Triptolide conjugates and uses thereof

Abstract

The present disclosure provides triptolide conjugates, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat conditions / diseases, such as those related to cancer, immune modulation, and / or inflammation.

Description

[0001] Related Applications

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 068,898, filed August 21, 2020, the entire contents of which are incorporated herein by reference. BACKGROUND

[0003] Triptolide, a bioactive compound isolated from the plant Tripterygium wilfordii Hook F, is widely used in traditional Chinese medicine for the treatment of diseases or conditions associated with immune modulation and anti-inflammation. Triptolide has attracted research interest in the last few decades due to its potential therapeutic applications in immune suppression, anti-inflammation, cancer treatment, and neuroprotection, among others. (Ziaei S., Halaby R. Immunosuppressive, anti-inflammatory and anti-cancer properties of triptolide: A mini review. 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 D.D., Saluja A.K., 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-κΒ / PUMA signal in rats. Ther. Clin. Risk Manag. 2106, 12, 817-824.)

[0004] However, several limitations exist in the preclinical development and clinical application of triptolide, including poor water solubility, a narrow therapeutic index, and a very short in vivo half-life. [Patil S., Lis L.G., Schumacher RJ, et al. Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts. Journal of Medicinal Chemistry (J. Med. Chem.) 2015, 58, 9334-44; and Zhao Y., Miao D., Hou S., Huang Q. Compositions of Schisandra Extracts and their methods.] [Methods Thereof.) WO2018 / 200143A2, 2018.] To address the poor water solubility of triptolide, the following precursors have been developed using the following chemical components: carboxyl group [Dai,D., Yuan,H., Musser,JH. Preparation of triptolide prodrugs having high aqueous solubility. WO 02070472, 2002], amino acid [Musser,JH. Synthesis of triptolide prodrugs having high aqueous solubility for immunosuppressive and anti-inflammatory treatment. WO 0012483, 2000], phosphonomethyl ester [Georg EG (Georg EG), Patil SP, Saluga AK, Chugh R., Vickers SM Triptolide Prodrugs WO2010129918A1, 2010], hydroquinone derived from carboxylic acid esters [Peng Z.].(Peng Z.), Liu M.), Du Q.), Yang Y.), Song W.), Chen Y. Preparation of water-soluble triptolide derivatives useful as anticancer agents. CN 110003304 A, 2019], polyethylene glycol [Lin Y.), Huang X.), Yan D. A water-soluble triptolide prodrug using polyethylene glycol as carrier, its preparation method and application. CN 104629036 A, 2015] or carboxylated chitosan [Zeng H.), Zhang Z.), Yan M. [Preparation method and application of triptolide-carboxylated chitosan conjugate in preparing drug for treating rheumatic arthritis, cancer and Alzheimer's disease. CN 109464675 A, 2019.] These prodrugs have better water solubility; however, compared with triptolide, their therapeutic index and / or half-life are not significantly changed due to the lack of targeting of the prodrugs and the rapid release of triptolide into the blood. To enhance the targeted nature of cancer treatment, triptolide has recently been combined with glucose transporters that allow glucose to be transported through tumors with overexpressed glucose transporters [He Q., Minn L., Wang Q., et al. Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation. Angewandte Chemie International Edition (Angew. Chem. Int. Ed. Engl.)].)2016,55(39),12035-9; and Liu J., He Q., Mi En 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 (Cetuximab-triptolide conjugate suppresses the growth of EGFR-overexpressing lung cancers through targeting RNA polymerase II) II.) Molecular Therapy - Oncolytic Therapy (Mol. Ther. Oncolytics) 2020, 18, 304-316.] Both of these conjugates showed higher therapeutic indices in preclinical models. Therefore, there is a need to develop triptolide conjugates with good water solubility, high therapeutic indices, and / or long half-lives.

[0005] This disclosure addresses this need by providing: triptolide conjugates having good water solubility, a high therapeutic index, and / or a long half-life; methods for preparing such compounds; pharmaceutical compositions and pharmaceuticals comprising such compounds; and methods for treating symptoms / diseases using such compounds. Summary of the Invention

[0006] On the one hand, a compound of formula (I), or an enantiomer, an enantiomeric mixture, a diastereomer, a diastereomeric mixture, or a pharmaceutically acceptable salt thereof, is provided:

[0007]

[0008] in

[0009] m1, m2, n1, and n2 are each independently 0-15;

[0010] R1, R2, and R3 are each independently OH, H, a halogen, or an unsubstituted or substituted C1-C group. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers;

[0011] M1 is selected from bonds, -C=O-, -OPO2-, -SO2-, -NH(CO)-, -(CO)NH-, -CH2OPO2-, -CH2OCO-

[0012] and -CH2O-;

[0013] M2 is selected from C and Si;

[0014] 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, 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 Cycloalkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, unsubstituted or substituted C1-C 10 A heterocyclic group or an unsubstituted or substituted peptide comprising 1-10 natural amino acids;

[0015] Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C. 10 Sub-heterocyclic groups;

[0016] Each L2 is independently an unsubstituted or substituted C1-C 10 Alkylene;

[0017] Each R is independently a C1-C that is either unsubstituted or substituted. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or unsubstituted or substituted C1-C groups. 10 Heterocyclic groups; and

[0018] X5 is attached to any one of R4, R5, R6, R7, and R8; the remaining R4, R5, R6, R7, and R8, which are not attached to X5, are independently H, OH, O(CO)NH2, halogen, or NH(Cl-C) 10 Acyl), unsubstituted or substituted O (C1-C) 10 Alkyl groups, unsubstituted or substituted O (C3-C) 10 cycloalkyl), unsubstituted or substituted O (C1-C) 10 Acyl), unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, unsubstituted or substituted C1-C 10 Heterocyclic groups, unsubstituted or substituted peptides comprising 1-10 amino acids, or glycosidic bonds formed with natural monosaccharides.

[0019] On the one hand, a compound of formula (II), or an enantiomer, an enantiomeric mixture, a diastereomer, a diastereomeric mixture, or a pharmaceutically acceptable salt thereof, is provided:

[0020]

[0021] in

[0022] n1 and n2 are each independently 0-15;

[0023] R1 and R2 are each independently OH, H, halogen, 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 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers;

[0024] 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, 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 Cycloalkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, unsubstituted or substituted C1-C 10 A heterocyclic group or an unsubstituted or substituted peptide comprising 1-10 natural amino acids;

[0025] Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C. 10 Sub-heterocyclic groups;

[0026] Each L2 is independently an unsubstituted or substituted C1-C 10 Alkylene;

[0027] Each R is independently a C1-C that is either unsubstituted or substituted. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or unsubstituted or substituted C1-C groups. 10 Heterocyclic groups; and

[0028] X3 is attached to any one of R3, R4, R5, R6, and R7, and the remaining R3, R4, R5, R6, and R7 not attached to X3 are each independently H, OH, O(CO)NH2, a halogen, an unsubstituted or substituted amino group, or an unsubstituted or substituted C1-C group. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, unsubstituted or substituted C1-C 10 Heterocyclic groups, unsubstituted or substituted peptides comprising 1-10 amino acids, or glycosidic bonds formed with natural monosaccharides.

[0029] On the one hand, a compound of formula (III), or an enantiomer, an enantiomeric mixture, a diastereomer, a diastereomeric mixture, or a pharmaceutically acceptable salt thereof, is provided:

[0030]

[0031] in

[0032] m1, m2 and m3 are each independently 0-15;

[0033] M1 is selected from the following: -CO-, -OPO2-, -SO2-, -CH2OPO2, -CH2OCO-, and -CH2O-.

[0034] R1, R2, and R3 are each independently OH, H, a halogen, or an unsubstituted or substituted C1-C group. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers;

[0035] 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, 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 Cycloalkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, unsubstituted or substituted C1-C 10A heterocyclic group or an unsubstituted or substituted peptide comprising 1-10 natural amino acids;

[0036] Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C. 10 Sub-heterocyclic groups;

[0037] Each L2 is independently an unsubstituted or substituted C1-C 10 Alkylene;

[0038] Each R is independently a C1-C that is either unsubstituted or substituted. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or unsubstituted or substituted C1-C groups. 10 Heterocyclic groups;

[0039] R4 is NHR', NHCOR', NHCOOR', CONHR', or COOR';

[0040] Each R' is H, 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 groups, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, unsubstituted or substituted C1-C 10 Heterocyclic groups or unsubstituted or substituted C1-C 10 Heterocyclic group (C1-C) 10 Alkyl); and

[0041] R5 is unsubstituted or substituted C1-C 10 Alkyl, unsubstituted or substituted C3-C 10Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted C1-C 10 Heterocyclic group.

[0042] On the one hand, a compound of formula (IV), or an enantiomer, an enantiomeric mixture, a diastereomer, a diastereomeric mixture, or a pharmaceutically acceptable salt thereof, is provided:

[0043]

[0044] in

[0045] n1 and n2 are each independently 0-15;

[0046] R1 and R2 are each independently OH, H, halogen, 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 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers;

[0047] 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, 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 Cycloalkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, unsubstituted or substituted C1-C 10 A heterocyclic group or an unsubstituted or substituted peptide comprising 1-10 natural amino acids;

[0048] Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C. 10 Sub-heterocyclic groups;

[0049] Each L2 is independently an unsubstituted or substituted C1-C 10 Alkylene;

[0050] Each R is independently a C1-C that is either unsubstituted or substituted. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or unsubstituted or substituted C1-C groups. 10 Heterocyclic groups; and

[0051] A represents unsubstituted or substituted C3-C. 15 Cycloalkyl, unsubstituted or substituted C1-C 15 Heterocyclic groups, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or oligosaccharides comprising 3 to 15 identical or different monosaccharides.

[0052] On the one hand, this article also provides a pharmaceutical composition comprising at least one of the compounds disclosed herein, or an enantiomer, an enantiomeric mixture, a diastereomer, an enantiomeric mixture, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0053] This article also provides a method for treating cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of the compound or any one of its enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, or pharmaceutically acceptable salts. In some embodiments, the cancer is hepatocellular carcinoma (HCC), lung cancer, breast cancer, pancreatic cancer, biliary tract cancer, colorectal cancer, or glioblastoma.

[0054] This article also provides a method for treating a disease or condition associated with immune modulation and / or inflammation in a subject of need, the method comprising administering to the subject a therapeutically effective amount of at least one of the compound or its enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, or pharmaceutically acceptable salts. In some embodiments, the disease or condition is associated with inflammatory diseases and / or autoimmune diseases. In some embodiments, diseases or conditions associated with inflammatory diseases and / or autoimmune diseases include membranous nephropathy (MN), lupus nephritis, systemic lupus erythematosus, kidney transplantation, renal fibrosis, inflammatory bowel disease, Crohn's disease, intestinal fibrosis, liver fibrosis, asthma, acute lung injury, pulmonary hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis, or psoriasis. Attached Figure Description

[0055] Figure 1 Tumor growth-treatment time curves for mice treated over a three-week period are shown: Group 1 (control group; 0.5% CMC-Na / carboxymethyl cellulose sodium ip 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).

[0056] Figure 2 The mean tumor weight of each mouse group after 21 days of treatment is shown: Group 1 (control group; 0.5% CMC-Na ip 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, orally, once daily).

[0057] Figure 3 Tumor growth-treatment time curves for mice treated over a four-week period are shown: Group 1 (control group; ip saline; 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).

[0058] Figure 4 The mean tumor weight of each mouse group after 28 days of treatment is shown: Group 1 (control group; ip saline; 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). Detailed Implementation

[0059] This disclosure provides triptolide conjugates that may possess properties desirable for preclinical development and clinical application, such as good water solubility, a high therapeutic index, and / or a longer half-life. Methods for preparing such compounds, pharmaceutical compositions and drugs comprising such compounds, and the use of such compounds to treat conditions / diseases, such as those related to cancer, immune modulation, and / or inflammation, are also provided.

[0060] compound

[0061] On the one hand, a compound of formula (I), or an enantiomer, an enantiomeric mixture, a diastereomer, a diastereomeric mixture, or a pharmaceutically acceptable salt thereof, is provided:

[0062]

[0063] in

[0064] m1, m2, n1, and n2 are each independently 0-15;

[0065] R1, R2, and R3 are each independently OH, H, a halogen, or an unsubstituted or substituted C1-C group. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers;

[0066] M1 is selected from bonds, -C=O-, -OPO2-, -SO2-, -NH(CO)-, -(CO)NH-, -CH2OPO2-, -CH2OCO-

[0067] and -CH2O-;

[0068] M2 is selected from C and Si;

[0069] 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, 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 Cycloalkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, unsubstituted or substituted C1-C 10 A heterocyclic group or an unsubstituted or substituted peptide comprising 1-10 natural amino acids;

[0070] Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C. 10 Sub-heterocyclic groups;

[0071] Each L2 is independently an unsubstituted or substituted C1-C 10 Alkylene;

[0072] Each R is independently a C1-C that is either unsubstituted or substituted. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or unsubstituted or substituted C1-C groups. 10 Heterocyclic groups; and

[0073] X5 is attached to any one of R4, R5, R6, R7, and R8; the remaining R4, R5, R6, R7, and R8, which are not attached to X5, are independently H, OH, O(CO)NH2, halogen, or NH(Cl-C) 10 Acyl), unsubstituted or substituted O (C1-C) 10 Alkyl groups, unsubstituted or substituted O (C3-C) 10 cycloalkyl), unsubstituted or substituted O (C1-C) 10 Acyl), unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, unsubstituted or substituted C1-C 10 Heterocyclic groups, unsubstituted or substituted peptides comprising 1-10 amino acids, or glycosidic bonds formed with natural monosaccharides.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] In some embodiments, R1 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ether. In some embodiments, R1 is OH. In some embodiments, R1 is hydrogen. In some embodiments, R1 is a halogroup. In some embodiments, R1 is an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, R1 is an unsubstituted or substituted C3-C alkyl group. 10 Cycloalkyl. In some embodiments, R1 is an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, R1 is an unsubstituted or substituted C1-C group. 10 Carboxylic ester. In some embodiments, R1 is an unsubstituted or substituted C1-C ester. 10 Alkyl ketone. In some embodiments, R1 is an unsubstituted or substituted C1-C ketone. 10 Alkyl ethers.

[0079] In some embodiments, R2 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C10 Alkyl ether. In some embodiments, R2 is OH. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halogroup. In some embodiments, R2 is an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, R2 is an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, R2 is an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, R2 is an unsubstituted or substituted C1-C group. 10 Carboxylic ester. In some embodiments, R2 is an unsubstituted or substituted C1-C ester. 10 Alkyl ketone. In some embodiments, R2 is an unsubstituted or substituted C1-C ketone. 10 Alkyl ethers.

[0080] In some embodiments, R3 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ether. In some embodiments, R3 is OH. In some embodiments, R3 is hydrogen. In some embodiments, R3 is a halogroup. In some embodiments, R3 is an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, R3 is an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, R3 is an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, R3 is an unsubstituted or substituted C1-C group. 10 Carboxylic ester. In some embodiments, R3 is an unsubstituted or substituted C1-C ester. 10 Alkyl ketone. In some embodiments, R3 is an unsubstituted or substituted C1-C ketone. 10 Alkyl ethers.

[0081] In some embodiments, M1 is any 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-.

[0082] In some embodiments, M2 is any of the following: C; and Si. In some embodiments, M2 is C. In some embodiments, M2 is Si.

[0083] In some embodiments, X1 is any of the following: a bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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. 10 Alkylene. In some embodiments, X1 is an unsubstituted or substituted C3-C 10 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 Heterocyclic group. In some embodiments, X1 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0084] In some embodiments, X2 is any of the following: a bond; 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 10Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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 Alkylene. In some embodiments, X2 is an unsubstituted or substituted C3-C 10 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 Heterocyclic group. In some embodiments, X2 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0085] In some embodiments, X3 is any of the following: a bond; 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 10Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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. 10 Alkylene. In some embodiments, X3 is an unsubstituted or substituted C3-C 10 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 Heterocyclic group. In some embodiments, X3 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0086] In some embodiments, X4 is any of the following: a bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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 Alkylene. In some embodiments, X4 is an unsubstituted or substituted C3-C 10 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 Heterocyclic group. In some embodiments, X4 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0087] In some embodiments, X5 is any of the following: a bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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. 10 Alkylene. In some embodiments, X5 is an unsubstituted or substituted C3-C 10 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 10Heterocyclic group. In some embodiments, X5 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0088] 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 Heterocyclic group. In some embodiments, each L1 is independently an unsubstituted or substituted aryl group. In some embodiments, each L1 is independently an unsubstituted or substituted heterocyclic group. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C group. 10 Sub-heterocyclic group.

[0089] In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; or unsubstituted or substituted C1-C... 10 Heterocyclic group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, each R is independently an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Carboxylic esters. In some embodiments, each R is independently an unsubstituted or substituted C1-C ester. 10 Alkyl ketones. In some embodiments, each R is independently an unsubstituted or substituted C1-C ketone. 10 Alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl group. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group.

[0090] In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; NH(Cl-C) 10 Acyl); unsubstituted or substituted O(C1-C) 10 Alkyl); unsubstituted or substituted O (C3-C) 10 cycloalkyl); unsubstituted or substituted O (C1-C2) 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; an unsubstituted or substituted peptide comprising 1-10 amino acids; and forming a glycosidic bond with a natural monosaccharide. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently H. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently OH. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently O(CO)NH2. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently a halogen. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently NH(Cl-C) 10 Acyl group). In some embodiments, X5 is attached to R4; and R5, R6, R7 and R8 are each independently unsubstituted or substituted O(C1-C1) groups. 10 Alkyl group). In some embodiments, X5 is attached to R4; and R5, R6, R7 and R8 are each independently unsubstituted or substituted O (C3-C4). 10 (Cycloalkyl). In some embodiments, X5 is attached to R4; and R5, R6, R7 and R8 are each independently unsubstituted or substituted O (C1-C2). 10 Acyl group). In some embodiments, X5 is attached to R4; and R5, R6, R7 and R8 are each independently unsubstituted or substituted C1-C. 10 Carboxylic esters. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently unsubstituted or substituted C1-C. 10 Alkyl ketone. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently unsubstituted or substituted C1-C. 10Alkyl ether. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently an unsubstituted or substituted aryl group. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently an unsubstituted or substituted heteroaryl group. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently a glycosidic bond and form a glycosidic bond with a native monosaccharide.

[0091] In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; NH(Cl-C) 10 Acyl); unsubstituted or substituted O(C1-C) 10 Alkyl); unsubstituted or substituted O (C3-C) 10 cycloalkyl); unsubstituted or substituted O (C1-C2) 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; an unsubstituted or substituted peptide comprising 1-10 amino acids; and forming a glycosidic bond with a natural monosaccharide. In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently H. In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently OH. In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently O(CO)NH2. In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently a halogen. In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently NH(Cl-C) 10 Acyl group). In some embodiments, X5 is attached to R6; and R4, R5, R7 and R8 are each independently unsubstituted or substituted O(C1-C1) groups. 10Alkyl group). In some embodiments, X5 is attached to R6; and R4, R5, R7 and R8 are each independently unsubstituted or substituted O (C3-C4). 10 (Cycloalkyl). In some embodiments, X5 is attached to R6; and R4, R5, R7 and R8 are each independently unsubstituted or substituted O (C1-C2). 10 Acyl group). In some embodiments, X5 is attached to R6; and R4, R5, R7 and R8 are each independently unsubstituted or substituted C1-C. 10 Carboxylic esters. In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently unsubstituted or substituted C1-C. 10 Alkyl ketone. In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently unsubstituted or substituted C1-C. 10 Alkyl ether. In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently an unsubstituted or substituted aryl group. In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently an unsubstituted or substituted heteroaryl group. In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group. In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X5 is attached to R6; and R4, R5, R7, and R8 are each independently a glycosidic bond and form a glycosidic bond with a native monosaccharide.

[0092] In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; NH(Cl-C) 10 Acyl); unsubstituted or substituted O(C1-C) 10 Alkyl); unsubstituted or substituted O (C3-C) 10 cycloalkyl); unsubstituted or substituted O (C1-C2) 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10Heterocyclic group; an unsubstituted or substituted peptide comprising 1-10 amino acids; and forming a glycosidic bond with a natural monosaccharide. In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently H. In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently OH. In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently O(CO)NH2. In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently a halogen. In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently NH(Cl-C) 10 Acyl group). In some embodiments, X5 is attached to R7; and R4, R5, R6 and R8 are each independently unsubstituted or substituted O(C1-C1) groups. 10 Alkyl group). In some embodiments, X5 is attached to R7; and R4, R5, R6 and R8 are each independently unsubstituted or substituted O (C3-C4). 10 (Cycloalkyl). In some embodiments, X5 is attached to R7; and R4, R5, R6 and R8 are each independently unsubstituted or substituted O (C1-C2). 10 Acyl group). In some embodiments, X5 is attached to R7; and R4, R5, R6 and R8 are each independently unsubstituted or substituted C1-C. 10 Carboxylic ester. In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently unsubstituted or substituted C1-C. 10 Alkyl ketone. In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently unsubstituted or substituted C1-C. 10 Alkyl ether. In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently an unsubstituted or substituted aryl group. In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently an unsubstituted or substituted heteroaryl group. In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group. In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X5 is attached to R7; and R4, R5, R6, and R8 are each independently a glycosidic bond and form a glycosidic bond with a native monosaccharide.

[0093] In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; NH(Cl-C) 10 Acyl); unsubstituted or substituted O(C1-C) 10 Alkyl); unsubstituted or substituted O (C3-C) 10 cycloalkyl); unsubstituted or substituted O (C1-C2) 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; an unsubstituted or substituted peptide comprising 1-10 amino acids; and forming a glycosidic bond with a natural monosaccharide. In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently H. In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently OH. In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently O(CO)NH2. In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently a halogen. In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently NH(Cl-C) 10 Acyl group). In some embodiments, X5 is attached to R8; and R4, R5, R6 and R7 are each independently unsubstituted or substituted O(C1-C1) groups. 10 Alkyl group). In some embodiments, X5 is attached to R8; and R4, R5, R6 and R7 are each independently unsubstituted or substituted O (C3-C4). 10 (Cycloalkyl). In some embodiments, X5 is attached to R8; and R4, R5, R6 and R7 are each independently unsubstituted or substituted O (C1-C2). 10 Acyl group). In some embodiments, X5 is attached to R8; and R4, R5, R6 and R7 are each independently unsubstituted or substituted C1-C. 10 Carboxylic ester. In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently unsubstituted or substituted C1-C. 10 Alkyl ketone. In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently unsubstituted or substituted C1-C. 10Alkyl ether. In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently an unsubstituted or substituted aryl group. In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently an unsubstituted or substituted heteroaryl group. In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group. In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X5 is attached to R8; and R4, R5, R6, and R7 are each independently a glycosidic bond and form a glycosidic bond with a native monosaccharide.

[0094] In some embodiments of Formula I, m1 and m2 are each independently 0, 1, 2, 3, or 4. In some embodiments, n1 and n2 are each 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-; and 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); and X5 is NH(CO)-L2, L2-(CO)NH, L2-O, or O-L2. In some embodiments, X5 is attached to R4; and R5, R6, R7, and R8 are each independently OH or NH(Cl-C) 10 Acyl group). In some embodiments, X5 is attached to R5; and R4, R6, R7 and R8 are each independently OH or NH (Cl-C). 10 Acyl group). In some embodiments, X5 is attached to R8; and R4, R5, R6 and R7 are each independently OH or NH (Cl-C). 10 Acyl group).

[0095] On the one hand, a compound of formula (II), or an enantiomer, an enantiomeric mixture, a diastereomer, a diastereomeric mixture, or a pharmaceutically acceptable salt thereof, is provided:

[0096]

[0097] in

[0098] n1 and n2 are each independently 0-15;

[0099] R1 and R2 are each independently OH, H, halogen, unsubstituted or substituted C1-C. 10Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers;

[0100] 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, 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 Cycloalkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, unsubstituted or substituted C1-C 10 A heterocyclic group or an unsubstituted or substituted peptide comprising 1-10 natural amino acids;

[0101] Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C. 10 Sub-heterocyclic groups;

[0102] Each L2 is independently an unsubstituted or substituted C1-C 10 Alkylene;

[0103] Each R is independently a C1-C that is either unsubstituted or substituted. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or unsubstituted or substituted C1-C groups. 10 Heterocyclic groups; and

[0104] X3 is attached to any one of R3, R4, R5, R6, and R7, and the remaining R3, R4, R5, R6, and R7 not attached to X3 are each independently H, OH, O(CO)NH2, a halogen, an unsubstituted or substituted amino group, or an unsubstituted or substituted C1-C group. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, unsubstituted or substituted C1-C 10 Heterocyclic groups, unsubstituted or substituted peptides comprising 1-10 amino acids, or glycosidic bonds formed with natural monosaccharides.

[0105] 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.

[0106] 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.

[0107] In some embodiments, R1 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group.10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ether. In some embodiments, R1 is OH. In some embodiments, R1 is hydrogen. In some embodiments, R1 is a halogroup. In some embodiments, R1 is an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, R1 is an unsubstituted or substituted C3-C alkyl group. 10 Cycloalkyl. In some embodiments, R1 is an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, R1 is an unsubstituted or substituted C1-C group. 10 Carboxylic ester. In some embodiments, R1 is an unsubstituted or substituted C1-C ester. 10 Alkyl ketone. In some embodiments, R1 is an unsubstituted or substituted C1-C ketone. 10 Alkyl ethers.

[0108] In some embodiments, R2 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ether. In some embodiments, R2 is OH. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halogroup. In some embodiments, R2 is an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, R2 is an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, R2 is an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, R2 is an unsubstituted or substituted C1-C group. 10 Carboxylic ester. In some embodiments, R2 is an unsubstituted or substituted C1-C ester. 10 Alkyl ketone. In some embodiments, R2 is an unsubstituted or substituted C1-C ketone. 10 Alkyl ethers.

[0109] In some embodiments, X1 is any of the following: bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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 Cl-C. 10 Alkylene. In some embodiments, X1 is an unsubstituted or substituted C3-C 10 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 10Heterocyclic group. In some embodiments, X1 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0110] In some embodiments, X2 is any of the following: a bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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 Cl-C. 10 Alkylene. In some embodiments, X2 is an unsubstituted or substituted C3-C 10Cycloalkylene. 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 Heterocyclic group. In some embodiments, X2 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0111] In some embodiments, X3 is any of the following: bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptide acids comprising 1-10 natural amino groups. 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 Cl-C. 10Alkylene. In some embodiments, X3 is an unsubstituted or substituted C3-C 10 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 Heterocyclic group. In some embodiments, X3 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0112] 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 Heterocyclic group. In some embodiments, each L1 is independently an unsubstituted or substituted aryl group. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C group. 10 Sub-heterocyclic group.

[0113] In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; or unsubstituted or substituted C1-C... 10 Heterocyclic group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, each R is independently an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Carboxylic esters. In some embodiments, each R is independently an unsubstituted or substituted C1-C ester. 10 Alkyl ketones. In some embodiments, each R is independently an unsubstituted or substituted C1-C ketone. 10Alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl group. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group.

[0114] In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; an unsubstituted or substituted peptide comprising 1-10 amino acids; and forming a glycosidic bond with a natural monosaccharide. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently H. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently OH. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently O(CO)NH2. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently a halogroup. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently an amino group. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently unsubstituted or substituted C3-C. 10 Cycloalkyl. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently unsubstituted or substituted C1-C. 10 Acyl group. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently unsubstituted or substituted C1-C. 10 Carboxylic esters. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently unsubstituted or substituted C1-C. 10Alkyl ketone. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently unsubstituted or substituted C1-C. 10 Alkyl ether. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently an unsubstituted or substituted aryl group. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently an unsubstituted or substituted heteroaryl group. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently a glycosidic bond and form a glycosidic bond with a native monosaccharide.

[0115] In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; an unsubstituted or substituted peptide comprising 1-10 amino acids; and forming a glycosidic bond with a natural monosaccharide. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently H. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently OH. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently O(CO)NH2. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently a halogroup. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently an amino group. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently an unsubstituted or substituted C1-C group. 10Alkyl group. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently unsubstituted or substituted C3-C. 10 Cycloalkyl. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently unsubstituted or substituted C1-C. 10 Acyl group. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently unsubstituted or substituted C1-C. 10 Carboxylic ester. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently unsubstituted or substituted C1-C. 10 Alkyl ketone. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently unsubstituted or substituted C1-C. 10 Alkyl ether. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently an unsubstituted or substituted aryl group. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently an unsubstituted or substituted heteroaryl group. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently a glycosidic bond and form a glycosidic bond with a native monosaccharide.

[0116] In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10Heterocyclic group; an unsubstituted or substituted peptide comprising 1-10 amino acids; and forming a glycosidic bond with a natural monosaccharide. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently H. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently OH. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently O(CO)NH2. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently a halogroup. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently an amino group. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently unsubstituted or substituted C3-C. 10 Cycloalkyl. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently unsubstituted or substituted C1-C. 10 Acyl group. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently unsubstituted or substituted C1-C. 10 Carboxylic ester. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently unsubstituted or substituted C1-C. 10 Alkyl ketone. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently unsubstituted or substituted C1-C. 10 Alkyl ether. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently an unsubstituted or substituted aryl group. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently an unsubstituted or substituted heteroaryl group. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently a glycosidic bond and form a glycosidic bond with a native monosaccharide.

[0117] In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; an unsubstituted or substituted peptide comprising 1-10 amino acids; and forming a glycosidic bond with a natural monosaccharide. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently H. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently OH. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently O(CO)NH2. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently a halogroup. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently an amino group. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently unsubstituted or substituted C3-C. 10 Cycloalkyl. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently unsubstituted or substituted C1-C. 10 Acyl group. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently unsubstituted or substituted C1-C. 10 Carboxylic ester. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently unsubstituted or substituted C1-C. 10 Alkyl ketone. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently unsubstituted or substituted C1-C. 10Alkyl ether. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently an unsubstituted or substituted aryl group. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently an unsubstituted or substituted heteroaryl group. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently a glycosidic bond and form a glycosidic bond with a native monosaccharide.

[0118] In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; an unsubstituted or substituted peptide comprising 1-10 amino acids; and forming a glycosidic bond with a natural monosaccharide. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently H. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently OH. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently O(CO)NH2. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently a halogroup. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently an amino group. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently unsubstituted or substituted C3-C. 10Cycloalkyl. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently unsubstituted or substituted C1-C. 10 Acyl group. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently unsubstituted or substituted C1-C. 10 Carboxylic ester. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently unsubstituted or substituted C1-C. 10 Alkyl ketone. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently unsubstituted or substituted C1-C. 10 Alkyl ether. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently an unsubstituted or substituted aryl group. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently an unsubstituted or substituted heteroaryl group. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently a glycosidic bond and form a glycosidic bond with a native monosaccharide.

[0119] In some embodiments of Formula II, n1 and n2 are each independently 0, 1, 2, 3, or 4. In some embodiments, R1 and R2 are each H. In some embodiments, X1 is a bond, NH(CO), (CO)NH, (C=O)-L1-(C=O), (C=O)-L1, L1-(C=O), and O; and L1 is unsubstituted or substituted C1-C. 10 Heterocyclic groups. 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; and R3, R5, R6, and R7 are each independently OH or a halide group. In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently OH or a halide group.

[0120] On the one hand, a compound of formula (III), or an enantiomer, an enantiomeric mixture, a diastereomer, a diastereomeric mixture, or a pharmaceutically acceptable salt thereof, is provided:

[0121]

[0122] in

[0123] m1, m2 and m3 are each independently 0-15;

[0124] M1 is selected from the following: -CO-, -OPO2-, -SO2-, -CH2OPO2, -CH2OCO-, and -CH2O-.

[0125] R1, R2, and R3 are each independently OH, H, a halogen, or an unsubstituted or substituted C1-C group. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers;

[0126] 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, 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 Cycloalkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, unsubstituted or substituted C1-C 10 A heterocyclic group or an unsubstituted or substituted peptide comprising 1-10 natural amino acids;

[0127] Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C. 10 Sub-heterocyclic groups;

[0128] Each L2 is independently an unsubstituted or substituted C1-C 10 Alkylene;

[0129] Each R is independently a C1-C that is either unsubstituted or substituted. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or unsubstituted or substituted C1-C groups. 10 Heterocyclic groups;

[0130] R4 is NHR', NHCOR', NHCOOR', CONHR', or COOR';

[0131] Each R' is H, 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 groups, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, unsubstituted or substituted C1-C 10 Heterocyclic groups or unsubstituted or substituted C1-C 10 Heterocyclic group (C1-C) 10 Alkyl); and

[0132] R5 is 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 Heterocyclic group.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] In some embodiments, M1 is any of the following: a 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-.

[0137] In some embodiments, R1 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ether. In some embodiments, R1 is OH. In some embodiments, R1 is hydrogen. In some embodiments, R1 is a halogroup. In some embodiments, R1 is an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, R1 is an unsubstituted or substituted C3-C alkyl group. 10 Cycloalkyl. In some embodiments, R1 is an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, R1 is an unsubstituted or substituted C1-C group. 10 Carboxylic ester. In some embodiments, R1 is an unsubstituted or substituted C1-C ester. 10 Alkyl ketone. In some embodiments, R1 is an unsubstituted or substituted C1-C ketone. 10 Alkyl ethers.

[0138] In some embodiments, R2 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10Alkyl ether. In some embodiments, R2 is OH. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halogroup. In some embodiments, R2 is an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, R2 is an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, R2 is an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, R2 is an unsubstituted or substituted C1-C group. 10 Carboxylic ester. In some embodiments, R2 is an unsubstituted or substituted C1-C ester. 10 Alkyl ketone. In some embodiments, R2 is an unsubstituted or substituted C1-C ketone. 10 Alkyl ethers.

[0139] In some embodiments, R3 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ether. In some embodiments, R3 is OH. In some embodiments, R3 is hydrogen. In some embodiments, R3 is a halogroup. In some embodiments, R3 is an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, R3 is an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, R3 is an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, R3 is an unsubstituted or substituted C1-C group. 10 Carboxylic ester. In some embodiments, R3 is an unsubstituted or substituted C1-C ester. 10 Alkyl ketone. In some embodiments, R3 is an unsubstituted or substituted C1-C ketone. 10 Alkyl ethers.

[0140] In some embodiments, X1 is any of the following: bond; 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-C10 Alkylene, unsubstituted or substituted C3-C 10 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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 Alkylene. In some embodiments, X1 is an unsubstituted or substituted C3-C 10 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 Heterocyclic group. In some embodiments, X1 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0141] In some embodiments, X2 is any of the following: a bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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 Alkylene. In some embodiments, X2 is an unsubstituted or substituted C3-C 10 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 Heterocyclic group. In some embodiments, X2 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0142] In some embodiments, X3 is any of the following: bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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 Alkylene. In some embodiments, X3 is an unsubstituted or substituted C3-C 10 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 Heterocyclic group. In some embodiments, X3 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0143] 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 Heterocyclic group. In some embodiments, each L1 is independently an unsubstituted or substituted aryl group. In some embodiments, each L1 is independently an unsubstituted or substituted heterocyclic group. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C group. 10 Sub-heterocyclic group.

[0144] In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; or unsubstituted or substituted C1-C... 10 Heterocyclic group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, each R is independently an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Carboxylic esters. In some embodiments, each R is independently an unsubstituted or substituted C1-C ester. 10 Alkyl ketones. In some embodiments, each R is independently an unsubstituted or substituted C1-C ketone. 10 Alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl group. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group.

[0145] In some embodiments, R4 is any 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'.

[0146] In some embodiments, each R' is independently an 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 group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10Heterocyclic group; or unsubstituted or substituted C1-C 10 Heterocyclic group (C1-C) 10 Alkyl group). In some embodiments, each R' is independently an unsubstituted or substituted C1-C alkyl group. 10 Alkyl group. In some embodiments, each R' is independently an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, each R' is independently an unsubstituted or substituted C3-C alkyl group. 10 cycloalkyl (C1-C) 10 Alkyl group). In some embodiments, each R' is independently an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, each R' is independently an unsubstituted or substituted C1-C group. 10 Carboxylic esters. In some embodiments, each R' is independently an unsubstituted or substituted C1-C ester. 10 Alkyl ketones. In some embodiments, each R' is independently an unsubstituted or substituted C1-C ketone. 10 Alkyl ether. In some embodiments, each R' is independently an unsubstituted or substituted aryl group. In some embodiments, each R' is independently an unsubstituted or substituted heteroaryl group. In some embodiments, each R' is independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group. In some embodiments, each R' is independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group (C1-C) 10 alkyl).

[0147] In some embodiments, R5 is 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 Heterocyclic group. In some embodiments, R5 is an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, R5 is an unsubstituted or substituted C3-C group. 10 Cycloalkyl. 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-C group. 10 Heterocyclic group.

[0148] 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 a bond. 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'; and R' is unsubstituted or substituted Cl-C. 10 Alkyl or unsubstituted or substituted C3-C 10 Cycloalkyl. In some embodiments, R5 is an unsubstituted or substituted C1-C alkyl group. 10 alkyl.

[0149] On the one hand, a compound of formula (IV), or an enantiomer, an enantiomeric mixture, a diastereomer, a diastereomeric mixture, or a pharmaceutically acceptable salt thereof, is provided:

[0150]

[0151] in

[0152] n1 and n2 are each independently 0-15;

[0153] R1 and R2 are each independently OH, H, halogen, 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 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers;

[0154] 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, 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 Cycloalkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, unsubstituted or substituted C1-C 10A heterocyclic group or an unsubstituted or substituted peptide comprising 1-10 natural amino acids;

[0155] Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C. 10 Sub-heterocyclic groups;

[0156] Each L2 is independently an unsubstituted or substituted C1-C 10 Alkylene;

[0157] Each R is independently a C1-C that is either unsubstituted or substituted. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or unsubstituted or substituted C1-C groups. 10 Heterocyclic groups; and

[0158] A represents unsubstituted or substituted C3-C. 15 Cycloalkyl, unsubstituted or substituted C1-C 15 Heterocyclic groups, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or oligosaccharides comprising 3 to 15 identical or different monosaccharides.

[0159] 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.

[0160] 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.

[0161] In some embodiments, R1 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ether. In some embodiments, R1 is OH. In some embodiments, R1 is hydrogen. In some embodiments, R1 is a halogroup. In some embodiments, R1 is an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, R1 is an unsubstituted or substituted C3-C alkyl group. 10 Cycloalkyl. In some embodiments, R1 is an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, R1 is an unsubstituted or substituted C1-C group. 10 Carboxylic ester. In some embodiments, R1 is an unsubstituted or substituted C1-C ester. 10 Alkyl ketone. In some embodiments, R1 is an unsubstituted or substituted C1-C ketone. 10 Alkyl ethers.

[0162] In some embodiments, R2 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C10 Alkyl ether. In some embodiments, R2 is OH. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a halogroup. In some embodiments, R2 is an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, R2 is an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, R2 is an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, R2 is an unsubstituted or substituted C1-C group. 10 Carboxylic ester. In some embodiments, R2 is an unsubstituted or substituted C1-C ester. 10 Alkyl ketone. In some embodiments, R2 is an unsubstituted or substituted C1-C ketone. 10 Alkyl ethers.

[0163] In some embodiments, X1 is any of the following: a bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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 Alkylene. In some embodiments, X1 is an unsubstituted or substituted C3-C 10 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 Heterocyclic group. In some embodiments, X1 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0164] In some embodiments, X2 is any of the following: a bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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 Alkylene. In some embodiments, X2 is an unsubstituted or substituted C3-C 10 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 Heterocyclic group. In some embodiments, X2 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0165] In some embodiments, X3 is any of the following: a bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural 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 Alkylene. In some embodiments, X3 is an unsubstituted or substituted C3-C 10 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 Heterocyclic group. In some embodiments, X3 is an unsubstituted or substituted peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 natural amino acids.

[0166] 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 Heterocyclic group. In some embodiments, each L1 is independently an unsubstituted or substituted aryl group. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C group. 10 Sub-heterocyclic group.

[0167] In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; or unsubstituted or substituted C1-C... 10 Heterocyclic group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, each R is independently an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Carboxylic esters. In some embodiments, each R is independently an unsubstituted or substituted C1-C ester. 10 Alkyl ketones. In some embodiments, each R is independently an unsubstituted or substituted C1-C ketone. 10 Alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl group. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group.

[0168] In some embodiments, A is unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 15 Heterocyclic groups; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; and oligosaccharides comprising 3 to 15 identical or different monosaccharides. In some embodiments, A is an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, A is an unsubstituted or substituted C1-C alkyl group. 15 Heterocyclic group. In some embodiments, A is an unsubstituted or substituted aryl group. In some embodiments, A is an unsubstituted or substituted heteroaryl group. In some embodiments, the unsubstituted or substituted heteroaryl group is an unsubstituted or substituted quinolinyl group or an unsubstituted or substituted acridine group. In some embodiments, A is an oligosaccharide comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 identical or different monosaccharides.

[0169] In some embodiments of Formula IV, n1 and n2 are each independently 0, 1, 2, 3, or 4. In some embodiments, R1 and R2 are each hydrogen. In some embodiments, X1 is a bond, (C=O)-L1, L1-(C=O) and O; and L1 is unsubstituted or substituted C1-C. 10 Heterocyclic group. 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 group.

[0170] On the one hand, a compound of formula (V), or an enantiomer, an enantiomeric mixture, a diastereomer, a diastereomeric mixture, or a pharmaceutically acceptable salt thereof, is provided:

[0171]

[0172] in

[0173] n, n1, and n2 are each independently between 0 and 15;

[0174] R1 and R2 are each independently OH, H, halogen, 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 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers;

[0175] X1, X2, and X4 are each independently a bond, 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 Cycloalkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, unsubstituted or substituted C1-C 10 A heterocyclic group or an unsubstituted or substituted peptide comprising 1-10 natural amino acids;

[0176] Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C. 10 Sub-heterocyclic groups;

[0177] Each L2 is independently an unsubstituted or substituted C1-C 10 Alkylene;

[0178] Each R is independently a C1-C that is either unsubstituted or substituted. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or unsubstituted or substituted C1-C groups. 10 Heterocyclic groups;

[0179] X4 is attached to any one of R3, R4, R5, R6, and R7, and the remaining R3, R4, R5, R6, and R7 not attached to X4 are each independently H, OH, O(CO)NH2, a halogen, an unsubstituted or substituted amino group, or an unsubstituted or substituted C1-C group. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, unsubstituted or substituted C1-C 10 Heterocyclic groups, unsubstituted or substituted peptides comprising 1-10 amino acids, or glycosidic bonds formed with natural monosaccharides;

[0180] R8 is OR 10 Or oligopeptide bonds formed with natural amino acids;

[0181] R 10 For unsubstituted or substituted C1-C 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or unsubstituted or substituted C1-C groups. 10 Heterocyclic groups; and

[0182] R9 is a side chain of H or a natural amino acid.

[0183] 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.

[0184] In some embodiments, R1 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ethers.

[0185] In some embodiments, R2 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ethers.

[0186] In some embodiments, X1 is any of the following: bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural amino acids.

[0187] In some embodiments, X2 is any of the following: a bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural amino acids.

[0188] In some embodiments, X4 is any of the following: bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural amino acids.

[0189] 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 Heterocyclic group. In some embodiments, each L1 is independently an unsubstituted or substituted aryl group. In some embodiments, each L1 is independently an unsubstituted or substituted heterocyclic group. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C group. 10 Sub-heterocyclic group.

[0190] In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; or unsubstituted or substituted C1-C... 10 Heterocyclic group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, each R is independently an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Carboxylic esters. In some embodiments, each R is independently an unsubstituted or substituted C1-C ester. 10 Alkyl ketones. In some embodiments, each R is independently an unsubstituted or substituted C1-C ketone. 10 Alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl group. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group.

[0191] In some embodiments, X4 is attached to R3; and R4, R5, R6, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; unsubstituted or substituted peptides comprising 1-10 amino acids; and forming glycosidic bonds with natural monosaccharides.

[0192] In some embodiments, X4 is attached to R4; and R3, R5, R6, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; unsubstituted or substituted peptides comprising 1-10 amino acids; and forming glycosidic bonds with natural monosaccharides.

[0193] In some embodiments, X4 is attached to R5; and R3, R4, R6, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; unsubstituted or substituted peptides comprising 1-10 amino acids; and forming glycosidic bonds with natural monosaccharides.

[0194] In some embodiments, X4 is attached to R6; and R3, R4, R5, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; unsubstituted or substituted peptides comprising 1-10 amino acids; and forming glycosidic bonds with natural monosaccharides.

[0195] In some embodiments, X4 is attached to R7; and R3, R4, R5, and R6 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; unsubstituted or substituted peptides comprising 1-10 amino acids; and forming glycosidic bonds with natural monosaccharides.

[0196] In some embodiments, R8 is OR 10 Or an oligopeptide bond formed with natural amino acids. In some embodiments, R8 is OR 10 In some embodiments, R8 is an oligopeptide bond formed with a natural amino acid.

[0197] In some embodiments, R 10 For unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; or unsubstituted or substituted C1-C... 10 Heterocyclic group. In some embodiments, R 10 For unsubstituted or substituted C1-C 10 Alkyl group. In some embodiments, R 10 For unsubstituted or substituted C3-C 10 Cycloalkyl. In some embodiments, R 10 For unsubstituted or substituted C1-C 10 Acyl group. In some embodiments, R 10 For unsubstituted or substituted C1-C 10 Carboxylate. In some embodiments, R 10 For unsubstituted or substituted C1-C 10 Alkyl ketones. In some embodiments, R 10 For unsubstituted or substituted C1-C 10 Alkyl ethers. In some embodiments, R 10 It is an unsubstituted or substituted aryl group. In some embodiments, R 10 It is an unsubstituted or substituted heteroaryl group. In some embodiments, R 10 For unsubstituted or substituted C1-C 10 Heterocyclic group.

[0198] 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.

[0199] On the one hand, a compound of formula (VI), or an enantiomer, an enantiomeric mixture, a diastereomer, a diastereomeric mixture, or a pharmaceutically acceptable salt thereof, is provided:

[0200]

[0201] in

[0202] n1 and n2 are each independently 0-15;

[0203] R1 and R2 are each independently OH, H, halogen, 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 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers;

[0204] 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, 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 Cycloalkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, unsubstituted or substituted C1-C 10 A heterocyclic group or an unsubstituted or substituted peptide comprising 1-10 natural amino acids;

[0205] Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C. 10 Sub-heterocyclic groups;

[0206] Each L2 is independently an unsubstituted or substituted C1-C 10 Alkylene;

[0207] Each R is independently a C1-C that is either unsubstituted or substituted. 10 Alkyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or unsubstituted or substituted C1-C groups. 10 Heterocyclic groups;

[0208] X3 is attached to any one of R3, R4, R5, R6, and R7, and the remaining R3, R4, R5, R6, and R7 not attached to X3 are each independently H, OH, O(CO)NH2, a halogen, an unsubstituted or substituted amino group, or an unsubstituted or substituted C1-C group. 10 Alkyl, unsubstituted or substituted C3-C 10Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, unsubstituted or substituted C1-C 10 Heterocyclic groups, unsubstituted or substituted peptides comprising 1-10 amino acids, or glycosidic bonds formed with natural monosaccharides; and

[0209] A1 represents unsubstituted or substituted C3-C. 15 Cycloalkyl, unsubstituted or substituted C1-C 15 Heterocyclic, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl or

[0210]

[0211] 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.

[0212] In some embodiments, R1 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ethers.

[0213] In some embodiments, R2 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ethers.

[0214] In some embodiments, X1 is any of the following: bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural amino acids.

[0215] In some embodiments, X2 is any of the following: a bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural amino acids.

[0216] In some embodiments, X3 is any of the following: bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural amino acids.

[0217] 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 Heterocyclic group. In some embodiments, each L1 is independently an unsubstituted or substituted aryl group. In some embodiments, each L1 is independently an unsubstituted or substituted heterocyclic group. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C group. 10 Sub-heterocyclic group.

[0218] In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; or unsubstituted or substituted C1-C... 10 Heterocyclic group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, each R is independently an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Carboxylic esters. In some embodiments, each R is independently an unsubstituted or substituted C1-C ester. 10 Alkyl ketones. In some embodiments, each R is independently an unsubstituted or substituted C1-C ketone. 10 Alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl group. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group.

[0219] In some embodiments, X3 is attached to R3; and R4, R5, R6, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; unsubstituted or substituted peptides comprising 1-10 amino acids; and forming glycosidic bonds with natural monosaccharides.

[0220] In some embodiments, X3 is attached to R4; and R3, R5, R6, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; unsubstituted or substituted peptides comprising 1-10 amino acids; and forming glycosidic bonds with natural monosaccharides.

[0221] In some embodiments, X3 is attached to R5; and R3, R4, R6, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; unsubstituted or substituted peptides comprising 1-10 amino acids; and forming glycosidic bonds with natural monosaccharides.

[0222] In some embodiments, X3 is attached to R6; and R3, R4, R5, and R7 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; unsubstituted or substituted peptides comprising 1-10 amino acids; and forming glycosidic bonds with natural monosaccharides.

[0223] In some embodiments, X3 is attached to R7; and R3, R4, R5, and R6 are each independently any of the following: H; OH; O(CO)NH2; a halogen group; an amino group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; unsubstituted or substituted C1-C 10 Heterocyclic group; unsubstituted or substituted peptides comprising 1-10 amino acids; and forming glycosidic bonds with natural monosaccharides.

[0224] In some embodiments, A1 is unsubstituted or substituted C3-C 15 Cycloalkyl; unsubstituted or substituted C1-C 15 Heterocyclic group; unsubstituted or substituted aryl group; unsubstituted or substituted heteroaryl group; or In some embodiments, A1 is unsubstituted or substituted C3-C 15 Cycloalkyl. In some embodiments, A1 is an unsubstituted or substituted C1-C 15 Heterocyclic group. In some embodiments, A1 is an unsubstituted or substituted aryl group. In some embodiments, A1 is an unsubstituted or substituted heteroaryl group. In some embodiments, A1 is...

[0225] On the one hand, a compound of formula (VII), or an enantiomer, an enantiomeric mixture, a diastereomer, a diastereomeric mixture, or a pharmaceutically acceptable salt thereof, is provided:

[0226]

[0227] in

[0228] n1 and n2 are each independently 0-15;

[0229] R1 and R2 are each independently OH, H, halogen, 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 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers;

[0230] 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, 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 Cycloalkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, unsubstituted or substituted C1-C 10 A heterocyclic group or an unsubstituted or substituted peptide comprising 1-10 natural amino acids;

[0231] Each L1 is independently an unsubstituted or substituted arylene, an unsubstituted or substituted heteroarylene, or an unsubstituted or substituted C1-C. 10 Sub-heterocyclic groups;

[0232] Each L2 is independently an unsubstituted or substituted C1-C 10 Alkylene;

[0233] Each R is independently a C1-C that is either unsubstituted or substituted. 10 Alkyl, unsubstituted or substituted C3-C10 Cycloalkyl, unsubstituted or substituted C1-C 10 Acyl, unsubstituted or substituted C1-C 10 Carboxylic esters, unsubstituted or substituted C1-C 10 Alkyl ketones or unsubstituted or substituted C1-C 10 Alkyl ethers, unsubstituted or substituted aryl groups, unsubstituted or substituted heteroaryl groups, or unsubstituted or substituted C1-C groups. 10 Heterocyclic groups; and

[0234] A2 is a linear or stellate poly(d-glutamic acid), poly(1-glutamic acid), or poly(dl-glutamic acid).

[0235] 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.

[0236] In some embodiments, R1 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ethers.

[0237] In some embodiments, R2 is OH; hydrogen; a halide group; an unsubstituted or substituted C1-C group. 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; or unsubstituted or substituted C1-C 10 Alkyl ethers.

[0238] In some embodiments, X1 is any of the following: bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural amino acids.

[0239] In some embodiments, X2 is any of the following: a bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural amino acids.

[0240] In some embodiments, X3 is any of the following: bond; 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 Cycloalkylene; unsubstituted or substituted arylene; unsubstituted or substituted heteroarylene; unsubstituted or substituted C1-C 10 Heterocyclic groups; and unsubstituted or substituted peptides comprising 1-10 natural amino acids.

[0241] 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 Heterocyclic group. In some embodiments, each L1 is independently an unsubstituted or substituted aryl group. In some embodiments, each L1 is independently an unsubstituted or substituted heterocyclic group. In some embodiments, each L1 is independently an unsubstituted or substituted C1-C group. 10 Sub-heterocyclic group.

[0242] In some embodiments, each R is independently an unsubstituted or substituted C1-C 10 Alkyl; unsubstituted or substituted C3-C 10 Cycloalkyl; unsubstituted or substituted C1-C 10 Acyl group; unsubstituted or substituted C1-C 10 Carboxylic esters; unsubstituted or substituted C1-C 10 Alkyl ketones; unsubstituted or substituted C1-C 10 Alkyl ethers; unsubstituted or substituted aryl groups; unsubstituted or substituted heteroaryl groups; or unsubstituted or substituted C1-C... 10 Heterocyclic group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Alkyl group. In some embodiments, each R is independently an unsubstituted or substituted C3-C group. 10 Cycloalkyl. In some embodiments, each R is independently an unsubstituted or substituted C1-C alkyl group. 10 Acyl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Carboxylic esters. In some embodiments, each R is independently an unsubstituted or substituted C1-C ester. 10 Alkyl ketones. In some embodiments, each R is independently an unsubstituted or substituted C1-C ketone. 10 Alkyl ether. In some embodiments, each R is independently an unsubstituted or substituted aryl group. In some embodiments, each R is independently an unsubstituted or substituted heteroaryl group. In some embodiments, each R is independently an unsubstituted or substituted C1-C group. 10 Heterocyclic group.

[0243] In some embodiments, A2 is a linear or stellate poly(d-glutamic acid); a linear or stellate poly(1-glutamic acid); or a linear or stellate poly(dl-glutamic acid). In some embodiments, A2 is a linear or stellate poly(d-glutamic acid). In some embodiments, A2 is a linear or stellate poly(1-glutamic acid). In some embodiments, A2 is a linear or stellate poly(dl-glutamic acid).

[0244] In any of the embodiments disclosed herein, the compound is any one of the compounds disclosed in any of the following tables.

[0245] Table 1.

[0246]

[0247]

[0248]

[0249] Table 2.

[0250]

[0251]

[0252]

[0253] Table 3.

[0254]

[0255]

[0256] Table 4.

[0257]

[0258]

[0259] Table 5.

[0260]

[0261]

[0262] Table 6.

[0263]

[0264]

[0265] In some embodiments, this document provides enantiomers, enantiomeric mixtures, diastereomers, diastereomeric mixtures, or pharmaceutically acceptable salts of the compounds described in any of the tables disclosed herein.

[0266] On the one hand, 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 also included within the scope of this disclosure.

[0267] In some embodiments, the compounds described herein have one or more stereocenters, and each stereocenter exists independently in either an R or S configuration. The compounds presented herein comprise all diastereomers, enantiomers, transisomers, and epiomers, as well as suitable mixtures thereof.

[0268] Synthetic compounds

[0269] The compounds described herein were synthesized using standard synthetic techniques or by methods known in the art in combination with those described herein.

[0270] Unless otherwise specified, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used.

[0271] The compounds were prepared using standard organic chemistry techniques known to those skilled in the art. Alternative reaction conditions, such as variations in solvent, reaction temperature, reaction time, and different chemical reagents and other reaction conditions, can be used to transform the synthesis described herein. Starting materials are available from commercial sources or can be readily prepared.

[0272] The compounds described herein can be prepared by the general synthetic routes described in the following schemes. Schemes A1-A4 each illustrate a non-limiting general synthetic route for the preparation of the compounds described herein.

[0273] Option A1

[0274]

[0275] Option A2

[0276]

[0277] Option A3

[0278]

[0279] Option A4

[0280]

[0281] Pharmaceutical Composition

[0282] On one hand, this document describes a pharmaceutical composition comprising the compound described herein, or an 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, delay agents, organic solvents, suspending agents, isotonic agents, buffers, emulsifiers, stabilizers, and preservatives.

[0283] In some embodiments, the pharmaceutical composition is formulated for administration to mammals via intravenous, subcutaneous, oral, inhalation, nasal, skin, or ocular administration.

[0284] In some embodiments, the pharmaceutical composition is in the form of tablets, pills, capsules, liquids, suspensions, gels, dispersants, solutions, emulsions, ointments, or lotions. In some embodiments, the pharmaceutical composition is in the form of tablets, pills, or capsules.

[0285] Treatment

[0286] This article also provides a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of any of the compounds disclosed herein, enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, or pharmaceutically acceptable salts thereof.

[0287] In some embodiments, the cancer is hepatocellular carcinoma (HCC), lung cancer, breast cancer, pancreatic cancer, biliary tract cancer, colorectal cancer, or glioblastoma. In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is biliary tract cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is glioblastoma.

[0288] The term "cancer" should refer to the proliferation of tumor cells with a distinctive characteristic of loss of normal control, resulting in unregulated growth, lack of differentiation, localized tissue invasion, and / or metastasis. As used herein, a tumor includes, but is not limited to, morphologically irregular cells in the tissues of a subject or host, and pathological proliferation of cells in the subject's tissues compared to normal proliferation in tissues of the same type. Additionally, a tumor includes invasive or non-invasive benign tumors and malignant tumors (e.g., colon tumors). Malignant tumors are distinguished from benign tumors by exhibiting a greater degree of dysplasia or loss of cell differentiation and orientation, and by possessing invasive and metastatic characteristics. The term cancer, also within this context, includes drug-resistant cancer and multidrug-resistant cancer. Examples of tumors or tumor formation from which the target cells of the present invention may originate include, but are not limited to, cancers (e.g., squamous cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma), specifically those of the bladder, bone, intestine, breast, cervix, colon (rectum), esophagus, head, kidney, liver, lung, nasopharynx, neck, ovary, pancreas, prostate, and stomach; leukemias such as acute myeloid leukemia, acute lymphoblastic leukemia, acute promyelocytic leukemia (APL), acute... T-cell lymphoblastic leukemia, adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, neutrophilic leukemia, and stem cell leukemia; benign and malignant lymphomas, specifically Burkitt's lymphoma, non-Hodgkin's lymphoma, and B-cell lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, specifically Ewing's sarcoma, angiosarcoma, and Kaposi's sarcoma. Tumors of the central nervous system include: sarcoma, liposarcoma, myoma, peripheral neuroepithelial tumor, and synovial sarcoma; glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioma, ganglioglioma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma, and schwannoma; germline tumors (e.g., colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer (e.g., small cell lung cancer, mixed small cell and non-small cell lung cancer, pleural mesothelioma, including metastatic pleural mesothelioma, small cell lung cancer, and non-small cell lung cancer), ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, and melanoma); mixed tumors, specifically carcinosarcoma and Hodgkin's disease; and tumors of mixed origin, such as Wilms' tumor and teratoma.The envisioned cancers also include, but are not limited to, ovarian cancer, breast cancer, colon cancer, head and neck cancer, medulloblastoma, and B-cell lymphoma.

[0289] This article also provides a method for treating a disease or condition associated with immune regulation and / or inflammation in a subject of need, the method comprising administering to the subject a therapeutically effective amount of at least one of the disclosed compounds, enantiomers, enantiomer mixtures, diastereomers, diastereomer mixtures, or pharmaceutically acceptable salts thereof.

[0290] In some embodiments, the disease or condition is associated with an inflammatory disease and / or an autoimmune disease. Examples of such diseases or conditions associated with inflammatory diseases and / or autoimmune diseases 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, liver fibrosis, asthma, acute lung injury, pulmonary hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis, or psoriasis. In some embodiments, the disease or condition associated with an inflammatory disease and / or autoimmune disease is any of the following: membranous nephropathy (MN), lupus nephritis, systemic lupus erythematosus, kidney transplantation, renal fibrosis, inflammatory bowel disease, Crohn's disease, intestinal fibrosis, liver fibrosis, asthma, acute lung injury, pulmonary hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis, or psoriasis.

[0291] definition

[0292] Various embodiments are described below. It should be noted that the specific embodiments are not intended to be an exhaustive description or a limitation on the broader aspects discussed herein. One aspect described in connection with a particular embodiment is not necessarily limited to the described embodiment and can be practiced with any other embodiment.

[0293] As used herein, “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. Where there is a use of a term that is unclear to those skilled in the art, “about” will mean up to ±10% of a particular item, taking into account the context in which it is used.

[0294] Unless otherwise specified herein or obviously contradicted by the context, the terms “a,” “an,” and “the,” and similar pronouns used in the context of describing elements (particularly in the context of the claims) should be interpreted as encompassing both the singular and plural. Unless otherwise specified herein, the descriptions of value ranges herein are intended only as a shorthand method of individually referring to each individual value falling within the range, and each individual value is incorporated into this specification as if individually described herein. Unless otherwise specified herein or obviously contradicted by the context, all methods described herein can be performed in any suitable order. Unless otherwise stated, the use of any and all example or exemplary language (e.g., “such”) provided herein is intended only to better illustrate the embodiments and does not constitute a limitation on the scope of the claims. None of the language in this specification should be construed as indicating that any unclaimed element is essential.

[0295] As used in this article, C1-C x Includes C1-C2, C1-C3...C1-C x By way of example only, a group designated as "C1-C4" indicates the presence of one to four carbon atoms in the portion, that is, a group containing 1, 2, 3, or 4 carbon atoms. Therefore, by way of example only, "C1-C4 alkyl" indicates the presence of one to four carbon atoms in an alkyl group, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0296] When a substituent is specified by its conventional chemical formula (written from left to right), it equally covers the chemically identical substituents produced when the structure is written from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0297] "alkyl" refers to an aliphatic hydrocarbon, either alone or as part of another molecule. The alkyl portion can be branched or straight-chain. In some embodiments, "alkyl" has 1 to 20 carbon atoms, i.e., C1-C2. 20 Alkyl. Whenever it appears, a numerical range such as “1 to 20” refers to every integer within a given range; for example, “1 to 20 carbon atoms” means that an alkyl group consists of 1, 2, 3, 4, 5, 6 carbon atoms, etc., up to 20 carbon atoms (inclusive). However, this definition also covers the occurrence of the term “alkyl” where no numerical range is specified. In some embodiments, the alkyl group is C1-C6 carbon. On one hand, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, and hexyl.

[0298] "alkylene" refers to a divalent alkyl group. Any of the monovalent alkyl groups mentioned above can be an alkylene group formed by extracting a second hydrogen atom from an alkyl group. In some embodiments, the alkylene group is C1-C6. 20 Alkylene. In other embodiments, the alkylene is C1-C. 10 Alkylene. In other embodiments, the alkylene is C1-C6 alkylene. In some embodiments, the alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene comprises one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene comprises two carbon atoms (e.g., C2 alkylene). In other embodiments, the alkylene comprises two to four carbon atoms (e.g., C2-C4 alkylene). Typical alkylenes include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0299] The term "alkenyl" refers to an alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl group. In some embodiments, the alkenyl group 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.

[0300] The term "alkynyl" refers to an alkyl group having at least one carbon-carbon triple bond. In one embodiment, the alkynyl group has the formula -C≡CR, where R represents the remainder of the alkynyl group. In some embodiments, R is H or an alkyl group. In some embodiments, the alkynyl group is selected from ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. Non-limiting examples of the alkynyl group include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0301] "Alkoxy" refers to -O (alkyl), where alkyl is as defined herein.

[0302] The term "alkylamine" refers to -N (alkyl) x Hy , where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

[0303] 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-ring polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups.

[0304] The term "carbocyclic" or "carbocyclic" refers to a ring or ring system in which the main chain forming the ring consists entirely of carbon atoms. Therefore, the term distinguishes a carbocyclic ring from a "heterocyclic ring" or "heterocycle" in which the main ring chain contains at least one atom different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocyclic ring is aromatic. In some embodiments, both rings of a bicyclic carbocyclic ring are aromatic. The carbocyclic ring comprises cycloalkyl and aryl groups.

[0305] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. On one hand, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is C6-C. 10 Aryl group. Depending on the structure, aryl groups can be monoradical or diradical (i.e., arylene).

[0306] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic nonaromatic group, wherein each atom in the ring-forming atoms (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic compound or a bridged compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the attachment point is located at a carbon atom of a nonaromatic ring. The cycloalkyl comprises a group 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, "cycloalkyl" is a monocyclic cycloalkyl. The cycloalkyl comprises, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc.

[0307] "Carbocycloalkyl" refers to the formula -R c - A carbocyclic group, wherein R cIt is an alkylene chain as defined above. The alkylene chain and carbocyclic group are optionally substituted as defined above.

[0308] The term "halogen" or alternatively "halogen" or "halide" refers to fluorine, chlorine, bromine, or iodine. In some embodiments, the halogen is fluorine, chlorine, or bromine.

[0309] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. On the other hand, fluoroalkyl groups are C1-C6 fluoroalkyl groups.

[0310] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, 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, etc.

[0311] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. In one aspect, heteroalkyl groups are C1-C6 heteroalkyl groups.

[0312] The term "heterocyclic" or "heterocyclic" refers to a heteroaromatic ring (also referred to as a heteroaryl group) and a heterocyclic alkyl ring (also referred to as a heteroalicyclic group) containing one to four heteroatoms in the ring, wherein each heteroatom in the ring is selected from O, S, and N, and wherein 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, the heterocycle is a monocyclic compound, a bicyclic compound, a polycyclic compound, a spirocyclic compound, or a bridged compound. Non-aromatic heterocyclic groups (also referred to as heterocyclic alkyl groups) comprise rings having 3 to 10 or 3 to 20 atoms in their ring system, and aromatic heterocyclic groups comprise rings having 5 to 10 atoms in their ring system. Heterocyclic groups comprise benzofused ring systems. Examples of non-aromatic heterocyclic groups include pyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinone, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazine, aziridinyl, aziridine, aziridine, oxaziridine, thioheptanyl, high-piperidinyl, oxaziridine, thioheptanyl, oxaziridine, diaziridine, thioaziridine, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxalyl, 1,3-dioxolaneyl, pyrazolinyl, dithiaylyl, and dioxalyl. Thiocyclopentyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, indololin-2-one, isoindololin-1-one, isoindololin-1,3-dione, 3,4-dihydroisoquinolin-1(2H)-one, 3,4-dihydroquinolin-2(1H)-one, isoindololin-1,3-dithio, benzo[d]oxazol-2(3H)-one, 1H-benzo[d]imidazo-2(3H)-one, benzo[d]thiazo-2(3H)-one, and quinazinyl. Examples of aromatic heterocyclic groups include pyridinyl, imidazole, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indoleyl, benzimidazolyl, benzofuranyl, cinnamyl, indazole, indoleazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindoleyl, pteridinyl, purineyl, oxadiazolyl, thiadiazolyl, furanyl, benzofuranyl, benzothiophene, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphridinyl, and furanpyridinyl. Where possible, the aforementioned groups are C-attached (or C-linked) or N-attached. For example, groups derived from pyrrole can be pyrrole-1-yl (N-attached) or pyrrole-3-yl (C-attached).Further, the 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). The heterocyclic group comprises a benzofused ring system. The non-aromatic heterocycle is optionally substituted with one or two oxo (=O) moieties, such as pyrrolidone-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0313] The term "heterocyclic group" refers to any monovalent group formed by removing a hydrogen atom from any ring atom of a heterocyclic compound as defined herein. Depending on the structure, a heterocyclic group can be a monoradical or a diradical (i.e., a subheterocyclic group).

[0314] The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group containing one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic and bicyclic heteroaryl groups. Monocyclic heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, pyridazinyl, triazinyl, oxadiazolyl, thiazolyl, and furazolidone. Bicyclic heteroaryl groups include indoleazine, indole, benzofuran, benzothiophene, inbenzoazole, imidazolyl, purine, quinazine, quinoline, isoquinoline, cinnamoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthidine, and pteridine. In some embodiments, the heteroaryl group contains 0-4 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group is C1-C. 10 Heteroaryl groups. In some embodiments, the monocyclic heteroaryl group is a C1-C5 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5- or 6-membered heteroaryl group. In some embodiments, the bicyclic heteroaryl group is a C6-C9 heteroaryl group. Depending on the structure, the heteroaryl group is a monoradical or a diradical (i.e., a heteroaryl group).

[0315] The term "heterocyclic alkyl" or "heterocyclic alicyclic" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl group is fused with an aryl or heteroaryl group. In some embodiments, the heterocyclic alkyl group is oxazolidinone, pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, piperidin-2-one, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-diketone, pyrrolidine-ketone, imidazoalkyl, imidazoalkyl-2-one, or thiazoalkyl-2-one. The term heterocyclic alicyclic also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. On one hand, the heterocyclic alkyl group is C1-C 20 Heterocyclic alkyl groups. On the one hand, heterocyclic alkyl groups are C1-C60. 14 Heterocyclic alkyl groups. On the one hand, heterocyclic alkyl groups are C1-C60. 10 Heterocyclic alkyl groups. On the one hand, heterocyclic alkyl groups are C2-C. 14 Heterocyclic alkyl groups. On the one hand, heterocyclic alkyl groups are C2-C. 10 Heterocyclic alkyl groups. On the other hand, heterocyclic alkyl groups are C4-C. 10 Heterocyclic alkyl groups. On the other hand, heterocyclic alkyl groups are C5-C6. 10 Heterocyclic alkyl groups. In some embodiments, the heterocyclic alkyl group contains 0-2 nitrogen atoms in the ring. In some embodiments, the heterocyclic alkyl group contains 0-2 nitrogen atoms, 0-2 oxygen atoms, and 0-1 sulfur atoms in the ring. Depending on the structure, the heteroaryl group is a monoradical or a diradical (i.e., a heteroarylene).

[0316] "Heterocyclic alkyl" refers to the formula -R c - A heterocyclic group, wherein R c The heterocyclic group is an alkylene chain as defined above. If the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic alkyl group is optionally substituted as defined above for the alkylene chain. The heterocyclic portion of the heterocyclic alkyl group is optionally substituted as defined above for the heterocyclic group.

[0317] The term "bond" or "single bond" refers to a chemical bond between two atoms, or, when the atoms connected by a bond are considered part of a larger substructure, a chemical bond between two parts. On the one hand, when the group referred to herein is a bond, the cited group is absent, thus allowing bonds to form between the remaining identified groups.

[0318] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is generally a recognized chemical entity that is embedded in or attached to a molecule.

[0319] The terms “optionally substituted” or “substituted” mean that the mentioned group is optionally substituted by one or more other groups, which are individually and independently selected from the following: D, halogen, -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, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some other embodiments, optional substituents are independently selected from D, halogens, -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 substituents are independently selected from D, halogens, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituted group is replaced by one or both of the aforementioned groups. In some embodiments, the optional substituents on the aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0320] As used herein, the term “acceptable” means, with respect to formulations, compositions or ingredients, that there is no lasting harmful effect on the overall health of the subject being treated.

[0321] As used herein, the terms “administer,” “administering,” “administration,” etc., refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), local administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be employed in conjunction with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0322] As used herein, the terms “co-administration” and the like are intended to cover the administration of a chosen therapeutic agent to a single patient and are intended to include treatment regimens in which the agent is administered via the same or different routes of administration or at the same or different times.

[0323] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an adequate amount of a drug or compound administered that will, to some extent, reduce one or more symptoms of the disease or condition being treated. Results include reduction and / or alleviation of signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising the compounds disclosed herein required to achieve a clinically significant reduction in the symptoms of a disease. Appropriate "effective" amounts may be optionally determined in any individual case using techniques such as dose escalation studies.

[0324] As used herein, the terms “enhance” or “enhancing” mean to increase or prolong the potency or duration of a desired effect. Therefore, in relation to enhancing the effect of a therapeutic agent, the term “enhancement” refers to the ability to increase or prolong the effect of another therapeutic agent on the system in terms of potency or duration. As used herein, “enhancing effective amount” refers to an amount sufficient to enhance the effect of another therapeutic agent in the desired system.

[0325] The terms “reagent kit” and “product” are used as synonyms.

[0326] As used in this article, the term "inhibition" refers to the partial or complete elimination of a potential effect, while an inhibitor is a compound that has the ability to inhibit.

[0327] The term "pharmaceutically acceptable salt" refers to a form of therapeutic agent consisting of a combination of a cationic form of the therapeutic agent and a suitable anion, or, in alternative embodiments, a combination of an anionic form of the therapeutic agent and a suitable cation.

[0328] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting the compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt". In some embodiments, the compound described herein (i.e., in its free base form) is basic and reacts with an organic or inorganic acid. 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-naphtholic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetaminobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); caprylic acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (caprylic acid); carbonic acid; cinnamic acid; citric acid; cyclohexylaminosulfonic acid; dodecyl sulfate; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactosic acid; gentian acid. ; glucoheponic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutamate; 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; pyruvic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanate; toluenesulfonic acid (p); and undecenoic acid.

[0329] In some embodiments, the compounds described herein are acidic and react with bases. In such cases, the acidic proton of the compounds described herein is replaced by a metal ion, such as lithium, sodium, potassium, magnesium, calcium, or aluminum ions. In some cases, the compounds described herein coordinate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucosamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids, such as, but not limited to, arginine and lysine. Acceptable inorganic bases for forming salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, etc. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucosamine, or ammonium salts.

[0330] It should be understood that references to pharmaceutically acceptable salts include solvation forms. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of solvent and is formed during the separation or purification of the compound using a pharmaceutically acceptable solvent, such as water, ethanol, etc. A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is an alcohol. The solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. Additionally, the compounds provided herein are optionally present in both non-solvated and solvated forms.

[0331] 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 ape and monkey species; farm animals such as cattle, horses, sheep, goats, pigs, etc.; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. On the one hand, mammals are humans.

[0332] As used herein, the terms “treat,” “treating,” or “treatment” include relieving, reducing, or improving at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing the remission of a disease or condition, reducing symptoms caused by a disease or condition, or preventing and / or treating the cessation of symptoms of a disease or condition.

[0333] The invention generally described herein will be more readily understood by referring to the following examples, which are provided by way of illustration and are not intended to limit the invention.

[0334] Unless otherwise indicated, as used above and throughout this specification, the following abbreviations should be understood to have the following meanings:

[0335] Acetyl group

[0336] AcOH (acetic acid)

[0337] Bn benzyl

[0338] DCC Dicyclohexylcarbodiimide

[0339] DCE dichloroethane

[0340] DCM dichloromethane

[0341] DIPEA or DIEA diisopropylethylamine

[0342] DMAP 4-(N,N-dimethylamino)pyridine

[0343] DMF (dimethylformamide)

[0344] DMSO (dimethyl sulfoxide)

[0345] Et Ethyl

[0346] EtOAc or EA (ethyl acetate)

[0347] HATU(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate)

[0348] HPLC (High Performance Liquid Chromatography)

[0349] Me methyl

[0350] MeOH (methanol)

[0351] MS mass spectrometry

[0352] NMR (Nuclear Magnetic Resonance)

[0353] PE petroleum ether

[0354] Room temperature

[0355] TFA (trifluoroacetic acid)

[0356] TEA Triethylamine

[0357] THF Tetrahydrofuran

[0358] Example

[0359] Example 1 – 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl)succinate (Compound 1)

[0360]

[0361] The following scheme illustrates the synthetic route for preparing the title compound.

[0362] Option 1.

[0363]

[0364] Option 2.

[0365]

[0366] Option 3.

[0367]

[0368] Preparation of (2R,3S,4R)-2-(hydroxymethyl)-3,4-dihydro-2H-pyran-3,4-diol (A2)

[0369] NaOMe (216 mg, 4.0 mmol, 0.4 equivalent) was added to a stirred solution of compound A1 (2.72 g, 10.0 mmol, 1.0 equivalent) in MeOH (20 mL) at 0 °C, and the mixture was stirred at rt. for 2 h. The reaction was quenched with NH4Cl (aqueous solution), then concentrated, the residue was absorbed with EA, washed with water and brine, and dried over Na2SO4. Concentration and purification by silica gel (PE-PE:EA = 5:1-DCM:MeOH = 20:1) gave compound A2 (1.5 mg, yield: 100%) as a colorless oil.

[0370] Preparation of (2R,3S,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran (A3)

[0371] NaH (1.8 mg, 45 mmol, 4.5 equivalents) was added to a stirred solution of compound A2 (1.5 g, 10.0 mmol, 1.0 equivalents) in DMF (50 mL) at 0 °C, and the mixture was stirred at rt. for 1 h. BnBr (7.7 mg, 45.0 mmol, 4.5 equivalents) was added, and the mixture was stirred at rt. overnight. The reaction was quenched with NH4Cl (aqueous solution), then concentrated, the residue was absorbed with EA, washed with water and brine, and dried over Na2SO4. Concentration and purification by silica gel (PE-PE:EA = 40:1-30:1) gave compound A3 (2.81 mg, yield: 68%) as a white solid.

[0372] Preparation of (4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-fluorotetrahydro-2H-pyran-2-ol (A4)

[0373] SelectFluor (2.44 g, 6.9 mmol, 1.2 equivalences) was added to a solution of compound A3 (2.39 mg, 5.75 mmol, 1.0 equivalences) in acetone (25 mL), and water (5 mL) and the resulting mixture were stirred overnight at rt. under a N2 atmosphere. The reaction was quenched with NH4Cl (aqueous solution) and then concentrated. The residue was absorbed with EA, washed with water and brine, and dried over Na2SO4. Concentration and purification by silica gel (PE-PE:EA = 20:1-10:1) provided compound A4 (2.1 mg, yield: 69%) as a colorless oil.

[0374] Preparation of (3R,4S,5R,6R)-acetic acid 4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-fluorotetrahydro-2H-pyran-2-yl ester (A6)

[0375] Ac₂O (1.9 g, 18.6 mmol, 4.0 equivalent) was added 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) at 0 °C. The mixture was stirred at rt. for 18 h. The mixture was diluted with EA, washed with water and brine, and dried over Na₂SO₄. Concentration and purification by silica gel (PE-PE:EA = 20:1-10:1) gave compound A6 (560 mg, yield: 77% total) as a colorless oil.

[0376] Preparation of (3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-fluorotetrahydro-2H-pyran-2-ol (A7)

[0377] NaOMe (10 mg, 0.17 mmol, 0.15 equivalent) was added to a stirred solution of compound A6 (560 mg, 1.13 mmol, 1.0 equivalent) in MeOH (12 mL) at 0 °C, and the mixture was stirred at rt. for 2 h. The reaction was quenched with NH4Cl (aqueous solution), then concentrated, the residue was absorbed with EA, washed with water and brine, and dried over Na2SO4. Concentration and purification by silica gel (PE-PE:EA = 5:1) gave compound A7 (390 mg, yield: 76%) as a white solid.

[0378] Preparation of (3R,4S,5R,6R)-2,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-3-fluorotetrahydro-2H-pyran (A8)

[0379] NaH (87 mg, 2.17 mmol, 1.4 equivalent) was added to a stirred solution of compound A7 (700 mg, 1.55 mmol, 1.0 equivalent) in DMF (10 mL) at 0 °C, and the mixture was stirred at rt. for 1 h. BnBr (371 mg, 2.17 mmol, 1.4 equivalent) was added, and the mixture was stirred at rt. overnight. The reaction was quenched with NH4Cl (aqueous solution), then concentrated, the residue was absorbed with EA, washed with water and brine, and dried over Na2SO4. Concentration and purification by silica gel (PE-PE:EA = 50:1-40:1) gave compound A8 (670 mg, yield: 80%) as a yellow solid.

[0380] Preparation of methyl ((2R,3R,4S,5R)-3,4,5,6-tetra(benzyloxy)tetrahydro-2H-pyran-2-yl)acetate (A9)

[0381] Add 1:5 HOAc / Ac2O (12 mL) to freshly condensed ZnCl2 (1.01 g, 7.41 mmol, 1.0 equivalent). Cool the mixture to 0 °C. Add a solution of compound A8 (630 mg, 1.23 mmol, 1.0 equivalent) in 1:5 HOAc / Ac2O (6 mL) dropwise, and stir the mixture at rt. for 1.5 h. Add water, and collect the precipitate by filtration. The filtrate is then dissolved in EA, washed with water and brine, and dried over Na2SO4. Concentration and purification by silica gel (PE:PE:EA = 40:1-30:1) yielded compound A9 (610 mg, 100% yield) as a pale yellow solid.

[0382] Preparation of ((2R,3R,4S,5R)-3,4,6-tris(benzyloxy)-5-fluorotetrahydro-2H-pyran-2-yl)methanol (A10)

[0383] NaOMe (13 mg, 0.25 mmol, 0.2 equivalent) was added to a stirred solution of compound A9 (610 mg, 1.23 mmol, 1.0 equivalent) in MeOH (20 mL) at 0 °C, and the mixture was stirred at rt. for 2 h. The reaction was quenched with NH4Cl (aqueous solution), then concentrated, the residue was absorbed with EA, washed with water and brine, and dried over Na2SO4. Concentration and purification by silica gel (PE-PE:EA = 5:1-DCM:MeOH = 20:1) gave compound A10 (400 mg, yield: 72%) as a colorless oil.

[0384] 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-dodecylhydrotris(epoxyvinyl)[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)

[0385] DCC (50 mg, 0.2174 mmol, 1.0 equivalent) and DMAP (30 mg, 0.239 mmol, 1.51 equivalent) were added to a solution of compound A10 (100 mg, 0.2174 mmol, 1.0 equivalent) in dry DCM (10 mL) at 0 °C. The mixture was stirred at rt. for 18 h. The mixture was absorbed with DCM, washed with hydrated brine, and dried over Na2SO4. Compound A11 (90 mg, yield: 46%) was given as a white solid by concentration and purification by preparative HPLC.

[0386] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl)succinate (Compound 1)

[0387] 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 rt. under H2 atmosphere. The mixture was filtered and concentrated, and the residue was purified by preparative HPLC to provide compound 1 (55 mg, yield: 87%) as a white solid.

[0388] Compound 1: 1H NMR (400MHz, CD3OD): 0.82 (d, J = 7.2Hz 3H), 0.93 (d, J = 6.8Hz 3H),1.03(s,3H),1.32-1.34(m,1H),1.48-1.52(m,1H),1.86-1.93(m,2H),2.03 -2.10(m,1H),2.22-2.29(m,2H),2.68-2.78(m,5H),3.33-3.35(m,1H),3.45(d, J=5.6Hz,1H),3.58-3.62(m,2H),3.85-3.98(m,2.3H),4.18-4.22(m,1.4H),4.3 5-4.42(m,0.8H),4.69-4.71(m,0.5H),4.79-4.84(m,1.5H),5.06(s,1H),5.25(d J=3.6Hz,0.6H).MS(ESI)[C 30 H 37 FO 13 The calculated value of [M+H](m / z) is 624.22, and the experimental value is 625.1.

[0389] Example 2 – 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl-4-oxo-4-(4-(4-oxo-4-(((3S,4S,5R,6S)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)butyryl)piperazin-1-yl)butyrate (Compound 2)

[0390]

[0391] The following scheme illustrates the synthetic route for preparing the title compound.

[0392] Option 4.

[0393]

[0394] Option 5.

[0395]

[0396] Preparation of (3R,4R,5S,6R)-6-(hydroxymethyl)-3-((E)-(4-methoxybenzyl)amino)tetrahydro-2H-pyran-2,4,5-triol (B2)

[0397] NaOH (200 mg, 5 mmol, 1.0 equivalent) was added to a stirred solution of compound B1 (1.08 g, 5.0 mmol, 1.0 equivalent) in water (8 mL) at 0 °C, and the mixture was stirred at rt. for 15 min. 4-Methoxybenzaldehyde (681 mg, 5 mmol, 1.0 equivalent) was added, and the resulting mixture was stirred at rt. for 1 h. The reaction was filtered and dried to give B2 (900 mg, yield: 60%) as a white solid.

[0398] Preparation of (3R,4R,5S,6R,E)-2,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-N-(4-methoxybenzylene)tetrahydro-2H-pyran-3-amine (B3)

[0399] NaH (605 mg, 15.13 mmol, 5.0 equivalent) was added in a stirred solution of compound B2 (900 mg, 3.03 mmol, 1 equivalent) in dry DMF (25 mL) at 0 °C, and the mixture was stirred at rt. for 30 min. (Bromomethyl)benzene (2.18 g, 12.73 mmol, 4.2 equivalent) was added, and the resulting mixture was stirred at rt. for 18 h. The reaction was quenched with NaCl, concentrated, and the residue was purified by silica gel (PE:EA = 50:1–30:1) to yield compound B3 (500 mg, yield: 25%) as a pale yellow oil.

[0400] Preparation of (3R,4R,5S,6R)-2,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-amine hydrochloride (B4)

[0401] The mixture of compound B3 (500 mg, 0.76 mmol, 1.0 equivalent) and 5N HCl (2 mL) in acetone (12 mL) was refluxed for 20 minutes. The mixture was cooled, and the precipitate was collected by filtration and dried to give compound B4 (300 mg, yield: 68%) as a white solid.

[0402] 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)butyryl)piperazine-1-carboxylate (B6)

[0403] HATU (99 mg, 0.2 mmol, 1.0 equivalent) and DIEA (78 mg, 0.6 mmol, 3 equivalent) were added to a solution of compound B4 (115 mg, 0.2 mmol, 1.0 equivalent) in dry DMF (5 mL) at 0 °C. The mixture was stirred at rt. for 18 h. The mixture was concentrated, the residue was absorbed with EA, washed with water and brine, and dried over Na2SO4. Concentration and purification by silica gel (PE-PE:EA = 20:1-10:1) yielded compound B6 (160 mg, yield: 99%) as a white solid.

[0404] 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)butyramide (B7)

[0405] TFA (1 mL) was added to a solution of compound B6 (160 mg, 0.198 mmol, 1.0 equivalent) in dry DCM (10 mL), and the mixture was stirred at rt. for 18 hours. The mixture was concentrated to produce compound B7 (123 mg, yield: 100%) in the form of a yellow oil.

[0406] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl-4-oxo-4-(4-(4-oxo-4-(((3S,4S,5R,6S)-2,4,5-tris(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)butyryl)piperazin-1-yl)butyrate (B9)

[0407] HATU (99 mg, 0.2 mmol, 1.0 equivalent) and DIEA (78 mg, 0.6 mmol, 3 equivalent) were added to a solution of compound B7 (123 mg, 0.2 mmol, 1.0 equivalent) in dry DMF (5 mL) at 0 °C. The mixture was stirred at rt. for 18 h. The mixture was concentrated, the residue was absorbed with EA, washed with water and brine, and dried over Na2SO4. The solution was concentrated and purified by silica gel (PE-PE:EA = 20:1-5:1) to give compound B9 (80 mg, yield: 37%) as a white solid.

[0408] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl-4-oxo-4-(4-(4-oxo-4-(((3S,4S,5R,6S)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)butyryl)piperazin-1-yl)butyrate (Compound 2)

[0409] 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 rt. under H2 atmosphere. The mixture was filtered and concentrated, and the residue was purified by preparative HPLC to give compound 2 (25 mg, yield: 42%) as a white solid.

[0410] Compound 2: 1 H NMR (400MHz, CD3OD): 0.81 (d, J = 6.8Hz 3H), 0.93 (d, J = 7.2Hz 3H),1.02(s,3H),1.31-1.37(m,2H),1.47-1.51(m,1H),1.85-1.97(m,2H),2.03 -2.07(m,1H),2.22-2.29(m,2H),2.55-2.58(m,2H),2.70-2.75(m,7H),3.34-3. 38(m,1H),3.44-3.48(m,1.5H),3.57-3.74(m,11H),3.78-3.86(m,2.4H),3.95( d,J=3.2Hz,1H),4.58-4.60(m,0.4H),4.79-4.81(m,1.6H),5.05(s,1H),5.07(d J=3.6Hz,1H).MS(ESI)[C 38 H 51 N3O 15 The calculated value of [M+H](m / z) is 789.33, and the experimental value is 790.2.

[0411] Example 3: 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl-4-oxo-4-(4-(4-oxo-4-(((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methoxy)butyryl)piperazin-1-yl)butyrate (Compound 3)

[0412]

[0413] The following scheme illustrates the synthetic route for preparing the title compound.

[0414] Option 6.

[0415]

[0416] Preparation of tert-butyl 4-(4-oxo-4-(((2R,3R,4S,5R)-3,4,5,6-tetra(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)butyryl)piperazine-1-carboxylate (C3)

[0417] DCC (45 mg, 0.2 mmol, 1.0 equivalent) and DMAP (27 mg, 0.22 mmol, 1.1 equivalent) were added 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) at 0 °C. The mixture was stirred at rt. for 18 h and diluted with EA, washed with water, then washed with brine, and dried over Na2SO4. After concentration and purification by silica gel (PE-PE:EA = 20:1), compound C3 (130 mg, yield: 80%) was obtained as a white solid.

[0418] Preparation of ((2R,3R,4S,5R)-3,4,5,6-tetra(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl 4-oxo-4-(piperazin-1-yl)butyrate (C4)

[0419] TFA (0.1 mL) was added to a solution of compound C3 (130 mg, 0.16 mmol, 1.0 equivalent) in dry DCM (5 mL), and the mixture was stirred at rt. for 18 hours. The mixture was concentrated to produce compound C4 (113 mg, yield: 100%) in the form of a yellow oil.

[0420] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl-4-oxo-4-(4-(4-oxo-4-(((2R,3R,4S,5R)-3,4,5,6-tetra(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)butyryl)piperazin-1-yl)butyrate (C6)

[0421] HATU (91 mg, 0.24 mmol, 1.0 equivalent) and DIEA (62 mg, 0.48 mmol, 3 equivalent) were added to a solution of compound C4 (113 mg, 0.16 mmol, 1.0 equivalent) in dry DMF (5 mL) at 0 °C. The mixture was stirred at rt. for 18 h and concentrated to produce a residue, which was absorbed with EA, washed with water and brine, and dried over Na2SO4. After concentration and purification by silica gel (PE-PE:EA = 20:1-10:1), compound C6 (100 mg, yield: 54%) was obtained as a white solid.

[0422] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl-4-oxo-4-(4-(4-oxo-4-(((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methoxy)butyryl)piperazin-1-yl)butyrate (Compound 3)

[0423] A mixture of compound C6 (80 mg, 0.0695 mmol, 1.0 equivalent) and Pd / C (10%, 40 mg) in MeOH (5 mL) was stirred overnight at rt. under H2 atmosphere. The mixture was filtered and concentrated, and then purified by preparative HPLC to give the title compound (25 mg, yield: 45%) as a white solid. MS (ESI) [C 38 H 50 N2O 16The calculated value of [m / z] is 790.32, and the experimental value is 791.2. [M+H] + HPLC: 214 nm, 9.845 / 9.941, 100%; 254 nm, 9.847 / 9.945 min, 100%.

[0424] Example 4: 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-dodecylhydrotris(epoxyvinyl)[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-tetra(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetamyl)acetamyl)acetate (Compound 4)

[0425]

[0426] The following scheme illustrates the synthetic route for preparing the title compound.

[0427] Option 7.

[0428]

[0429] Preparation of ethyl acetate 2-(((2R,3R,4S,5R)-3,4,5,6-tetra(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)ethyl acetate (D2)

[0430] NaH (48 mg, 1.2 mmol, 1.2 equivalents) was added to a solution of compound D1 (540 mg, 1.0 mmol, 1.0 equivalents) in dry DMF (40 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 h. Ethyl 2-bromoethyl (200 mg, 1.2 mmol, 1.2 equivalents) was added, and the resulting mixture was stirred overnight at rt. The reaction mixture was quenched with brine, concentrated, and the residue was absorbed with EA, washed with water, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (PE~EA:50:1) to give compound D2 (300 mg, yield: 48%) as a colorless oil.

[0431] Preparation of 2-(((2R,3R,4S,5R)-3,4,5,6-tetra(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetic acid (D3)

[0432] LiOHH2O (101 mg, 2.4 mmol, 5.0 equivalent) was added to a solution of compound D2 (300 mg, 0.48 mmol, 1.0 equivalent) in THF (6 mL) and water (2 mL). The mixture was stirred overnight at rt under N2 atmosphere. The mixture was concentrated, and the residue was acidified to pH 4–5 with 2N HCl, extracted with EA and washed with water, dried over Na2SO4, concentrated, and the residue was purified by silica gel column chromatography (PE–EA = 2:1) to give compound D3 (mg, yield: 38%) as a colorless oil.

[0433] Preparation of methyl 2-(2-(2-(((2R,3R,4S,5R)-3,4,5,6-tetra(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetamyl)acetamyl)methyl acetate (D4)

[0434] DIEA (77 mg, 0.6 mmol, 3.3 equivalents) was added to a solution of compound D3 (110 mg, 0.18 mmol, 1.0 equivalents), compound 3' (34 mg, 0.18 mmol, 1.0 equivalents), and HATU (90 mg, 0.234 mmol, 1.3 equivalents) in dry DMF (5 mL) at 0 °C, and the resulting mixture was stirred overnight at rt. under N2 atmosphere. The reaction mixture was quenched with water, concentrated, and the residue was diluted with EA, washed with water, and dried over Na2SO4. After concentration, the residue was purified by silica gel column chromatography (PE-EA = 5:1) to give compound D4 (165 mg, yield: 70%) as a white solid.

[0435] Preparation of 2-(2-(2-(((2R,3R,4S,5R)-3,4,5,6-tetra(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetamyl)acetamyl)acetic acid (D5)

[0436] LiOHH₂O (48 mg, 1.14 mmol, 5.0 equivalent) was added to a solution of compound D4 (165 mg, 0.227 mmol, 1.0 equivalent) in THF (6 mL) and water (2 mL). The mixture was stirred overnight at rt under N₂ atmosphere. The mixture was concentrated, and the residue was acidified to pH 4–5 with 2N HCl, extracted with EA and washed with water, and dried over Na₂SO₄. After concentration, the residue was purified by silica gel column chromatography (PE–EA = 2:1) to give compound D5 (160 mg, yield: 99%) as a white solid.

[0437] 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-dodecylhydrotris(epoxyvinyl)[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-tetra(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetamyl)acetamyl)acetate (D6)

[0438] DCC (56 mg, 0.27 mmol, 1.0 equivalent) and DMAP (catalyst) were added to a solution of compound D5 (160 mg, 0.23 mmol, 1.0 equivalent) in dry DCM (5 mL) at 0 °C, and the resulting mixture was stirred overnight at rt. under N2 atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and purified by preparative HPLC to give compound D6 (72 mg, yield: 30%) as a white solid.

[0439] 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-dodecylhydrotris(epoxyvinyl)[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-tetra(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)acetamyl)acetamyl)acetate (Compound 4)

[0440] Pd / C (36 mg, 10%) was added to a solution of compound D6 (72 mg, 0.068 mmol, 1.0 equivalence) in MeOH (6 mL), and the mixture was stirred at rt. for 6 h under H2 atmosphere. The mixture was filtered, and the filtrate was concentrated and purified by preparative HPLC to give the title compound (13 mg, yield: 28%) as a white solid. MS (ESI) [C 32 H 42 N2O 15 The calculated value of [M+H](m / z) is 694.26, and the experimental value is 695.4. + HPLC: 220 nm, 8.904 min, 100%; 254 nm, 8.906 min, 100%.

[0441] Example 5: 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl 4-(4-(4-(((6-chloro-2-methoxyacridin-9-yl)amino)pentyl)piperazin-1-yl)-4-oxobutyrate (Compound 5)

[0442]

[0443] The following scheme illustrates the synthetic route for preparing the title compound.

[0444] Option 8.

[0445]

[0446] Preparation of tert-butyl 4-(4-oxopentyl)piperazine-1-carboxylate (E2)

[0447] K₂CO₃ (3.7 g, 26.9 mmol, 1.3 equivalents) was added to compound E1 (2.5 g, 20.7 mmol, 1.0 equivalents) and tert-butyl piperazine-1-carboxylate (7.7 g, 41.4 mmol, 2.0 equivalents) in a stirred solution of DMF (30 mL) at rt. After stirring overnight at 65 °C, the mixture was poured into ice water (200 mL) and extracted with EtOAc (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 chromatography (DCM:MeOH = 20:1 to 10:1) to give product E2 (2.3 g, yield: 41%) as a yellow oil.

[0448] Preparation of tert-butyl 4-(4-((benzyloxy)imino)pentyl)piperazine-1-carboxylate (E4)

[0449] NaOAc (3.5 g, 42.5 mmol, 5.0 equivalent) was added 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 equivalent) in MeOH (10 mL), followed by the addition of water (20 mL) at rt. After stirring at 100 °C (oil bath) for 1 hour, the mixture was concentrated to remove the organic solvent, then diluted with EtOAc (200 mL), and the aqueous layer was further extracted with EtOAc (200 mL x 2). All EA layers were combined and washed with brine (200 mL), dried over Na2SO4, and concentrated. A yellow solid was formed upon concentration. The solid was collected by filtration, yielding fraction 1 of the product (E4, 1.91 g, yield: 59%). The filtrate was concentrated and purified by silica gel column chromatography (PE:EA = 4:1; 1:1, then DCM:MeOH = 10:1) to yield fraction 2 of the product in the form of a yellow oil (500 mg, yield: 16%). A total of 2.4 g of product was obtained, with a yield of 75%.

[0450] Preparation of tert-butyl 4-(4-aminopentyl)piperazine-1-carboxylate (E5)

[0451] Raney Ni (approximately 5 mL in water) was added to a mixture of E4 (1.91 g, 5.08 mmol) and NH3OH (2 mL) in MeOH (20 mL). After stirring at 50 °C for 5.5 hours under H2, the mixture was filtered. The filtrate was concentrated and diluted with water (100 mL), extracted with EtOAc, all EA layers were combined and washed with brine, dried over Na2SO4 and concentrated to produce a product in the form of a yellow oil (E5, 1.3 g, yield: 94%), which could be used in the next step without further purification.

[0452] Preparation of tert-butyl 4-(4-((6-chloro-2-methoxyacridin-9-yl)amino)pentyl)piperazine-1-carboxylate (E7)

[0453] 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 stirred at 105 °C (oil bath) for 0.5 h. E5 (635 mg, 2.34 mmol, 1.3 equivalent) was added to the mixture, and stirring was continued for another 1.0 h. After cooling to rt, the mixture was diluted with DCM (5 mL) and subjected to silica gel column chromatography (Biotage, 25 g, DCM containing MeOH, 0-50%, 254 nm). A portion of the product was collected and concentrated to yield a product as a yellow solid (E7, 597 mg, 64% yield).

[0454] Preparation of 6-chloro-2-methoxy-N-(5-(piperazin-1-yl)pent-2-yl)acridin-9-amine (E8)

[0455] The mixture of E7 (100 mg, 0.195 mmol) and TFA (0.2 mL) in DCM (5 mL) was stirred at rt. for 18 hours. The mixture was concentrated to produce crude E8 (100 mg) in the form of a yellow solid.

[0456] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl 4-(4-(4-(((6-chloro-2-methoxyacridin-9-yl)amino)pentyl)piperazin-1-yl)-4-oxobutyrate (Compound 5)

[0457] HATU (97 mg, 0.254 mmol, 1.3 equivalence) and DIEA (63 mg, 0.488 mmol, 2.5 equivalence) were added to a solution of E8 (100 mg, 0.195 mmol, 1.0 equivalence) and E9 (90 mg, 0.195 mmol, 1.0 equivalence) in dry DMF (5 mL) at 0 °C. The mixture was stirred at rt. for 18 h. The mixture was concentrated and the residue was purified by preparative HPLC to give compound 5 (30 mg, yield: 18%) as a yellow solid. MS (ESI) [C 47 H 55 The calculated value of ClN4O9](m / z) was 854.37, and the experimental value was 428.6. [1 / 2M+H]+.HPLC: 220nm, 9.948, 100%; 254nm, 9.95min, 100%.

[0458] Example 6: 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl 3-((S)-6-acetamido-2-((tert-butoxycarbonyl)amino)hexaneamino)propionate (Compound 6)

[0459]

[0460] The following scheme illustrates the synthetic route for preparing the title compound.

[0461] Option 9.

[0462]

[0463] Preparation of (S)-3-(6-acetamido-2-((tert-butoxycarbonyl)amino)hexaneamino)propionate benzyl ester (F2)

[0464] Step 1: Toluene (50 mL) containing 3-aminopropionic acid (1.8 g, 20.0 mmol, 1.0 equivalent), BnOH (4.3 g, 40.0 mmol, 2.0 equivalent), and PTSA (4.2 g, 22.0 mmol, 1.1 equivalent) was stirred under reflux overnight. The solvent was then removed under vacuum and diluted with EA / PE (approximately 1 / 10, v / v, 100 mL). The solid was collected by filtration and dried under vacuum to produce benzyl 3-aminopropionic acid (PTSA salt) as a pale yellow solid (6.8 g, 97% yield).

[0465] Step 2: HOBt (405 mg, 3.0 mmol, 1.5 equivalence) was added to THF (10 mL) containing (S)-6-acetamido-2-((tert-butoxycarbonyl)amino)hexanoic acid (compound F1, 576 mg, 2.0 mmol, 1.0 equivalence) in an ice-water bath. After stirring for 10 minutes, DMAP (244 mg, 2.0 mmol, 1.0 equivalence) and subsequently DCC (824 mg, 4.0 mmol, 2.0 equivalence) were added to CHCl3 (10 mL), and stirring was continued for another 15 minutes. K2CO3 (414 mg, 3.0 mmol, 1.5 equivalence) and benzyl 3-aminopropionate (PTSA salt) (843 mg, 2.4 mmol, 1.2 equivalence) were added. The resulting mixture was stirred overnight at rt. Undissolved white solids were filtered off, the filtrate was concentrated and partitioned between EA (200 mL) and water (200 mL), the aqueous layer was further extracted with EA (200 mL), all EA layers were combined and washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column evaporation (DCM containing MeOH, 0-20%) to produce a product in the form of a pale yellow oil (F2, 768 mg, yield 85%).

[0466] Preparation of (S)-3-(6-acetamido-2-((tert-butoxycarbonyl)amino)hexaneamino)propionic acid (F3)

[0467] A mixture of Pd / C (5%, 80 mg) and F2 (220 mg, 0.50 mmol) in MeOH (10 mL) was stirred overnight at rt under H2. The catalyst was filtered off, and the filtrate was concentrated to produce a product (F3, 177 mg, quantified) in the form of a white foamy solid.

[0468] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl 3-((S)-6-acetamido-2-((tert-butoxycarbonyl)amino)hexaneamino)propionate (Compound 6)

[0469] Add to the white, turbid mixture of F3 (45 mg, 0.125 mmol, 2.0 equivalents) in CHCl3 / THF (1 / 1, 4 mL). MS (approximately 800 mg) was added and stirred at rt for 0.5 hours under N2. The mixture was cooled in an ice-water bath, and CHCl3 (0.5 mL) containing DCC (29 mg, 0.138 mmol, 2.2 equivalents) was added, followed by PPY (4-pyrrolylpyridine, 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. The mixture was stirred and gently heated to rt overnight. The mixture was diluted with DCM / EA (approximately 20 mL), filtered, and the filtrate was concentrated and purified by flash column distillation (DCM containing 0-10% MeOH). A portion of the product was collected to produce a crude product, which was further purified by preparative HPLC (ODS, water containing ACN, 20-95%, 214 nm). The crude product was then concentrated and lyophilized to produce the desired product (compound 6) as a white solid and unreacted triptolide was recovered. 1H NMR (CDCl3, 400MHz) δ0.91 (d, 3H, J = 7.2Hz), 1.01 (d, 3H, J = 6.8Hz), 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=7.2Hz),5.89(bs,1H),7.07(bs,1H).MS(ESI)[M+H] + Calculated value of (m / z): 702.3, experimental value: 702.3.

[0470] Example 7: 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl((1-methyl-2-nitro-1H-imidazol-5-yl)methyl)carbonate (Compound 7)

[0471]

[0472] The following scheme illustrates the synthetic route for preparing the title compound.

[0473] Option 10.

[0474]

[0475] Preparation of ethyl 1-methyl-2-nitro-1H-imidazolium-5-carboxylate (G2)

[0476] G1 (600 mg, 3.55 mmol, 1.0 equivalent) was added dropwise to a solution of NaNO2 (1713 mg, 24.85 mmol, 7.0 equivalent) in H2O (5 mL) at -5 °C under a N2 atmosphere. The mixture was heated to rt and incubated overnight. The reaction mixture was extracted with DCM, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (PE:EA = 20:1) to give compound G2 (360 mg, yield: 51%) as yellow crystals.

[0477] Preparation of (1-methyl-2-nitro-1H-imidazol-5-yl)methanol (G3)

[0478] Compound G2 (405 mg, 2.03 mmol, 1.0 equivalent) was added to a solution of THF / MeOH (8 mL / 2 mL) and cooled to 0 °C. Then, a solution of THF / H2O (4 mL / 2 mL) containing NaBH4 (231 mg, 6.09 mmol, 3.0 equivalent) and LiBr (530 mg, 6.09 mmol, 3.0 equivalent) was added dropwise at below 10 °C. The mixture was stirred overnight at rt under a N2 atmosphere. NH4Cl was added at 0 °C, and stirring was extended for 30 minutes. The precipitate was filtered and washed with THF. The filtrate was concentrated, and the residue was absorbed into a mixture of EA / MeOH (98 / 2, V / V). The resulting solution was passed through a silica gel pad to produce compound G3 (263 mg, yield: 65%) as pale yellow to orange crystals.

[0479] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl(4-nitrophenyl) carbonate (G6)

[0480] Dry pyridine (17 μL, 0.15 mmol, 1.5 equivalent) was added to a solution of compound G4 (36 mg, 0.1 mmol, 1.0 equivalent) in dry DCM (2 mL) at 0 °C under N2 atmosphere. Compound G5 (30 mg, 0.15 mmol, 1.5 equivalent) was added, and the mixture was stirred overnight at rt under N2 atmosphere. The mixture was quenched with 1N HCl, extracted with DCM, washed with brine, dried over Na2SO4, and concentrated under vacuum to yield compound G6 (52 mg, yield: 100%) as a white solid, which was used directly in the next step without further purification.

[0481] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl((1-methyl-2-nitro-1H-imidazol-5-yl)methyl)carbonate (Compound 7)

[0482] Et3N (31 mg, 0.3 mmol, 1.0 equivalent) and DMAP (3 mg, 0.02 mmol, 0.2 equivalent) were added to a solution of compound G6 (52 mg, 0.1 mmol, 1.0 equivalent) and compound G3 (19 mg, 0.12 mmol, 1.2 equivalent) in dry DCM (5 mL) under N2 atmosphere and at 0 °C. The mixture was stirred overnight at rt. The mixture was quenched with saturated NH4Cl, extracted with DCM, washed with brine, and dried over Na2SO4. After concentration, the residue was purified by preparative HPLC to give the title compound (compound 7, 15 mg, yield: 27%) as a white solid. 1 H-NMR(CDCl3,400MHz):0.85(d,J=6.8Hz,3H),0.97(d,J=7.2Hz,3H),1.05(s,3H),1 .19-1.25(m,1H),1.55-1.60(m,1H),1.88-1.95(m,2H),2.13-2.22(m,2H),2.30-2.3 5(m,1H),2.67-2.71(m,1H),3.49(d,J=5.6Hz,1H),3.55(s,1H),3.84(d,J=3.2Hz,1H ),4.06(s,3H),4.68(s,2H),4.82(s,1H),5.21-5.29(m,2H),7.27(s,1H).MS(ESI)[C26 H 29 N3O 10 The calculated value of [m / z] is 543.52, and the experimental value is 544.1. [M+H] + HPLC: 220 nm, 12.204 min, 99.97%; 254 nm, 12.205 min, 99.94%.

[0483] Example 8: Synthesis of a conjugate of triptolide and tri-glucosamine (Compound 8)

[0484]

[0485] The following scheme illustrates the synthetic route for preparing the title compound.

[0486] Option 11.

[0487]

[0488] Preparation of compound H2

[0489] The solution of H1 (1.0 g, 1.0638 mmol, 1.0 equivalent) in TFA (10 mL) was stirred at rt for 1 hour, then diluted and concentrated with toluene. The residue was co-evaporated with toluene and dried under reduced pressure using a high vacuum pump to obtain H2 in the form of TFA salt. The product was used for the next reaction without any further purification (1.0 g, yield: 100%).

[0490] Preparation of compound H3

[0491] A solution of H2 (1.0 g, 1.0638 mmol, 1.0 equivalent) in pyridine (10 mL) was supplemented with dihydro-2H-pyran-2,6(3H)-dione (728 mg, 6.3830 mmol, 6.0 equivalent). The solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was concentrated, and the residue was purified by preparative HPLC to obtain H3 (710 mg, yield: 68.3% for both steps) as a white solid.

[0492] Preparation of compound H4

[0493] (2R,3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol hydrochloride (661 mg, 3.0658 mmol, 6.0 equivalent) and DIPEA (785 mg, 6.1316 mmol, 12 equivalent) were added to a solution of H3 (660 mg, 0.5110 mmol, 1.0 equivalent) in DMF (20 mL) under N2 atmosphere at 0 °C. The mixture was stirred for 5 min, then HATU (971 mg, 2.5550 mmol, 5.0 equivalent) was added and stirred for another 18 h. LCMS showed the reaction was complete. H2O (5.0 mL) was added and stirred for 30 min. The reaction mixture was then concentrated, and the residue was purified by preparative HPLC to yield H4 (628 mg, yield: 84%) as a white solid.

[0494] Preparation of compound H5

[0495] Pd / C, 10% (160 mg, catalyst), was added to a solution of H4 (828 mg, 0.5653 mmol, 1.0 equivalence) in MeOH / H2O (30 / 5 mL) and stirred overnight under H2. LCMS showed the reaction was complete. The reaction was filtered, and the filtrate was concentrated to give compound H5 (676 mg, yield: 90%) as a white solid.

[0496] Preparation of compound 8

[0497] H5 (347 mg, 0.2608 mmol, 1.2 equivalents) and DIPEA (83 mg, 0.6519 mmol, 3.0 equivalents) were added to a solution of compound H5-1 (100 mg, 0.2173 mmol, 1.0 equivalents) in DMF (6 mL) at 0 °C under a 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 another two hours. LCMS showed 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 preparative HPLC to give the triptolide tri-glucosamine conjugate (compound 8) (105 mg, yield: 27%) as a white solid.

[0498] Example 9: Synthesis of a conjugate of triptolide and tri-glucose (Compound 9)

[0499]

[0500] The following scheme illustrates the synthetic route for preparing the title compound.

[0501] Option 12.

[0502]

[0503]

[0504] Preparation of compound I2

[0505] DBU (228 mg, 1.5 mmol, 0.5 equivalence) and trichloroacetonitrile (2.59 g, 18 mmol, 6.0 equivalence) were added to a solution of compound I1 (1.044 g, 3.0 mmol, 1.0 equivalence) in DCM (20 mL) at 0 °C. The solution was then heated to room temperature and stirred overnight. TLC showed that the reaction was complete. The reaction was concentrated and the residue was purified by flash column evaporation to obtain 1.3 g of the desired product compound I2.

[0506] Preparation of compound I3

[0507] Benzyl 5-hydroxyvalerate (826 mg, 3.9716 mmol, 1.5 equivalent) and TMSOTf (118 mg, 0.5295 mmol, 0.2 equivalent) were added to a solution of compound I2 (1.3 g, 2.6477 mmol, 1.0 equivalent) in DCM (15 mL) at 0 °C. The solution was stirred for 3 h. Then TEA (0.5 mL) was added and stirred for another 30 min. LCMS showed that the reaction was complete. The reaction was quenched with water and extracted with DCM. The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC to obtain compound I3 (500 mg, yield: 35% for both steps) as a colorless oil.

[0508] Preparation of compound I4

[0509] Pd / C (10%, 80 mg) was added to a solution of compound I3 (500 mg, 0.9294 mmol, 1.0 equivalent) in MeOH (10 mL). The mixture was stirred under H2 for 5 hours. LCMS showed that the reaction was complete. The reaction was filtered and concentrated to obtain the desired product (I4, 380 mg, yield: 91%) as a white solid.

[0510] Preparation of compound I5

[0511] Compound I4-1 (240 mg, 0.2570 mmol, 1.0 equivalent), DIEA (329 mg, 2.57 mmol, 10 equivalent), and HATU (488 mg, 1.285 mmol, 5.0 equivalent) were added to a solution of compound I4 (380 mg, 0.8482 mmol, 3.3 equivalent) in DMF (8.0 mL). The mixture was then stirred overnight. LCMS showed that the reaction was complete. The reaction was quenched with water and stirred for 30 min. The solution was concentrated and the residue was dissolved in water and extracted with DCM. The organic phase was dried, filtered, and concentrated. The residue was purified by preparative HPLC to give compound I5 (380 mg, yield: 76%) as a white solid.

[0512] Preparation of compound I6

[0513] MeONa (21 mg, 0.3938 mmol, 2.0 equivalent) was added to a solution of compound I5 (380 mg, 0.1969 mmol, 1.0 equivalent) in MeOH (8.0 mL). The mixture was stirred for 5 hours. LCMS showed the reaction was complete. The reaction was concentrated, and the residue was purified by preparative HPLC to give compound I6 (220 mg, yield: 79%) as a white solid.

[0514] Preparation of compound I7

[0515] Pd / C (10%, 40 mg, catalyst) was added to a solution of compound I6 (220 mg, 0.1543 mmol, 1.0 equivalent) in MeOH (10.0 mL). The mixture was stirred under H2 for 5 hours. LC-MS showed the reaction was complete. The solution was concentrated to give compound I7 (200 mg, yield: 100%) as a white solid. Exact mass: 1291.67.

[0516] Preparation of compound 9

[0517] Compound I7-1 (71 mg, 0.1548 mmol, 1.0 equivalent) and DIPEA (40 mg, 0.3096 mmol, 2.0 equivalent) were added to a solution of compound I7 (200 mg, 0.1548 mmol, 1.0 equivalent) in DMF (6 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred for 5 minutes. Then HATU (88 mg, 0.2322 mmol, 1.5 equivalent) was added, and the mixture was stirred for another two hours. LCMS showed 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 preparative HPLC to give compound 9 (120 mg, yield: 45%) as a white solid. 1H-NMR(DMSO-d6,400MHz):0.75(d,J=6.6Hz,3H),0.86(d,J=6.6Hz,3H),0.91(s,3H),1.27-1.33(m,2H),1.41-1.44(m,6H),1.47-1.52 (m,13H),1.80(s,9H),1.86-1.90(m,2H),2.04(t,J=7.2Hz,1H),2.28(t,J=6.6Hz,1H),3.01-3.06(m,13H),3.29(t,J=6.0Hz,1H),3.4 1-3.44(m,3H),3.47-3.55(m,20H),3.64-3.65(m,3H),3.67-3.72(m,7H),3.95(s,1H),4.23(d,J=8.4Hz,3H),4.46(d,J=4.2Hz,3H),4 .54(d,J=6.0Hz,3H),4.57(t,J=5.4Hz,3H),4.76-4.87(m,2H),4.96(s,1H),7.26(s,1H),7.73(t,J=5.4Hz,3H),7.83(t,J=5.4Hz,3H).

[0518] Example 10: Synthesis of a conjugate of triptolide and tri-GalNHAc (Compound 10)

[0519]

[0520] The following scheme illustrates the synthetic route for preparing the title compound.

[0521] Option 13.

[0522]

[0523]

[0524] Preparation of di-tert-butyl 3,3'-((2-amino-2-((3-(tert-butoxy)-3-oxopropoxy)methyl)propane-1,3-diyl)bis(oxy))dipropionate (J3)

[0525] Under a nitrogen atmosphere at below 15°C, a solution of compound J1 (1.21 g, 10 mmol, 1.0 equivalent) in DMSO (2 mL) was treated with 5 M NaOH (0.2 mL, 1.0 mmol, 0.1 equivalent), followed by the addition of compound J2 (4.36 g, 34 mmol, 3.4 equivalent) dropwise. The mixture was allowed to stand under a nitrogen atmosphere for 24 hours. The reaction mixture was cooled to 0°C and diluted with water, extracted with EA, washed with brine, dried over Na2SO4, and concentrated to yield compound J3 as a pale yellow oil, which was used in the next step (4.0 g) without further purification.

[0526] Preparation of di-tert-butyl 3,3'-((2-(((benzyloxy)carbonyl)amino)-2-((3-(tert-butoxy)-3-oxopropoxy)methyl)propane-1,3-diyl)bis(oxy))dipropionate (J4)

[0527] 25% Na₂CO₃ (16.8 g, 39.55 mmol, 5.0 equivalent) was added to a solution of compound J3 (4.0 g, 7.91 mmol, 1.0 equivalent) in DCM (40 mL) at 0 °C under a N₂ atmosphere, followed by dropwise addition of Cb₂Cl (2.7 g, 15.82 mmol, 2.0 equivalent), and the mixture was stirred overnight at rt. The mixture was diluted with DCM and quenched with water, washed with brine, dried over Na₂SO₄, concentrated, and purified by silica gel column chromatography (PE:EA = 10:1–7:1) to yield compound J4 (2.8 g, yield: 55%) as a colorless oil.

[0528] Preparation of 3,3'-((2-(((benzyloxy)carbonyl)amino)-2-((2-carboxyethoxy)methyl)propane-1,3-diyl)bis(oxy))dipropionic acid (J5)

[0529] A solution of compound J4 (2.8 g, 4.37 mmol, 1.0 equivalent) in HCOOH (40 mL) was stirred overnight at rt. The mixture was concentrated and dried under vacuum to yield compound J5 in the form of a yellow oil, which was used without further purification (2.27 g).

[0530] Preparation of compound J7

[0531] HATU (5.1 g, 13.37 mmol, 3.5 equivalents) and DIPEA (3.0 g, 22.92 mmol, 6.0 equivalents) were added to a solution of compound J5 (1.8 g, 3.82 mmol, 1.0 equivalents) and compound J6 (2.7 g, 15.28 mmol, 4.0 equivalents) in DMF (30 mL) under N2 atmosphere and at 0 °C. The mixture was stirred overnight at rt. The reaction was quenched with cooling water, extracted with DCM, washed with saturated NaHCO3 and brine, dried over Na2SO4, concentrated and purified by preparative HPLC to give compound J7 (3.12 g, yield: 87%) as a white solid.

[0532] Preparation of (1,19-diamino-10-((3-((3-aminopropyl)amino)-3-oxopropoxy)methyl)-5,15-dioxo-8,12-dioxa-4,16-diazanonadecan-10-yl)carbamate (J8)

[0533] A solution of compound J7 (870 mg, 0.925 mmol, 1.0 equivalent) in TFA (5 mL) was stirred at rt for 1 hour. The mixture was diluted with toluene and concentrated, and the residue was co-evaporated with toluene and dried under reduced pressure using a high vacuum pump to produce J8 as a TFA salt. This product was used in subsequent reactions without any further purification (591 mg, yield: 100%).

[0534] Preparation of benzyl 5-hydroxyvalerate (J10)

[0535] 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 rt and concentrated. The residue was suspended in acetone (50 mL) and TBAB (0.8 g, 2.5 mmol, 0.05 equivalent) and BnBr (10.2 g, 60 mmol, 1.2 equivalent) were added. The mixture was heated to reflux overnight. The acetone was removed under vacuum to produce an oily residue, which was dissolved in EA and washed with saturated NaHCO3 and brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA = 5:1 to 1:1) to produce compound J10 (3.6 g, yield: 34%) in colorless oil form.

[0536] Preparation of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-6,7-dimethyldiacetic acid ester (J12)

[0537] TMSOTf (1333 mg, 6.0 mmol, 1.5 equivalence) was added to a solution of compound J11 (1557 mg, 4.0 mmol, 1.0 equivalence) in DCE (5 mL) and stirred at 55 °C for 2 hours. The mixture was then stirred overnight at rt. The mixture was poured into ice-cold saturated NaHCO3, extracted with DCM, washed with water and brine, dried over Na2SO4, and concentrated to yield compound J12 in the form of a black gel. This compound was used in the next step without any further purification (1.3 g, yield: 99%).

[0538] Preparation of (3aR,5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-6,7-diacetic acid diester (J13)

[0539] 4A powdered molecular sieve was added 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 equivalent) in DCE (15 mL), and the mixture was stirred at rt for 30 min under N2 atmosphere. TMSOTf (0.44 g, 1.98 mmol, 0.5 equivalent) was added to the reaction, and the mixture was stirred at rt for 12 h. 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 preparative HPLC to yield compound J13 (358 mg, yield: 13%) as a colorless oil.

[0540] Preparation of 5-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)valerate (J14)

[0541] 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 the mixture was stirred overnight at rt under a H2 atmosphere. The mixture was filtered, the filtrate was concentrated, and dried under reduced pressure using a high vacuum pump to produce J14 as a colorless oil, which was used in the next step without any further purification (285 mg, yield: 95%).

[0542] Preparation of compound J15

[0543] HATU (233 mg, 0.61 mmol, 4.0 equivalent) and DIPEA (198 mg, 1.53 mmol, 10.0 equivalent) were added to a solution of compound J14 (240 mg, 0.54 mmol, 3.5 equivalent) in DMF (5 mL) under a nitrogen atmosphere at 0 °C. The mixture was stirred at rt for 30 min, and then a solution of compound J8 (100 mg, 0.153 mmol, 1.0 equivalent) in DMF (2 mL) was added and stirred at rt for 3 h. The reaction mixture was concentrated, and water was added to the residue. The mixture was extracted with DCM, washed with saturated NaHCO3 and brine, and dried over Na2SO4. Compound J15 (185 mg, yield: 63%) was obtained as a white solid after concentration and purification by preparative HPLC.

[0544] Preparation of (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-( ((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentamido)propyl)amino)-3-oxopropoxy)methyl)-5,11,21,27-tetraoxo-14,18-dioxa-6,10,22,26-tetraaza-hexa-16-yl)benzyl carbamate (J16)

[0545] NaOMe (95 mg, 1.759 mmol, 20 equivalents) was added to a solution of compound J15 (175 mg, 0.091 mmol, 1.0 equivalents) in MeOH (5 mL) and the mixture was stirred at rt for 2 h. The mixture was concentrated and the residue was purified by preparative HPLC to give compound J16 (126 mg, yield: 92%) as a white solid.

[0546] 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)pentamido)propyl)amino)-3-oxopropoxy)methyl)-10-amino-5,15-dioxo-8,12-dioxa-4,16-diazanonadecan-1,19-diyl)bis(5-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentamido) (J17)

[0547] A solution of compound J16 (126 mg, 0.081 mmol, 1.0 equivalent) in MeOH (5 mL) and DMF (2.5 mL) was added with 10% Pd / C (15 mg) and stirred overnight at rt under H2 atmosphere. The mixture was filtered, the filtrate was concentrated and dried under reduced pressure using a high vacuum pump to produce J17 in the form of a yellow oil, which was used in the next step (110 mg) without any further purification.

[0548] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl21-(((2R,3R,4R,5R,6R)-3-acetyl) Amino-4,5-dihydroxy-6-(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)pentamido)propyl)amino)-3-oxopropoxy)methyl)-4,11,17-trioxo-8-oxa-5,12,16-triazacotetraane-1-ester (J18)

[0549] HATU (39 mg, 0.101 mmol, 1.3 equivalence) and DIPEA (31 mg, 0.234 mmol, 3.0 equivalence) were added to a solution of compound J18 (40 mg, 0.086 mmol, 1.1 equivalence) in DMF (5 mL) under N2 atmosphere at 0 °C, and the mixture was stirred at rt for 1 h. Then, a solution of compound 17 (110 mg, 0.078 mmol, 1.0 equivalence) in DMF (2 mL) was added and stirred at rt for 3 h. The reaction mixture was concentrated and purified by preparative HPLC to give the title compound (compound 10) (40 mg, yield: 29%) as a white solid.

[0550] 1 H-NMR(DMSO-d6,600MHz):0.75(d,J=6.6Hz,3H),0.86(d,J=6.6Hz,3H),0.91(s,3H),1.27-1.33(m,2H),1.41-1.44(m,6H),1.47-1.52(m,13H) ,1.80(s,9H),1.86-1.90(m,2H),2.04(t,J=7.2Hz,1H),2.28(t,J=6.6 Hz,1H),3.01-3.06(m,13H),3.29(t,J=6.0Hz,1H),3.41-3.44(m,3H),3 .47-3.55(m,20H),3.64-3.65(m,3H),3.67-3.72(m,7H),3.95(s,1H), 4.23(d,J=8.4Hz,3H),4.46(d,J=4.2Hz,3H),4.54(d,J=6.0Hz,3H),4.5 7(t,J=5.4Hz,3H),4.76-4.87(m,2H),4.96(s,1H),7.20(s,1H),7.62(d,J=9.0Hz,3H),7.73(t,J=5.4Hz,3H),7.83(t,J=5.4Hz,3H).MS(ESI)[C 85 H 136 N 10 O 35 The calculated value of [M+H](m / z) is 1856.92, and the experimental value is 1858.3. + HPLC: 220 nm, 15.981 min, 91.23%; 254 nm, 15.984 min, 85.11%.

[0551] Example 11: 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl 3-((S)-6-acetamido-2-(adamantane-1-carbamoyl)hexaneamino)propionate (Compound 11)

[0552]

[0553] The following scheme illustrates the synthetic route for preparing the title compound.

[0554] Option 14.

[0555]

[0556] Preparation of (S)-3-(6-acetamido-2-aminohexaneamino)propionate benzyl ester (K1-1)

[0557] TFA (0.5 mL) was added to DCM (5.0 mL) containing (S)-3-(6-acetamido-2-((tert-butoxycarbonyl)amino)hexaneamino)propionate (KS-1, 240 mg, 0.54 mmol, 1.0 equivalent) and stirred overnight at 0 °C under N2. LC-MS showed the reaction was complete and the desired product was detected. The solvent was removed to produce a crude product (S)-3-(6-acetamido-2-aminohexaneamino)propionate (K1-1, 186 mg, yield: theoretical value) as a pale yellow oil, which was used directly in the next step. MS (ESI) chemical formula: [C 18 H 28 N3O4] + Calculated value of [m / z]: 350.2, Experimental value: 350.2(M+H) + .

[0558] Preparation of (S)-3-(6-acetamido-2-(adamantane-1-formamido)hexaneamino)benzyl propionate (K1-2)

[0559] DIEA (346 mg, 2.675 mmol, 3.0 equivalence) and HATU (244 mg, 0.641 mmol, 1.2 equivalence) were added to a solution of adamantane-1-carboxylic acid (97 mg, 0.54 mmol, 1.0 equivalence) in DMF (5.0 mL) at 0 °C. After stirring for 0.5 hours, DMF (1.0 mL) containing (S)-3-(6-acetamido-2-aminohexaneamino)propionate (K1-1, 186 mg, 0.54 mmol, 1.0 equivalence) was added dropwise, and the mixture was stirred overnight at rt under N2. LC-MS showed that the reaction was complete and the desired product was detected. After concentration, the residue was purified by preparative HPLC to yield the desired product, (S)-3-(6-acetamido-2-(adamantane-1-carbamoyl)hexaneamino)benzyl propionate, in the form of a pale yellow oil (K1-2, 273 mg, yield: theoretical). MS (ESI) chemical formula: [C 29 H 41 N3O5] + Calculated value of [m / z]: 512.3, Experimental value: 512.3(M+H) + .

[0560] Preparation of (S)-3-(6-acetamido-2-(adamantane-1-carbamoyl)hexaneamino)propionic acid (K1-3)

[0561] Pd / C (30 mg) was added to MeOH (20.0 mL) containing benzyl (S)-3-(6-acetamido-2-(adamantane-1-carbamoyl)hexaneamino)propionate (K1-2, 273 mg, 0.54 mmol, 1.0 equivalent) and stirred overnight at rt under H2. LC-MS showed that the reaction was complete and the desired product was formed. The solvent was removed and the residue was purified by preparative HPLC to yield the desired product (S)-3-(6-acetamido-2-(adamantane-1-carbamoyl)hexaneamino)propionate (K1-3, 144 mg, yield: 64.0%) as a pale yellow oil. MS (ESI) chemical formula: [C 22 H 36 N3O5] + Calculated value of [m / z]: 422.3, Experimental value: 422.3(M+H) + .

[0562] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl 3-((S)-6-acetamido-2-(adamantane-1-carbamoyl)hexaneamino)propionate (Compound 11)

[0563] DCC (60 mg, 0.287 mmol, 2.2 equivalence) and PPY (43 mg, 0.287 mmol, 2.2 equivalence) were added to a solution of (S)-3-(6-acetamido-2-(adamantane-1-carbamoyl)hexaneamino)propionic acid (K1-3, 110 mg, 0.261 mmol, 2.0 equivalence) in THF / CHCl3 (0.5 / 0.5 mL) at 0 °C under N2 and stirred for 15 min. Then, THF / CHCl3 (0.5 / 0.5 mL) containing triptolide (47 mg, 0.130 mmol, 1.0 equivalence) was added dropwise and stirred overnight at 0 °C to room temperature under N2. LC-MS showed the reaction was complete and the desired product was detected. The solvent was removed and the residue was purified by FLASH and preparative HPLC to produce the desired product (compound 11, 68 mg, yield: 69%) as a white solid. 1 H NMR (400MHz, CDCl3) δ (ppm): 0.92 (d, 3H, J = 6.4Hz), 1.02 (d, 3H, J = 6.8Hz), 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),2.60-2.7 0 (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). MS (ESI) chemical formula: [C 42 H 58 N3O 10 ]+ Calculated value of [m / z]: 764.4, Experimental value: 764.4 (M+H) + .

[0564] Example 12: 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl 4-(4-(3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-6-yl)oxy)propyl)piperazin-1-yl)-4-oxobutyrate (Compound 12)

[0565]

[0566] The following scheme illustrates the synthetic route for preparing the title compound.

[0567] Option 15.

[0568]

[0569]

[0570] Preparation of 4-bromo-6-methoxyquinoline (L2)

[0571] PBr3 (2.98 g, 11.0 mmol, 1.1 equivalent) was added to a solution of compound L1 (1.75 g, 10.0 mmol, 1.0 equivalent) in DMF (25 mL). The mixture was stirred at rt. for 18 hours under a N2 atmosphere. The mixture was treated with NaHCO3 (aqueous solution) until the pH was about 8-9, and extracted with EA. The combined extract was washed with water and brine, dried over Na2SO4, concentrated, and purified by silica gel (PE:EA = 5:1) to give compound L2 (1.75 g, yield: 74%) as a white solid.

[0572] Preparation of 4-bromoquinoline-6-ol (L3)

[0573] HBr (10 mL) was added to a solution of compound L2 (1.67 g, 7.0 mmol, 1.0 equivalent) in HOAc (20 mL), and the resulting mixture was refluxed overnight under a N2 atmosphere. The reaction mixture was concentrated to produce crude compound L3 (1.4 g, yield: 89%) as a yellow solid.

[0574] Preparation of 6-(benzyloxy)-4-bromoquinoline (L4)

[0575] K₂CO₃ (690 mg, 5 mmol, 2.5 equivalents) was added to a solution of compound L3 (448 mg, 2 mmol, 1.0 equivalents) in DMF (10 mL), followed by the addition of BnBr (359 mg, 2.1 mmol, 1.05 equivalents). The mixture was stirred at rt. for 18 hours under a N₂ atmosphere. The mixture was concentrated and purified by silica gel (PE:EA = 5:1) to yield crude compound L4 (400 mg, yield: 64%) as a yellow solid.

[0576] Preparation of 6-(benzyloxy)quinoline-4-carboxynitrile (L5)

[0577] A mixture of compound L4 (1.45 g, 4.62 mmol, 1.0 equivalent), Zn(CN)2 (813 mg, 6.92 mmol, 1.5 equivalent), and Pd(PPh3)4 (320 mg, 0.77 mmol, 0.06 equivalent) in dry DMF (25 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was concentrated, the residue was diluted with EA and washed with water, dried over Na2SO4, concentrated, and purified by silica gel (PE:EA = 5:1) to give compound L5 (1.27 g, yield: 83%) as a yellow solid.

[0578] Preparation of 6-(benzyloxy)quinoline-4-carboxylic acid (L6)

[0579] KOH (258 mg, 4.61 mmol, 4.0 equivalent) was added to a solution of compound L5 (300 mg, 1.15 mmol, 1.0 equivalent) in ethane-1,2-diol (8 mL), and the mixture was stirred overnight at 130 °C under a nitrogen atmosphere. The mixture was acidified to a pH of about 4-5 with 2N HCl, the precipitate was filtered, and dried to give compound L6 (300 mg, yield: 93%) as a grayish-white solid.

[0580] Preparation of 6-hydroxyquinoline-4-carboxylic acid (L7)

[0581] Pd / C (20 mg, 10%) was added to a solution of compound L6 (200 mg, 0.716 mmol, 1.0 equivalent) in MeOH (10 mL), and the mixture was stirred at rt. for 6 hours under H2 atmosphere. The mixture was filtered, and the filtrate was concentrated to give compound L7 (135 mg, yield: 100%) as a grayish-white solid.

[0582] Preparation of 6-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)quinoline-4-carboxylic acid (L9)

[0583] A mixture of compound L7 (135 mg, 0.716 mmol, 1.0 equivalent), compound L8 (257 mg, 0.6454 mmol, 0.9 equivalent), and CS2CO3 (700 mg, 2.148 mmol, 3.0 equivalent) in dry DMF (20 mL) was stirred overnight at 60 °C under a nitrogen atmosphere. This mixture containing L9 was used in the next step without further treatment.

[0584] Preparation of tert-butyl 4-(3-((4-(((2-ethoxy-2-oxoethyl)carbamoyl)quinoline-6-yl)oxy)propyl)piperazine-1-carboxylic acid (L11)

[0585] Compound L10 (100 mg, 0.716 mmol, 1.0 equivalent), HATU (360 mg, 0.947 mmol, 1.3 equivalent), and DIEA (0.5 mL) were added to the reaction mixture of compound L9, and the resulting mixture was stirred overnight at rt. under N2 atmosphere. The mixture was concentrated, and the residue was purified by silica gel (DCM:MeOH = 50:1) to give compound L11 (175 mg, yield: 49%) as a yellow solid.

[0586] Preparation of 2-(6-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)quinoline-4-carboxamido)acetic acid (L12)

[0587] LiOHH2O (44 mg, 1.05 mmol, 3.0 equivalent) was added to a solution of compound L11 (175 mg, 0.35 mmol, 1.0 equivalent) in THF (6 mL) and water (6 mL), and the mixture was stirred overnight at RT under a N2 atmosphere. The mixture was acidified to a pH of about 4-5 with 2N HCl and then concentrated to produce crude compound L12 as a grayish-white solid.

[0588] Preparation of (S)-1-2-methyl-4,4-difluoropyrrolidine-1,2-dicarboxylic acid tert-butyl ester (L16)

[0589] 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 DCM (10 mL) containing DAST (3.36 g, 20.84 mmol, 2.6 equivalent) was added. The resulting mixture was stirred overnight at rt under N2. The solution was added to ice water, concentrated, and the residue was diluted with EA, washed with water (20 mL × 3) and brine (20 mL × 3), dried over Na2SO4, concentrated under vacuum, and purified by flash chromatography on silica gel (PE:EA = 20:1-4:1) to give compound L16 as a yellow oil (2.0 g, yield: 94%).

[0590] Preparation of (S)-2-carbamoyl-4,4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (L17)

[0591] NH3 was added to a solution of compound L16 (2.0 g, 7.547 mmol, 1.0 equivalence) in MeOH (30 mL). The resulting mixture was stirred overnight at 50 °C. The reaction was concentrated under vacuum and purified by flash chromatography on silica gel (PE:EA = 12:1–4:1) to give compound L17 as a yellow solid (1.82 g, yield: 96%).

[0592] Preparation of (S)-2-cyano-4,4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (L18)

[0593] 2,4,6-trichloro-1,3,5-triazine (1.87 g, 10.2 mmol, 1.5 equivalent) was added to a solution of compound L17 (1.7 g, 6.8 mmol, 1.0 equivalent) in DMF (20 mL) at 0 °C. The resulting mixture was stirred at rt for 1 hour under N2. The solution was added to ice water, concentrated, and the residue was diluted with EA, washed with water (20 mL × 3) and brine (20 mL × 3), dried over Na2SO4, concentrated under vacuum, and purified by flash chromatography on silica gel (PE:EA = 50:1–20:1) to give compound L18 as a white solid (1.4 g, yield: 83%).

[0594] Preparation of (S)-4,4-difluoropyrrolidine-2-carboxynitrile (C)

[0595] TFA (0.1 mL) was added to a solution of compound L18 (81 mg, 0.35 mmol, 1.0 equivalent) in DCM (4 mL) at 0 °C. The resulting mixture was stirred at rt for 6 hours under N2. The mixture was concentrated to produce crude compound C (100 mg, yield: 100%) in the form of a brown oil.

[0596] Preparation of (S)-4-(3-((4-((2-(2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)quinoline-6-yl)oxy)propyl)piperazine-1-carboxylic acid tert-butyl ester (L13)

[0597] Compound C (100 mg), HATU (172 mg, 0.45 mmol, 1.3 equivalence), and DIEA (0.5 mL) were added to the reaction mixture of crude compound L12, and the resulting mixture was stirred overnight at rt. under N2 atmosphere. The mixture was concentrated, and the residue was purified by silica gel (DCM:MeOH = 50:1) to yield compound L13 (70 mg) as a yellow solid.

[0598] Preparation of tert-butyl piperazine-1-carboxylate (L14)

[0599] TFA (0.1 mL) was added to a solution of compound L13 (70 mg) in DCM (4 mL) at 0 °C. The resulting mixture was stirred at rt for 6 hours under N2. The mixture was concentrated to produce crude compound L14 (60 mg, yield: 100%) as a yellow solid.

[0600] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl 4-(4-(3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-6-yl)oxy)propyl)piperazin-1-yl)-4-oxobutyrate (Compound 12)

[0601] Compound B (28 mg, 0.06 mmol, 1.0 equivalent), HATU (30 mg, 0.078 mmol, 1.3 equivalent), and DIEA (0.1 mL) were added to the reaction mixture of crude compound L14, and the resulting mixture was stirred overnight at rt. under N2 atmosphere. The mixture was concentrated, and the residue was purified by preparative HPLC to yield the title compound (compound 12) (10 mg) as a yellow solid. 1H-NMR(CD3OD,400MHz):0.81(d,J=4.4Hz,3H),0.93(d,J=4.8Hz,3H),1.02(s,3H),1.29-1.32(m,4H)1.46(m,2H),1.88-1.90(m,1H) ,1.93-1.97(m,1H),2.08-2.11(m,2H),2.19-2.26(m,2H),2.48-2.53(m,2H),2.58-2.60(m,2H),2.65-2.67(m,2H),2.70-2.75(m,6 H),2.87-2.95(m,1H),3.44(d,J=4.0Hz,1H),3.59-3.62(m,4H),3.94(d,J=1.6Hz,1H),4.10-4.17(m,1H),4.28-4.35(m,3H),4.78- 4.81(m,2H),5.05(s,1H),5.11-5.13(m,1H),7.45-7.47(m,1H),7.56-7.57(m,1H),7.95-7.98(m,2H),8.74-8.75(m,2H).MS(ESI)[C 48 H 54 F2N6O 11 The calculated value of [M+H](m / z) is 928.38, and the experimental value is 929.3. + HPLC: 214 nm, 11.762 min, 98.726%; 254 nm, 11.764 min, 98.896%.

[0602] Example 13: Synthesis of a conjugate of triptolide and tri-GalNHAc (Compound 13)

[0603]

[0604] The following scheme illustrates the synthetic route for preparing the title compound.

[0605] Option 16.

[0606]

[0607] Preparation of (6-hydroxyhexyl)carbamate (M2)

[0608] Et3N (2.22 g, 21.99 mmol, 3.0 equivalent) was added to a solution of compound M1 (860 mg, 7.33 mmol, 1.0 equivalent) in DCM (10 mL), followed by Cb2-Cl (1.12 g, 6.60 mmol, 0.9 equivalent). The resulting mixture was stirred overnight at rt under N2. Water was added, the mixture was concentrated under vacuum, and purified by flash chromatography on silica gel (PE:EA = 20:1–4:1) to give compound M2 as a white solid (660 mg, yield: 37%).

[0609] Preparation of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((6-(((benzyloxy)carbonyl)amino)hexyl)oxy)tetrahydro-2H-pyran-3,4-diacetic acid diester (M4)

[0610] Sc(OTf)3 (98 mg, 0.199 mmol, 0.1 equivalent) was added 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). The resulting mixture was stirred overnight at 90 °C under N2. The reaction was passed through NaHCO3. 3(水溶液) Quenching and concentrating (10 mL), the residue was diluted with water and extracted with EA (15 mL × 3). The combined organic layers were washed with water (20 mL × 3) and brine (20 mL × 3), respectively, and dried over Na₂SO₄. After concentration under vacuum and purification by flash chromatography on silica gel (PE:EA = 50:1-8:1), compound M4 was obtained as a colorless oil (700 mg, yield: 61%).

[0611] Preparation of (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((6-aminohexyl)oxy)tetrahydro-2H-pyran-3,4-diacetate diester (M5)

[0612] Pd / C (80 mg, 10%) was added to a solution of compound M4 (700 mg, 1.20 mmol, 1.0 equivalent) in MeOH (10 mL). The resulting mixture was stirred at rt for 1 hour under H2. The mixture was filtered, and the filtrate was concentrated under vacuum to give compound M5 (530 mg, yield: 95%) as a white solid.

[0613] Preparation of compound M7

[0614] HATU (515 mg, 1.356 mmol, 3.5 equivalences) was added to a solution of compound M5 (530 mg, 1.188 mmol, 3.5 equivalences) and compound M6 (160 mg, 0.339 mmol, 1.0 equivalences) in DMF (8 mL) at 0 °C, followed by the addition of DIEA (437 mg, 3.39 mmol, 10.0 equivalences). The resulting mixture was stirred overnight at 0 °C under N2. The reaction was quenched with water (10 mL), concentrated under vacuum, and purified by HPLC to give compound M7 as a white solid (310 mg, yield: 52%).

[0615] Preparation of compound M8

[0616] NaOMe (30 mg) was added to a solution of compound M7 (310 mg, 0.569 mmol, 1.0 equivalent) in MeOH (8 mL). The resulting mixture was stirred overnight under N2 at rt, then concentrated under vacuum and purified by HPLC to give a white solid (230 mg, yield: 94%).

[0617] Pd / C (50 mg, 10%) was added to MeOH (8 mL) containing 230 mg of freshly prepared white solid (0.167 mmol, 1.0 equivalence). The resulting mixture was stirred at rt for 1 hour under H2. The mixture was filtered, and the filtrate was concentrated under vacuum to yield compound M8 (200 mg, yield: 95%) as a white solid.

[0618] Preparation of compound 13

[0619] DIEA (62 mg, 0.483 mmol, 1.0 equivalence) was added to a solution of compound M8 (200 mg, 0.161 mmol, 1.0 equivalence) and compound M9 (74 mg, 0.161 mmol, 1.0 equivalence) in DMF (8 mL) at 0 °C, followed by the addition of HATU (92 mg, 0.241 mmol, 1.5 equivalence). The resulting mixture was stirred overnight at 0 °C under N2. The reaction was quenched with water (10 mL), concentrated under vacuum, and purified by HPLC to give compound 13 as a white solid (120 mg, yield: 44%). MS (ESI) [C 78 H 125 N7O 33 ] + The calculated value of (m / z) was 1687.83, and the experimental values ​​were 1687 and 1688 [M+H]+. HPLC: 254 nm, no absorption; 220 nm, 9.946 min, 99.73%.

[0620] Example 14: Synthesis of a conjugate of triptolide and tri-GalNHAc (Compound 14)

[0621]

[0622] The following scheme illustrates the synthetic route for preparing the title compound.

[0623] Option 17.

[0624]

[0625]

[0626] Preparation of (1,7-bis((3-aminopropyl)amino)-4-(3-((3-aminopropyl)amino)-3-oxopropyl)-1,7-dioxohept-4-yl)carbamate (N2)

[0627] TFA (5 mL) was added to a solution of compound N1 (500 mg, 0.59 mmol, 1.0 equivalent) in DCM (2 mL) at 0 °C and stirred at rt for 2 h. 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 produce N2 in the form of a TFA salt, which was used in subsequent reactions without any further purification (323 g, yield >95%).

[0628] Preparation of N4

[0629] HATU (894 mg, 2.35 mmol, 4.0 equivalence) and DIPEA (760 mg, 5.88 mmol, 10.0 equivalence) were added to a solution of compound N3 (950 mg, 2.06 mmol, 3.5 equivalence) in DMF (10 mL) under a nitrogen atmosphere at 0 °C. The mixture was stirred at rt for 30 min, and then a solution of compound N2 (323 mg, 0.59 mmol, 1.0 equivalence) in DMF (2 mL) was added and stirred at rt overnight. The reaction mixture was concentrated and the residue was quenched with cooling water. After extraction with DCM, the organic phase was washed with saturated NaHCO3, water, and brine, dried over Na2SO4, and concentrated. The residue was purified by C18 column chromatography to give compound N4 (1.0 g, yield: 90%) as a white solid.

[0630] 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)hexaneamino)propyl)-4-(3-((3-(6-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexaneamino)propyl)amino)-3-oxopropyl)-4-aminoheptanediamide (N5)

[0631] 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 rt for 2 h under a N2 atmosphere. The mixture was concentrated, and the residue was purified by preparative HPLC (water containing 20% ​​to 40% ACN) to yield the compound as a white solid (760 mg, yield: 96%).

[0632] 10% Pd / C (15 mg) was added to a solution of freshly prepared solid (410 mg, 0.27 mmol, 1.0 equivalence) in MeOH (10 mL) and stirred at rt for 2 hours under H2 atmosphere. The mixture was filtered and concentrated to produce N5 as a white solid, which was used in the next step without any further purification (335 mg, yield: 89%).

[0633] 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-dodecylhydrotris(epoxyvinyl)[2',3':4b,5;2",3":6,7;2"',3"':8a,9]phenanthro[1,2-c]furan-8-yl-4-((1,29-bis(((2S,3R,4R,5R,6R)-3-acetyl) Amino-4,5-dihydroxy-6-(hydroxymethyl)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)hexaneamino)propyl)amino)-3-oxopropyl)-6,12,18,24-tetraoxo-7,11,19,23-tetraazanonadecan-15-yl)amino)-4-oxobutyrate (compound 14)

[0634] HATU (121 mg, 0.32 mmol, 1.3 equivalence) and DIPEA (95 mg, 0.74 mmol, 3.0 equivalence) were added to a solution of compound N5 (335 mg, 0.25 mmol, 1.0 equivalence) and compound N6 (124 mg, 0.27 mmol, 1.1 equivalence) in DMF (10 mL) under a nitrogen atmosphere at 0 °C. The mixture was stirred at rt for 2 h. The reaction mixture was concentrated and purified by preparative HPLC (water containing 18% to 38% ACN) to give compound 14 (170 mg, yield: 36%) as a white solid. 1 H-NMR(DMSO-d6,400MHz):0.72(d,J=6.8Hz,3H),0.83(d,J=6.8Hz,3H),0.91(s,3H),1.20-1.31(m,9H),1.41-1.50(m,19H),1 .80(s,9H),1.86-1.90(m,2H),2.04(t,J=7.2Hz,1H),2.28(t,J=6.6Hz,1H),3.01-3.06(m,13H),3.29(t,J=6.0Hz,1H),3.41- 3.44(m,3H),3.47-3.55(m,20H),3.64-3.65(m,3H),3.67-3.72(m,7H),3.95(s,1H),4.23(d,J=8.4Hz,3H),4.47(d,J=4.2Hz, 3H),4.54-4.60(m,6H),4.74-4.87(m,2H),4.96(s,1H),7.29(s,1H),7.62(d,J=9.2Hz,3H),7.75(t,J=5.6Hz,6H).MS(ESI)[C 85 H 136 N 10 O 32 The calculated value of [m / z] is 1808.92, and the experimental value is 1809.3, [M+H] + HPLC: 220 nm, 9.042 min, 99.36%; 254 nm, 9.043 min, 100%.

[0635] Example 15 - In vivo anti-cancer assessment

[0636] Huh-7 HCC animal model

[0637] To evaluate the antitumor efficacy of the triptolide conjugate disclosed in this paper against solid tumors, huh-7 cells (approximately 10 × 10⁻⁶ cells per cell line) were used. 6 (One cell) was injected into the right side of a male nude mouse. When the tumor reached approximately 150 mm... 3When determining the tumor volume, mice were randomly divided into 4 groups of 7 or 8 mice each and treated as follows. Tumor volume was measured twice weekly and estimated using the following formula: Tumor volume (V) = (L × W × W) ÷ 2, where W is the tumor width and L is the tumor length.

[0638] 1. Group 1 served as the control group, in which mice were administered a mordant (0.5% CMC-Na / sodium carboxymethyl cellulose, ip) daily for 3 weeks;

[0639] 2. Group 2 was the test group, in which mice were administered compound 1 (2.0 mg / kg, ip) daily for 3 weeks;

[0640] 3. Group 3 was the test group, in which mice were administered compound 2 (2.0 mg / kg, ip) daily for 3 weeks; and

[0641] 4. Group 4 was the positive control group, in which mice were administered lenvatinib (5.0 mg / kg, orally) daily for 3 weeks.

[0642] Tumor growth-treatment time curve at Figure 1 The diagram shows that as early as 4 days after treatment, the triptolide conjugate group (for the group treated with compound 1, V = 245 mm) showed significant improvement. 3 And for the group treated with compound 2, V = 315 mm 3 ) and lenvatinib group (V=381mm) 3 Both showed improvement compared to the control group (V = 598 mm). 3 Tumor growth was significantly reduced. This significant inhibition of tumor growth persisted until the end of the experiment. By the end of treatment, compared to the mean tumor volume before treatment, the mean tumor volume in the control group and the lenvatinib group increased by 15-fold and 9-fold, respectively, while the mean tumor volume in the triptolide conjugate treatment group increased by only 2.0-fold and 2.7-fold, respectively, compared to the mean tumor volume before treatment. Figure 2 The mean tumor weight after 21 days of treatment shown in the figure indicates that the tumor inhibition rate of the treated groups was 88.3% for the compound 1 treatment group, 84.4% for the compound 2 treatment group, and 42.3% for the lenvatinib treatment group.

[0643] HepG-2HCC animal model

[0644] To evaluate the antitumor efficacy of the novel triptolide conjugate against solid tumors, HepG-2 cells (approximately 10 × 10⁻⁶ cells) were used. 6 (One cell) was injected into the right side of a male nude mouse. When the tumor reached approximately 150 mm... 3To determine the tumor volume, mice were randomly divided into 5 groups of 8 mice each and treated as follows. Tumor volume was measured twice weekly and estimated using the following formula: Tumor volume (V) = (L × W × W) ÷ 2, where W is the tumor width and L is the tumor length.

[0645] 1. Group 1 served as the control group, in which mice were administered a carrier (ip saline) daily for 4 weeks;

[0646] 2. In group 2, mice were administered conjugate 4 (2.0 mg / kmg, ip) daily for 4 weeks;

[0647] 3. In group 3, mice were administered conjugate 8 (6.0 mg / kmg, ip) daily for 4 weeks;

[0648] 4. In group 4, mice were administered conjugate 9 (6.0 mg / kg ip) daily for 4 weeks;

[0649] 5. In group 5, mice were administered conjugate 10 (6.0 mg / kmg, ip) daily for 4 weeks.

[0650] Tumor growth-treatment time curve at Figure 3 The study showed that tumors in mice began to shrink after 4 weeks of treatment with triptolide conjugates. After 28 days of treatment, the tumor size in the catalyst group increased 17.72-fold, while the tumors in all mice treated with triptolide conjugates (compounds / conjugates 4, 8, 9, and 10, respectively) gradually shrank to disappearance. Figure 3 The mouse body weight change-treatment time curve was observed in... Figure 4 The results show that, compared to the catalyst, the triptolide conjugate has no significant systemic toxicity in mice.

[0651] Although certain embodiments have been illustrated and described, it should be understood that changes and modifications may be made therein by those skilled in the art without departing from the broader aspects of the art as defined in the claims.

[0652] The embodiments illustratively described herein may be practiced appropriately in the absence of any element or elements, limitations or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” “containing,” etc., should be read broadly without limitation. Furthermore, the terminology and expressions used herein are for descriptive purposes and not for limitation, and are not intended to be used without any equivalents of the features or portions thereof shown and described, but it should be recognized that various modifications may be made within the scope of the claimed technology. Additionally, the phrase “consistently composed of…” will be understood to include those specifically described elements and additional elements that do not materially affect the essential and novel features of the claimed technology. The phrase “consisting of…” does not include any unspecified elements.

[0653] This disclosure is not limited to the specific embodiments described herein. Many modifications and variations can be made to the invention without departing from the spirit and scope of the invention, which will be apparent to those skilled in the art. In addition to those listed herein, functionally equivalent methods and compositions within the scope of this disclosure will be apparent to those skilled in the art based on the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. This disclosure is limited only by the terms of the appended claims and the entire scope of equivalents obtained by granting those claims. It should be understood that this disclosure is not limited to the specific methods, reagents, compounds, or compositions that may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be restrictive.

[0654] Furthermore, where features or aspects of this disclosure are described in accordance with the Markush Group, those skilled in the art will recognize that this disclosure is also described in accordance with any individual member or subgroup of the Markush Group.

[0655] As those skilled in the art will understand, for any and all purposes, especially for the purpose of providing written description, all scopes disclosed herein also include any and all possible subscopes and combinations thereof. Any listed scope can be readily considered sufficiently descriptive and implements the same scope being decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can be readily decomposed into lower thirds, middle thirds, and upper thirds, etc. As those skilled in the art will also understand, all languages ​​such as “at most,” “at least,” “greater than,” “less than,” etc., include the numbers stated and refer to a scope that can be subsequently decomposed into subscopes as discussed above. Finally, as those skilled in the art will understand, a scope includes each individual member.

[0656] All publications, patent applications, granted patents, and other documents mentioned in this specification are incorporated herein by reference, as each individual publication, patent application, granted patent, and other document is specifically and individually indicated as incorporated in its entirety by reference. If any definition contained in the text incorporated by reference contradicts a definition in this disclosure, the contained definition is excluded.

[0657] Other embodiments are described in the claims.

Claims

1. A compound of formula I, or its enantiomers, diastereomers, or pharmaceutically acceptable salts thereof. (I) in m1, m2, n1, and n2 are each independently 0, 1, 2, 3, or 4; R1, R2, and R3 are each independently OH, H, or a halogen group; M1 is selected from bond, -C=O-, -NH(CO)-, -(CO)NH- and -CH2O-; M2 is C; X1, X2, X3, X4, and X5 are each independently a bond, C=O, SS, NH(CO), (CO)NH, L2-NH(CO), NH(CO)-L2, (CO)NH-L2-NH(CO), L2-O, O-L2, or unsubstituted C1-C. 10 Alkylene; Each L2 is independently an unsubstituted C1-C 10 Alkylene; and X5 is attached to any one of R4, R5, R6, R7, and R8; the remaining R4, R5, R6, R7, and R8, which are not attached to X5, are independently H, OH, O(CO)NH2, halogen, or NH(Cl-C) 10 Acyl) or unsubstituted O (C1-C) 10 alkyl).

2. The compound according to claim 1, or its enantiomers, diastereomers, or pharmaceutically acceptable salts, wherein R1, R2, and R3 are each H.

3. The compound according to claim 1, or its enantiomers, diastereomers, or pharmaceutically acceptable salts thereof, wherein M1 is -C=O-, -NH(CO)-, or -(CO)NH-; and M2 is C.

4. The compound according to claim 1, or its enantiomers, diastereomers, or pharmaceutically acceptable salts, wherein X1 is a bond and X2 is NH(CO) or (CO)NH.

5. The compound according to claim 1, or its enantiomers, diastereomers or pharmaceutically acceptable salts thereof, wherein X3 is O; X4 is (CO)NH-L2-NH(CO); and X5 is NH(CO)-L2, L2-(CO)NH, L2-O or O-L2.

6. The compound according to claim 1, or its enantiomers, diastereomers, or pharmaceutically acceptable salts, wherein X5 is attached to R4; and R5, R6, R7, and R8 are each independently OH or NH (Cl-C 10 Acyl group).

7. The compound according to claim 1, or its enantiomers, diastereomers, or pharmaceutically acceptable salts, wherein X5 is attached to R5; and R4, R6, R7, and R8 are each independently OH or NH (Cl-C). 10 Acyl group).

8. The compound according to claim 1, or its enantiomers, diastereomers, or pharmaceutically acceptable salts, wherein X5 is attached to R8; and R4, R5, R6, and R7 are each independently OH or NH (Cl-C 10 Acyl group).

9. A compound having a structure selected from any of the following: 、 、 、 and ， Or its enantiomers, diastereomers or pharmaceutically acceptable salts.

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

11. Use of a compound according to any one of claims 1 to 9, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease or condition in a subject in need, wherein the disease or condition is (i) cancer selected from hepatocellular carcinoma, lung cancer, breast cancer, pancreatic cancer, biliary tract cancer, colorectal cancer, and glioblastoma; or (ii) an inflammatory disease and / or an autoimmune disease selected from membranous nephropathy, lupus nephritis, systemic lupus erythematosus, renal fibrosis, inflammatory bowel disease, Crohn's disease, intestinal fibrosis, liver fibrosis, asthma, acute lung injury, pulmonary hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis, and psoriasis.

12. The use according to claim 11, wherein the disease or symptom is cancer, the cancer being selected from hepatocellular carcinoma, lung cancer, breast cancer, pancreatic cancer, biliary tract cancer, colorectal cancer, and glioblastoma.

13. The use according to claim 11, wherein the disease or condition is associated with an inflammatory disease and / or an autoimmune disease selected from membranous nephropathy, lupus nephritis, systemic lupus erythematosus, renal fibrosis, inflammatory bowel disease, Crohn's disease, intestinal fibrosis, liver fibrosis, asthma, acute lung injury, pulmonary hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis, and psoriasis.

14. Use of the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating cancer, wherein the cancer is selected from hepatocellular carcinoma, lung cancer, breast cancer, pancreatic cancer, biliary tract cancer, colorectal cancer, and glioblastoma.

15. Use of the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating inflammatory diseases and / or autoimmune diseases, wherein the inflammatory diseases and / or autoimmune diseases are selected from membranous nephropathy, lupus nephritis, systemic lupus erythematosus, renal fibrosis, inflammatory bowel disease, Crohn's disease, intestinal fibrosis, liver fibrosis, asthma, acute lung injury, pulmonary hypertension, pulmonary fibrosis, diabetic nephropathy, diabetic cardiomyopathy, rheumatoid arthritis, and psoriasis.

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