colorectum), esophagus, head, kidneys, liver, lungs, nasopharynx, neck, ovaries, pancreas, prostate, and stomach; leukemias, e.g., acute myeloid leukemia, acute lymphoblastic leukemia, acute promyelocytic leukemia (APL), acute T cell carcinoma. Lymphoblastic leukemia, adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, neutrophilic leukemia and stem cell leukemia; benign and malignant lymphomas, especially Burkitt lymphoma, non-Hodgkin lymphoma and B-cell lymphoma; benign and malignant melanoma; bone Myeloproliferative disorders; sarcomas, especially Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, and synovial sarcoma; tumors of the central nervous system (e.g., glioma, astrocytoma, oligodendroglioma, ependymal cell tumor, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and Schwannoma); germline tumors (e.g., colon cancer, breast cancer, prostate cancer, cervical cancer, uterine Cancers that may be considered include, but are not limited to, ovarian cancer, breast cancer, colon cancer, head and neck cancer, medulloblastoma, and B-cell lymphoma.

[0161] Methods for treating immunomodulatory and / or inflammatory diseases or disorders in subjects requiring such treatment are also provided herein, comprising administering a therapeutically effective amount of any one of the compounds, enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, or pharmaceutically acceptable salts disclosed herein to a subject.

[0162] In some embodiments, the disease or disorder is associated with an inflammatory and / or autoimmune disease. Examples of such inflammation-related diseases or disorders and / or inflammations include, but are not limited to, membranous nephropathy (MN), lupus nephritis, systemic lupus erythematosus, kidney transplantation, renal fibrosis, inflammatory bowel disease, Crohn's disease, intestinal fibrosis, hepatic fibrosis, asthma, acute lung injury, pulmonary arterial hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis, and psoriasis. In some embodiments, the inflammation-related disease or disorder and / or inflammation is any one of membranous nephropathy (MN), lupus nephritis, systemic lupus erythematosus, kidney transplantation, renal fibrosis, inflammatory bowel disease, Crohn's disease, intestinal fibrosis, hepatic fibrosis, asthma, acute lung injury, pulmonary arterial hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis, or psoriasis.

[0163] definition Various embodiments are described below. It should be noted that no particular embodiment is intended to be exhaustive or to limit the scope to broader embodiments discussed herein. An embodiment described in conjunction with a specific embodiment is not necessarily limited to that embodiment and may be practiced in conjunction with any other embodiment(s).

[0164] Where used herein, “about” is understood by those skilled in the art and varies to some extent depending on the context in which it is used. Where there is a use of a term not obvious to those skilled in the art, “about” means up to plus or minus 10% of the special term, considering the context in which it is used.

[0165] The terms “a,” “an,” and “the” in the context of describing elements (especially in the context of the following claims), and the use of similar references, should be interpreted as encompassing both singular and plural, unless otherwise indicated herein or clearly inconsistent with the context. The enumeration of value ranges herein is intended to function simply as a concise way of referring individually to each distinct value falling within the range, unless otherwise indicated herein, and each distinct value is incorporated herein as if it were individually enumerated herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly inconsistent with the context. Any and all examples or illustrative language (e.g., “etc.”) provided herein are intended simply to better illustrate embodiments and do not limit the scope of claims unless otherwise specified. No language herein should be interpreted as indicating any non-claimed element as essential.

[0166] When used in this specification, C1 to C x is C1~C2, C1~C3……C1~C x This includes. For example only, a group designated as "C1-C4" indicates that the part has one to four carbon atoms, i.e., a group containing one carbon atom, two carbon atoms, three carbon atoms, or four carbon atoms. Therefore, for example only, "C1-C4 alkyl" indicates that the alkyl group has one to four carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0167] When substituents are identified by their conventional chemical formulas written from left to right, they equally encompass chemically identical substituents resulting from writing the structure from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0168] The "alkyl" group refers to an aliphatic hydrocarbon group, either by itself or as part of another molecule. Alkyl groups can be branched or linear. In some embodiments, the "alkyl" group consists of 1 to 20 carbon atoms, i.e., C1-C2. 20 Alkyl. Wherever it appears herein, a numerical range such as “1 to 20” refers to each integer within a given range; for example, “1 to 20 carbon atoms” means that an alkyl group consists of up to 20 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, and so on, but this definition also includes appearances of the term “alkyl” where a numerical range is not specified. In some embodiments, the alkyl group is C1-C6 alkyl. In one embodiment, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0169] The "alkylene" group refers to a divalent alkyl group. Any of the monovalent alkyl groups described above can be alkylenes obtained by abstracting a second hydrogen atom from an alkyl group. In some embodiments, the alkylene is C1-C 20 In other embodiments, the alkylene is C1-C 10It is an alkylene. In other embodiments, the alkylene is a C1-C6 alkylene. In certain embodiments, the alkylene contains one to four carbon atoms (e.g., a C1-C4 alkylene). In other embodiments, the alkylene contains one to three carbon atoms (e.g., a C1-C3 alkylene). In other embodiments, the alkylene contains one to two carbon atoms (e.g., a C1-C2 alkylene). In other embodiments, the alkylene contains one carbon atom (e.g., a C1 alkylene). In other embodiments, the alkylene contains two carbon atoms (e.g., a C2 alkylene). In other embodiments, the alkylene contains two to four carbon atoms (e.g., a C2-C4 alkylene). Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-.

[0170] The term "alkenyl" refers to an alkyl group that has at least one carbon-carbon double bond. In one embodiment, the alkenyl group has the formula -C(R)=CR2, where R is the rest of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, the alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0171] The term "alkynyl" refers to an alkyl group that has at least one carbon-carbon triple bond. In one embodiment, the alkynyl group has the formula -C≡CR, where R refers to the rest of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, the alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0172] The "alkoxy" group refers to an -O(alkyl) group, where alkyl is as defined herein.

[0173] The term "alkylamine" is -N(alkyl) x H y The base is such that x is 0 and y is 2, or x is 1 and y is 1, or x is 2 and y is 0.

[0174] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. The term "aromatic" includes both carbocyclic aryl ("aryl," e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups.

[0175] The term "carbocyclic" or "carbocyclic" refers to a ring or ring system in which all atoms forming the ring skeleton are carbon atoms. The term thus distinguishes a carbocyclic from a "heterocyclic" ring or "heterocyclic" ring, in which the ring skeleton contains at least one atom other than carbon. In some embodiments, at least one of the two rings in a bicyclic carbocyclic is aromatic. In some embodiments, both rings in a bicyclic carbocyclic are aromatic. Carbocyclics include cycloalkyl and aryl compounds.

[0176] As used herein, the term “aryl” refers to an aromatic ring in which each of the ring-forming atoms is a carbon atom. In one embodiment, the aryl is phenyl or naphthyl. In some embodiments, the aryl is phenyl. In some embodiments, the aryl is C6-C 10 It is an aryl group. Depending on the structure, the aryl group is either a monoradical or a diradical (i.e., an arylene group).

[0177] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic non-aromatic group in which each of the ring-forming atoms (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or crosslinked compound. In some embodiments, the cycloalkyl is optionally condensed with an aromatic ring, and the attachment site is a carbon atom other than the aromatic ring carbon atom. Examples of cycloalkyl groups include those having 3 to 10 ring atoms. In some embodiments, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic cycloalkyl. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl compounds include adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norborneyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.

[0178] "Carbocyclylalkyl" is a compound of the formula -R c - Refers to the carbocyclyl group, in the formula, R c This is an alkylene chain as defined above. The alkylene chain and carbocyclyl group are optionally substituted as defined above.

[0179] The terms "halo" or, alternatively, "halogen" or "halide" refer to fluoro, chloro, bromo, or iodine. In some embodiments, the halo is fluoro, chloro, or bromo.

[0180] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. In one embodiment, fluoroalkyls are C1-C6 fluoroalkyls.

[0181] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one embodiment, the fluoroalkyl group is a C1-C6 fluoroalkyl group. In some embodiments, the fluoroalkyl group is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0182] The term "heteroalkyl" refers to an alkyl group in which one or more of the alkyl backbone atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. In heteroalkyls, the carbon atoms of the heteroalkyl are attached to the rest of the molecule. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl.

[0183] The term “heterocyclic” or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in a ring(s), where each heteroatom in the ring(s) is selected from O, S, and N, and each heterocyclic group has 3 to 20 or 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. In some embodiments, heterocyclics are monocyclic, bicyclic, polycyclic, spirocyclic, or bridging compounds. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) contain rings having 3 to 10 or 3 to 20 atoms in their ring system, and aromatic heterocyclic groups contain rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-condensed ring systems. Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinol, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azilidinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, and dithio These include lanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indoline-2-onyl, isoindoline-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinoline-1(2H)-onyl, 3,4-dihydroquinoline-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazole-2(3H)-onyl, 1H-benzo[d]imidazole-2(3H)-onyl, benzo[d]thiazole-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, sinnolinyl, indazolyl, indolidinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, flazanyl, benzoflazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthylidinyl, and phlopyridinyl. The aforementioned groups are, where possible, either carbon-bonded (or carbon-linked) or nitrogen-bonded. For example, groups derived from pyrrole include both pyrrole-1-yl (N-attached) or pyrrole-3-yl (C-attached). Furthermore, groups derived from imidazole include imidazole-1-yl or imidazole-3-yl (both N-attached) or imidazole-2-yl, imidazole-4-yl or imidazole-5-yl (all C-attached). Heterocyclic groups include benzo-condensed ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidine-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0184] The term "heterocyclyl" refers to any monovalent radical form obtained by removing a hydrogen atom from any ring atom of a heterocyclic compound as defined herein. Depending on the structure, the heterocyclyl group is either a monoradical or a diradical (i.e., a heterocyclylene group).

[0185] The terms “heteroaryl” or, alternatively, “heteroaromatic” refer to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Exemplary examples of heteroaryl groups include monocyclic and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and flazanil. Bicyclic heteroaryls include indidine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolidine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryls contain 0 to 4 nitrogen atoms in the ring. In some embodiments, the heteroaryl ring contains 1 to 4 N atoms. In some embodiments, the heteroaryl ring contains 0 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom. In some embodiments, the heteroaryl ring contains 1 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom. In some embodiments, the heteroaryl ring contains C1 to C 10 It is a heteroaryl group. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl group. In some embodiments, the monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl group. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl group. Depending on the structure, the heteroaryl group is a monoradical or a diradical (i.e., a heteroarylene group).

[0186] A "heterocycloalkyl" group or "heteroalicyclic" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, heterocycloalkyls are condensed with aryl or heteroaryl groups. In some embodiments, heterocycloalkyls are oxazolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidine-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinyl, imidazolidinyl, imidazolidinyl-2-onyl, or thiazolidinyl-2-onyl. The term heteroalicyclic includes all cyclic forms of carbohydrates, including monosaccharides, disaccharides, and oligosaccharides, but is not limited to the following. In one embodiment, the heterocycloalkyl is C1-C 20 It is a heterocycloalkyl. In one embodiment, the heterocycloalkyl is C1-C 14 It is a heterocycloalkyl. In one embodiment, the heterocycloalkyl is C1-C 10 It is a heterocycloalkyl. In one embodiment, the heterocycloalkyl is C2-C 14 It is a heterocycloalkyl. In one embodiment, the heterocycloalkyl is C2~C 10 It is a heterocycloalkyl. In another embodiment, the heterocycloalkyl is C4-C 10 It is a heterocycloalkyl. In another embodiment, the heterocycloalkyl is C5-C 10 It is a heterocycloalkyl group. In some embodiments, the heterocycloalkyl group contains 0 to 2 nitrogen atoms in the ring. In some embodiments, the heterocycloalkyl group contains 0 to 2 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 1 sulfur atom in the ring. Depending on the structure, the heteroaryl group is a monoradical or a diradical (i.e., a heteroarylene group).

[0187] "Heterocyclylalkyl" is a compound of formulas -R c - Refers to the heterocyclyl group, in the formula, R cThis is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, then the heterocyclyl is optionally attached to the alkyl group with a nitrogen atom. The alkylene chain of the heterocyclylalkyl group is optionally substituted as defined above for the alkylene chain. The heterocyclyl portion of the heterocyclylalkyl group is optionally substituted as defined above for the heterocyclyl group.

[0188] The terms “bond” or “single bond” refer to a chemical bond between two atoms, or between two parts when the atoms joined by the bond are considered as part of a larger substructure. In one embodiment, if the group described herein is a bond, the referenced group is absent, thereby allowing a bond to be formed between the remaining identified groups.

[0189] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is often perceived as a chemical entity embedded within or attached to a molecule.

[0190] The terms "optionally substituted" or "substituted" mean that the referenced group is optionally substituted with one or more additional groups selected individually and independently from D, halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituent is independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1~C4 alkyl), -C(=O)NH2, -C(=O)NH(C1~C4 alkyl), -C(=O)N(C1~C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1~C4 alkyl), -S(=O)2N(C1~C4 alkyl)2, C1~C4 alkyl, C3~C6 cycloalkyl, C1~C4 fluoroalkyl, C1~C4 heteroalkyl, C1~C4 alkoxy, C1~C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1~C4 alkyl, and -S(=O)2C1-C4 alkyl. In some embodiments, the optional substituent is independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituted group is substituted with one or two of the preceding groups. In some embodiments, the optional substituent on an aliphatic carbon atom (acyclic or cyclic) is oxo (=O).

[0191] With respect to a formulation, composition, or component, the term “acceptable” means that it does not have any lasting adverse effect on the overall health of the subject being treated.

[0192] The terms “administer,” “give delivery,” and “dosage,” as used herein, refer to methods that can be used to enable the delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art will be familiar with the administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0193] When used herein, terms such as “concurrent administration” are meant to encompass the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which the drugs are administered by the same or different routes of administration or at the same or different times.

[0194] The terms “effective dose” or “therapeutic effective dose,” as used herein, refer to a sufficient amount of an administered drug or compound that alleviates, to some extent, one or more symptoms of the disease or condition being treated. Results may include a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired modification of the biological system. For example, “effective dose” for therapeutic use is the amount of a composition containing the compound as disclosed herein that is required to provide a clinically significant reduction in disease symptoms. The appropriate “effective” dose in any individual case may, at their discretion, be determined using techniques such as dose-escalation studies.

[0195] The terms “enhance” or “enhance” as used herein mean increasing or extending a desired effect in either potency or duration. Therefore, with respect to enhancing the effect of a therapeutic agent, “enhance” refers to the ability to increase or extend the effect of another therapeutic agent on a system in either potency or duration. “Enhancement dose” as used herein refers to an appropriate amount for enhancing the effect of another therapeutic agent on a desired system.

[0196] The terms "kit" and "manufacturing article" are used synonymously.

[0197] As used herein, the term "inhibit" refers to the partial or complete elimination of a potential effect, whereas an inhibitor is a compound that has the ability to inhibit.

[0198] The term "pharmaceutically acceptable salt" refers to a cationic form of a therapeutically active drug in combination with a suitable anion, or, in an alternative embodiment, a therapeutically active drug form consisting of the anionic form of a therapeutically active drug in combination with a suitable cation.

[0199] In some embodiments, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with an acid to provide a “pharmaceutically acceptable acid addition salt.” In some embodiments, the compounds described herein (i.e., the free base form) are basic and react with an organic or inorganic acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphor acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecyl sulfate; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptate Examples include nic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphate; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0200] In some embodiments, the compounds described herein are acidic and react with bases. In these situations, the acidic protons of the compounds described herein are replaced by metal ions, such as lithium, sodium, potassium, magnesium, calcium, or aluminum ions. In some cases, the compounds described herein coordinate with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine, but are not limited to those listed below. In other cases, the compounds described herein form salts with amino acids such as arginine and lysine, but are not limited to those listed below. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, and lithium hydroxide. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, magnesium salts, meglumine salts, N-methylglucamine salts, or ammonium salts.

[0201] References to pharmaceutically acceptable salts should be understood to include solvated forms. In some embodiments, solvates are formed during the process of isolating or purifying a compound in a pharmaceutically acceptable solvent such as water or ethanol, containing either stoichiometric or non-stoichiometric amounts of solvent. Hydrates are formed when the solvent is water, or alkoxides are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein exist in both non-solvated and solvated forms, at the option of choice.

[0202] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0203] The terms “to treat,” “to treat,” or “treatment,” as used herein, include reducing, alleviating or improving at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, for example, preventing the onset of a disease or condition, mitigating a disease or condition, causing a regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping the symptoms of a disease or condition, either preventively or therapeutically.

[0204] The present invention, as generally described herein, will be more readily understood by referring to the following examples, which are provided for illustrative purposes and are not intended to limit the invention.

[0205] As used above and throughout the description of this invention, the following abbreviations should be understood to have the following meanings unless otherwise indicated: Acetyl Acetic acid (ACOH) Bn Benzyl DCC (Dicyclohexylcarbodiimide) DCE Dichloroethane DCM Dichloromethane DIPEA or DIEA: Diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DMF Dimethylformamide DMSO (Dimethyl Sulfoxide) Et ethyl HCl or EA ethyl acetate HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) HPLC (High-Performance Liquid Chromatography) Me methyl MeOH methanol MS mass spectrometry NMR nuclear magnetic resonance PE (Petroleum Ether) Rt. Room temperature TFA (Trifluoroacetic Acid) TEA (Triethylamine) THF (Tetrahydrofuran) [Examples]

[0206] Synthesis of ((2R,3S,4S,5R)-5-fluoro-3,4,6-trihydroxytetrahydro-2H-pyran-2-yl)methyl((5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl)succinate (compound 1)

[0207] [ka]

[0208] The following scheme shows the synthetic route used to prepare the title compound.

[0209] Scheme 1. [ka]

[0210] Scheme 2. [ka]

[0211] Scheme 3. [ka]

[0212] Preparation of (2R,3S,4R)-2-(hydroxymethyl)-3,4-dihydro-2H-pyran-3,4-diol (A2)

[0213] To a stirred solution of compound A1 (2.72 g, 10.0 mmol, 1.0 equivalent) in MeOH (20 mL), NaOMe (216 mg, 4.0 mmol, 0.4 equivalents) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction product was quenched with NH4Cl (aqueous solution), then concentrated, the residue was dissolved in EA, washed with water and brine, and dried over Na2SO4. Concentration and purification with silica gel (PE~PE:EA=5:1~DCM:MeOH=20:1) yielded compound A2 as a colorless oil (1.5 g, yield: 100%).

[0214] Preparation of (2R,3S,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran(A3)

[0215] To a stirred solution of compound A2 (1.5 g, 10.0 mmol, 1.0 equivalent) in DMF (50 mL), NaH (1.8 g, 45 mmol, 4.5 equivalents) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. BnBr (7.7 g, 45.0 mmol, 4.5 equivalents) was added, and the mixture was stirred overnight at room temperature. The reaction product was quenched with NH4Cl (aqueous solution), then concentrated, the residue was dissolved in EA, washed with water and brine, and dried over Na2SO4. Concentration and purification with silica gel (PE~PE:EA = 40:1~30:1) yielded compound A3 as a white solid (2.81 g, yield: 68%).

[0216] Preparation of (4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-fluorotetrahydro-2H-pyran-2-ol (A4)

[0217] Selectfluor (2.44 g, 6.9 mmol, 1.2 equivalents) was added to a solution of compound A3 (2.39 g, 5.75 mmol, 1.0 equivalent) in acetone (25 mL) and water (5 mL), and the resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The reaction product was quenched with NH4Cl (aqueous solution) and then concentrated. The residue was dissolved in EA, washed with water and brine, and dried over Na2SO4. Concentration and purification with silica gel (PE~PE:EA = 20:1~10:1) yielded compound A4 as a colorless oil (2.1 g, yield: 69%).

[0218] Preparation of (3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-fluorotetrahydro-2H-pyran-2-ylacetate (A6)

[0219] To a solution of compound A4 (2.1 g, 4.64 mmol, 1.0 equivalent) and DMAP (57 mg, 0.46 mmol, 0.1 equivalent) in pyridine (25 mL), Ac2O (1.9 g, 18.6 mmol, 4.0 equivalent) was added at 0°C. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with EA, washed with water and brine, and dried over Na2SO4. Concentration and purification with silica gel (PE~PE:EA = 20:1~10:1) yielded compound A6 as a colorless oil (560 mg, yield: 77% total).

[0220] Preparation of (3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-fluorotetrahydro-2H-pyran-2-ol (A7)

[0221] To a stirred solution of compound A6 (560 Mg, 1.13 mmol, 1.0 equivalent) in MeOH (12 mL), NaOMe (10 mg, 0.17 mmol, 0.15 equivalents) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction product was quenched with NH4Cl (aqueous solution), then concentrated, the residue was dissolved in EA, washed with water and brine, and dried over Na2SO4. Concentration and purification with silica gel (PE~PE:EA = 5:1) yielded compound A7 as a white solid (390 mg, yield: 76%).

[0222] Preparation of (3R,4S,5R,6R)-2,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-3-fluorotetrahydro-2H-pyran(A8)

[0223] To a stirred solution of compound A7 (700 mg, 1.55 mmol, 1.0 equivalent) in DMF (10 mL), NaH (87 mg, 2.17 mmol, 1.4 equivalents) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. BnBr (371 mg, 2.17 mmol, 1.4 equivalents) was added, and the mixture was stirred overnight at room temperature. The reaction product was quenched with NH4Cl (aqueous solution), then concentrated, the residue was dissolved in EA, washed with water and brine, and dried over Na2SO4. Concentration and purification with silica gel (PE~PE:EA = 50:1~40:1) yielded compound A8 as a yellow solid (670 mg, yield: 80%).

[0224] Preparation of ((2R,3R,4S,5R)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-yl)methylacetate (A9)

[0225] To newly dissolved ZnCl2 (1.01 g, 7.41 mmol, 1.0 equivalent), 12 mL of 1:5 HOAc / Ac2O was added. The mixture was cooled to 0°C. A solution of compound A8 (630 mg, 1.23 mmol, 1.0 equivalent) in 6 mL of 1:5 HOAc / Ac2O was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. Water was added, and the precipitate was collected by filtration. The filtrate was then dissolved in EA, washed with water and brine, and dried over Na2SO4. Concentration and purification with silica gel (PE~PE:EA = 40:1~30:1) yielded compound A9 as a pale yellow solid (610 mg, yield: 100%).

[0226] Preparation of ((2R,3R,4S,5R)-3,4,6-tris(benzyloxy)-5-fluorotetrahydro-2H-pyran-2-yl)methanol (A10)

[0227] To a stirred solution of compound A9 (610 mg, 1.23 mmol, 1.0 equivalent) in MeOH (20 mL), NaOMe (13 mg, 0.25 mmol, 0.2 equivalents) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction product was quenched with NH4Cl (aqueous solution), then concentrated, the residue was dissolved in EA, washed with water and brine, and dried over Na2SO4. Concentration and purification with silica gel (PE~PE:EA=5:1~DCM:MeOH=20:1) yielded compound A10 as a colorless oil (400 mg, yield: 72%).

[0228] Preparation of (5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyleno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl(((2R,3R,4S,5R)-3,4,6-tris(benzyloxy)-5-fluorotetrahydro-2H-pyran-2-yl)methyl)succinate (A11)

[0229] To a solution of compound A10 (100 mg, 0.2174 mmol, 1.0 equivalent) and compound B (100 mg, 0.2174 mmol, 1.0 equivalent) in dry DCM (10 mL), DCC (50 mg, 0.239 mmol, 1.1 equivalents) and DMAP (30 mg, 0.239 mmol, 1.51 equivalents) were added at 0°C. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with DCM, washed with water and brine, and dried over Na2SO4. Concentration and purification by prep-HPLC provided compound A11 as a white solid (90 mg, yield: 46%).

[0230] Preparation of ((2R,3S,4S,5R)-5-fluoro-3,4,6-trihydroxytetrahydro-2H-pyran-2-yl)methyl((5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl) succinate (compound 1)

[0231] A mixture of compound A11 (90 mg, 0.112 mmol, 1.0 equivalent) and Pd / C (10%, 50 mg) in MeOH (10 mL) was stirred overnight at room temperature under an H2 atmosphere. The mixture was filtered, concentrated, and the residue was purified by prep-HPLC to provide compound 1 as a white solid (55 mg, yield: 87%).

[0232] Compound 1: 1H NMR (CD3OD, 400 MHz): 0.82 (d, J=7.2 Hz 3 H), 0.93 (d, J=6.8 Hz 3 H), 1.03 (s, 3 H), 1.32-1.34 (m, 1 H), 1.48-1.52 (m, 1 H), 1.86-1.93 (m, 2 H), 2.03-2.10 (m, 1 H), 2.22-2.29 (m, 2 H), 2.68-2.78 (m, 5 H), 3.33-3.35 (m, 1 H), 3.45 (d, J=5.6 Hz, 1 H), 3.58-3.62 (m, 2 H), 3.85-3.98 (m, 2.3 H), MS (ESI) [C 30 H 37 FO 13 Calculated value of ] (m / z) 624.22, measured value 625.1, [M+H]+. [Examples]

[0233] Synthesis of (5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl4-oxo-4-(4-(4-oxo-4-(((3S,4S,5R,6S)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)butanoyl)piperazine-1-yl)butanoate (compound 2)

[0234] [ka]

[0235] The following scheme shows the synthetic route used to prepare the title compound.

[0236] Scheme 4. [ka]

[0237] Scheme 5. [ka]

[0238] Preparation of (3R,4R,5S,6R)-6-(hydroxymethyl)-3-((E)-(4-methoxybenzylidene)amino)tetrahydro-2H-pyran-2,4,5-triol (B2)

[0239] To a stirred solution of compound B1 (1.08 g, 5.0 mmol, 1 equivalent) in water (8 mL), NaOH (200 mg, 5 mmol, 1.0 equivalent) was added at 0°C, and the mixture was stirred at room temperature for 15 minutes. 4-methoxybenzaldehyde (681 mg, 5 mmol, 1.0 equivalent) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction product was filtered and dried to obtain compound B2 as a white solid (900 mg, yield: 60%).

[0240] Preparation of (3R,4R,5S,6R,E)-2,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-N-(4-methoxybenzylidene)tetrahydro-2H-pyran-3-amine (B3)

[0241] To a stirred solution of compound B2 (900 mg, 3.03 mmol, 1 equivalent) in dry DMF (25 mL), NaH (605 mg, 15.13 mmol, 5.0 equivalents) was gradually added at 0°C, and the mixture was stirred at room temperature for 30 minutes. (Bromomethyl)benzene (2.18 g, 12.73 mmol, 4.2 equivalents) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction product was quenched with NaCl, concentrated, and the residue was purified using silica gel (PE~PE:EA = 50:1~30:1) to obtain compound B3 as a pale yellow oil (500 mg, yield: 25%).

[0242] Preparation of (3R,4R,5S,6R)-2,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (B4)

[0243] A mixture of compound B3 (500 mg, 0.76 mmol, 1.0 equivalent) in acetone (12 mL) and 5N HCl (2 mL) was refluxed for 20 minutes. The mixture was cooled, the precipitate was collected by filtration, and the mixture was dried to obtain compound B4 as a white solid (300 mg, yield: 68%).

[0244] Preparation of tert-butyl 4-(4-oxo-4-(((3R,4R,5S,6R)-2,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)amino)butanoyl)piperazine-1-carboxylate (B6)

[0245] To a solution of compound B4 (115 mg, 0.2 mmol, 1.0 equivalent) and compound B5 (57 mg, 0.2 mmol, 1.0 equivalent) in dry DMF (5 mL), HATU (99 mg, 0.26 mmol, 1.3 equivalents) and DIEA (78 mg, 0.6 mmol, 3 equivalents) were added at 0°C. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated, the residue was dissolved with EA, washed with water and brine, and dried over Na2SO4. By concentration and purification using silica gel (PE~PE:EA = 20:1~10:1), compound B6 was obtained as a white solid (160 mg, yield: 99%).

[0246] Preparation of 4-oxo-4-(piperazin-1-yl)-N-((3R,4R,5S,6R)-2,4,5-tris(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)butanamide (B7)

[0247] To a solution of compound B6 (160 mg, 0.198 mmol, 1.0 equivalent) in dried DCM (10 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 18 hours. By concentrating the mixture, compound B7 was obtained as a yellow oil (123 mg, yield: 100%).

[0248] Preparation of (5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyleno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl4-oxo-4-(4-(4-oxo-4-(((3S,4S,5R,6S)-2,4,5-tris(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)butanoyl)piperazin-1-yl)butanoate (B9)

[0249] To a solution of compound B7 (123 mg, 0.2 mmol, 1.0 equivalent) and compound B8 (92 mg, 0.2 mmol, 1.0 equivalent) in dry DMF (5 mL), HATU (99 mg, 0.26 mmol, 1.3 equivalents) and DIEA (78 mg, 0.6 mmol, 3 equivalents) were added at 0°C. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated, the residue was dissolved in EA, washed with water and brine, and dried over Na2SO4. By concentration and purification using silica gel (PE~PE:EA = 20:1~5:1), compound B9 was obtained as a white solid (80 mg, yield: 37%).

[0250] Preparation of (5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl4-oxo-4-(4-(4-oxo-4-(((3S,4S,5R,6S)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)butanoyl)piperazin-1-yl)butanoate (compound 2)

[0251] A mixture of compound B9 (80 mg, 0.0755 mmol, 1.0 equivalent) and Pd / C (10%, 20 mg) in MeOH (5 mL) was stirred overnight at room temperature under an H2 atmosphere. The mixture was filtered, concentrated, and the residue was purified by prep-HPLC to obtain compound 2 as a white solid (25 mg, yield: 42%).

[0252] Compound 2: 1H NMR (CD3OD, 400 MHz): 0.81 (d, J=6.8 Hz 3 H), 0.93 (d, J=7.2 Hz 3 H), 1.02 (s, 3 H), 1.31-1.37 (m, 2 H), 1.47-1.51 (m, 1 H), 1.85-1.97 (m, 2 H), 2.03-2.07 (m, 1 H), 2.22-2.29 (m, 2 H), 2.55-2.58 (m, 2 H), 2.70-2.75 (m, 7 H), 3.34-3.38 (m, 1 H), 3.44-3.48 (m, 1.5 H), 3.57-3.74 (m, 11H), MS (ESI) [C 38 H 51 N3O 15 Calculated value for ] (m / z) is 789.33, measured value is 790.2, [M+H]+. [Examples]

[0253] Synthesis of (6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl4-oxo-4-(4-(4-oxo-4-(((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methoxy)butanoyl)piperazine-1-yl)butanoate (compound 3)

[0254] [ka]

[0255] The following scheme shows the synthetic route used to prepare the title compound.

[0256] Scheme 6. [ka]

[0257] Preparation of tert-butyl 4-(4-oxo-4-(((2R,3R,4S,5R)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)butanoyl)piperazine-1-carboxylate (C3)

[0258] To a solution of compound C1 (58 mg, 0.2 mmol, 1.0 equivalent) and compound C2 (108 mg, 0.2 mmol, 1.0 equivalent) in dried DCM (5 mL), DCC (45 mg, 0.22 mmol, 1.1 equivalent) and DMAP (27 mg, 0.22 mmol, 1.1 equivalent) were added at 0°C. The mixture was stirred at room temperature for 18 hours, diluted with EA, washed with water and then brine, and dried over Na2SO4. Concentration and purification with silica gel (PE~PE:EA = 20:1) yielded compound C3 as a white solid (130 mg, yield: 80%).

[0259] Preparation of ((2R,3R,4S,5R)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl4-oxo-4-(piperazin-1-yl)butanoate (C4)

[0260] To a solution of compound C3 (130 mg, 0.16 mmol, 1.0 equivalent) in dry DCM (5 mL), TFA (0.1 mL) was added, and the mixture was stirred at room temperature for 18 hours. By concentrating the mixture, compound C4 was obtained as a yellow oil (113 mg, yield: 100%).

[0261] Preparation of (6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyleno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl4-oxo-4-(4-(4-oxo-4-(((2R,3R,4S,5R)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)butanoyl)piperazin-1-yl)butanoate (C6)

[0262] To a solution of compound C4 (113 mg, 0.16 mmol, 1.0 equivalent) and compound C5 (74 mg, 0.16 mmol, 1.0 equivalent) in dry DMF (5 mL), HATU (91 mg, 0.24 mmol, 1.5 equivalents) and DIEA (62 mg, 0.48 mmol, 3 equivalents) were added at 0°C. The mixture was stirred at room temperature for 18 hours and concentrated to obtain a residue, which was dissolved in EA, washed with water and brine, and dried on Na2SO4. Concentration and purification using silica gel (PE~PE:EA = 20:1~10:1) yielded compound C6 as a white solid (100 mg, yield: 54%).

[0263] Preparation of (6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl4-oxo-4-(4-(4-oxo-4-(((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methoxy)butanoyl)piperazine-1-yl)butanoate (compound 3)

[0264] A mixture of compound C6 (80 mg, 0.0695 mmol, 1.0 eq) and Pd / C (10%, 40 mg) in MeOH (5 mL) was stirred at room temperature overnight under a H2 atmosphere. The mixture was filtered, concentrated, and then purified by pre-HPLC to obtain the title compound as a white solid (25 mg, yield: 45%). [C 38 H 50 N2O 16 (m / z) Calculated value for MS (ESI) 790.32, measured value 791.2, [M + H] + . HPLC: 214 nm, 9.845 / 9.941, 100%; 254 nm, 9.847 / 9.945 min, 100%.

Example

[0265] (6aS,7aR,8R,8aS,9aS,9bS,llaS,10bS)-8a-Isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyrheno)[2’,3’:4b,5;2’’,3’’:6,7;2’”’,3’”’:8a,9]phenanthro[1,2-c]furan-8-yl 2-(2-(2-(((2R,3R,4S,5R)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetamido)acetamido)acetate (Compound 4) Synthesis

[0266]

Chem.

[0267] The following scheme shows the synthetic route used to prepare the title compound.

[0268] Scheme 7.

Chem.

[0269] Preparation of ethyl 2-(((2R,3R,4S,5R)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetate (D2)

[0270] To a solution of compound D1 (540 mg, 1.0 mmol, 1.0 equivalent) in dry DMF (40 mL), NaH (48 mg, 1.2 mmol, 1.2 equivalents) was gradually added. The mixture was stirred at room temperature under an N2 atmosphere for 0.5 hours. Ethyl 2-bromoacetate (200 mg, 1.2 mmol, 1.2 equivalents) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with brine, concentrated, the residue dissolved in EA, washed with water, and dried over Na2SO4. The mixture was concentrated, and the residue was purified by column chromatography on silica gel (PE~EA:50:1) to obtain compound D2 as a colorless oil (300 mg, yield: 48%).

[0271] Preparation of 2-(((2R,3R,4S,5R)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetic acid (D3)

[0272] To a solution of compound D2 (300 mg, 0.48 mmol, 1.0 equivalent) in THF (6 mL) and water (2 mL), LiOHH2O (101 mg, 2.4 mmol, 5.0 equivalents) was added, and the mixture was stirred overnight at room temperature under an N2 atmosphere. The mixture was concentrated, the residue was acidified to pH=4-5 with 2N HCl, extracted with EA, washed with water, and dried over Na2SO4. The mixture was concentrated, and the residue was purified by column chromatography on silica gel (PE~EA=2:1) ​​to obtain compound D3 as a colorless oil (mg, yield: 38%).

[0273] Preparation of methyl 2-(2-(2-(((2R,3R,4S,5R)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetamide)acetamide)acetate (D4)

[0274] To a solution of compound D3 (110 mg, 0.18 mmol, 1.0 equivalent), compound 3' (34 mg, 0.18 mmol, 1.0 equivalent), and HATU (90 mg, 0.234 mmol, 1.3 equivalents) in dry DMF (5 mL), DIEA (77 mg, 0.6 mmol, 3.3 equivalents) was added at 0°C, and the resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The reaction mixture was quenched with water, concentrated, the residue was diluted with EA, washed with water, and dried over Na2SO4. After concentration, the residue was purified by column chromatography on silica gel (PE~EA=5:1) to obtain compound D4 as a white solid (165 mg, yield: 70%).

[0275] Preparation of 2-(2-(2-(((2R,3R,4S,5R)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetamide)acetamide)acetic acid (D5)

[0276] To a solution of compound D4 (165 mg, 0.227 mmol, 1.0 equivalent) in THF (6 mL) and water (2 mL), LiOHH2O (48 mg, 1.14 mmol, 5.0 equivalents) was added, and the mixture was stirred overnight at room temperature under an N2 atmosphere. The mixture was concentrated, the residue was acidified to pH=4-5 with 2N HCl, extracted with EA, washed with water, and dried over Na2SO4. After concentration, the residue was purified by column chromatography on silica gel (PE~EA=2:1) ​​to obtain compound D5 as a white solid (160 mg, yield: 99%).

[0277] Preparation of (6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyleno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenantro[1,2-c]furan-8-yl2-(2-(2-(((2R,3R,4S,5R)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetamide)acetamide)acetate (D6)

[0278] To a solution of compound D5 (160 mg, 0.23 mmol, 1.0 equivalent) and compound A (82 mg, 0.23 mmol, 1.0 equivalent) in dried DCM (5 mL), DCC (56 mg, 0.27 mmol, 1.2 equivalents) and DMAP (cat.) were added at 0°C, and the resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the filtrate was purified by pre-HPLC to obtain compound D6 as a white solid (72 mg, yield: 30%).

[0279] Preparation of (6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyleno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenantro[1,2-c]furan-8-yl2-(2-(2-(((2R,3R,4S,5R)-3,4,5,6-tetrakis(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetamide)acetamide)acetate (compound 4)

[0280] To a solution of compound D6 (72 mg, 0.068 mmol, 1.0 equivalent) in MeOH (6 mL), Pd / C (36 mg, 10%) was added, and the mixture was stirred at room temperature under an H2 atmosphere for 6 hours. The mixture was filtered, the filtrate was concentrated, and the title compound was obtained as a white solid by pre-HPLC (13 mg, yield: 28%). [C 32 H 42 N2O 15 MS(ESI) calculated value for ](m / z) 694.26, measured value 695.4, [M+H] + . HPLC: 220nm, 8.904min, 100%; 254nm, 8.906min, 100%. [Examples]

[0281] Synthesis of (5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl4-(4-(4-((6-chloro-2-methoxyacrylidine-9-yl)amino)pentyl)piperazine-1-yl)-4-oxobutanoate (compound 5)

[0282] [ka]

[0283] The following scheme shows the synthetic route used to prepare the title compound.

[0284] Scheme 8. [ka]

[0285] Preparation of tert-butyl 4-(4-oxopentyl)piperazine-1-carboxylate (E2)

[0286] K2CO3 (3.7 g, 26.9 mmol, 1.3 equivalents) was added at room temperature to a stirred solution of compound E1 (2.5 g, 20.7 mmol, 1.0 equivalent) and tert-butylpiperazine-1-carboxylate (7.7 g, 41.4 mmol, 2.0 equivalents) in DMF (30 mL). After stirring overnight at 65 °C, the mixture was poured into cold water (200 mL) and extracted with siRNA (200 mL x 3). All EA layers were combined, washed with brine (200 mL x 3), dried over Na2SO4, and concentrated. The residue was purified by silica gel column (DCM:MeOH = 20:1 to 10:1) to obtain product E2 as a yellow oil (2.3 g, yield: 41%).

[0287] Preparation of tert-butyl 4-(4-((benzyloxy)imino)pentyl)piperazine-1-carboxylate (E4)

[0288] To a stirred mixture of E2 (2.3 g, 8.5 mmol, 1.0 equivalent) and O-benzylhydroxylamine hydrochloride (1.5 g, 9.4 mmol, 1.05 equivalents) in MeOH (10 mL), NaOAc (3.5 g, 42.5 mmol, 5.0 equivalents) was added, followed by the addition of water (20 mL) at room temperature. After stirring at 100 °C (oil bath) for 1 hour, the mixture was concentrated to remove the organic solvent, then diluted with SiO2 (200 mL), the aqueous layer was further extracted with SiO2 (200 ml x 2), all EA layers were combined, washed with brine (200 mL), dried over Na2SO4, and concentrated. The product was concentrated to form a yellow solid, which was then collected by filtration to obtain the first portion of the product (E4, 1.91 g, yield: 59%). The filtrate was concentrated and purified by silica gel column (PE:EA=4:1;1:1, then DCM:MeOH=10:1) to obtain the second portion of the product as a yellow oil (500 mg, yield: 16%), for a total of 2.4 g of product with a yield of 75%.

[0289] Preparation of tert-butyl 4-(4-aminopentyl)piperazine-1-carboxylate (E5)

[0290] A mixture of E4 (1.91 g, 5.08 mmol) and NH3OH (2 mL) in MeOH (20 mL) was mixed with Raney Ni (approximately 5 mL in water). After stirring under H2 at 50°C for 5.5 hours, the mixture was filtered. The filtrate was concentrated, diluted with water (100 mL), extracted with ethyl acetate, all EA layers were combined, washed with brine, dried over Na2SO4, and concentrated to obtain a product as a yellow oil (E5, 1.3 g, yield: 94%), which was used in the next step without further purification.

[0291] Preparation of tert-butyl 4-(4-((6-chloro-2-methoxyacrylidine-9-yl)aminopentyl)piperazine-1-carboxylate (E7)

[0292] E6 (500 mg, 1.8 mmol, 1.0 equivalent) was mixed with phenol (2.0 g) in a 25 mL flask, and the mixture was then stirred at 105 °C (oil bath) for 0.5 hours. E5 (635 mg, 2.34 mmol, 1.3 equivalents) was added to the above mixture, and stirring was maintained for a further 1.0 hour. After cooling to room temperature, the mixture was diluted with DCM (5 mL), and passed through a silica gel column (Biotage, 25 g, MeOH in DCM, 0-50%, 254 nm). The product portion was collected and concentrated to obtain the product as a yellow solid (E7, 597 mg, 64% yield).

[0293] Preparation of 6-chloro-2-methoxy-N-(5-(piperazine-1-yl)pentan-2-yl)acridine-9-amine (E8)

[0294] A mixture of E7 (100 mg, 0.195 mmol) and TFA (0.2 mL) in DCM (5 mL) was stirred at room temperature for 18 hours. By concentrating the mixture, crude E8 was obtained as a yellow solid (100 mg).

[0295] Preparation of (5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl4-(4-(4-((6-chloro-2-methoxyacrylidine-9-yl)amino)pentyl)piperazine-1-yl)-4-oxobutanoate (compound 5)

[0296] To a solution of E8 (100 mg, 0.195 mmol, 1.0 equivalent) and E9 (90 mg, 0.195 mmol, 1.0 equivalent) in dry DMF (5 mL), HATU (97 mg, 0.254 mmol, 1.3 equivalents) and DIEA (63 mg, 0.488 mmol, 2.5 equivalents) were added at 0°C. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated, and the residue was purified by pre-HPLC to obtain compound 5 as a yellow solid (30 mg, yield: 18%). [C 47 H 55 MS(ESI) calculated value for ClN4O9 (m / z) was 854.37, measured value was 428.6, [1 / 2M+H]+. HPLC: 220nm, 9.948, 100%; 254nm, 9.95 min, 100%. [Examples]

[0297] Synthesis of (5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl3-((S)-6-acetamido-2-((tert-butoxycarbonyl)amino)hexanamide)propanoate (compound 6)

[0298] [ka]

[0299] The following scheme shows the synthetic route used to prepare the title compound.

[0300] Scheme 9. [ka]

[0301] Preparation of (S)-benzyl 3-(6-acetamido-2-((tert-butoxycarbonyl)amino)hexanamide)propanoate (F2)

[0302] Step 1: 3-aminopropanoic acid (1.8 g, 20.0 mmol, 1.0 equivalent), BnOH (4.3 g, 40.0 mmol, 2.0 equivalents), and PTSA (4.2 g, 22.0 mmol, 1.1 equivalents) were stirred overnight under reflux in toluene (50 mL). Then, the solvent was removed under vacuum, the mixture was diluted with EA / PE (approximately 1 / 10, v / v, 100 mL), the solid was collected by filtration, and dried under vacuum to obtain benzyl 3-aminopropanoate (PTSA salt) as a pale yellow solid (6.8 g, 97% yield).

[0303] Step 2: (S)-6-acetamido-2-((tert-butoxycarbonyl)amino)hexanoic acid (compound F1, 576 mg, 2.0 mmol, 1.0 equivalent) in THF (10 mL) was added to HOBt (405 mg, 3.0 mmol, 1.5 equivalents) under an ice bath. After stirring for 10 minutes, DMAP (244 mg, 2.0 mmol, 1.0 equivalent) was added, followed by DCC (824 mg, 4.0 mmol, 2.0 equivalents) in CHCl3 (10 mL), and the mixture was stirred for a further 15 minutes. K2CO3 (414 mg, 3.0 mmol, 1.5 equivalents) and benzyl 3-aminopropanoate (PTSA salt) (843 mg, 2.4 mmol, 1.2 equivalents) were added. The resulting mixture was stirred overnight at room temperature. The insoluble white solid was filtered off, the filtrate was concentrated, and the mixture was partitioned between EA (200 mL) and water (200 mL). The aqueous layer was further extracted with EA (200 mL), all EA layers were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column (MeOH in DCM, 0-20%) to obtain the product as a pale yellow oil (F2, 768 mg, yield 85%).

[0304] Preparation of (S)-3-(6-acetamido-2-((tert-butoxycarbonyl)amino)hexaneamide)propanoic acid (F3)

[0305] A mixture of Pd / C (5%, 80 mg) and F2 (220 mg, 0.50 mmol) in MeOH (10 mL) was stirred overnight at room temperature under H2. The catalyst was filtered off, and the filtrate was concentrated to obtain the product as a white foamy solid (F3, 177 mg, quantified).

[0306] Preparation of (5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenantro[1,2-c]furan-8-yl3-((S)-6-acetamido-2-((tert-butoxycarbonyl)amino)hexanamide)propanoate (compound 6)

[0307] A white, turbid mixture of F3 (45 mg, 0.125 mmol, 2.0 equivalents) in CHCl3 / THF (1 / 1, 4 mL) was mixed with 4 Å MS (approximately 800 mg) and stirred at room temperature under N2 for 0.5 hours. The mixture was cooled in an ice bath, and DCC (29 mg, 0.138 mmol, 2.2 equivalents) in CHCl3 (0.5 mL) was added, followed by PPY (4-pyrrolidinopyridine, 20 mg, 0.138 mmol, 2.2 equivalents). After stirring at the same temperature for 0.5 hours, triptolide (22 mg, 0.062 mmol, 1.0 equivalent) was added. Stirring was maintained, and the mixture was gently warmed overnight to maximum room temperature. The mixture was diluted with DCM / EA (approximately 20 mL), filtered, the filtrate was concentrated, and purified by flash column (0-10% MeOH in DCM). The product portion was recovered to obtain the crude product, which was further purified by Pre-HPLC (ODS, ACN in water, 20-95%, 214 nm). Subsequently, the desired product was obtained as a white solid (compound 6) by concentration and freeze-drying, and the unreacted triptolide was recovered. 1H NMR (CDCl3, 400MHz) δ 0.91 (d, 3H, J = 7.2 Hz ), 1.01 (d, 3H, J = 6.8 Hz), 1.088 (s, 3H), 1.24-1.32 (m, 2H), 1.38-1.44 (m, 1H), 1.47 (s, 9H), 1.57-1.72 (m, 4H), 1.81-1.94 (m, 2H), 2.01 (s, 3H), 2.16-2.27 (m, 2H),2.36-2.40 (m, 1H), 3.66-2.76 (m, 3H), 3.28 (bs, 2H), 3.56-3.65 (m, 4H), 3.98 (s, 1H), 4.24 (m, 1H), 4.73 (s, 2H), 5.14 (s, 1H) ,5.33 (d, 1H, J = 7.2 Hz), 5.89 (bs, 1H),7.07 (bs, 1H).MS (ESI) [M+H] + Calculated value (m / z): 702.3, Measured value: 702.3 [Examples]

[0308] Synthesis of (6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl((1-methyl-2-nitro-1H-imidazole-5-yl)methyl) carbonate (compound 7)

[0309] [ka]

[0310] The following scheme shows the synthetic route used to prepare the title compound.

[0311] Scheme 10. [ka]

[0312] Preparation of ethyl 1-methyl-2-nitro-1H-imidazole-5-carboxylate (G2)

[0313] A solution of NaNO2 (1713 mg, 24.85 mmol, 7.0 equivalents) in H2O (5 mL) was added dropwise to a solution of G1 (600 mg, 3.55 mmol, 1.0 equivalent) in AcOH (4 mL) under an N2 atmosphere at -5°C. The mixture was warmed overnight at room temperature. The reaction mixture was extracted with DCM and dried over Na2SO4. Compound G2 was obtained as yellow crystals (360 mg, yield: 51%) by concentration and purification by column chromatography on silica gel (PE:EA=20:1).

[0314] Preparation of (1-methyl-2-nitro-1H-imidazole-5-yl)methanol (G3)

[0315] A solution of compound G2 (405 mg, 2.03 mmol, 1.0 equivalent) in THF / MeOH (8 mL / 2 mL) was cooled to 0°C, and then NaBH4 (231 mg, 6.09 mmol, 3.0 equivalent) and LiBr (530 mg, 6.09 mmol, 3.0 equivalent) in THF / H2O (4 mL / 2 mL) were added dropwise at less than 10°C. The mixture was stirred overnight at room temperature under an N2 atmosphere. NH4Cl was added at 0°C, stirring was extended for 30 minutes, the precipitate was filtered, washed with THF, the filtrate was concentrated, the residue was dissolved in a mixture of EA / MeOH (98 / 2, V / V), and the resulting solution was passed through a silica gel pad to obtain compound G3 as pale yellow to orange crystals (263 mg, yield: 65%).

[0316] Preparation of (6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl(4-nitrophenyl) carbonate (G6)

[0317] To a solution of compound G4 (36 mg, 0.1 mmol, 1.0 equivalent) in dry DCM (2 mL), dry pyridine (17 μL, 0.15 mmol, 1.5 equivalents) was added at 0°C under an N2 atmosphere. Compound G5 (30 mg, 0.15 mmol, 1.5 equivalents) was added, and the mixture was stirred overnight at room temperature under an N2 atmosphere. The mixture was quenched with 1N HCl, extracted with DCM, washed with brine, and dried over Na2SO4. By concentration under vacuum, compound G6 was obtained as a white solid (52 mg, yield: 100%), which was used directly in the next step without further purification.

[0318] Preparation of (6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl((1-methyl-2-nitro-1H-imidazole-5-yl)methyl) carbonate (compound 7)

[0319] To a solution of compound G6 (52 mg, 0.1 mmol, 1.0 equivalent) and compound G3 (19 mg, 0.12 mmol, 1.2 equivalents) in dry DCM (5 mL), Et3N (31 mg, 0.3 mmol, 3.0 equivalents) and DMAP (3 mg, 0.02 mmol, 0.2 equivalents) were added at 0°C under an N2 atmosphere. The mixture was stirred overnight at room temperature. The mixture was quenched with saturated NH4Cl, extracted with DCM, washed with brine, and dried over Na2SO4. After concentration, the residue was purified by Prep-HPLC to obtain the title compound as a white solid (compound 7, 15 mg, yield: 27%). 1 H-NMR (CDCl3, 400MHz): 0.85 (d, J=6.8 Hz, 3 H), 0.97 (d, J=7.2 Hz, 3 H), 1.05 (s, 3 H), 1.19-1.25 (m, 1 H), 1.55-1.60 (m, 1 H), 1.88-1.95 (m, 2 H), 2.13-2.22 (m, 2 H), 2.30-2.35 (m, 1 H), 2.67-2.71 (m, 1 H), 3.49 (d, J=5.6 Hz, 1 H), 3.55 (s, 1 H), 3.84 (d, J=3.2 Hz, 1 H), 4.06 (s, 3H), 4.68 (s, 2H), 4.82 (s, 1 H), 5.21-5.29 (m, 2 H), 7.27 (s, 1 H). MS (ESI) [C 26 H 29 N3O 10 Calculated value (m / z) 543.52, measured value 544.1, [M+H] + HPLC: 220 nm, 12.204 min, 99.97%; 254 nm, 12.205 min, 99.94%. [Examples]

[0320] Synthesis of a conjugate (compound 8) of triptolide and tri-glucosamine

[0321] [ka]

[0322] The following scheme shows the synthetic route used to prepare the title compound.

[0323] Scheme 11. [ka]

[0324] Preparation of compound H2

[0325] A solution of H1 (1.0 g, 1.0638 mmol, 1.0 equivalent) in TFA (10 mL) was stirred at room temperature for 1 hour, then diluted with toluene, concentrated, and the residue was co-evaporated with toluene. The residue was dried under reduced pressure using a high vacuum pump to obtain H2 as the TFA salt, which was used for the next reaction without any optional further purification (1.0 g, yield: 100%).

[0326] Preparation of compound H3

[0327] Dihydro-2H-pyran-2,6(3H)-dione (728 mg, 6.3830 mmol, 6.0 equivalents) was added to a solution of H2 (1.0 g, 1.0638 mmol, 1.0 equivalent) in pyridine (10 mL). The solution was stirred overnight at room temperature. LC-MS indicated that the reaction was complete. The solution was concentrated, and the residue was purified by Prep-HPLC to obtain H3 as a white solid (710 mg, yield: 68.3% in two steps).

[0328] Preparation of compound H4

[0329] To a solution of H3 (660 mg, 0.5110 mmol, 1.0 equivalent) in DMF (20 mL), (2R,3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol hydrochloride (661 mg, 3.0658 mmol, 6.0 equivalents) and DIPEA (785 mg, 6.1316 mmol, 12 equivalents) were added at 0°C under an N2 atmosphere. The mixture was stirred for 5 minutes, then HATU (971 mg, 2.5550 mmol, 5.0 equivalents) was added, and the mixture was stirred for a further 18 hours. LC-MS indicated that the reaction was complete. H2O (5.0 ml) was added, and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated, and the residue was purified by Prep-HPLC to obtain H4 as a white solid (628 mg, yield: 84%).

[0330] Preparation of compound H5

[0331] To a solution of H4 (828 mg, 0.5653 mmol, 1.0 equivalent) in MeOH / H2O (30 / 5 mL), Pd / C, 10% (160 mg, cat.) was added and the mixture was stirred overnight under H2. LC-MS indicated that the reaction was complete. The mixture was filtered, and the filtrate was concentrated to obtain compound H5 as a white solid (676 mg, yield: 90%).

[0332] Preparation of compound 8

[0333] To a solution of compound H5-1 (100 mg, 0.2173 mmol, 1.0 equivalent) in DMF (6 mL), H5 (347 mg, 0.2608 mmol, 1.2 equivalents) and DIPEA (83 mg, 0.6519 mmol, 3.0 equivalents) were added at 0°C under an N2 atmosphere. The mixture was stirred for 5 minutes. Then, HATU (107 mg, 0.2825 mmol, 1.3 equivalents) was added to the mixture and stirred for a further 2 hours. LC-MS indicated that the reaction was complete. Water (3.0 ml) was added and stirred for 30 minutes. The mixture was then concentrated, and the residue was purified by Prep-HPLC to obtain triptolidtri-glucosamine conjugate (compound 8) as a white solid (105 mg, yield: 27%). [Examples]

[0334] Synthesis of a conjugate (compound 9) of triptolide and tri-glucose.

[0335] [ka]

[0336] The following scheme shows the synthetic route used to prepare the title compound.

[0337] Scheme 12. [ka] JPEG0007846090000054.jpg149147

[0338] Preparation of compound I2

[0339] To a solution of compound I1 (1.044 g, 3.0 mmol, 1.0 equivalent) in DCM (20 mL), DBU (228 mg, 1.5 mmol, 0.5 equivalent) and trichloroacetonitrile (2.59 g, 18 mmol, 6.0 equivalent) were added at 0°C. The mixture was then heated to room temperature and stirred overnight. TLC indicated that the reaction was complete. The mixture was concentrated, and the residue was purified by flash column to obtain 1.3 g of the desired product, compound I2.

[0340] Preparation of compound I3

[0341] To a solution of compound I2 (1.3 g, 2.6477 mmol, 1.0 equivalent) in DCM (15 mL), benzyl 5-hydroxypentanoate (826 mg, 3.9716 mmol, 1.5 equivalents) and TMSOTf (118 mg, 0.5295 mmol, 0.2 equivalents) were added at 0°C. The solution was stirred for 3 hours. Then, TEA (0.5 mL) was added and stirred for a further 30 minutes. LC-MS indicated that the reaction was complete. It was quenched with water and extracted with DCM. The organic phase was dried, filtered, and concentrated. By purifying the residue by Prep-HPLC, compound I3 was obtained as a colorless oil (500 mg, yield: 35% in two steps).

[0342] Preparation of compound I4

[0343] To a solution of compound I3 (500 mg, 0.9294 mmol, 1.0 equivalent) in MeOH (10 ml), Pd / C (10%, 80 mg) was added. The mixture was stirred under H2 for 5 hours. LC-MS indicated that the reaction was complete. By filtering and concentrating the mixture, the desired product was obtained as a white solid (I4, 380 mg, yield: 91%).

[0344] Preparation of compound I5

[0345] Compound I4-1 (240 mg, 0.2570 mmol, 1.0 equivalent), DIEA (329 mg, 2.57 mmol, 10 equivalents), and HATU (488 mg, 1.285 mmol, 5.0 equivalents) were added to a solution of compound I4 (380 mg, 0.8482 mmol, 3.3 equivalents) in DMF (8.0 mL). The mixture was then stirred overnight. LC-MS indicated that the reaction was complete. The mixture was quenched with water and stirred for 30 minutes. The solution was concentrated, the residue was dissolved in water, and extracted by DCM. The organic phase was dried, filtered, and concentrated. By purifying the residue by Prep-HPLC, compound I5 was obtained as a white solid (380 mg, yield: 76%).

[0346] Preparation of compound I6

[0347] To a solution of compound I5 (380 mg, 0.1969 mmol, 1.0 equivalent) in MeOH (8.0 mL), MeONa (21 mg, 0.3938 mmol, 2.0 equivalents) was added. The mixture was stirred for 5 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated, and the residue was purified by Prep-HPLC to obtain compound I6 as a white solid (220 mg, yield: 79%).

[0348] Preparation of compound I7

[0349] To a solution of compound I6 (220 mg, 0.1543 mmol, 1.0 equivalent) in MeOH (10.0 mL), Pd / C (10%, 40 mg, cat.) was added. The mixture was stirred under H2 for 5 hours. LC-MS indicated that the reaction was complete. By concentrating the solution, compound I7 was obtained as a white solid (200 mg, yield: 100%). Accurate mass: 1291.67.

[0350] Preparation of compound 9

[0351] Compound I7-1 (71 mg, 0.1548 mmol, 1.0 equivalent) and DIPEA (40 mg, 0.3096 mmol, 2.0 equivalents) were added to a solution of compound I7 (200 mg, 0.1548 mmol, 1.0 equivalent) in DMF (6 mL) under an N2 atmosphere at 0°C. The mixture was stirred for 5 minutes. Then, HATU (88 mg, 0.2322 mmol, 1.5 equivalents) was added and the mixture was stirred for a further 2 hours. LC-MS indicated that the reaction was complete. Water (3.0 ml) was added and the mixture was stirred for 30 minutes. The mixture was then concentrated, and the residue was purified by Prep-HPLC to obtain compound 9 as a white solid (120 mg, yield: 45%). 1H-NMR (DMSO-d6, 400MHz): 0.75 (d, J=6.6 Hz, 3 H), 0.86 (d, J=6.6 Hz, 3 H), 0.91 (s, 3 H), 1.27-1.33 (m, 2 H), 1.41-1.44 (m, 6 H), 1.47-1.52 (m, 13 H), 1.80 (s, 9 H), 1.86-1.90 (m, 2 H), 2.04 (t, J=7.2 Hz, 1 H), 2.28 (t, J=6.6 Hz, 1 H), 3.01-3.06 (m, 13 H), 3.29 (t, J=6.0 Hz, 1 H), 3.41-3.44 (m, 3 H), 3.47-3.55 (m, 20 H), 3.64-3.65 (m, 3 H), 3.67-3.72 (m, 7 H), 3.95 (s, 1 H), 4.23 (d, J=8.4 Hz, 3 H), 4.46 (d, J=4.2 Hz, 3 H), 4.54 (d, J=6.0 Hz, 3 H), 4.57 (t, J=5.4 Hz, 3 H), 4.76-4.87 (m, 2 H), 4.96 (s, 1 H), 7.26 (s, 1 H), 7.73 (t, J=5.4 Hz, 3 H), 7.83 (t, J=5.4 Hz, 3 H). [Examples]

[0352] Synthesis of a conjugate (compound 10) of triptolide and tri-GalNHAc

[0353] [ka]

[0354] The following scheme shows the synthetic route used to prepare the title compound.

[0355] Scheme 13. [ka] JPEG0007846090000057.jpg113150

[0356] Preparation of di-tert-butyl 3,3'-((2-amino-2-((3-(tert-butoxy)-3-oxopropoxy)methyl)propane-1,3-diyl)bis(oxy))dipropanoate (J3)

[0357] To a solution of compound J1 (1.21 g, 10 mmol, 1.0 equivalent) in DMSO (2 ml), 5 M NaOH (0.2 mL, 1.0 mmol, 0.1 equivalent) was added under an N2 atmosphere at below 15°C, followed by compound J2 (4.36 g, 34 mmol, 3.4 equivalents), which was added dropwise. The mixture was left to reach room temperature under an N2 atmosphere for 24 hours. The reaction mixture was cooled to 0°C, diluted with water, extracted with EA, washed with brine, dried over Na2SO4, and concentrated to obtain compound J3 as a pale yellow oil, which was used for the next step without any further purification (4.0 g).

[0358] Preparation of di-tert-butyl 3,3'-((2-(((benzyloxy)carbonyl)amino)-2-((3-(tert-butoxy)-3-oxopropoxy)methyl)propane-1,3-diyl)bis(oxy))dipropanoate (J4)

[0359] To a solution of compound J3 (4.0 g, 7.91 mmol, 1.0 equivalent) in DCM (40 mL), 25% Na2CO3 (16.8 g, 39.55 mmol, 5.0 equivalents) was added at 0°C under an N2 atmosphere. Then, CbzCl (2.7 g, 15.82 mmol, 2.0 equivalents) was added dropwise, and the mixture was stirred overnight at room temperature. The mixture was diluted with DCM, quenched with water, washed with brine, dried on Na2SO4, concentrated, and purified by column chromatography on silica gel (PE:EA = 10:1 to 7:1) to obtain compound J4 as a colorless oil (2.8 g, yield: 55%).

[0360] Preparation of 3,3'-((2-(((benzyloxy)carbonyl)amino)-2-((2-carboxyethoxy)methyl)propane-1,3-diyl)bis(oxy))dipropanoic acid (J5)

[0361] A solution of compound J4 (2.8 g, 4.37 mmol, 1.0 equivalent) in HCOOH (40 mL) was stirred overnight at room temperature. The mixture was concentrated and dried under vacuum to obtain compound J5 as a yellow oil, which was used without further purification (2.27 g).

[0362] Preparation of compound J7

[0363] To a solution of compound J5 (1.8 g, 3.82 mmol, 1.0 equivalent) and compound J6 (2.7 g, 15.28 mmol, 4.0 equivalents) in DMF (30 mL), HATU (5.1 g, 13.37 mmol, 3.5 equivalents) and DIPEA (3.0 g, 22.92 mmol, 6.0 equivalents) were added at 0°C under an N2 atmosphere. The mixture was stirred overnight at room temperature. The reaction product was quenched with cooling water, extracted with DCM, washed with saturated NaHCO3 and brine, dried over Na2SO4, concentrated, and purified by Prep-HPLC to obtain compound J7 as a white solid (3.12 g, yield: 87%).

[0364] Preparation of benzyl(1,19-diamino-10-((3-((3-aminopropyl)amino)-3-oxopropoxy)methyl)-5,15-dioxo-8,12-dioxa-4,16-diazanonadecane-10-yl)carbamate (J8)

[0365] A solution of compound J7 (870 mg, 0.925 mmol, 1.0 equivalent) in TFA (5 mL) was stirred at room temperature for 1 hour. The mixture was diluted with toluene, concentrated, and the residue was co-evaporated with toluene. J8 was obtained as the TFA salt by drying under reduced pressure using a high vacuum pump, and this was used for the next reaction without any optional further purification (591 mg, yield: 100%).

[0366] Preparation of benzyl 5-hydroxypentanoate (J10)

[0367] A solution of compound J9 (5.0 g, 50 mmol, 1.0 equivalent) and NaOH (2.0 g, 50 mmol, 1.0 equivalent) in H2O (50 mL) was stirred overnight at 70°C. The mixture was cooled to room temperature, concentrated, and the residue was suspended in acetone (50 mL). TBAB (0.8 g, 2.5 mmol, 0.05 equivalent) and BnBr (10.2 g, 60 mmol, 1.2 equivalents) were added, and the mixture was heated overnight under reflux. The acetone was removed under vacuum to obtain an oily residue, which was dissolved in EA, washed with saturated NaHCO3 and brine, dried on Na2SO4, concentrated, and purified by column chromatography on silica gel (PE:EA = 5:1 to 1:1) to obtain compound J10 as a colorless oil (3.6 g, yield: 34%).

[0368] Preparation of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyldiacetate (J12)

[0369] To a solution of compound J11 (1557 mg, 4.0 mmol, 1.0 equivalent) in DCE (5 mL), TMSOTf (1333 mg, 6.0 mmol, 1.5 equivalents) was added and stirred at 55°C for 2 hours, then the mixture was stirred overnight at room temperature. The mixture was poured into ice-cold saturated NaHCO3, extracted with DCM, washed with water and brine, dried over Na2SO4, and concentrated to obtain compound J12 as a dark gum, which was used for the next step without any optional further purification (1.3 g, yield: 99%).

[0370] Preparation of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diyldiacetate (J13)

[0371] To a solution of compound J12 (1.3 g, 3.95 mmol, 1.0 equivalent) and compound J10 (1.23 g, 5.92 mmol, 1.5 equivalents) in DCE (15 mL), 4A Power Molecular Sieve was added and the mixture was stirred at room temperature under an N2 atmosphere for 30 minutes. TMSOTf (0.44 g, 1.98 mmol, 0.5 equivalents) was added to the reaction mixture and the mixture was stirred at room temperature for 12 hours. The mixture was poured into ice-cold saturated NaHCO3, extracted with DCM, washed with water and brine, dried over Na2SO4, concentrated, and the residue was purified by Prep-HPLC to obtain compound J13 as a colorless oil (358 mg, yield: 13%).

[0372] Preparation of 5-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentanoic acid (J14)

[0373] To a solution of compound J13 (358 mg, 0.67 mmol, 1.0 equivalent) in MeOH (1 mL) and EA (5 mL), 10% Pd / C (36 mg) was added and stirred overnight at room temperature under an H2 atmosphere. The mixture was filtered, the filtrate was concentrated, and J14 was dried under reduced pressure using a high vacuum pump to obtain J14 as a colorless oil, which was used for the next step without optional further purification (285 mg, yield: 95%).

[0374] Preparation of compound J15

[0375] To a solution of compound J14 (240 mg, 0.54 mmol, 3.5 equivalents) in DMF (5 mL), HATU (233 mg, 0.61 mmol, 4.0 equivalents) and DIPEA (198 mg, 1.53 mmol, 10.0 equivalents) were added at 0°C under an N2 atmosphere. The mixture was stirred at room temperature for 30 minutes, then a solution of compound J8 (100 mg, 0.153 mmol, 1.0 equivalent) in DMF (2 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, water was added to the residue, extracted with DCM, washed with saturated NaHCO3 and brine, and dried over Na2SO4. Concentration and purification by Prep-HPLC yielded compound J15 as a white solid (185 mg, yield: 63%).

[0376] Benzyl(1-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-31-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-16-((3-((3-(5-(((2 Preparation of S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentanamido)propyl)amino)-3-oxopropoxy)methyl)-5,11,21,27-tetraoxo-14,18-dioxa-6,10,22,26-tetraazahentricontan-16-yl)carbamate (J16)

[0377] To a solution of compound J15 (175 mg, 0.091 mmol, 1.0 equivalent) in MeOH (5 mL), NaOMe (95 mg, 1.759 mmol, 20 equivalents) was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by Prep-HPLC to obtain compound J16 as a white solid (126 mg, yield: 92%).

[0378] Preparation of (R,R,R,S,R)-N,N'-(10-((3-((3-(5-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentanamide)propyl)amino)-3-oxopropoxy)methyl)-10-amino-5,15-dioxo-8,12-dioxa-4,16-diazanonadecane-1,19-diyl)bis(5-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentanamide)(J17)

[0379] To a solution of compound J16 (126 mg, 0.081 mmol, 1.0 equivalent) in MeOH (5 mL) and DMF (2.5 mL), 10% Pd / C (15 mg) was added and stirred overnight at room temperature under an H2 atmosphere. The mixture was filtered, the filtrate was concentrated, and J17 was obtained as a yellow oil by drying under reduced pressure using a high vacuum pump, which was used for the next step without any optional further purification (110 mg).

[0380] (6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenantro[1,2-c]furan-8-yl21-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6- Preparation of (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-6,6-bis((3-((3-(5-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentanamide)propyl)amino)-3-oxopropoxy)methyl)-4,11,17-trioxo-8-oxa-5,12,16-triazahenicosan-1-oate (J18)

[0381] To a solution of compound J18 (40 mg, 0.086 mmol, 1.1 equivalents) in DMF (5 mL), HATU (39 mg, 0.101 mmol, 1.3 equivalents) and DIPEA (31 mg, 0.234 mmol, 3.0 equivalents) were added at 0°C under an N2 atmosphere. The mixture was stirred at room temperature for 1 hour. Then, a solution of compound 17 (110 mg, 0.078 mmol, 1.0 equivalent) in DMF (2 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by Prep-HPLC to obtain the title compound (compound 10) as a white solid (40 mg, yield: 29%). 1 H-NMR (DMSO-d6, 600MHz): 0.75 (d, J=6.6 Hz, 3 H), 0.86 (d, J=6.6 Hz, 3 H), 0.91 (s, 3 H), 1.27-1.33 (m, 2 H), 1.41-1.44 (m, 6 H), 1.47-1.52 (m, 13 H), 1.80 (s, 9 H), 1.86-1.90 (m, 2 H), 2.04 (t, J=7.2 Hz, 1 H), 2.28 (t, J=6.6 Hz, 1 H), 3.01-3.06 (m, 13 H), 3.29 (t, J=6.0 Hz, 1 H), 3.41-3.44 (m, 3 H), 3.47-3.55 (m, 20 H), 3.64-3.65 (m, 3 H), 3.67-3.72 (m, 7 H), 3.95 (s, 1 H), 4.23 (d, J=8.4 Hz, 3 H), 4.46 (d, J=4.2 Hz, 3 H), 4.54 (d, J=6.0 Hz, 3 H), 4.57 (t, J=5.4 Hz, 3 H), 4.76-4.87 (m, 2 H), 4.96 (s, 1 H), 7.20 (s, 1 H), 7.62 (d, J=9.0 Hz, 3 H), 7.73 (t, J=5.4 Hz, 3 H), 7.83 (t, J=5.4 Hz, 3 H). MS (ESI) [C 85 H 136 N 10 O 35 Calculated value (m / z) 1856.92, measured value 1858.3, [M+H]+ HPLC: 220 nm, 15.981 min, 91.23%; 254 nm, 15.984 min, 85.11%. [Examples]

[0382] Synthesis of (5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl3-((S)-6-acetamido-2-(adamantan-1-carboxyamide)hexanamide)propanoate (compound 11)

[0383] [ka]

[0384] The following scheme shows the synthetic route used to prepare the title compound.

[0385] Scheme 14. [ka]

[0386] Preparation of (S)-benzyl 3-(6-acetamido-2-aminohexanamide)propanoate (K1-1)

[0387] (S)-benzyl 3-(6-acetamido-2-((tert-butoxycarbonyl)amino)hexanoamide)propanoate (KS-1, 240 mg, 0.54 mmol, 1.0 equivalent) in DCM (5.0 mL) was added to TFA (0.5 mL), and the mixture was stirred overnight under N2 at 0°C. LC-MS indicated that the reaction was complete and the desired product was detected. By removing the solvent, the crude product (S)-benzyl 3-(6-acetamido-2-aminohexanoamide)propanoate (K1-1, 186 mg, yield: theoretical) was obtained as a pale yellow oil, which was used directly for the next step. Chemical formula: [C] 18 H 28 N3O4] + MS(ESI) calculated value for [m / z]: 350.2, measured value: 350.2(M+H) + .

[0388] Preparation of (S)-benzyl 3-(6-acetamido-2-(adamantan-1-carboxyamide)hexanamide)propanoate (K1-2)

[0389] To a solution of adamantane-1-carboxylic acid (97 mg, 0.54 mmol, 1.0 equivalent) in DMF (5.0 mL), DIEA (346 mg, 2.675 mmol, 3.0 equivalents) and HATU (244 mg, 0.641 mmol, 1.2 equivalents) were added at 0°C. After stirring for 0.5 hours, (S)-benzyl 3-(6-acetamido-2-aminohexanamide)propanoate (K1-1, 186 mg, 0.54 mmol, 1.0 equivalent) in DMF (1.0 mL) was added dropwise, and the mixture was stirred overnight at room temperature under N2. LC-MS indicated that the reaction was complete and the desired product was detected. After concentration, the residue was purified by Prep-HPLC to obtain the desired product (S)-benzyl 3-(6-acetamido-2-(adamantan-1-carboxyamide)hexaneamide)propanoate (K1-2, 273 mg, yield: theoretical) as a pale yellow oil. Chemical formula: [C 29 H 41 N3O5] + MS(ESI) calculated value for [m / z]: 512.3, measured value: 512.3 (M+H)+ .

[0390] Preparation of (S)-3-(6-acetamido-2-(adamantan-1-carboxamide)hexaneamide)propanoic acid (K1-3)

[0391] (S)-benzyl 3-(6-acetamido-2-(adamantan-1-carboxamide)hexanamide)propanoate (K1-2, 273 mg, 0.54 mmol, 1.0 equivalent) in MeOH (20.0 mL) was added to Pd / C (30 mg) and stirred overnight at room temperature under H2. LC-MS indicated that the reaction was complete and the desired product was formed. After removing the solvent and purifying the residue by Prep-HPLC, the desired product (S)-3-(6-acetamido-2-(adamantan-1-carboxamide)hexanamide)propanoic acid (K1-3, 144 mg, yield: 64.0%) was obtained as a pale yellow oil. Chemical formula: [C] 22 H 36 N3O5] + MS(ESI) calculated value for [m / z]: 422.3, measured value: 422.3 (M+H) + .

[0392] Preparation of (5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenantro[1,2-c]furan-8-yl3-((S)-6-acetamido-2-(adamantan-1-carboxyamide)hexanamide)propanoate (compound 11)

[0393] A solution of (S)-3-(6-acetamido-2-(adamantan-1-carboxamide)hexaneamide)propanoic acid (K1-3, 110 mg, 0.261 mmol, 2.0 equivalents) in THF / CHCl3 (0.5 / 0.5 mL) was added to DCC (60 mg, 0.287 mmol, 2.2 equivalents) and PPY (43 mg, 0.287 mmol, 2.2 equivalents) at 0°C, stirred under N2 for 15 minutes at 0°C, and then triptolide (47 mg, 0.130 mmol, 1.0 equivalent) in THF / CHCl3 (0.5 / 0.5 mL) was added dropwise, and the mixture was stirred overnight under N2 from 0°C to room temperature. LC-MS indicated that the reaction was complete and the desired product was detected. After removing the solvent and purifying the residue by FLASH and Prep-HPLC, the desired product was obtained as a white solid (compound 11, 68 mg, yield: 69%). 1 H NMR (400 MHz, CDCl3) δ (ppm): 0.92 (d, 3H, J = 6.4 Hz), 1.02 (d, 3H, J = 6.8 Hz), 1.08 (s, 3H), 1.20-1.45 (m, 6H), 1.50-1.68 (m, 4H), 1.72-1.80 (m, 8H), 1.86-1.92 (m, 6H), 1.92-2.02 (m, 2H), 2.03 (s, 3H), 2.09 (s, 3H), 2.14-2.50 (m, 3H), 2.60-2.70 (m, 2H) , 2.70-2.80 (m, 1H) , 3.10-3.40 (m, 2H) ,3.57 (d, 2H, J = 5.2 Hz) , 3.60-3.74 (m, 3H) , 3.99 (d, 2H, J = 2.8 Hz) , 4.54-4.64 (m, 1H) , 4.73 (s, 2H) , 5.15 (s, 1H) , 6.00-6.20 (m, 1H) , 6.53 (d, 1H, J = 7.6 Hz) , 7.09 (t, 1H, J = 5.6 Hz). Calculated MS (ESI) chemical formula: [C 42 H 58 N3O 10 ] + [m / z]: 764.4, Measured value: 764.4 (M+H)+ . [Examples]

[0394] Synthesis of (6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyleno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenantro[1,2-c]furan-8-yl4-(4-(3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-6-yl)oxy)propyl)piperazine-1-yl)-4-oxobutanoate (compound 12)

[0395] [ka]

[0396] The following scheme shows the synthetic route used to prepare the title compound.

[0397] Scheme 15. [ka] JPEG0007846090000062.jpg65148

[0398] Preparation of 4-bromo-6-methoxyquinoline (L2)

[0399] To a solution of compound L1 (1.75 g, 10.0 mmol, 1.0 equivalent) in DMF (25 mL), PBr3 (2.98 g, 11.0 mmol, 1.1 equivalents) was gradually added, and the mixture was stirred at room temperature under an N2 atmosphere for 18 hours. The mixture was treated with NaHCO3 (aqueous solution) to a pH of approximately 8-9 and extracted with EA. The combined extract was washed with water and brine and dried over Na2SO4. After concentration and purification with silica gel (PE:EA = 5:1), compound L2 was obtained as a white solid (1.75 g, yield: 74%).

[0400] Preparation of 4-bromoquinoline-6-ol (L3)

[0401] To a solution of compound L2 (1.67 g, 7.0 mmol, 1.0 equivalent) in HOAc (20 mL), HBr (10 mL) was added, and the resulting mixture was refluxed overnight under an N2 atmosphere. By concentrating the reaction mixture, crude compound L3 was obtained as a yellow solid (1.4 g, yield: 89%).

[0402] Preparation of 6-(benzyloxy)-4-bromoquinoline (L4)

[0403] To a solution of compound L3 (448 mg, 2 mmol, 1.0 equivalent) in DMF (10 mL), K2CO3 (690 mg, 5 mmol, 2.5 equivalents) was added, followed by BnBr (359 mg, 2.1 mmol, 1.05 equivalents). The mixture was stirred at room temperature under an N2 atmosphere for 18 hours. The mixture was concentrated and purified using silica gel (PE:EA = 5:1) to obtain crude compound L4 as a yellow solid (400 mg, yield: 64%).

[0404] Preparation of 6-(benzyloxy)quinoline-4-carbonitrile (L5)

[0405] A mixture of compound L4 (1.45 g, 4.62 mmol, 1.0 equivalent), Zn(CN)2 (813 mg, 6.92 mmol, 1.5 equivalents), and Pd(PPh3)4 (320 mg, 0.77 mmol, 0.06 equivalents) in dry DMF (25 mL) was stirred overnight at 100°C under an N2 atmosphere. The reaction mixture was concentrated, the residue was diluted with EA, washed with water, and dried over Na2SO4. The mixture was concentrated, and the residue was purified with silica gel (PE:EA = 5:1) to obtain compound L5 as a yellow solid (1.27 g, yield: 83%).

[0406] Preparation of 6-(benzyloxy)quinoline-4-carboxylic acid (L6)

[0407] To a solution of compound L5 (300 mg, 1.15 mmol, 1.0 equivalent) in ethane-1,2-diol (8 mL), KOH (258 mg, 4.61 mmol, 4.0 equivalents) was added, and the mixture was stirred overnight at 130°C under an N2 atmosphere. The mixture was acidified with 2N HCl to a pH of approximately 4-5, the precipitate was filtered, and the mixture was dried to obtain compound L6 as an off-white solid (300 mg, yield: 93%).

[0408] Preparation of 6-hydroxyquinoline-4-carboxylic acid (L7)

[0409] To a solution of compound L6 (200 mg, 0.716 mmol, 1.0 equivalent) in MeOH (10 mL), Pd / C (20 mg, 10%) was added, and the mixture was stirred at room temperature under an H2 atmosphere for 6 hours. The mixture was filtered, and the filtrate was concentrated to obtain compound L7 as an off-white solid (135 mg, yield: 100%).

[0410] Preparation of 6-(3-(4-(tert-butoxycarbonyl)piperazine-1-yl)propoxy)quinoline-4-carboxylic acid (L9)

[0411] A mixture of compound L7 (135 mg, 0.716 mmol, 1.0 equivalent), compound L8 (257 mg, 0.6454 mmol, 0.9 equivalents), and CS2CO3 (700 mg, 2.148 mmol, 3.0 equivalents) in dry DMF (20 mL) was stirred overnight at 60°C under an N2 atmosphere. This mixture, containing L9, was used for the next step without further treatment.

[0412] Preparation of tert-butyl 4-(3-((4-((2-ethoxy-2-oxoethyl)carbamoyl)quinoline-6-yl)oxy)propyl)piperazine-1-carboxylate (L11)

[0413] Compound L10 (100 mg, 0.716 mmol, 1.0 equivalent), HATU (360 mg, 0.947 mmol, 1.3 equivalents), and DIEA (0.5 mL) were added to the reaction mixture of compound L9, and the resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The mixture was concentrated, and the residue was purified with silica gel (DCM:MeOH = 50:1) to obtain compound L11 as a yellow solid (175 mg, yield: 49%).

[0414] Preparation of 2-(6-(3-(4-(tert-butoxycarbonyl)piperazine-1-yl)propoxy)quinoline-4-carboxamide)acetic acid (L12)

[0415] To a solution of compound L11 (175 mg, 0.35 mmol, 1.0 equivalent) in THF (6 mL) and water (6 mL), LiOHH2O (44 mg, 1.05 mmol, 3.0 equivalents) was added, and the mixture was stirred overnight at room temperature under an N2 atmosphere. The mixture was acidified with 2N HCl to a pH of approximately 4-5, and then concentrated to obtain crude compound L12 as an off-white solid.

[0416] Preparation of (S)-1-tert-butyl2-methyl4,4-difluoropyrrolidine-1,2-dicarboxylate (L16)

[0417] A solution of compound L15 (1.95 g, 8.01 mmol, 1.0 equivalent) in DCM (30 mL) was stirred at 0°C, and then DAST (3.36 g, 20.84 mmol, 2.6 equivalents) in DCM (10 mL) was added. The resulting mixture was stirred overnight at room temperature under N2. The solution was added to ice water and concentrated, the residue was diluted with EA, washed with water (20 mL x 3) and brine (20 mL x 3), and dried on Na2SO4. Compound L16 was obtained as a yellow oil (2.0 g, yield: 94%) by concentration under vacuum and purification by flash chromatography on silica gel (PE:EA = 20:1~4:1).

[0418] Preparation of (S)-tert-butyl 2-carbamoyl-4,4-difluoropyrrolidine-1-carboxylate (L17)

[0419] NH3 was added to a solution of compound L16 (2.0 g, 7.547 mmol, 1.0 equivalent) in MeOH (30 mL). The resulting mixture was stirred overnight at 50°C. The reaction product was concentrated under vacuum and purified by flash chromatography on silica gel (PE:EA = 12:1-4:1) to obtain compound L17 as a yellow solid (1.82 g, yield: 96%).

[0420] Preparation of (S)-tert-butyl 2-cyano-4,4-difluoropyrrolidine-1-carboxylate (L18)

[0421] To a solution of compound L17 (1.7 g, 6.8 mmol, 1.0 equivalent) in DMF (20 mL), 2,4,6-trichloro-1,3,5-triazine (1.87 g, 10.2 mmol, 1.5 equivalents) was added at 0°C. The resulting mixture was stirred at room temperature under N2 for 1 hour. The solution was added to ice water, concentrated, the residue diluted with EA, washed with water (20 mL x 3) and brine (20 mL x 3), and dried on Na2SO4. Compound L18 was obtained as a white solid by concentration under vacuum and purification by flash chromatography on silica gel (PE:EA = 50:1~20:1) (1.4 g, yield: 83%).

[0422] Preparation of (S)-4,4-difluoropyrrolidine-2-carbonitrile(C)

[0423] To a solution of compound L18 (81 mg, 0.35 mmol, 1.0 equivalent) in DCM (4 mL), TFA (0.1 mL) was added at 0°C. The resulting mixture was stirred at room temperature under N2 for 6 hours. By concentrating the mixture, crude compound C was obtained as a brown oil (100 mg, yield: 100%).

[0424] Preparation of (S)-tert-butyl4-(3-((4-((2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-6-yl)oxy)propyl)piperazine-1-carboxylate (L13)

[0425] Compound C (100 mg), HATU (172 mg, 0.45 mmol, 1.3 equivalents), and DIEA (0.5 mL) were added to the reaction mixture of crude compound L12, and the resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The mixture was concentrated, and the residue was purified with silica gel (DCM:MeOH = 50:1) to obtain compound L13 as a yellow solid (70 mg).

[0426] Preparation of tert-butyl 4-(3-((4-((2-((2R)-2-cyano-4,4-difluorocyclopentyl)-2-oxoethyl)carbamoyl)quinoline-6-yl)oxy)propyl)piperazine-1-carboxylate (L14)

[0427] To a solution of compound L13 (70 mg) in DCM (4 mL), TFA (0.1 mL) was added at 0°C. The resulting mixture was stirred at room temperature under N2 for 6 hours. By concentrating the mixture, crude compound L14 was obtained as a yellow solid (60 mg, yield: 100%).

[0428] Preparation of (6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyreno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenantro[1,2-c]furan-8-yl4-(4-(3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-6-yl)oxy)propyl)piperazine-1-yl)-4-oxobutanoate (compound 12)

[0429] Compound B (28 mg, 0.06 mmol, 1.0 equivalent), HATU (30 mg, 0.078 mmol, 1.3 equivalents), and DIEA (0.1 mL) were added to the reaction mixture of crude compound L14, and the resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The mixture was concentrated, and the residue was purified by pre-HPLC to obtain the title compound (compound 12) as a yellow solid (10 mg). 1H-NMR (CD3OD, 400MHz): 0.81 ( d, J=4.4 Hz, 3 H), 0.93 ( d, J=4.8Hz, 3 H), 1.02 (s, 3 H), 1.29-1.32 (m, 4 H) 1.46 (m, 2 H), 1.88-1.90 (m, 1 H), 1.93-1.97 (m, 1 H), 2.08-2.11 (m, 2 H), 2.19-2.26 (m, 2 H), 2.48-2.53 (m, 2H), 2.58-2.60 (m, 2 H), 2.65-2.67 (m, 2 H), 2.70-2.75 (m, 6H), 2.87-2.95 (m, 1 H), 3.44 (d, J=4.0 Hz, 1 H), 3.59-3.62 (m, 4 H), 3.94 (d, J=1.6 Hz, 1 H), 4.10-4.17 (m, 1 H), 4.28-4.35 (m, 3 H), 4.78-4.81 (m, 2 MS (ESI) [C 48 H 54 F2N6O 11 Calculated value (m / z) 928.38, measured value 929.3, [M+H] + HPLC: 214nm, 11.762min, 98.726%; 254nm, 11.764min, 98.896%. [Examples]

[0430] Synthesis of a conjugate (compound 13) of triptolide and tri-GalNHAc

[0431] [ka]

[0432] The following scheme shows the synthetic route used to prepare the title compound.

[0433] Scheme 16. [ka]

[0434] Preparation of benzyl(6-hydroxyhexyl)carbamate (M2)

[0435] To a solution of compound M1 (860 mg, 7.33 mmol, 1.0 equivalent) in DCM (10 mL), Et3N (2.22 g, 21.99 mmol, 3.0 equivalents) was added, followed by Cbz-Cl (1.12 g, 6.60 mmol, 0.9 equivalents). The resulting mixture was stirred overnight at room temperature under N2. Water was added, and the mixture was concentrated under vacuum. Compound M2 was then purified by flash chromatography on silica gel (PE:EA = 20:1-4:1) to obtain compound M2 as a white solid (660 mg, yield: 37%).

[0436] Preparation of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((6-(((benzyloxy)carbonyl)amino)hexyl)oxy)tetrahydro-2H-pyran-3,4-diyldiacetate (M4)

[0437] To a solution of compound M2 (500 mg, 1.99 mmol, 1.0 equivalent) and compound M3 (775 mg, 1.99 mmol, 1.0 equivalent) in DCE (15 mL), Sc(OTf)3 (98 mg, 0.199 mmol, 0.1 equivalent) was added. The resulting mixture was stirred overnight at 90°C under N2. The reaction product was quenched with NaHCO3 (aqueous) (10 mL), concentrated, and the residue was diluted with water and extracted with EA (15 mL x 3). The combined organic layers were washed separately with water (20 mL x 3) and brine (20 mL x 3) and dried on Na2SO4. Compound M4 was obtained as a colorless oil by concentration under vacuum and purification by flash chromatography on silica gel (PE:EA = 50:1-8:1) (700 mg, yield: 61%).

[0438] Preparation of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((6-aminohexyl)oxy)tetrahydro-2H-pyran-3,4-diyldiacetate (M5)

[0439] To a solution of compound M4 (700 mg, 1.20 mmol, 1.0 equivalent) in MeOH (10 mL), Pd / C (80 mg, 10%) was added. The resulting mixture was stirred at room temperature under H2 for 1 hour. After filtration, the filtrate was concentrated under vacuum to obtain crude compound M5 (530 mg, yield: 95%) as a white solid.

[0440] Preparation of compound M7

[0441] To a solution of compound M5 (530 mg, 1.188 mmol, 3.5 equivalents) and compound M6 (160 mg, 0.339 mmol, 1.0 equivalent) in DMF (8 mL), HATU (515 mg, 1.356 mmol, 4.0 equivalents) was added, followed by DIEA (437 mg, 3.39 mmol, 10.0 equivalents) at 0°C. The resulting mixture was stirred overnight at 0°C under N2. The reaction product was quenched with water (10 mL), concentrated under vacuum, and purified by HPLC to obtain compound M7 as a white solid (310 mg, yield: 52%).

[0442] Preparation of compound M8

[0443] To a solution of compound M7 (310 mg, 0.569 mmol, 1.0 equivalent) in MeOH (8 mL), NaOMe (30 mg) was added. The resulting mixture was stirred overnight at room temperature under N2, then concentrated under vacuum, and purified by HPLC to obtain a white solid (230 mg, yield: 94%).

[0444] A freshly prepared white solid (230 mg, 0.167 mmol, 1.0 equivalent) in MeOH (8 mL) was added to Pd / C (50 mg, 10%). The resulting mixture was stirred at room temperature under H2 for 1 hour. After filtration, the filtrate was concentrated under vacuum to obtain crude compound M8 (200 mg, yield: 95%) as a white solid.

[0445] Preparation of compound 13

[0446] To a solution of compound M8 (200 mg, 0.161 mmol, 1.0 equivalent) and compound M9 (74 mg, 0.161 mmol, 1.0 equivalent) in DMF (8 mL), DIEA (62 mg, 0.483 mmol, 3.0 equivalents) was added, followed by HATU (92 mg, 0.241 mmol, 1.5 equivalents) at 0°C. The resulting mixture was stirred overnight at 0°C under N2. The reaction product was quenched with water (10 mL), concentrated under vacuum, and purified by HPLC to obtain compound 13 as a white solid (120 mg, yield: 44%). [C 78 H 125 N7O 33 ] + MS(ESI) calculation value for (m / z) was 1687.83, and the measured value was 1687,1688[M+H]+. HPLC: 254nm, no absorption; 220nm, 9.946 min, 99.73%. [Examples]

[0447] Synthesis of a conjugate (compound 14) of triptolide and tri-GalNHAc

[0448] [ka]

[0449] The following scheme shows the synthetic route used to prepare the title compound.

[0450] Scheme 17. [ka]

[0451] Preparation of benzyl(1,7-bis((3-aminopropyl)amino)-4-(3-((3-aminopropyl)amino)-3-oxopropyl)-1,7-dioxoheptan-4-yl)carbamate (N2)

[0452] To a solution of compound N1 (500 mg, 0.59 mmol, 1.0 equivalent) in DCM (2 mL), TFA (5 mL) was added at 0°C and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with toluene and concentrated. The residue was co-evaporated with toluene and dried under reduced pressure using a high vacuum pump to obtain N2 as the TFA salt, which was used for the next reaction without any optional further purification (323 g, yield over 95%).

[0453] Preparation of N4

[0454] To a solution of compound N3 (950 mg, 2.06 mmol, 3.5 equivalents) in DMF (10 mL), HATU (894 mg, 2.35 mmol, 4.0 equivalents) and DIPEA (760 mg, 5.88 mmol, 10.0 equivalents) were added at 0°C under an N2 atmosphere. The mixture was stirred at room temperature for 30 minutes, then a solution of compound N2 (323 mg, 0.59 mmol, 1.0 equivalent) in DMF (2 mL) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was quenched with cooled water. After extraction with DCM, the organic phases were washed with saturated NaHCO3, water, and brine, respectively, dried over Na2SO4, and concentrated. By purifying the residue by C18 column, compound N4 was obtained as a white solid (1.0 g, yield: 90%).

[0455] Preparation of N1,N7-bis(3-(6-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexanamide)propyl)-4-(3-((3-(6-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexanamide)propyl)amino)-3-oxopropyl)-4-aminoheptanediamide (N5)

[0456] To a solution of compound N4 (1.0 g, 0.53 mmol, 1.0 equivalent) in MeOH (10 mL), NaOMe (29 mg, 0.53 mmol, 1.0 equivalent) was added and the mixture was stirred at room temperature under an N2 atmosphere for 2 hours. The mixture was concentrated, and the residue was purified by Prep-HPLC (20%-40% ACN in water) to obtain the compound as a white solid (760 mg, yield: 96%).

[0457] To a solution of a freshly prepared solid (410 mg, 0.27 mmol, 1.0 equivalent) in MeOH (10 mL), 10% Pd / C (15 mg) was added and the mixture was stirred at room temperature under an H2 atmosphere for 2 hours. The mixture was filtered and concentrated to obtain N5 as a white solid, which was used for the next step without any optional further purification (335 mg, yield: 89%).

[0458] (6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxyleno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenantro[1,2-c]furan-8-yl4-((1,29-bis(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(H Preparation of droxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-15-(3-((3-(6-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexanamide)propyl)amino)-3-oxopropyl)-6,12,18,24-tetraoxo-7,11,19,23-tetraazanonacosan-15-yl)amino)-4-oxobutanoate (compound 14)

[0459] To a solution of compound N5 (335 mg, 0.25 mmol, 1.0 equivalent) and compound N6 (124 mg, 0.27 mmol, 1.1 equivalents) in DMF (10 mL), HATU (121 mg, 0.32 mmol, 1.3 equivalents) and DIPEA (95 mg, 0.74 mmol, 3.0 equivalents) were added at 0°C under an N2 atmosphere. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by Prep-HPLC (18%-38% ACN in water) to obtain compound 14 as a white solid (170 mg, yield: 36%). 1H-NMR (DMSO-d6, 400MHz): 0.72 (d, J=6.8 Hz, 3 H), 0.83 (d, J=6.8 Hz, 3 H), 0.91 (s, 3 H), 1.20-1.31 (m, 9 H), 1.41-1.50 (m, 19 H), 1.80 (s, 9 H), 1.86-1.90 (m, 2 H), 2.04 (t, J=7.2 Hz, 1 H), 2.28 (t, J=6.6 Hz, 1 H), 3.01-3.06 (m, 13 H), 3.29 (t, J=6.0 Hz, 1 H), 3.41-3.44 (m, 3 H), 3.47-3.55 (m, 20 H), 3.64-3.65 (m, 3 H), 3.67-3.72 (m, 7 H), 3.95 (s, 1 H), 4.23 (d, J=8.4 Hz, 3 H), 4.47 (d, J=4.2 Hz, 3 H), 4.54-4.60 (m, 6 H), 4.74-4.87 (m, 2 H), 4.96 (s, 1 H), 7.29 (s, 1 H), 7.62 (d, J=9.2 Hz, 3 H), 7.75 (t, J=5.6 Hz, 6 H). MS (ESI) [C 85 H 136 N 10 O 32 Calculated value (m / z) 1808.92, measured value 1809.3, [M+H] + HPLC: 220 nm, 9.042 min, 99.36%; 254 nm, 9.043 min, 100%. [Examples]

[0460] In vivo cancer chemotherapy evaluation Huh-7HCC Animal Models

[0461] To evaluate the antitumor effect of the triptolide conjugates disclosed herein against solid tumors, huh-7 cells (approximately 10 × 10) were used. 6 The cells were injected into the right flank of a male nude mouse. The tumor was approximately 150 mm. 3When the tumor volume reached a certain level, the mice were randomly divided into four groups of 7 or 8 mice each and treated as described below. Tumor volume was measured twice per week and estimated using the formula: Tumor volume (V) = (L × W × W) ÷ 2, where W is the tumor width and L is the tumor length. 1. Group 1 was a control group in which mice were administered a vehicle (0.5% CMC-Na / carboxymethylcellulose sodium, ip) daily for 3 weeks; 2. Group 2 was a study group in which mice were administered compound 1 (2.0 mg / kg, ip) daily for 3 weeks; 3. Group 3 was the test group in which mice were administered compound 2 (2.0 mg / kg, ip) daily for 3 weeks; 4. Group 4 was a positive control group in which mice were administered lenvatinib (5.0 mg / kg, orally) daily for 3 weeks.

[0462] The tumor growth-time curve for the treatment is shown in Figure 1, and as early as 4 days after treatment, the triptolide conjugate group (for compound 1 treatment group, V=245mm) showed tumor growth. 3 And for the two compound treatment groups, 315 mm 3 ) and the lenvatinib group (V=381mm 3 Both of the control group (V=598mm) 3 This indicates a significant reduction in tumor growth compared to the control group. Significant tumor growth inhibition persisted until the end of the experiment. By the end of treatment, the mean tumor volume in the control and lenvatinib groups increased by up to 15-fold and 9-fold, respectively, compared to pre-treatment, while the mean tumor volume in the triptolide conjugate treatment group increased by up to 2.0-fold and 2.7-fold, respectively, compared to pre-treatment. The tumor inhibition rates in the treatment groups, based on the mean tumor weight after 21 days of treatment shown in Figure 2, were 88.3% for the compound 1 treatment group, 84.4% for the compound 2 treatment group, and 42.3% for the lenvatinib treatment group.

[0463] HepG-2 HCC Animal Models

[0464] To evaluate the antitumor effect of novel triptolide conjugates against solid tumors, we used HepG-2 cells (approximately 10 × 10⁻¹⁴). 6 Cells were injected into the right flank of male nude mice. The tumor was approximately 150 mm. 3 When the tumor volume reached a certain level, the mice were randomly divided into five groups of eight mice each and treated as described below. Tumor volume was measured twice per week and estimated using the formula: Tumor volume (V) = (L × W × W) ÷ 2, where W is the tumor width and L is the tumor length. 1. Group 1 consisted of mice that were administered a vehicle (ip brine) daily for 4 weeks; 2. In Group 2, mice were administered conjugate 4 (2.0 mg / kg, ip) daily for 4 weeks; 3. In group 3, mice were administered conjugate 8 (6.0 mg / kg, ip) daily for 4 weeks; 4. In group 4, mice were administered conjugate 9 (6.0 mg / kg, ip) daily for 4 weeks; 5. In group 5, mice were administered conjugate 10 (6.0 mg / kg, ip) daily for 4 weeks;

[0465] The tumor growth-time treatment curve is shown in Figure 3, indicating that tumors began to shrink in mice after 4 weeks of treatment with triptolide conjugates. After 28 days of treatment, tumor size in the vehicle group increased 17.72 times, while tumor size in all mice treated with triptolide conjugates (compounds / conjugates 4, 8, 9, and 10, respectively) gradually decreased and disappeared (Figure 3). The mouse body weight change-time treatment curve is shown in Figure 4, indicating that triptolide conjugates did not have significant systemic toxicity to mice compared to the vehicle.

[0466] While certain embodiments are illustrated and described, it should be understood that variations and modifications can be made therein according to the ordinary skills of the art, without departing from the broader aspects of the art as defined in the following claims.

[0467] The embodiments described herein as exemplary may be practiced in the absence of any element(s) or element(s), limitation(s) or limitation(s) not specifically disclosed herein. Therefore, terms such as “including,” “containing,” and “containing” should be read broadly and unrestrictively. Additionally, the terms and expressions used herein are intended as descriptive terms, not limiting terms, and in the use of such terms and expressions there is no intention to exclude any equivalent or part of the features shown and described, although it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “becoming required from” is understood to include elements such as those specifically enumerated, as well as additional elements that do not substantially affect the fundamental and novel features of the claimed technology. The phrase “consisting of” excludes any elements not specifically identified.

[0468] This disclosure is not limited to the specific embodiments described in this application. Many modifications and variations can be made without departing from the spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of this disclosure are, in addition to those enumerated herein, apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. This disclosure, together with the entire scope of equivalents to which such claims are granted, should be limited only by the terminology of the appended claims. This disclosure should be understood as not being limited to specific methods, reagents, compounds, or compositions that can naturally be varied. Furthermore, the terminology used herein should be understood as being for the purpose of describing only specific embodiments and not intended to be limiting.

[0469] In addition, if any feature or aspect of this disclosure is described from the perspective of the Markush Group, a person skilled in the art will recognize that the disclosure is also described from the perspective of any individual member or subgroup member of the Markush Group.

[0470] As will be understood by those skilled in the art, for any and all purposes, and in particular in terms of providing written descriptions, all scopes disclosed herein also encompass any and all possible sub-scopes and combinations thereof. Any listed scope can be readily recognized as sufficiently describing and enabling that the same scope can be divided into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope considered herein can readily be divided into lower thirds, middle thirds, upper thirds, etc. Furthermore, as will be understood by those skilled in the art, all terms, such as “maximum,” “at least,” “greater than,” “less than,” etc., include the listed numbers and refer to scopes that can be subsequently divided into the sub-scopes considered above. Finally, as will be understood by those skilled in the art, the scope includes each individual member.

[0471] All publications, patent applications, issued patents, and other documents referenced in this specification are incorporated herein by reference as if each individual publication, patent application, issued patent, or other document were specifically and individually indicated to be incorporated by reference in whole. Definitions contained in the text incorporated by reference are excluded to the extent that they conflict with the definitions in this disclosure.

[0472] Other embodiments are described in the following claims.

Claims

1. Compounds of formula I, or their enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, or pharmaceutically acceptable salts: (In the formula, I understand １ , m ２ , n １ , n ２ Each of these ranges independently from 0 to 15; R １ , R ２ and R ３ Each of these is independently OH, H, or halo; M １ is selected from the group consisting of a bond, -C=O-, -NH(CO)-, -(CO)NH-, and -CH ２ O-; M ２ is C; X １ , X ２ , X ３ , X ４ and X ５ These are, independently, bonds: C=O, S-S, NH(CO), (CO)NH, L ２ -NH(CO), NH(CO)-L ２ (CO)NH-L ２ -NH(CO), L2-O, O-L ２ , non-substitutive or substituted C １ ~C １０ It is alkylene; Each L ２ Each of these is independently a non-substitutive or substituted C １ ~C １０ It is alkylene; X 5 is R ４ , R ５ , R ６ , R ７ and R ８ It is attached to one of the following; X ５ The remaining R that is not attached ４ , R ５ , R ６ , R ７ and R ８ These are H, OH, O(CO)NH, each independently. ２ Hello, NH(C) １ ~C １０ O(C) (acyl), unsubstituted or substituted １ ~C １０ Alkyl), unsubstituted or substituted O(C) １ ~C １０ C (acyl), unsubstituted or substituted １ ~C １０ (They are either carboxyl esters or form glycosidic bonds with natural monosaccharides.)

2. I understand １ and m ２ The compound according to claim 1, or its enantiomer, enantiomer mixture, diastereomer mixture, or pharmaceutically acceptable salt thereof, wherein each is independently 0, 1, 2, 3, or 4.

3. n １ and n ２ The compound according to claim 1 or 2, or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof, wherein each is independently 0, 1, 2, 3, or 4.

4. R １ , R ２ and R ３ The compound according to any one of claims 1 to 3, wherein each is H, or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof.

5. M １ However, -C=O-, -NH(CO)-, or -(CO)NH-; M ２ A compound according to any one of claims 1 to 4, wherein C is the enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof.

6. X １ X is a combination, ２ The compound according to any one of claims 1 to 5, wherein the compound is NH(CO) or (CO)NH, or an enantiomer, enantiomer mixture, diastereomer mixture, or pharmaceutically acceptable salt thereof.

7. X ３ O is X ４ (CO)NH-L ２ -NH(CO); X ５ is NH(CO)-L ２ , L ２ - (CO)NH, L ２ -O, or O-L ２ The compound according to any one of claims 1 to 6, or its enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof.

8. X ５ However, R ４ It is attached to; R ５ , R ６ , R ７ and R ８ However, each is independent of OH or NH(C) １ ~C １０ A compound according to any one of claims 1 to 7, or an enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof, which is an acyl.

9. X ５ However, R ５ It is attached to; R ４ , R ６ , R ７ and R ８ However, each is independent of OH or NH(C) １ ~C １０ A compound according to any one of claims 1 to 7, or an enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof, which is an acyl.

10. X ５ However, R ８ It is attached to; R ４ , R ５ , R ６ and R ７ However, each is independent of OH or NH(C) １ ~C １０ A compound according to any one of claims 1 to 7, or an enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof, which is an acyl.

11. The compound according to claim 1, or an enantiomer, enantiomer mixture, diastereomer mixture, or pharmaceutically acceptable salt thereof, having a structure selected from any one of the following structures. and

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or an enantiomer thereof, an enantiomer mixture, a diastereomer, a diastereomer mixture, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

13. Use of a compound according to any one of claims 1 to 11, or an enantiomer, enantiomer mixture, diastereomer, diastereomer mixture, or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or disorder in a subject requiring its use.

14. The use according to claim 13, wherein the disease or disorder is a cancer selected from hepatocellular carcinoma (HCC), lung cancer, breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, and glioblastoma.

15. The use according to claim 13, wherein the disease or disorder is related to an inflammatory and / or autoimmune disease selected from membranous nephropathy (MN), lupus nephritis, systemic lupus erythematosus, kidney transplantation, renal fibrosis, inflammatory bowel disease, Crohn's disease, intestinal fibrosis, hepatic fibrosis, asthma, acute lung injury, pulmonary arterial hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis, and psoriasis.

16. The pharmaceutical composition according to claim 12 for use in treating cancer selected from hepatocellular carcinoma (HCC), lung cancer, breast cancer, pancreatic cancer, bile duct cancer, colorectal cancer, and glioblastoma.

17. The pharmaceutical composition according to claim 12 for use in treating inflammatory and / or autoimmune diseases selected from membranous nephropathy (MN), lupus nephritis, systemic lupus erythematosus, kidney transplantation, renal fibrosis, inflammatory bowel disease, Crohn's disease, intestinal fibrosis, hepatic fibrosis, asthma, acute lung injury, pulmonary arterial hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis, and psoriasis.

18. Use of a compound in the preparation of a medicament for treating cancer or inflammatory and / or autoimmune disease, wherein the medicament comprises the compound according to any one of claims 1 to 11.

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