Pharmaceutical complex, pharmaceutical composition and use thereof

Abstract

The invention provides a medicine complex, a medicine composition and application thereof. The drug complex comprises a structure shown as the following: Z-(linker-[R] m) n. In the formula, Z is a drug compound, R is a sugar, and m and n are independently integers from 1 to 6. The drug compound Z is a hepatitis virus target drug, a hepatitis B virus (HBV) drug, an apoptosis protein (IAP) antagonist, a multiple drug resistance (MDR) inhibitor or an analogue, a precursor, a prodrug and a derivative thereof.

Description

Technical Field

[0001] The present disclosure relates to a drug conjugate, and more particularly to a drug composition comprising such a drug conjugate, and use of the drug conjugate or drug composition in preparing a drug for treating hepatitis B, hepatitis C, viral hepatitis or other viral infections. Background Art

[0002] Tenofovir and Entecavir are first-line drugs used to treat hepatitis B. However, these types of drugs (nucleoside / nucleotide analogs) must be taken regularly and continuously to suppress the level of virus in the body. If the drug is stopped inappropriately or if there is a problem with the immune system, it often leads to very serious viral rebound and acute exacerbations of the hepatitis. Therefore, other treatments may be needed.

[0003] Inhibitor of apoptosis proteins (IAPs) are a family of anti-apoptotic proteins that play an important role in evading apoptosis because they can block apoptosis-signaling pathways and promote survival. In addition to cancer treatment, many IAP inhibitors (or IAP antagonists) have been shown to have the potential to treat hepatitis B. For example, birinapant (a synthetic small molecule) has been tested in clinical trials for the treatment of hepatitis B. However, from clinical studies, side effects such as cranial nerve palsies (or Bell's palsies) were observed when birinapant was used in combination with hepatitis B virus (HBV) drugs (e.g., tenofovir or entecavir). For another IAP inhibitor, APG-1387, its potential to treat patients with chronic hepatitis B has been recognized, but further clinical studies are still ongoing.

[0004]

[0005] Further investigation and analysis are needed to realize the full potential of IAP inhibitors and carbohydrate's liver targeting in the treatment of hepatitis B, hepatitis C or hepatitis-related diseases. Summary of the invention

[0006] In the present disclosure, a drug complex is provided that is more effective than conventional drugs in the treatment of hepatitis B. In addition, a drug composition comprising such a drug complex is described, as well as a method of treating hepatitis using the drug complex or drug composition.

[0007] According to some embodiments of the present disclosure, the drug complex has a structure shown in formula (I):

[0008] Z-(Linker-[R] m ) n Formula (I)

[0009] Wherein, in formula (I), Z is a drug compound, R is a sugar, and m and n are independently integers of 1 to 6.

[0010] In some embodiments, the drug compound Z is a hepatitis virus targeted drug, a hepatitis B virus (HBV) drug, a hepatitis C virus (HCV) drug, an inhibitor of apoptosis protein (IAP) antagonist, a multidrug resistance (MDR) inhibitor, or an analog, precursor, prodrug, or derivative thereof.

[0011] In some embodiments, the drug compound Z is selected from the group consisting of: Tenofovir, Tenofovir diisoproxil, Tenofovir alafenamide, Entecavir, Telbivudine, Adefovir, Adefovir dipivoxil, Lamivudine, Interferon-α-2A, Interferon-α-2B, Birinapant, Monomer Birinapant, Birinapant), LCL161, GDC-0152, GDC-0917, CUDC-427, APG-1387, DeBio-1143, Selgantolimod, BI-82, Zosuquidar, Glecaprevir, Pibrentasvir, Ombitasvir, Paritaprevir, Ritonavir, Sofosbuvir, Velpatasvir, Ledipasvir, Voxilaprevir, Daclatasvir, Asunaprevir, Telaprevir, Elbasvir, Grazoprevir, Ribavarin, Telaprevir, EDP-239, Alisporivir, Filibuvir, Mericitabine, Danoprevir, Velpatasvir, or their analogs, precursors, prodrugs, or derivatives.

[0012] In some embodiments, the sugar R is a monosaccharide, a disaccharide, a trisaccharide, a tetrasaccharide, an oligosaccharide, a polysaccharide or a derivative thereof.

[0013] In some embodiments, the linker is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylalkyl ... lalkenyl、heterocyclylalkynyl、aryl、heteroaryl、heterocyclyl、cycloalkyl、cycloalkenyl、alkylarylalkyl、alkylarylalkenyl、alkylarylalkynyl、alkenylarylalkyl、alkenylarylalkenyl、alkenylarylalkynyl、alkenylarylalkyl、alkenylarylalkenyl、alkenylarylalkynyl、alkenylarylalkyl、alkenylarylalkenyl、alkenylarylalkynyl、alkenylarylalkyl、alkenylarylalkenyl、alkenylarylalkynyl、alkenylarylalkynyl、alkenylarylalkyl、alkenylarylalkynyl ... rylalkynyl), alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl lkenylheteroarylalkynyl), alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl,alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, and alkynylhereroaryl, wherein one or more methylene groups may be interrupted or terminated by O, S, S(O), SO2, N(R8), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl; wherein R8 is hydrogen, acyl, aliphatic, or substituted aliphatic. aliphatic).

[0014] In some embodiments, the linker is selected from any one of the group consisting of Formula (LX1) to Formula (LX30):

[0015]

[0016]

[0017]

[0018]

[0019]

[0020]

[0021]

[0022]

[0023]

[0024] Wherein, in Formula (LX1) to Formula (LX30), Z is the position where the linker is bonded to the drug compound, and R is the position where the linker is bonded to the sugar.

[0025] In some embodiments, the sugar R is a monosaccharide, a disaccharide, and a trisaccharide, wherein the monosaccharide, the disaccharide, and the trisaccharide are independently unsubstituted or substituted with an acetyl group or an N-acetyl group, and wherein the drug compound Z is selected from the group consisting of: Entecavir, Adefovir, Telbivudine, Lamivudine, Tenofovir, GDC-0152, DeBio-1143, LCL161, Birinapant, and analogs, precursors, prodrugs, and derivatives thereof.

[0026] In some embodiments, in the drug complex, the drug compound Z is coupled to the linker to form a carbamate linkage (>NC(=O)-O-), an amide linkage (RC(=O)-N<), a carbonate linkage (RO-C(=O)-OR') or an ester linkage (RC(=O)-OR').

[0027] In some embodiments, the linker comprises at least triazole.

[0028] In some embodiments, the structure shown in formula (I) is further represented by formula (II):

[0029] Z-(Linker-[R] m )2 Formula (II)

[0030] Wherein, in formula (II), Z is the drug compound, R is the sugar, and m is independently an integer from 1 to 3.

[0031] In some embodiments, the structure represented by formula (I) is further represented by any one of formulas (IA1) to (IA4):

[0032]

[0033] In some embodiments, the structure represented by formula (I) is further represented by any one of formulas (IB1) to (IB11):

[0034]

[0035]

[0036]

[0037]

[0038]

[0039] In some embodiments, the structure represented by formula (I) is further represented by any one of formulas (IC1) to (IC11):

[0040]

[0041]

[0042]

[0043]

[0044] In some embodiments, the structure represented by formula (I) is further represented by any one of formulas (ID1) to (ID5):

[0045]

[0046]

[0047] In some embodiments, the structure shown in formula (I) is further represented by formula (IE1):

[0048]

[0049] In some embodiments, the structure represented by formula (I) is further represented by formula (IF1) or formula (IF2):

[0050] In some embodiments, the structure shown in formula (I) is further represented by formula (IG1):

[0051]

[0052] In some embodiments, the structure represented by formula (I) is further represented by any one of formula (IH1) to formula (IH3):

[0053] In some embodiments, the structure represented by formula (I) is further represented by formula (IJ1) or formula (IJ2):

[0054]

[0055]

[0056] According to some embodiments of the present disclosure, the pharmaceutical composition comprises:

[0057] Active ingredient, wherein the active ingredient comprises a drug complex having a structure shown in formula (I):

[0058] Z-(Linker-[R] m ) n Formula (I)

[0059] wherein, in formula (I), Z is a drug compound, R is a sugar, and m and n are independently integers from 1 to 6; and

[0060] At least one or more pharmaceutically acceptable excipients.

[0061] In some embodiments, the drug complex includes a first drug complex represented by formula (I), wherein in formula (I), the drug compound Z is a first drug compound X selected from the group consisting of: tenofovir, tenofovir diisoproxil, tenofovir alafenamide, entecavir, telbivudine, adefovir, adefovir dipivoxil, lamivudine, interferon-α-2A, interferon-α-2B, selgantolimod, BI-82 and zosuquidar, and analogs, precursors, prodrugs, derivatives thereof, or any HBV drug.

[0062] In some embodiments, the first drug complex of formula (I) is further represented by any one of formulas (IA1) to (IA4), any one of formulas (IC1) to (IC11), or formula (IE1), or formula (IF1), or formula (IF2), or formula (IG1):

[0063]

[0064]

[0065]

[0066]

[0067]

[0068] In some embodiments, the drug complex further includes a second drug complex represented by formula (I), and wherein in formula (I), the drug compound Z is a second drug compound Y, which is selected from the group consisting of Birinapant, monomer Birinapant, Xevinapant, LCL161, GDC-0152, GDC-0917, CUDC-427, APG-1387, DeBio-1143 or its analogs, precursors, prodrugs, derivatives, or any IAP inhibitor.

[0069] In some embodiments, the second drug complex of formula (I) is further represented by any one of formulas (IB1) to (IB11), any one of formulas (ID1) to (ID5), any one of formulas (IH1) to (IH3), or formula (IJ1) or formula (IJ2):

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077] In some embodiments, the first drug complex is a compound represented by formula (IA1), and the second drug complex is a compound represented by formula (IB1):

[0078]

[0079]

[0080] In some embodiments, the first drug complex and the second drug complex are each administered at a dose of 0.1 mg / kg to 100 mg / kg.

[0081] In some embodiments, the sugar R is a monosaccharide, a disaccharide, a trisaccharide, a tetrasaccharide, an oligosaccharide, a polysaccharide or a derivative thereof.

[0082] In some embodiments, the linker is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, heterocyclo, cycloalkyl, cycloalkenyl, alkarylalkyl, alkarylalkenyl, alkarylalkynyl, alkarylalkyl, alkarylalkenyl, alkarylalkynyl, alkynearalkyl, alkynearalkenyl, alkynearalkynyl, Alkheteroaralkyl, alkheteroaralkenyl, alkheteroaralkynyl, alkenheteroaralkyl, alkenheteroaralkenyl, alkenheteroaralkynyl, alkyneheteroaralkyl, alkyneheteroaralkenyl, alkyneheteroaralkynyl, alkyneheterocycloalkyl, alkyneheterocycloalkenyl, alkyneheterocycloalkynyl, alkyneheterocycloalkyl, alkyneheterocycloalkenyl, alkyneheterocycloalkynyl, alkyneheterocycloalkyl, alkyneheterocycloalkenyl, alkyneheterocycloalkynyl, alkaryl, alkaryl, alkaryl, alkaryl, alkaryl, alkaryl, and alkarylheteroaryl, wherein one or more methylene groups may be replaced by O, S, S(O), SO2, N(R) 8 ), C(O), substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic group; wherein R 8 is hydrogen, acyl, aliphatic or substituted aliphatic.

[0083] In some embodiments, the pharmaceutical composition is prepared into tablets, capsules, granules, powders, solutions, syrups, sprays, injections or inhalations.

[0084] In some embodiments, the at least one or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, extenders, binders, blending agents, surfactants, emulsifiers, dispersing agents, defoamers, lubricants, nonstick agents, blenders, coating materials, glidants, anti-sticking agents, diluents, dyes, pigments, dispersants, wetting agents, and combinations thereof.

[0085] According to some embodiments, a method of treating hepatitis is described, wherein the method comprises administering a therapeutically effective dose of the drug complex to a patient suffering from hepatitis (hepatitis B, hepatitis C, viral hepatitis, etc.).

[0086] According to some embodiments, a method of treating hepatitis is described, wherein the method comprises administering a pharmaceutical composition to a patient suffering from hepatitis.

[0087] In some embodiments, the drug complex or drug composition of the present disclosure is more effective than conventional drugs in treating hepatitis B. For example, compared with conventional hepatitis B treatment methods, the drug complex or drug composition can further reduce the levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), while increasing the level of hepatitis B surface antibody (anti-HBsAg). Through preliminary evaluation, the inventors also found that modifying HCV drugs to form drug complexes with similar linkers and sugars may also be expected to provide more effective hepatitis C treatment.

[0088] To make the above content clearer and easier to understand, the embodiments are described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0089] The accompanying drawings are included to provide a further understanding of the present disclosure and are incorporated in and constitute a part of this specification. The accompanying drawings illustrate exemplary embodiments of the present disclosure and together with the description serve to explain the principles of the present disclosure.

[0090] Figure 1 A flow chart showing the synthesis of the drug complex of formula (IA1);

[0091] Figure 2 A flow chart showing the synthesis of the drug conjugate of formula (IB1);

[0092] Figure 3 A flow chart showing the synthesis of the drug complex of formula (IC1);

[0093] Figure 4 A flow chart showing the synthesis of the drug complex of formula (ID1);

[0094] Figure 5 A flow chart showing the synthesis of the drug complex of formula (IE1);

[0095] Figure 6 A flow chart showing the synthesis of the drug complex of formula (IF1);

[0096] Figure 7 A flow chart showing the synthesis of the drug complex of formula (IG1);

[0097] Figure 8 A flow chart showing the synthesis of the drug complex of formula (IH1);

[0098] Fig. 9 A flow chart showing the synthesis of the drug complex of formula (IJ1);

[0099] Fig.10 Graph showing HBsAg levels of different entecavir-based hepatitis B treatment groups in an in vitro cell line experiment according to some embodiments of the present disclosure;

[0100] Fig.11 A graph showing HBsAg levels in an in vitro cell line experiment of different Birinapant-based hepatitis B treatment groups according to some embodiments of the present disclosure;

[0101] Fig.12 Graph showing HBsAg levels in in vitro cell line experiments of different tenofovir-based hepatitis B treatment groups according to some embodiments of the present disclosure;

[0102] Fig.13 A graph showing HBsAg levels in an in vitro cell line experiment of different LCL161-type hepatitis B treatment groups according to some embodiments of the present disclosure;

[0103] Fig.14 Graph showing HBsAg levels in in vitro cell line experiments of different Telbivudine-based or Adefovir-based hepatitis B treatment groups according to some embodiments of the present disclosure;

[0104] Fig.15 Graph showing HBsAg levels and HBeAg levels (HBeAg levels) of in vitro cell line experiments of different hepatitis B treatment groups according to some embodiments of the present disclosure;

[0105] Fig.16A A graph showing HBsAg levels and HBeAg levels in in vitro cell line experiments of different hepatitis B treatment groups according to some embodiments of the present disclosure;

[0106] Fig. 16B A graph showing the hepatitis B virus (HBV) DNA levels (HBV DNA levels) of in vitro cell line experiments of different hepatitis B treatment groups according to some embodiments of the present disclosure;

[0107] Fig.17A and Fig. 17B A graph showing HBsAg levels in animal experiments of different hepatitis B treatment groups according to some embodiments of the present disclosure;

[0108] Fig.18A and Fig.18B A graph showing HBeAg levels in animal experiments of different hepatitis B treatment groups according to some embodiments of the present disclosure;

[0109] Fig.19A and Fig.19B A graph showing HBV DNA levels in animal experiments of different hepatitis B treatment groups according to some embodiments of the present disclosure;

[0110] Fig. 20 The results of observation on hair loss in C3H mice after administration of different hepatitis B treatment groups according to some embodiments of the present disclosure are as follows;

[0111] Fig.21 For some embodiments of the present disclosure, the anti-HBsAg levels of animal experiments in different hepatitis B treatment groups are shown;

[0112] Fig.22A and Fig. 22B The figure is a graph of HBsAg levels in an animal experiment of an entecavir-based hepatitis B treatment group according to some embodiments of the present disclosure;

[0113] Fig.23A and Fig. 23B The figure is a graph of HBeAg levels in an animal experiment of an entecavir-based hepatitis B treatment group according to some embodiments of the present disclosure;

[0114] Fig.24A and Fig. 24B The figure is a graph of HBV DNA levels in an animal experiment of an entecavir-based hepatitis B treatment group according to some embodiments of the present disclosure;

[0115] Fig.25A and Fig.25B A graph showing HBsAg levels in animal experiments of a Birinapant-based hepatitis B treatment group according to some embodiments of the present disclosure;

[0116] Fig.26A and Fig.26B A graph showing HBeAg levels in animal experiments of Birinapant-based hepatitis B treatment groups according to some embodiments of the present disclosure;

[0117] Fig.27A and Fig.27BGraph showing HBV DNA levels in birinapant-based hepatitis B treatment groups in animal experiments according to some embodiments of the present disclosure. DETAILED DESCRIPTION

[0118] In the present disclosure, a drug complex having a structure shown in formula (I) is described:

[0119] Z-(Linker-[R] m ) n Formula (I)

[0120] Wherein, in formula (I), Z is a drug compound, R is a sugar, and m and n are independently integers of 1 to 6.

[0121] In an exemplary embodiment, the drug compound Z is a hepatitis virus target drug, a hepatitis B virus (HBV) drug, a hepatitis C virus (HCV) drug, an inhibitor of apoptosis protein (IAP) antagonist, a multidrug resistance (MDR) inhibitor, or an analog, precursor, prodrug, or derivative thereof. In an exemplary embodiment, since the drug complex is used to treat hepatitis B, the drug compound Z used is selected from HBV drugs or IAP antagonists. In some embodiments, the drug complex is used for the treatment of hepatitis C. In some other embodiments, the drug complex is used for the treatment of human immunodeficiency virus (HIV). However, the present disclosure is not limited thereto. In some optional embodiments, when the drug complex is used to treat other diseases, other types of drugs can be used to form the drug complex shown in formula (I).

[0122] In some embodiments, when the drug compound Z is a HBV drug or an IAP antagonist, the drug compound Z is selected from the group consisting of: Tenofovir, Tenofovir diisoproxil, Tenofovir alafenamide, Entecavir, Telbivudine, Adefovir, Adefovir dipivoxil, Lamivudine, Interferon-α-2A, Interferon-α-2B, Birinapant, Monomer Birinapant, Birinapant), Xevinapant, LCL161, GDC-0152, GDC-0917, CUDC-427, APG-1387, Selgantolimod, BI-82, and Zosuquidar or their analogs, precursors, prodrugs, derivatives. For example, Tenofovir, Tenofovir diisoproxil, Tenofovir alafenamide, Entecavir, Telbivudine, Adefovir, Adefovir dipivoxil, Lamivudine, Interferon-α-2A, Interferon-α-2B, Selgantolimod, BI-82, and Zosuquidar are HBV drugs, and Birinapant, monomer Birinapant, LCL161, GDC-0152, GDC-0917, CUDC-427, and APG-1387 are IAP antagonists. However, the present disclosure is not limited thereto, and other HBV drugs, IAP antagonists, or analogs, precursors, derivatives thereof known in the art may be exemplified.

[0123] In some other embodiments, when the drug compound Z is an HCV drug, the drug compound Z is selected from the group consisting of Glecaprevir, Pibrentasvir, Ombitasvir, Paritaprevir, Ritonavir, Sofosbuvir, Velpatasvir, Ledipasvir, Voxilaprevir, Daclatasvir, r), Asunaprevir, Telaprevir, Elbasvir, Grazoprevir, Ribavarin, Telaprevir, EDP-239, Alisporivir, Filibuvir, Mericitabine, Danoprevir, and Velpatasvir, or their analogs, precursors, prodrugs, or derivatives.

[0124] HBV drugs (or their analogs, precursors, derivatives):

[0125]

[0126] IAP antagonists (or their analogs, precursors, derivatives):

[0127]

[0128] In some embodiments, the sugar R can be a monosaccharide, a disaccharide, a trisaccharide, a tetrasaccharide, an oligosaccharide, a polysaccharide, or a derivative thereof. The term "monosaccharide" may include allose, altrose, arabinose, cladinose, erythrose, erythrulose, fructose, D-fucitol, L-fucitol, fucosamine, fucose, fuculose, galactosamine, D-galactosaminitol, N-acetyl-galactosamine, galactose, glucosamine, N-acetyl-glucosamine, glucosaminitol, glucose, glucose-6-phosphate, gulose glyceraldehyde, and d-galactosamine. The monosaccharides may be in the D- or L-configuration.Monosaccharides may also be deoxy sugars (alcoholic hydroxyl groups are replaced by hydrogen), amino sugars (alcoholic hydroxyl groups are replaced by amine groups), thio sugars (alcoholic hydroxyl groups are replaced by thiol groups, or C=O is replaced by C=S, or the ring oxygen in a cyclic form is replaced by sulfur), seleno sugars, telluro sugars, aza sugars (ring carbons are replaced by nitrogen), imino sugars (ring oxygens are replaced by nitrogen), phosphano sugars (ring oxygens are replaced by phosphorus), phospha sugars (ring carbons are replaced by phosphorus), C-substituted monosaccharides (hydrogens on non-terminal carbon atoms are replaced by carbon), unsaturated monosaccharides, alditols (carbonyl groups are replaced by CHOH), aldonic acids (aldehyde groups are replaced by carboxyl groups), ketoaldonic acids, uronic acids, aldaric acids, and the like. Aminose sugars include amino monosaccharides, preferably galactosamine, glucosamine, mannosamine, fucosamine, quinovosamine, neuraminic acid, muramic acid, lactosediamine, acosamine, bacillosamine, daunosamine, desosamine, forosamine, garosamine, kanosamine, kansosamine, mycaminose, mycosamine, perosamine, pneumosamine, purpurosamine, and rhodosamine. In some embodiments, monosaccharides and analogs thereof may be further substituted.

[0129] In some embodiments, the linker in Formula (I) is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, heterocyclo, cycloalkyl, cycloalkenyl, alkarylalkyl, alkarylalkenyl, alkarylalkynyl, alkarylalkyl, alkarylalkenyl, alkarylalkynyl, alkynearalkyl, alkynearalkenyl, alkynearalkyl, alkynearalkenyl, alkynear Alkynyl, alkanehteroaralkyl, alkanehteroaralkenyl, alkanehteroaralkynyl, alkenehteroaralkyl, alkenehteroaralkenyl, alkenehteroaralkynyl, alkyneheteroaralkyl, alkyneheteroaralkenyl, alkyneheteroaralkynyl, alkanehterocycloalkyl, alkanehterocycloalkenyl, alkanehterocycloalkynyl, alkenehterocycloalkyl, alkenehterocycloalkenyl, alkenehterocycloalkynyl, alkyneheterocycloalkyl, alkenehterocycloalkenyl, alkenehterocycloalkynyl, alkyneheterocycloalkyl, alkyneheterocycloalkenyl, alkyneheterocycloalkynyl, alkaryl, alkenaryl, alkynearyl, alkanheteroaryl, alkenheteroaryl, and alkyneheteroaryl, wherein one or more methylene groups may be replaced by O, S, S(O), SO2, N(R 8 ), C(O), substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic group; wherein R 8 is hydrogen, acyl, aliphatic or substituted aliphatic.

[0130] In some embodiments, one, two or more linkers and one, two or more sugar R may be conjugated to a drug compound Z (e.g., n is 1 to 6). In addition, one, two or more sugar R may be conjugated to a linker (e.g., m is 1 to 6). In other words, the drug compound Z may be monovalent, bivalent, trivalent, or multivalent. In an exemplary embodiment, although one linker is shown to be connected to one sugar R, the present disclosure is not limited thereto. In some optional embodiments, two or more sugar Rs, or two or more drug compounds Z may be connected with one linker. In other words, the linker may have a branched structure. In certain embodiments, the linker comprises at least triazole. In some other embodiments, the drug compound Z in the drug complex is conjugated to a linker to form a carbamate bond (>NC(=O)-O-), an amide bond (RC(=O)-N<), a carbonate bond (RO-C(=O)-OR'), or an ester bond (RC(=O)-OR').

[0131] In some embodiments, the linker in formula (I) comprises L 1 (L 2 ) p Group, where L 1 The group is connected to the drug compound Z, and L 2 The group will be L1 The group is attached to the sugar R, wherein p is an integer from 1 to 4. 1 The group may include a carbamate, amide, ester, amidine, carboximidate, sulfonate, sulfate, sulfonamide, thioether, ether, imine, imide, thioamide, carbonate, thiocarbamide, carbamide, triazole, amine, oxime, thiocarbonate, thioester or thiocarbamate group, and the group is linked to the drug compound Z. L 2 The group is a single bond, an alkyl group containing 1 to 50 carbon atoms, an alkoxy group containing 1 to 50 carbon atoms, an alkenyl group containing 2 to 50 carbon atoms, or an alkenyloxy group containing 2 to 50 carbon atoms, and in the above-mentioned groups, the alkyl group, alkoxy group, alkenyl group, and alkenyloxy group may be straight chain or branched, at least one -CH2- may be substituted by -CO-, -COO-, -OCO-, -S-, -O-, or -NH-, at least one -CH2CH2- may be substituted by -CH=CH- or -C=C-, and at least one hydrogen in the above-mentioned -CH2-, -CH=, or -NH- may be substituted by halogen, trifluoromethyl, an alkyl group containing 1 to 20 carbon atoms, an alkoxy group containing 1 to 20 carbon atoms, or an alkanoyl group containing 1 to 20 carbon atoms, and at least one of the above-mentioned -O- may be substituted by phosphate, phosphonate, phosphinate, phosphine oxide, or the like. oxide, phosphoramide, phosphoramidate, (phosphite), phosphonite, phosphine, aminophosphine, phosphoramidite, phosphonamidite, phosphonamide, phosphinamide, or phosphorodiamidite groups.

[0132] In certain embodiments, L 1The group is a carbamate, amide, carbonate or ester, and L 2 The group is an alkyl group containing 1 to 20 carbon atoms, an alkoxy group containing 1 to 20 carbon atoms, an alkenyl group containing 2 to 20 carbon atoms, or an alkenyloxy group containing 2 to 20 carbon atoms, and the alkyl, alkoxy, alkenyl, and alkenyloxy groups in the above groups can be straight chain or branched, at least one -CH2- can be substituted by -CO-, -COO-, -OCO-, -S-, -O-, or -NH-, and at least one -CH2CH2- can be substituted by -CH=CH-.

[0133] In some embodiments, the linker has the structure:

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143] In the linkers (LX1) to (LX30) shown above, Z is the position where the linker is bound to the drug, and R is the position where the linker is bound to the sugar. Sugar R can be coupled to the linker through any free hydroxyl groups / free leaving groups on sugar R. In other words, the position where the linker is connected to the sugar is not particularly limited, as long as the linker is covalently linked to sugar R. In a similar manner, the linker can be coupled to drug compound Z through any free leaving group on drug compound Z. In some other embodiments, the linker can be omitted. In other words, drug compound Z can be directly coupled to sugar R.

[0144] In some embodiments, the structure shown in formula (I) is further represented by formula (II):

[0145] Z-(Linker-[R] m )2 Formula (II)

[0146] Wherein, in formula (II), Z is a drug compound, R is a sugar, and m is independently an integer from 1 to 3.

[0147] In other words, in formula (II), there are two sugar chains connected to the drug compound Z via a linker, and the sugars in the two sugar chains are selected from monosaccharides, disaccharides or trisaccharides.

[0148] In some embodiments, the structure represented by formula (I) is an entecavir-based compound, which is further represented by any one of formulas (IA1) to (IA3):

[0149]

[0150] In some other embodiments, the structure represented by formula (I) is an entecavir-based compound, which is further represented by any one of formulas (IA4) to (IA13):

[0151]

[0152]

[0153]

[0154] In some embodiments, the structure represented by Formula (I) is a birinapant-based compound, which is further represented by any one of Formulas (IB1) to (IB5):

[0155]

[0156]

[0157]

[0158] In some other embodiments, the structure represented by formula (I) is a birinapant-based compound, which is further represented by any one of formulas (IB6) to (IB19):

[0159]

[0160]

[0161]

[0162]

[0163]

[0164] In some embodiments, the structure represented by formula (I) is a tenofovir-based compound, which is further represented by any one of formulas (IC1) to (IC11):

[0165]

[0166]

[0167]

[0168]

[0169] In some embodiments, the structure represented by formula (I) is a LCL161-based compound, which is further represented by any one of formulas (ID1) to (ID4):

[0170]

[0171]

[0172] In some other embodiments, the structure shown in formula (I) is a LCL161-based compound, which is further represented by any one of formula (ID5) and formula (ID6):

[0173]

[0174] In some embodiments, the structure represented by formula (I) is a Telbivudine-based compound, which is further represented by formula (IE1):

[0175]

[0176] In some embodiments, the structure represented by formula (I) is an adefovir-based compound, which is further represented by formula (IF1):

[0177]

[0178]

[0179] In some other embodiments, the structure shown in formula (I) is an adefovir-based compound, which is further represented by formula (IF2):

[0180]

[0181] In some embodiments, the structure represented by formula (I) is a lamivudine-based compound, which is further represented by any one of formula (IG1) and formula (IG2):

[0182]

[0183] In some embodiments, the structure represented by formula (I) is a GDC-0152-based compound, which is further represented by any one of formula (IH1) to formula (IH4):

[0184]

[0185]

[0186] In some embodiments, the structure represented by formula (I) is a DeBio-1143-based compound, which is further represented by any one of formula (IJ1) and formula (IJ2):

[0187]

[0188] In some other embodiments, the pharmaceutical composition includes an active ingredient (active pharmaceutical ingredient) and at least one or more pharmaceutically acceptable excipients. For example, the active ingredient includes a drug complex having a structure shown in the above formula (I). In some embodiments, the drug complex includes a first drug complex represented by formula (I), and in formula (I), the drug compound Z is a first drug compound X, which is selected from the group consisting of: tenofovir, tenofovir diisoproxil, tenofovir alafenamide, entecavir, telbivudine, adefovir, adefovir dipivoxil, lamivudine, interferon-α-2A, interferon-α-2B, selgantolimod, BI-82 and zosuquidar, and analogs, precursors, prodrugs, and derivatives thereof. For example, the first drug complex represented by formula (I) is further represented by any one of the aforementioned formulas (IA1) to (IA3), any one of the formulas (IC1) to (IC11), formula (IE1) or formula (IF1). In some embodiments, the drug complex includes a second drug complex represented by formula (I), and wherein in formula (I), the drug compound Z is a second drug compound Y selected from the group consisting of: Birinapant, monomer Birinapant, Xevinapant, LCL161, GDC-0152, GDC-0917, CUDC-427, APG-1387, DeBio-1143 and analogs, precursors, prodrugs, and derivatives thereof. For example, the second drug complex represented by formula (I) is further represented by any one of the aforementioned formulas (IB1) to (IB5) or any one of the formulas (ID1) to (ID4).

[0189] In some embodiments, by combining a drug complex comprising a first drug compound X (HBV drug) and a second drug compound Y (IAP antagonist) in a drug composition, the therapeutic effect of hepatitis B can be effectively improved. In an exemplary embodiment, the first drug complex comprising the first drug compound X is a compound represented by formula (IA1), and the second drug complex comprising the second drug compound Y is a compound represented by formula (IB1).

[0190]

[0191] In an exemplary embodiment, the first drug complex and the second drug complex are administered at a dose of 0.1 mg / kg to 100 mg / kg, respectively. In some embodiments, the drug composition is prepared into tablets, capsules, granules, powders, solutions, syrups, sprays, injections or inhalations. In some embodiments, the at least one or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, extenders, binders, blending agents, surfactants, emulsifiers, dispersing agents, defoamers, lubricants, nonstick agents, blenders, coating materials, glidants, anti-sticking agents, diluents, dyes, pigments, dispersants, wetting agents and combinations thereof. For example, the excipients can be used alone or in combination.

[0192] In some other embodiments, methods for treating hepatitis (e.g., hepatitis B, hepatitis C, viral hepatitis, etc.) are described. For example, the method comprises administering a therapeutically effective amount of the above-mentioned drug complex to a patient suffering from hepatitis (hepatitis B, hepatitis C, viral hepatitis, etc.), or administering a drug composition to a patient suffering from hepatitis (hepatitis B, hepatitis C, hepatitis C, viral hepatitis, etc.). Compared with conventional hepatitis B treatment methods, by administering the drug complex or drug composition disclosed herein, the level of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and / or hepatitis B virus (HBV) DNA may be further reduced, while the level of hepatitis B surface antibody (anti-HBsAg) may be further increased. Similarly, modifying HCV drugs to form drug complexes with similar linkers and sugars may also be expected to provide more effective hepatitis C treatments.

[0193] Examples

[0194] In order to demonstrate that the drug complex or drug composition disclosed herein is superior to conventional methods in treating hepatitis (eg, hepatitis B), the following experiment was performed.

[0195] Synthesis example

[0196] The drug complex used in the experimental examples was synthesized according to the following experimental examples.

[0197] Synthesis Example A1: Synthesis of the drug complex of formula (IA1)

[0198] according to Figure 1 The drug complex of formula (IA1) was synthesized according to the scheme shown. Specifically, (3R, 4R, 5S, 6R)-6-(hydroxymethyl)-5-(((2S, 3R, 4S, 5R, 6R)-3, 4, 5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2, 3, 4-triol (20.00 g, 55.51 mmol) and sodium acetate (9.11 g, 111.02 mmol) were dissolved in acetic anhydride (Ac2O, 60 mL, 634.71 mmol) and refluxed at 90°C for 2 hours. The mixture was quenched with NaHCO3(aq) and extracted with ethyl acetate (EtOAc). The combined organics were dried over MgSO4 and concentrated. The crude product, compound 3, was used in the next step without purification.

[0199] Compound 3 solution ((3R,4S,5R,6R)-6-(acetoxymethyl)-5-(((2S,3R,4S,5S,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2,3,4-triacetate) (8.89 g, 13.09 mmol), Compound 1 (6-azidohexan-1-ol) (7.91 g, 55.23 mmol) and MS (1.00 g) was mixed in DCM (70 mL), BF3·OEt2 (6.6 mL, 52.38 mmol) was added at 0°C, stirred for 15 minutes, and then reacted at room temperature for 12 hours. The mixture was quenched with NaHCO3 (aq) and extracted with DCM. The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography using EtOAc:hexane (1:2) as the eluent to give compound 4 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-((6-azidohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate)) (3.34 g, 4.46 mmol, 34% yield).

[0200] A solution of compound 4 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-((6-azidohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) (500 mg, 0.66 mmol) was added to a 1M THF solution of PMe3 (1.32 mL, 1.32 mmol) in THF (5 mL) at 0°C. After warming to room temperature, the reaction mixture was stirred for 12 hours. The mixture was concentrated under reduced pressure to evaporate and remove the solvent. The crude product, compound 5, was used in the next step without purification.

[0201] Compound 54 ((1S, 2R, 4S) -4- (2-amino-6-oxo-1, 6-dihydro-9H-purin-9-yl) -2- (hydroxymethyl) -3-methylenecyclopentyl acetate) (195 mg, 0.61 mmol) was dissolved in tetrahydrofuran (THF) (3 mL) and dimethylformamide (DMF) (1 mL), and a solution of NMM (338 μL, 2.42 mmol) and 4-nitrophenyl chloroformate (244 mg, 1.21 mmol) in tetrahydrofuran (THF) (3 mL) was added at 0° C. Then, the reaction mixture was stirred at room temperature for 12 hours. A solution (THF 3 mL) of compound 5 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-((6-aminohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) (365 mg, 0.50 mmol) was added to the reaction mixture and stirred at room temperature for another 12 hours. The mixture was concentrated and purified by silica gel column chromatography using EtOAc:hexane (1:1) as eluent to give the product compound 89 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-6-((6-((((1R,3S,5S)-5-acetoxy-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-methylenecyclopentyl)methoxy)carbonyl)amino)hexyl)oxy)-2-(acetoxymethyl)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) (193 mg, 0.17 mmol, 34% yield).

[0202] Compound 89 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-6-((6-(((((1R,3S,5S)-5-acetoxy-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-methylenecyclopentyl)methoxy)carbonyl)amino)hexyl)oxy)-2-(acetoxymethyl)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) (193 mg, 0.17 mmol) was dissolved in methanol (MeOH) (2 mL), and NaOMe (15 mg, 0.28 mmol) was added at 0°C. After warming to room temperature, the reaction mixture was stirred for 12 hours. Neutralize with Amberlite IR-120 (H) until pH reaches 7. Filter the solution and remove the solvent. Purify the resulting substance by reverse phase silica gel column chromatography to obtain the product compound 90 ((1R, 3S, 5S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-5-hydroxy-2-methylenecyclopentyl)methyl (6-(((2R, 3R, 4R, 5S, 6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S, 3R, 4S, 5R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)hexyl)carbamate) (40 mg, 0.05 mmol, yield 30%). Compound 90 corresponds to the structure of formula (IA1).

[0203] The NMR analysis results of compound 90 are as follows: 1 H-NMR (400MHz, CD3OD): δ7.74 (s, 1H), 5.54-5.48 (m, 1H), 5.29-5.27 (m, 1H), 4.57 (s, 1H), 4.37-4.26 (m, 6H), 3.92-3.67 (m, 8H), 3.60-3.46 (m, 8H), 3.42-3.37 (m, 1H), 3.26-3.21 (m, 1H), 3.14-3.09 (m, 2H), 2.88-2.83 (m, 1H), 2.54-2.45 (m, 1H), 2.26-2.19 (m, 1H), 1.65-1.34 (m, 10H). The NMR results confirmed that the structure of formula (IA1) was obtained. From ESI-MS, a peak of a molecular weight corresponding to the structure of formula (IA1) was also identified.

[0204] Synthesis Examples A2 to A4: Synthesis of Drug Complexes of Formula (IA2) to (IA4)

[0205] In Synthesis Examples A2 to A4, the drug complexes of Formula (IA2) to Formula (IA4) were synthesized using organic synthesis techniques similar to Synthesis Example A1, and the synthesis process is not repeated. In order to prove that the drug complexes of Formula (IA2) to Formula (IA4) were successfully obtained, NMR and ESI-MS analyses were performed.

[0206] The NMR analysis results of the obtained drug complex of formula (IA2) are as follows: 1 H-NMR (400MHz, D2O): δ7.96-7.80 (br, 2H), 5.53-4.97 (br, 7H), 4.54-3.99 (m, 10H), 3.97-3.37 (m, 28H), 3.31-2.97 (m, 10H), 2.87-2.77 (m, 3H), 2.39-1.76 (m, 10H), 1.59-1.1 (m, 20H). The NMR results confirmed that the structure of formula (IA2) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IA2) was also identified.

[0207] The NMR analysis results of the obtained drug complex of formula (IA3) are as follows: 1 H-NMR (400MHz, CD3OD): δ8.07(s,1H),7.74(s,1H),5.52-5.48(m,1H),5.28-5.27(m,2H) ,5.25-5.24(m,1H),4.79-4.78(m,1H),4.49-4.28(m,8H),3.92-3.68(m,7H),3.62-3.48( m, 7H), 3.43-3.39 (m, 1H), 3.27-3.23 (m, 1H), 2.91-2.88 (m, 1H), 2.47-2.40 (m, 1H), 2.27-2.21 (m, 1H), 1.91-1.84 (m, 2H), 1.62-1.55 (m, 2H), 1.44-1.37 (m, 2H), 1.33-1.26 (m, 2H). The NMR results confirmed that the structure of formula (IA3) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IA3) was also identified.

[0208] The NMR analysis results of the obtained drug complex of formula (IA4) are as follows: 1H-NMR (400MHz, CD3OD): δ7.75(s,1H),7.72(s,1H),5.52-5.48(m,1H),5.27-5.26(m,1H),4.38-4. 34(m,7H),4.28-4.26(m,1H),3.91-3.68(m,7H),3.60-3.47(m,7H),3.41-3.37(m,1H),3.26-3.21( m, 1H), 2.90-2.85 (m, 1H), 2.77-2.73 (m, 2H), 2.53-2.46 (m, 1H), 2.45-2.41 (m, 2H), 2.26-2.20 (m, 1H), 2.03-1.96 (m, 2H), 1.93-1.85 (m, 2H), 1.64-1.56 (m, 2H), 1.46-1.39 (m, 2H), 1.35-1.28 (m, 2H). The NMR results confirmed that the structure of formula (IA4) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IA4) was also identified.

[0209] Synthesis Example B1: Synthesis of the drug complex of formula (IB1)

[0210] according to Figure 2 The drug complex of formula (IB1) was synthesized according to the scheme shown. Specifically, ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-((6-(phenoxy)-6-oxohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate (600 mg, 0.71 mmol) was dissolved in methanol (5 mL), 10% palladium carbon (60 mg, 0.1 w%) was added, and stirred for 3 hours under hydrogen atmosphere. The mixture was filtered through celite to remove palladium carbon, and the solvent was evaporated under reduced pressure to obtain a crude product compound (Compound 24). The crude product Compound 24 was used in the next step without purification.

[0211] Compound 80 (dibenzyl 5,5'-((6,6'-difluoro-1H,1'H-[2,2'-bisindole]-3,3'-diyl)bis(methylene))(3S,3'S,5R,5'R)-bis(3-ethoxypyrrolidine-1-carboxylate)) (300 mg, 0.34 mmol) was added to a solution of THF (30 mL), and 10 wt % of palladium on carbon (30 mg) was added. The reaction mixture was stirred at room temperature and reacted for 2 hours under a hydrogen atmosphere. After the reaction was completed, the resulting material was filtered and concentrated. The desired product was obtained as a yellow solid, named ((3S,3'S,5R,5'R)-((6,6'-difluoro-1H,1'H-[2,2'-bisindole]-3,3'-diyl)bis(methylene))bis(pyrrolidine-5,3-diyl)diacetate), numbered as compound 81.

[0212] Compound 81 (132 mg, 0.24 mmol) and compound 24 (6-(((2R,3R,4S,5R,6R)-3,4-diacetoxy-6-(acetoxymethyl)-5-(((2S,3R,4S,5S,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)hexanoic acid) (533 mg, 0.71 mmol) were dissolved in DCM (10 mL), and then HATU (280 mg, 0.74 mmol) and DIPEA (800 μL, 5.87 mmol) were added and stirred at room temperature for 12 hours. The mixture was purified by silica gel column chromatography to give a compound designated as compound 133 (450 mg, 0.22 mmol, yield 93%).

[0213] Compound 133 (450 mg, 0.21 mmol) was dissolved in a solution of methanol (6 mL) and dichloromethane (6 mL), and NaOMe (32 mg, 0.60 mmol) was added at 0°C. After warming to room temperature, the reaction mixture was stirred for 1 hour. The reaction was terminated with Amberlite IR-120 (H) and filtered off. The generated substance was purified by reverse phase silica gel column chromatography to obtain the product compound 134 (1,1'-((3S,3'S,5R,5'R)-((6,6'-difluoro-1H,1'H-[2,2'-bisindole]-3,3'-diyl)bis(methylene))bis(3-hydroxypyrrolidine-5,1-diyl))bis(6-(((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)hexan-1-one)) (200 mg, 0.15 mmol, yield 67%). The structure corresponding to compound 134 is formula (IB1).

[0214] The NMR analysis results of compound 134 (Formula (IB1)) are as follows: 1 H-NMR (400MHz, d-DMSO): δ12.11(s,1H),7.86-7.82(m,2H),7.41-7.38(m,2H),6.96- 6.90(m,2H),5.64(s,2H),5.11-5.08(m,3H),4.83-4.79(m,4H),4.66-4.63(m,4H),4. 56-4.49 (m, 8H), 4.25-4.17 (m, 5H), 3.84-3.38 (m, 32H), 3.31-3.22 (m, 10H), 2.47-2.41 (m, 4H), 1.95-1.83 (m, 4H), 1.75-1.72 (m, 4H), 1.67-1.62 (m, 4H), 1.51-1.46 (m, 4H). The NMR results confirmed that the structure of formula (IB1) was obtained. From ESI-MS, the peak of the molecular weight corresponding to the structure of formula (IB1) was also identified.

[0215] Synthesis Examples B2 to B11: Synthesis of Drug Complexes of Formula (IB2) to (IB11)

[0216] In Synthesis Examples B2 to B11, the drug complexes of Formula (IB2) to Formula (IB11) were synthesized using organic synthesis techniques similar to Synthesis Example B1, and the synthesis process is not repeated. In order to prove that the drug complexes of Formula (IB2) to Formula (IB11) were successfully obtained, NMR and ESI-MS analyses were performed.

[0217] The NMR analysis results of the obtained drug complex of formula (IB2) are as follows: 1 H-NMR (400MHz, CD3OD): δ8.21(s,2H),7.99-7.89(m,2H),7.14-7.10(m,2H),6.94-6.9 0(m,2H),5.16-5.07(m,4H),4.91-4.88(m,8H),4.65-4.53(m,4H),4.48-4.35(m,4H),4 .29-4.16 (m, 4H), 3.96-3.39 (m, 16H), 2.93-2.62 (m, 10H), 2.48-2.26 (m, 6H), 2.16-1.99 (m, 4H), 1.91-1.54 (m, 8H), 1.40-1.31 (m, 4H), 1.15-1.12 (m, 2H), 0.92-0.87 (m, 2H). The NMR results confirmed that the structure of formula (IB2) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IB2) was also identified.

[0218] The NMR analysis results of the obtained drug complex of formula (IB3) are as follows: 1 H-NMR (400MHz, D6-DMSO): δ11.30(s,2H),8.22-8.05(m,3H),7.90-7.81(m,2H),7.36- 7.28(m,1H),7.14-7.05(m,2H),6.97-6.80(m,2H),4.96-4.88(m,2H),4.76-4.58(m,8H ), 4.56-4.33 (m, 6H), 4.18-4.03 (m, 2H), 3.71-3.61 (m, 2H), 3.58-3.48 (m, 3H), 3.48-3.34 (m, 7H), 3.31-3.15 (m, 6H), 2.87-2.74 (m, 2H), 1.94-1.78 (m, 2H), 1.45-1.11 (m, 6H). The NMR results confirmed that the structure of formula (IB3) was obtained. From ESI-MS, the peak of the molecular weight corresponding to the structure of formula (IB3) was also identified.

[0219] The NMR analysis results of the obtained drug complex of formula (IB4) are as follows: 1H-NMR (400MHz, D6-DMSO): δ11.30(s,2H),8.24-8.12(m,3H),7.90-7.80(m,2H),7.37-7.30(m,1H) ),7.14-7.05(m,2H),6.97-6.81(m,2H),5.20-5.05(m,4H),4.94-4.76(m,6H),4.71-4.56(m,10H ), 4.55-4.41 (m, 4H), 4.40-4.28 (m, 4H), 4.24-4.02 (m, 4H), 3.84-3.73 (m, 3H), 3.68-3.57 (m, 4H), 3.56-3.38 (m, 8H), 3.08-2.97 (m, 3H), 2.86-2.73 (m, 2H), 1.95-1.79 (m, 2H), 1.45-1.11 (m, 7H). The NMR results confirmed that the structure of formula (IB4) was obtained. From ESI-MS, the peak of the molecular weight corresponding to the structure of formula (IB4) was also identified.

[0220] The NMR analysis results of the obtained drug complex of formula (IB5) are as follows: 1 H-NMR (400MHz, DMSO): δ13.87 (s, 2H), 8.21 (s, 2H), 7.58-7.52 (m, 4H), 7.08-7.05 (m, 2H), 6.89-6.84 (m, 2H), 5.11-5.07 (m, 4H), 4.67-4.65 (m, 4H), 4.30-4.10 (m, 12H), 3.75-3.23 (m, 42H), 3.05-2.93 (m, 10H), 1.80-1.70 (m, 4H), 1.51-1.47 (m, 4H), 1.35-1.30 (m, 4H), 1.26-1.20 (m, 4H). The NMR results confirmed that the structure of formula (IB5) was obtained. From ESI-MS, a peak corresponding to the molecular weight of the structure of formula (IB5) was also identified.

[0221] The NMR analysis results of the obtained drug complex of formula (IB6) are as follows: 1H-NMR (400MHz, CD3OD): δ7.86-7.81(m,2H),7.45-7.41(m,2H),6.88-6.81(m,2H),4.60- 4.53(m,6H),4.47-4.42(m,6H),4.36-4.33(m,4H),4.24-4.21(m,2H),4.08-4.00(m,2H) ,3.84-3.66 (m, 20H), 3.59-3.45 (m, 20H), 3.24-3.19 (m, 2H), 7.45-7.41 (m, 2H), 2.30-2.25 (m, 4H), 2.13-1.86 (m, 8H), 1.67-1.59 (m, 12H), 1.41-1.38 (m, 12H), 1.13-1.09 (m, 6H). The NMR results confirmed that the structure of formula (IB6) was obtained. From ESI-MS, the peak of the molecular weight corresponding to the structure of formula (IB6) was also identified.

[0222] The NMR analysis results of the obtained drug complex of formula (IB7) are as follows: 1 H-NMR (400MHz, CD3OD): δ7.75-7.71 (m, 1H), 7.54-7.51 (m, 1H), 7.08 (s, 1H), 7.07-6.99 (m, 1H), 6.85-6.75 (m, 1H), 4.53-4.26 (m, 5H), 3.96-3.68 (m, 6H), 3.60-3.36 (m, 7H), 3.27-3.00 (m, 4H), 2.39-2.34 (m, 2H), 2.19-2.12 (m, 1H), 2.00-1.87 (m, 2H), 1.75-1.66 (m, 2H), 1.54-1.47 (m, 2H). The NMR results confirmed that the structure of formula (IB7) was obtained. From ESI-MS, a peak corresponding to the molecular weight of the structure of formula (IB7) was also identified.

[0223] The NMR analysis results of the obtained drug complex of formula (IB8) are as follows: 1H-NMR (400MHz,CDCl3):δ8.74-8.72(m,2H),8.44-8.41(m,2H),7.47-7.43(m,2H),5.37-5.28(m,2H),5.03-4.95(m,4H),4.33-4.23(m,2H),4.07-4.03(m,2H),3.99-3.93(m,2H).3.72-3.65(m,2H).3.46-3.38(m,2H).2.92-2.85(m,4H).2.28-2.22(m,2H).2.09-2.01(m,24H).1.72-1.50(m,28H). The NMR results confirmed that the structure of formula (IB8) was obtained. From ESI-MS, a peak corresponding to the molecular weight of the structure of formula (IB8) was also identified.

[0224] The NMR analysis results of the obtained drug complex of formula (IB9) are as follows: 1 H-NMR (400MHz, CD3OD): δ7.86-7.80 (m, 2H), 7.35-7.31 (m, 2H), 6.87-6.80 (m, 2H), 4.56-4.52 (m, 2H), 4.45-.4.40 (m, 2H), 3.88-3.37 (m, 22H), 3.31-3.17 (m, 8H), 2.49-2.40 (m, 2H), 2.11-1.52 (m, 20H), 1.32-1.24 (m, 2H). The NMR results confirmed that the structure of formula (IB9) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IB9) was also identified.

[0225] The NMR analysis results of the obtained drug complex of formula (IB10) are as follows: 1 H-NMR (400MHz, CD3OD): δ7.57-7.52 (m, 2H), 7.44-7.41 (m, 2H), 6.91-6.85 (m, 2H), 7.57-7.52 (m, 2H), 5.40-5.28 (m, 4H), 5.03-4.94 (m, 4H), 4.33-4.23 (m, 8H), 4.12-3.78 (m, 6H), 3.82-3.61 (m, 2H), 3.50-3.26 (m, 2H), 2.25-2.00 (m, 24H), 1.87-1.62 (m, 16H), 1.48-1.46 (m, 10H). The NMR results confirmed that the structure of formula (IB10) was obtained. From ESI-MS, a peak corresponding to the molecular weight of the structure of formula (IB10) was also identified.

[0226] The NMR analysis results of the obtained drug complex of formula (IB11) are as follows:1 H-NMR (400MHz, CD3OD): δ8.04-8.00 (m, 2H), 7.86-7.80 (m, 1H), 7.38-7.31 (m, 1H), 7.12-7.08 (m, 2H), 6.88-6.84 (m, 2H), 5.04-4.91 (m, 4H), 4.73-4.42 (m, 16H), 4.30-4.19 (m, 2H), 3.81-3.37 (m, 16H), 8.04-8.00 (m, 2H), 3.22-2.91 (m, 6H), 2.05-1.86 (m, 4H), 1.71-1.24 (m, 6H). The NMR results confirmed that the structure of formula (IB11) was obtained. From ESI-MS, a peak corresponding to the molecular weight of the structure of formula (IB11) was also identified.

[0227] Synthesis Example C1: Synthesis of the drug complex of formula (IC1)

[0228] according to Figure 3 The drug complex of formula (IC1) was synthesized according to the scheme shown. Specifically, (R)-1-(6-amino-9H-purine-9-yl)propan-2-ol (300.00 mg, 1.55 mmol) was dissolved in dry DMF (7 mL), and then chloromethyl 4-nitrobenzoate (350.71 mg, 1.74 mmol) and DIPEA (301.15 mg, 2.33 mmol) were added. Stir at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and washed with 10% LiCl (aq.), H2O and NH4Cl (aq.). The organic layers were combined, dried with MgSO4, filtered and concentrated. The resulting crude product compound 67 was directly used in the next step without purification.

[0229] Compound 67 ((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl(4-nitrophenyl)carbonate) (1.86 g, 5.18 mmol), propargylamine (712.74 mg, 12.94 mmol) and DIPEA (669.52 mg, 5.18 mmol) were added to dry THF (30 mL) and stirred at room temperature for 18 hours. After removing the solvent, the resulting material was purified by silica gel column chromatography (eluent: 0-5% MeOH in EtOAc) to give Compound 68 ((R)-1-(6-amino-9H-purin-9-yl)propan-2-ylprop-2-yn-1-ylcarbamate) (707.00 mg, 2.58 mmol, 49.8%).

[0230] Compound 68 ((R)-1-(6-amino-9H-purin-9-yl)propan-2-ylpropyn-1-ylcarbamate) (174.44 mg, 0.64 mmol) and compound 15 ((2R, 3S, 4S, 5S, 6R)-2-((6-azidohexyl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol) (161.83 mg, 0.53 mmol) were dissolved in 2.5 mL of water, and then L-ascorbic acid (36.99 mg, 0.21 mmol) and copper sulfate pentahydrate (26.25 mg, 0.11 mmol) dissolved in 2.5 mL of water were added. The reaction mixture was stirred at room temperature for 1 to 2 hours. The obtained material was purified by C18 column chromatography (using 0-12% acetonitrile in water as eluent) to give compound 105 ((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl((1-(6-(((2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-oxy)hexyl)-1H-1,2,3-triazol-4-yl)methyl)carbamate) (152.30 mg, 0.26 mmol, yield 49.1%). Compound 105 corresponds to formula (IC1).

[0231] The NMR analysis results of compound 105 (Formula (IC1)) are as follows: 1 H-NMR (400MHz, D2O): δ8.12 (s, 1H), 8.10 (s, 1H), 7.50 (s, 1H), 5.17-5.14 (m, 1H), 4.38-4.03 (m, 7H), 3.90-3.43 (m, 8H), 1.83-1.74 (m, 2H), 1.49-1.16 (m, 9H). The NMR results confirmed that the structure of formula (IC1) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IC1) was also identified.

[0232] Synthesis Examples C2 to C11: Synthesis of Drug Complexes of Formula (IC2) to (IC11)

[0233] In Synthesis Examples C2 to C11, the drug complexes of Formula (IC2) to Formula (IC11) were synthesized using organic synthesis techniques similar to Synthesis Example C1, and the synthesis process is not repeated. In order to prove that the drug complexes of Formula (IC2) to Formula (IC11) were successfully obtained, NMR and ESI-MS analyses were performed.

[0234] The NMR analysis results of the obtained drug complex of formula (IC2) are as follows: 1H-NMR (400MHz, D2O): δ8.20(s,1H),8.15(s,1H),7.56(s,1H),5.23-5.19(m,1H),4.47-4.09(m,7H),3.97-3.86(m,2 H),3.78-3.74(m,1H),3.67-3.61(m,1H),3.55-3.40(m,3H),3.31-3.27(m,1H)1.89-1.80(m,2H),1.58-1.21(m,9H). 1 H-NMR (400MHz, d6-DMSO): □δ□8.13(s,1H),8.06(s,1H),7.77(s,1H),7.65(t, 1H),7.19(s,2H),5.08-5.00(m,1H),4.95-4.88(m,3H),4.48-4.46(m,1H),4.3 2-4.26(m,4H),4.16-4.08(m,3H),3.76-3.64(m,2H),3.15-3.00(m,4H),2.94- 2.90(m,1H),1.77(p,2H),1.48(p,2H),1.32(p,2H),1.22(p,2H),1.13(d,3H). The NMR results confirmed that the structure of formula (IC2) was obtained. From ESI-MS, a peak corresponding to the molecular weight of the structure of formula (IC2) was also identified.

[0235] The NMR analysis results of the obtained drug complex of formula (IC3) are as follows: 1 H-NMR (400MHz, d6-DMSO): δ8.13(s,1H),8.03(s,1H),7.17(s,2H),7.08(t,1H ),5.12-5.10(m,2H),5.04-4.98(m,1H)4.81(s,br,1H),4.66(s,br,2H),4.57 -4.52(m,2H),4.30-4.16(m,4H),3.77-3.73(m,2H),3.61-3.40(m,8H),3.03- 2.97(m,1H),2.88(q,2H),1.51-1.46(m,2H),1.34-1.21(m,6H),1.12(d,3H). The NMR results confirmed that the structure of formula (IC3) was obtained. From ESI-MS, a peak corresponding to the molecular weight of the structure of formula (IC3) was also identified.

[0236] The NMR analysis results of the obtained drug complex of formula (IC4) are as follows: 1H-NMR (400MHz, D2O): δ8.15 (s, 1H), 8.12 (s, 1H), 7.51 (s, 1H), 5.19-5.15 (m, 1H), 4.47-3.93 (m, 10H), 3.87-3.53 (m, 11H), 3.32-3.27 (m, 1H), 1.85-1.74 (m, 2H), 1.56-1.52 (m, 2H), 1.37-1.18 (m, 7H). The NMR results confirmed that the structure of formula (IC4) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IC4) was also identified.

[0237] The NMR analysis results of the obtained drug complex of formula (IC5) are as follows: 1 H-NMR (400MHz, D2O): δ8.19 (s, 1H), 8.15 (s, 1H), 7.55 (s, 1H), 5.22-5.19 (m, 1H), 4.47-4.09 (m, 7H), 3.97-3.76 (m, 4H), 3.72-3.60 (m, 3H), 3.56-3.52 (m, 1H), 1.88-1.73 (m, 2H), 1.60-1.56 (m, 2H) 1.40-1.21 (m, 7H). The NMR results confirmed that the structure of formula (IC5) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IC5) was also identified.

[0238] The NMR analysis results of the obtained drug complex of formula (IC6) are as follows: 1 H-NMR (400MHz, D2O): δ8.08(s,1H),8.05(s,1H),7.54(s,1H),5.14-5.05(m,1 H),4.43-4.17(m,9H),4.16-3.97(m,3H),3.95-3.83(m,5H),3.82-3.63(m,12H ),3.63-3.44(m,10H),3.28-3.19(m,2H),3.18-2.97(m,5H),2.23-2.16(m,4H) ,2.15-1.91(m,4H),1.91-1.78(m,2H),1.56-1.30(m,8H),1.30-1.13(m,10H). The NMR results confirmed that the structure of formula (IC6) was obtained. From ESI-MS, a peak corresponding to the molecular weight of the structure of formula (IC6) was also identified.

[0239] The NMR analysis results of the obtained drug complex of formula (IC7) are as follows: 1H-NMR (400MHz, D2O): δ8.11 (s, 1H), 8.07 (s, 1H), 7.58 (s, 1H), 5.14-5.05 (m, 1H), 4.44-4.00 (m, 15H), 3.97-3.42 (m, 47H), 3.28-3.18 (m, 3H), 3.14-2.99 (m, 7H), 2.45-2.34 (m, 7H), 2.18-1.99 (m, 5H), 1.58-1.13 (m, 32H). The NMR results confirmed that the structure of formula (IC7) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IC7) was also identified.

[0240] The NMR analysis results of the obtained drug complex of formula (IC8) are as follows: 1 H-NMR (400MHz, D2O): δ8.16 (s, 1H), 8.11 (s, 1H), 7.51 (s, 1H), 5.41-5.38 (m, 2H), 5.19-5.16 (m, 1H), 4.43-4.17 (m, 6H), 4.08-3.40 (m, 22H), 3.30-3.25 (m, 1H), 1.85-1.75 (m, 2H), 1.55-1.52 (m, 2H), 1.37-1.16 (m, 7H). The NMR results confirmed that the structure of formula (IC8) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IC8) was also identified.

[0241] The NMR analysis results of the obtained drug complex of formula (IC9) are as follows: 1 H-NMR (400MHz, D2O): δ8.15 (s, 1H), 8.12 (s, 1H), 7.50 (s, 1H), 5.18-5.14 (m, 1H), 4.46-4.04 (m, 7H), 3.93-3.42 (m, 8H), 1.97 (s, 3H), 1.84-1.74 (m, 2H), 1.44-1.14 (m, 9H). The NMR results confirmed that the structure of formula (IC9) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IC9) was also identified.

[0242] The NMR analysis results of the obtained drug complex of formula (IC10) are as follows: 1H-NMR (400MHz, D2O): δ8.18-7.98 (m, 2H), 7.71-7.43 (m, 1H), 7.28-7.16 (m, 2H), 7.11-6.95 (m, 2H), 5.58-5.39 (m, 1H), 5.19-4.92 (m, 2H), 4.51-4.47 (d, 1H, J = 7.8 Hz), 4.41-3.91 (m, 5H), 3.90-3.65 (m, 10H), 3.65-3.53 (m, 2H), 1.37-1.27 (d, 3H, J = 6.3 Hz). The NMR results confirmed that the structure of formula (IC10) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IC10) was also identified.

[0243] The NMR analysis results of the obtained drug complex of formula (IC11) are as follows: 1 H-NMR (400MHz, D2O): δ8.14-7.97 (m, 2H), 7.03-6.79 (m, 5H), 5.19-5.06 (m, 1H), 5.06-4.99 (d, 1H, J = 7.8), 4.45-4.15 (m, 3H), 4.08-3.61 (m, 11H), 3.61-3.44 (m, 3H), 1.33-1.24 (d, 3H, J = 6.2Hz). The NMR results confirmed that the structure of formula (IC11) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IC11) was also identified.

[0244] Synthesis Example D1: Synthesis of the drug complex of formula (ID1)

[0245] according to Figure 4 The drug complex of formula (ID1) was synthesized by the scheme shown. Specifically, compound 3 ((3R, 4S, 5R, 6R)-6-(acetoxymethyl)-5-(((2S, 3R, 4S, 5S, 6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2,3,4-triacetate) (6.87 g, 10.1 mmol), compound 22 (benzyl 6-hydroxyhexanoate) (4.50 g, 20.02 mmol) and A solution of molecular sieves (1.00 g) in dichloromethane (70 mL) was added with BF3. OEt2 (5.1 mL, 4.05 mmol) and stirred at 0°C for 15 minutes, then the temperature was allowed to rise to room temperature and stirred for 12 hours. The mixture was quenched with NaHCO3 (aq.) and extracted with dichloromethane. The combined organic phases were dried with MgSO4 and then concentrated. The residue was purified by silica gel column chromatography using ethyl acetate:hexane (1:2) as eluent to give compound 23 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-((6-(benzyloxy)-6-oxohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) (2.52 g, 3.00 mmol, 30% yield).

[0246] Compound 23 ((2R, 3S, 4S, 5R, 6S)-2-(acetoxymethyl)-6-(((2R, 3R, 4S, 5R, 6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-((6-(phenoxy)-6-oxohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) (600 mg, 0.71 mmol) was dissolved in methanol (MeOH) (5 mL), 10% Pd / C (60 mg, 0.1 wt%) was added, and stirred for 3 hours under hydrogen atmosphere. The mixture was filtered through celite to remove Pd / C, and the solvent was evaporated under reduced pressure to concentrate. The crude product Compound 24 without purification was directly used in the next reaction.

[0247] Compound 24 (6-(((2R,3R,4S,5R,6R)-3,4-diacetoxy-6-(acetoxymethyl)-5-(((2S,3R,4S,5S,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)hexanoic acid) (448 mg, 0.60 mmol) and (S)-(4-fluorophenyl)(2-(pyrrolidin-2-yl)thiazol-4-yl)methanone (200 mg, 0.64 mmol) were dissolved in acetonitrile (ACN, 10 mL), HATU (450 mg, 1.20 mmol) and NMM (350 μL, 3.19 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated and purified by silica gel column chromatography to give the product compound 123 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-((6-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-6-oxohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) (435 mg, 0.43 mmol, 72% yield).

[0248] To synthesize compound 124, 435 mg (0.43 mmol) of compound 123 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-((6-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidinyl)-6-oxohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) was dissolved in 20 mL of methanol (MeOH), and then 330 mg (6.11 mmol) of sodium methoxide (NaOMe) was added at 0°C. After the addition, the reaction mixture was warmed to room temperature (RT) and stirred for 1 hour. Subsequently, the reaction mixture was neutralized with Amberlite IR-120(H) resin until pH 7 was reached. The solution was filtered and the solvent was removed. Purification by reverse phase silica gel column chromatography gave compound 124 (6-(((2R, 3R, 4R, 5S, 6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S, 3R, 4S, 5R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-1-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidinyl)hexane-1-one) (200 mg, 0.28 mmol, 65% yield). Compound 124 corresponds to the structure of formula (ID1).

[0249] The NMR analysis results of compound 105 (Formula (ID1)) are as follows: 1 H-NMR (400MHz, CD3OD): δ8.34-8.32 (m, 1H), 8.26-8.23 (m, 2H), 7.28-7.24 (m, 2H), 5.54-5.45 (m, 2H), 4.37-4.21 (m, 3H), 3.92-3.66 (m, 10H), 3.60-3.37 (m, 8H), 3.25-3.13 (m, 2H), 2.51-2.31 (m, 4H), 2.21-2.04 (m, 2H), 1.70-1.64 (m, 4H), 1.53-1.47 (m, 2H). The NMR results confirmed that the structure of formula (ID1) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (ID1) was also identified.

[0250] Synthesis Examples D2 to D5: Synthesis of Drug Complexes of Formula (ID2) to (ID5)

[0251] In Synthesis Examples D2 to D5, the drug complexes of Formula (ID2) to Formula (ID5) were synthesized using organic synthesis techniques similar to Synthesis Example D1, and the synthesis process is not repeated. In order to prove that the drug complexes of Formula (ID2) to Formula (ID5) were successfully obtained, NMR and ESI-MS analyses were performed.

[0252] The NMR analysis results of the obtained drug complex of formula (ID2) are as follows: 1 H-NMR (400MHz, D2O): δ8.22(s,1H),7.89-7.78(m,2H),7.24-7.15(m,2H),5.26-5.15(m,1H),4. 90-4.81(m,1H),4.488(d,J=7.24,1H),4.387(d,J=8,1H),4.19-4.09(m,2H),4.04-3.95(m,H), 3.94-3.81 (m, 3H), 3.79-3.42 (m, 11H), 3.32-3.23 (m, 1H), 2.51-2.30 (m, 1H), 2.12-1.89 (m, 3H), 1.88-1.72 (m, 1H), 1.61-1.45 (m, 2H), 1.44-1.16 (m, 3H), 1.01-0.89 (m, 2H), 0.86-0.72 (m, 2H). The NMR results confirmed that the structure of formula (ID2) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (ID2) was also identified.

[0253] The NMR analysis results of the obtained drug complex of formula (ID3) are as follows: 1 H-NMR (400MHz, D2O): δ8.20(s,1H),7.95-7.91(m,2H),7.78(s,1H),7.35-7.31(m,2H),5 .40-5.35(m,2H),5.27-5.24(m,2H),4.93-4.90(m,1H),4.41-4.39(m,2H),4.25-4.22(m, 2H), 3.98-3.41 (m, 29H), 3.30-3.25 (m, 1H), 2.54-2.45 (m, 1H), 2.12-2.02 (m, 4H), 1.87-1.83 (m, 1H), 1.74-1.66 (m, 2H), 1.53-1.45 (m, 2H), 1.25-1.19 (m, 2H), 1.14-1.08 (m, 2H). The NMR results confirmed that the structure of formula (ID3) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (ID3) was also identified.

[0254] The NMR analysis results of the obtained drug complex of formula (ID4) are as follows: 1 H-NMR (400MHz, D2O): δ8.20(s,1H),8.15(s,1H),7.98(s,1H),7.96-7.83(m,3H),7.78(s,1H),7.27(m,2H),5.31 -5.16(m,3H),4.90-4.84(m,1H),4.42-4.34(m,6H),4.28-4.20(m,2H),4.12-4.03(m,2H),3.92-3.83(m,5H),3.8 2-3.62 (m, 7H), 3.61-3.44 (m, 10H), 3.25-3.18 (m, 3H), 3.13-2.98 (m, 6H), 2.48-2.35 (m, 2H), 2.26-2.17 (m, 2H), 2.16-2.08 (m, 2H), 2.07-1.90 (m, 6H), 1.88-1.76 (m, 2H), 1.56-1.43 (m, 4H), 1.43-1.32 (m, 4H), 1.3-1.13 (m, 10H). The NMR results confirmed that the structure of formula (ID4) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (ID4) was also identified.

[0255] The NMR analysis results of the obtained drug complex of formula (ID5) are as follows: 1 H-NMR (400MHz, D2O): δ8.25 (s, 1H), 8.05-8.01 (m, 2H), 7.30-7.25 (m, 2H), 5.44-5.41 (m, 1H), 4.90-4.89 (m, 1H), 4.46-4.44 (m, 1H), 3.94-3.53 (m, 18H), 8.34-8.32 (m, 1H), 2.43-2.06 (m, 7H), 1.64-1.09 (m, 18H). The NMR results confirmed that the structure of formula (ID5) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (ID5) was also identified.

[0256] Synthesis Example E1: Synthesis of the drug complex of formula (IE1)

[0257] according to Figure 5The drug complex of formula (IE1) was synthesized according to the scheme shown. Specifically, 1-((2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (300.37 mg, 1.24 mmol) and imidazole (168.83 mg, 2.48 mmol) were added to dry DMF (0.6 mL). A solution of TBSCl (186.89 mg, 1.24 mmol) in dry DMF (0.6 mL) was added at 0°C and stirred for 30 minutes. The mixture was then warmed to room temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride solution and aqueous sodium bicarbonate solution. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give compound 60 (1-((2S,4R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxytetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione) (377.10 mg, 1.06 mmol, 85.4% yield).

[0258] To a solution of compound 60 (1-((2S,4R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxytetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione) (950.00 mg, 2.66 mmol) in dry dichloromethane (DCM, 26 mL) were added 4-dimethylaminopyridine (DMAP, 422.12 mg, 3.46 mmol) and acetic anhydride (Ac2O, 407.34 mg, 3.99 mmol). The mixture was stirred at room temperature for 6 hours. After removing the solvent, the resulting material was dissolved in ethyl acetate and washed with aqueous ammonium chloride solution (NH4Cl(aq.)). The combined organic layers were dried over magnesium sulfate (MgSO4), filtered and concentrated to give compound 61 ((2S,3R,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl acetate) (1060.09 mg, 2.66 mmol, quantitative yield).

[0259] Compound 61 ((2S,3R,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-acetic acid 3-ester) (530.05 mg, 1.33 mmol) was added to THF (9 mL). 1M TBAF in THF (2 mL) was added at 0 degrees Celsius and stirred for 1.5 hours. After removal of the solvent, purification was performed using silica gel column chromatography with a mobile phase of 40% hexane in ethyl acetate to give compound 62 ((2S,3R,5S)-2-(hydroxymethyl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl acetate)))) (266.40 mg, 0.94 mmol, 70.6%).

[0260] Compound 62 ((2S,3R,5S)-2-(hydroxymethyl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl acetate))) (310.00 mg, 1.09 mmol) was dissolved in dry dichloromethane (7 mL), and 4-nitrophenyl chloroformate (330.56 mg, 1.64 mmol) and diisopropylethylamine (DIPEA) (351.56 mg, 2.72 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 2 hours. After removing the solvent, the resulting material was dissolved in ethyl acetate and washed with water and aqueous ammonium chloride solution. The combined organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product compound 63 was used directly in the next step without purification.

[0261] Compound 63 ((2S,3R,5S)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-((((4-nitrophenoxy)carbonyl)oxy)methyl)tetrahydrofuran-3-yl acetate) (489.80 mg, 1.09 mmol) was added to dry THF (7 mL). Compound 5 ((2R,3S,4S,5R,6S) -2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-((6-aminohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate) (1.16 g, 1.58 mmol) and DIPEA (351.56 mg, 2.72 mmol). The reaction mixture was heated to 70° C. and stirred for 18 hours. After removing the solvent, the mixture was dissolved in ethyl acetate and washed with water and NH4Cl (aq.). The combined organic layers were dried over MgSO4, filtered and concentrated. Silica gel column chromatography was used for purification using ethyl acetate containing 14.3% hexane as the eluent to finally obtain compound 97 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-6-((6-(((((2S,3R,5S)-3-acetoxy-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)carbonyl)amino)hexyl)oxy)-2-(acetoxymethyl)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate) (474.60 mg, 0.45 mmol, 41.3%).

[0262] Compound 97 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-6-((6-(((((2S,3R,5S)-3-acetoxy-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)carbonyl)amino)hexyl)oxy)-2-(acetoxymethyl)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) (210.00 mg, 0.20 mmol) was dissolved in methanol (MeOH, 2 mL). NaOMe (27.01 mg, 0.50 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was neutralized with resin until the pH value reached 7. The solution was filtered and the solvent was removed. Purification by C18 column chromatography (0-20% MeOH in H2O as eluent) afforded Compound 98 (((2S,3R,5S)-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl(6-(((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4S,-5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)hexyl)carbamate) (51.30 mg, 0.07 mmol, 35.0% yield), which corresponds to the structure of Formula (IE1).

[0263] The NMR analysis results of compound 98 (Formula (IE1)) are as follows: 1 H-NMR (400 MHz, D2O): δ7.51 (s, 1H), 6.28-6.24 (t, 1H), 4.53-4.41 (m, 4H), 4.29-4.17 (m, 2H), 3.99-3.54 (m, 13H), 3.33-3.29 (m, 1H), 3.12-3.09 (t, 2H), 2.46-2.31 (m, 2H), 1.89 (s, 3H), 1.60-1.32 (m, 8H). The NMR results confirmed that the structure of formula (IB11) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IB11) was also identified.

[0264] Synthesis Example F1: Synthesis of the drug complex of formula (IF1)

[0265] according to Figure 6The drug complex of formula (IF1) was synthesized by the scheme shown. Specifically, 2-(6-amino-9H-purine-9-yl)ethanol (500.00 mg, 2.79 mmol) was added to dry DMF (5.5 mL), followed by 4-nitrophenyl chloroformate (1.52 g, 7.54 mmol) and DIPEA (1.08 g, 8.37 mmol). After stirring at room temperature for 18 hours in a nitrogen environment, the reaction mixture became a yellow solution and a precipitate was produced. Subsequently, the reaction mixture was diluted with water, and the resulting light yellow solid (Compound 58) was collected. Next, the light yellow solid was dissolved in dry THF (18 mL), and propargylamine (384.46 mg, 6.98 mmol) and DIPEA (360.61 mg, 2.79 mmol) were added. After stirring at room temperature for 4 hours in a nitrogen environment, an orange solution with a precipitate was finally obtained. The solvent was removed under reduced pressure, and the precipitate was washed with ethyl acetate and acetone to give Compound 59 (2-(6-amino-9H-purin-9-yl)ethyl prop-2-ynylcarbamate) (314.90 mg, 1.21 mmol, yield 43.4%).

[0266] Compound 59 (2-(6-amino-9H-purin-9-yl)ethylprop-2-yn-1-ylcarbamate) (83.28 mg, 0.32 mmol) and compound 6 ((2S,3R,4S,5R,6R)-2-(((2R,3S,4R,5R,6R)-6-((6-azidohexyl)oxy)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol) (122.90 mg, 0.26 mmol) were dissolved in methanol (2 mL), and then a green solution of L-ascorbic acid (18.65 mg, 0.11 mmol) and copper sulfate pentahydrate (13.25 mg, 0.05 mmol) in water (2 mL) was added. The reaction mixture was stirred at room temperature for 1 to 2 hours to form a yellow-green solution. Methanol was evaporated and then purified using C18 column chromatography (using 0-15% acetonitrile / water as eluent) to obtain compound 96 (2-(6-amino-9H-purin-9-yl)ethyl ((1-(6-(((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)hexyl)-1H-1,2,3-triazol-4-yl)methyl)carbamate) (70.70 mg, 0.10 mmol, yield 38.5%). This compound 96 corresponds to the structure of formula (IF1).

[0267] The NMR analysis results of compound 96 (Formula (IF1)) are as follows: 1 H-NMR (400 MHz, D2O): δ8.19 (s, 1H), 8.17 (s, 1H), 7.66 (s, 1H), 4.53-4.44 (m, 7H), 4.28-4.23 (m, 3H), 4.02-3.97 (m, 2H), 3.91-3.57 (m, 12H), 3.36-3.32 (m, 1H), 1.90-1.79 (m, 2H), 1.61-1.57 (m, 2H), 1.35-1.18 (m, 4H). The NMR results confirmed that the structure of formula (IB11) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IB11) was also identified.

[0268] Synthesis Example F2: Synthesis of the drug complex of formula (IF2)

[0269] In Synthesis Example F2, the drug complex of formula (IF2) was synthesized using an organic synthesis technique similar to that of Synthesis Example F1, and the synthesis process is not repeated here. In order to prove that the drug complex of formula (IF2) was successfully obtained, NMR and ESI-MS analyses were performed.

[0270] The NMR analysis results of the obtained drug complex of formula (IF2) are as follows: 1 H-NMR (400 MHz, D2O): δ 8.23 ​​(s, 1H), 8.16 (s, 1H), 4.48-4.46 (m, 5H), 4.00-3.54 (m, 15H), 2.88-2.85 (m, 2H), 1.58-1.55 (m, 2H), 1.27-1.07 (m, 6H). The NMR results confirmed that the structure of formula (IB11) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IB11) was also identified.

[0271] Synthesis Example G1: Synthesis of the drug complex of formula (IG1)

[0272] according to Figure 7 The drug complex of formula (IC1) was synthesized by the scheme shown. Specifically, lamivudine (2.00 g, 8.72 mmol) was dissolved in acetonitrile (90 mL), acetic anhydride (1 mL, 8.99 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was then diluted in water, and the resulting precipitate was collected. The crude product compound 64 (N-(1-((2R,5S)-2-(hydroxymethyl)-1,3-oxane-5-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)acetamide) (2.03 g, crude yield 85%) was directly used in the next step without purification.

[0273] Compound 64 (N-(1-((2R,5S)-2-(hydroxymethyl)-1,3-oxathian-5-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)acetamide) (1.00 mg, 3.69 mmol) was dissolved in THF (40 mL), CDI (1.20 g, 7.37 mmol) was added and stirred at 50° C. for 3 hours. Then, prop-2-yn-1-amine (0.90 mL, 14.74 mmol) was added and stirred at 50° C. for 12 hours. The solvent was removed under reduced pressure. The obtained material was purified by silica gel column chromatography using EtOAc:MeOH (5%) as eluent to provide the product compound 65 (((2R,5S)-5-(4-acetamido-2-oxopyrimidin-1(2H)-yl)-1,3-oxathian-2-yl)methylprop-2-yn-1-ylcarbamate) (0.72 g, 2.04 mmol, yield 55%).

[0274] Compound 65 (((2R,5S)-5-(4-acetamido-2-oxypyrimidin-1(2H)-yl)-1,3-oxosulfane-2-yl)methylprop-2-yn-1-ylcarbamate) (260 mg, 0.72 mmol) was dissolved in 5 mL of methanol (MeOH). 40 mg (0.72 mmol) of sodium methoxide (NaOMe) was added at 0°C. After addition, the reaction mixture was allowed to warm to room temperature (RT) and stirred for 15 minutes. The reaction mixture was neutralized using Amberlite IR-120(H) until the pH reached 7. After filtering the solution, the solvent was removed. The crude product, compound 66, was used in the next step without purification.

[0275] Compound 66 (((2R,5S)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-1,3-thiazolidin-2-yl)methylprop-2-yn-1-ylcarbamate) (223 mg, 0.72 mmol) and compound 6 ((2S,3R,4S,5R,6R)-2-(((2R,3S,4R,5R,6R)-6-((6-azidohexyl)oxy)-4,5-dihydroxy 4-(2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol) (280 mg, 0.60 mmol) was dissolved in THF (3 mL), and then a solution of CuSO4·H2O (30 mg, 0.12 mmol) and ascorbic acid (42 mg, 0.24 mmol) in H2O (3 mL) was added and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to remove THF and the resulting material was purified by reverse phase silica gel column chromatography using ACN:H2O (15%) as eluent to give the product Compound 99 (((2R,5S)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-1,3-thiazolidin-2-yl)methyl ((1-(6-(((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)hexyl)-1H-1,2,3-triazol-4-yl)methyl)carbamate) (300 mg, 0.39 mmol, 64% yield). Compound 99 corresponds to the structure of formula (IG1).

[0276] The NMR analysis results of compound 99 (Formula (IG1)) are as follows: 1 H-NMR (400MHz, CD3OD): δ7.85-7.83(m,1H),7.82(s,1H),6.29-6.27(m,1H),5.88-5 .87(m,1H),5.40-5.39(m,1H),4.58(s,1H),4.54-4.34(m,7H),4.29-4.27(m,1H),3. 91-3.68 (m, 7H), 3.60-3.47 (m, 7H), 3.41-3.38 (m, 1H), 3.26-3.22 (m, 1H), 3.14-3.10 (m, 1H), 1.90-1.83 (m, 2H), 1.63-1.56 (m, 2H), 1.46-1.38 (m, 2H), 1.34-1.26 (m, 2H). The NMR results confirmed that the structure of formula (IG1) was obtained. From ESI-MS, the peak of the molecular weight corresponding to the structure of formula (IG1) was also identified.

[0277] Synthesis Example H1: Synthesis of the Drug Complex of Formula (IH1)

[0278] according to Figure 8 The drug complex of formula (IC1) was synthesized by the scheme shown. Specifically, trifluoroacetic acid (3 mL, 39.18 mmol) was added to a dichloromethane (3 mL) solution containing 500 mg (0.97 mmol) of tert-butyl ((S)-1-cyclohexyl-2-oxo-2-((S)-2-((4-phenyl-1,2,3-thiadiazol-5-yl)carbamoyl)pyrrolidin-1-yl)ethyl)carbamate and stirred at room temperature. After the reaction was completed, the solvent and trifluoroacetic acid were removed under reduced pressure. The crude product Compound 70 ((S)-1-((S)-2-amino-2-cyclohexylacetyl)-N-(4-phenyl-1,2,3-thiadiazol-5-yl)pyrrolidine-2-carboxamide trifluoroacetate) (yield equivalent) was used directly in the next step without purification.

[0279] Compound 24 (6-(((2R,3R,4S,5R,6R)-3,4-diacetoxy-6-(acetoxymethyl)-5-(((2S,3R,4S,5S,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)hexanoic acid) (720 mg, 0.96 mmol) and compound 70((S)-1-((S)-2-amino-2-cyclohexylacetyl)-N-(4-phenyl-1,2,3-thiadiazol-5-yl)pyrrolidine-2-carboxamide trifluoroacetate) (512 mg, 0.97 mmol) was dissolved in acetonitrile (10 mL), HATU (370 mg, 0.97 mmol) and NMM (0.5 mL, 4.54 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The mixture was purified by silica gel column chromatography to give compound 113 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-((6-(((S)-1-cyclohexyl-2-oxo-2-((S)-2-((4-phenyl-1,2,3-thiadiazol-5-yl)aminoacyl)pyrrolidin-1-yl)ethyl)amino)-6-oxohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) (550 mg, 0.48 mmol, 50% yield).

[0280] Compound 113 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-((6-(((S)-1-cyclohexyl-2-oxo-2-((S)-2-((4-phenyl-1,2,3-thiadiazol-5-yl)carbamoyl)pyrrolidinyl)ethyl)amino)-6-oxohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) (550 mg, 0.48 mmol) was dissolved in MeOH (10 mL), and NaOMe (350 mg, 6.48 mmol) was added at 0°C. After heating to room temperature, the reaction was stirred until completion. The reaction was terminated using Amberlite IR-120 (H) and filtered off. The resulting material was purified by reverse phase silica gel column chromatography to provide product compound 114 ((S)-1-((S)-2-cyclohexyl-2-(6-(((2R, 3R, 4R, 5S, 6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S, 3R, 4S, 5R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)hexanamide)acetyl)-N-(4-phenyl-1,2,3-thiadiazole-5-yl)pyrrolidine-2-carboxamide) (180 mg, 0.21 mmol, yield 44%). Compound 114 corresponds to the structure of formula (IH1).

[0281] The NMR analysis results of compound 114 (Formula (IH1)) are as follows: 1 H-NMR (400MHz, CD3OD): δ7.76-7.74(m,2H),7.61-7.58(m,2H),7.54-7.50(m ,1H),4.58(s,1H),4.42-4.26(m,4H),4.04-3.99(m,1H),3.91-3.67(m,9H), 3.60-3.46(m,7H),3.40-3.36(m,1H),3.25-3.20(m,1H),2.25-2.04(m,7H), 1.85-1.58(m,10H),1.44-1.36(m,2H),1.24-1.16(m,2H),1.10-0.97(m,2H). The NMR results confirmed that the structure of formula (IH1) was obtained. From ESI-MS, a peak corresponding to the molecular weight of the structure of formula (IH1) was also identified.

[0282] Synthesis Examples H2-H3: Synthesis of Drug Complexes of Formulas (IH2)-(IH3)

[0283] In Synthesis Examples H2-H3, the drug complexes of Formula (IH2) to Formula (IH3) were synthesized using organic synthesis techniques similar to Synthesis Example H1, and the synthesis process is not repeated. In order to prove that the drug complexes of Formula (IH2) to Formula (IH3) were successfully obtained, NMR and ESI-MS analyses were performed.

[0284] The NMR analysis results of the drug complex of formula (IH2) are as follows: 1 H-NMR (400MHz, CD3OD): δ7.75-7.72 (m, 2H), 7.62-7.57 (m, 2H), 7.55-7.51 (m, 1H), 4.52 (s, 4H), 4.37-4.34 (m, 1H), 4.29-4.27 (m, 1H), 3.91-3.37 (m, 15H), 3.25-3.21 (m, 1H), 2.43-2.39 (m, 2H), 2.21-2.01 (m, 4H), 1.67-1.60 (m, 4H), 1.47-1.39 (m, 2H). The NMR results confirmed that the structure of formula (IH2) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IH2) was also identified.

[0285] The NMR analysis results of the drug complex of formula (IH3) are as follows: 1 H-NMR (400MHz, D6-DMSO): δ8.16-8.04(m,1H),7.95-7.79(br,2H),7.62-7.29(br,3H),5.22-5.14(m,1H ),5.09(d,1H,J=3.6),4.91-4.80(m,1H),4.70-4.57(m,4H),2.11-1.77(br,4H),4.50(d,1H,J=4.4),4.4 5-4.23 (m, 4H), 4.23-4.17 (m, 1H), 4.15-3.97 (m, 2H), 3.86-3.75 (m, 1H), 3.73-3.56 (m, 4H) 3.56-3.40 (m, 4H), 3.09-3.01 (m, 1H), 2.30-2.18 (br, 1H), 2.02-1.68 (br, 4H), 1.63-1.47 (br, 3H), 1.39-1.16 (br, 3H). The NMR results confirmed that the structure of formula (IH3) was obtained. From ESI-MS, the peak of the molecular weight corresponding to the structure of formula (IH3) was also identified.

[0286] Synthesis Example J1: Synthesis of the Drug Complex of Formula (IJ1)

[0287] according to Fig. 9The drug complex of formula (IC1) was synthesized according to the scheme shown. Specifically, 200 mg (0.35 mmol) of tert-butyl ((5S,10aR)-8-(benzhydrylcarbamoyl)-3-(3-methylbutyryl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazon-5-yl)carbamate was dissolved in 3 mL of dichloromethane (DCM), and 3 mL of trifluoroacetic acid (TFA, 39.18 mmol) was added and stirred at room temperature. After the reaction was completed, the solvent and TFA were removed by reduced pressure distillation. The resulting crude product compound 74 ((5S,10aR)-5-amino-N-benzyl-3-(3-methylbutyryl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazon-8-carboxamide trifluoroacetate) was directly used in the next step without purification.

[0288] Compound 24 (6-(((2R,3R,4S,5R,6R)-3,4-diacetate-6-(acetatemethyl)-5-(((2S,3R,4S,5S,6R)-3,4,5-triacetate-6-(acetatemethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)hexanoic acid) (390 mg, 0.52 mmol) and compound 74 ((5S, 10aR)-5-amino-N-benzyl-3-(3-methylbutyryl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazooctane-8-carboxamide trifluoroacetate) (207 mg, 0.35 mmol) was added to acetonitrile (5 mL), followed by HATU (265 mg, 0.69 mmol) and NMM (0.2 mL, 1.86 mmol), and stirred at room temperature for 12 hours. The mixture was purified by silica gel column chromatography to give Compound 118 ((2R,3S,4S,5R,6S)-2-(acetate methyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetate-2-(acetate methyl)-6-((6-(((5S,10aR)-8-(benzylcarbamoyl)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazaoctan-5-yl)amino)-6-oxohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) (320 mg, 0.26 mmol, yield 75%).

[0289] Compound 118 ((2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-diacetoxy-2-(acetoxymethyl)-6-((6-(((5S,10aR)-8-(benzhydrylcarbamoyl)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazaoctan-5-yl)amino)-6-oxohexyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate) (320 mg, 0.26 mmol) was dissolved in methanol (10 mL), and sodium methoxide (200 mg, 3.70 mmol) was added at 0°C. After heating to room temperature, the mixture was stirred until the reaction was completed. The reaction mixture was quenched with Amberlite IR-120 (H) and filtered to remove. Compound 119 ((5S, 10aR)-N-diphenylmethyl-5-(6-(((2R, 3R, 4R, 5S, 6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S, 3R, 4S, 5R, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)hexanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazaoctane-8-carboxamide) (90 mg, 0.10 mmol, yield 38%) was obtained by reverse phase silica gel column chromatography purification. Compound 118 corresponds to the structure of formula (IJ1).

[0290] The NMR analysis results of compound 118 (Formula (IJ1)) are as follows: 1 H-NMR (400MHz, CD3OD): δ7.36-7.25 (m, 10H), 6.14 (s, 1H), 4.83-4.81 (m, 1H), 4.77-4.76 (m, 1H), 4.59 (s, 1H), 4.35-4.33 (m, 1H), 4.23-4.18 (m, 1H), 3.94-3.33 (m, 17H), 2.48-1.40 (m, 21H), 0.98-0.94 (m, 6H). The NMR results confirmed that the structure of formula (IJ1)) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IJ1)) was also identified.

[0291] Synthesis Example J2: Synthesis of the Drug Complex of Formula (IJ2)

[0292] In Synthesis Example J2, the drug complex of formula (IJ2) was synthesized using an organic synthesis technique similar to that of Synthesis Example J1, and the synthesis process is not repeated here. In order to prove that the drug complex of formula (IJ2) was successfully obtained, NMR and ESI-MS analyses were performed.

[0293] The NMR analysis results of the obtained drug complex of formula (IJ2) are as follows: 1 H-NMR (400MHz, D6-DMSO): δ8.92-8.86(m,1H),8.11(s,H),7.37-7.21(m,10H),6.91-6.85(m,1H) ,6.07(d,1H,J=8.8),5.19-5.06(m,2H),4.84(d,1H,J=12.0),4.80-4.76(m,2H),4.70-4.60(m,4H ), 4.54-4.41 (m, 4H), 4.36-4.30 (m, 4H), 4.23-4.18 (m, 2H), 4.13-4.04 (m, 2H), 4.01-3.41 (m, 2H), 3.25-2.99 (m, 4H), 2.34-2.13 (m, 4H), 2.13-1.92 (m, 4H), 1.90-1.46 (m, 10H), 1.40-1.18 (m, 5H). The NMR results confirmed that the structure of formula (IJ2) was obtained. From ESI-MS, the peak corresponding to the molecular weight of the structure of formula (IJ2) was also identified.

[0294] Experimental example:

[0295] In the following experimental examples, in vitro cell line evaluation and in vivo animal experiments were performed to demonstrate that the disclosed method is superior to conventional methods in treating hepatitis B. The following materials and methods can be applied to all experimental examples.

[0296] [Cell lines and culture conditions]-HepG22.2.15 cells

[0297] In the following experimental examples, when HepG22.2.15 cells (a cell line expressing hepatitis B virus) were used, the cells were maintained in Dulbecco's modified Eagle medium (DMEM) (GibcoBRL, Grand Island, NY, USA), plus 10% fetal bovine serum (Hyclone, Logan, UT, USA), 100 U / mL penicillin, 100 U / mL streptomycin. HepG2.2.15 cells were inoculated at the same density and used as a medium control. The experimental groups consisted of the substances administered at the concentrations specified by the manufacturer. All cultures were grown in a humidified incubator at 37°C and 5% CO2.

[0298] [Hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) detection]

[0299] HepG22.2.15 cells are inoculated into 12-well microtiter plates. On day zero, cells are washed several times with PBS and treated with a tetracycline-free culture medium containing a test drug or a vehicle control group. Each test compound is screened in triplicate at a concentration. On the 3rd, 6th and / or 9th day, the culture medium is removed and replaced with a fresh culture medium containing the compound. After 24 hours, the culture medium is collected and clarified by centrifugation (SorvallRT-6000D centrifuge, 1,000rpm, 5 minutes). The culture medium of HepG22.2.15 cell culture is harvested 3 days, 6 days and 9 days after HBV infection, and the AXSYM system kit (AbbottDiagnostika) is used.

[0300] [Cell lines and culture conditions]-HepAD38 cells

[0301] In the following experimental paradigm, when HepAD38 cells (a cell line expressing hepatitis B virus) were used, the cells were maintained in Dulbecco's modified Eagle's / F-12 medium (DMEM / F-12; GIBCOBRL / Life Technologies, Gaithersburg, Md.). Production of HBV particles was induced in the HepAD38 cell line by incubation in medium lacking tetracycline. When HepAD38 cells were used for HBV collection, tetracycline was removed from the cell culture for 9 days and then treated with test drugs or dimethyl sulfoxide (DMSO) vehicle controls.

[0302] [Hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) detection]

[0303] HepAD38 cells were inoculated into 12-well microtiter plates (inoculated with 2x105 cells / well) and grown for 3 days in the presence of 0.3mg tetracycline per mL. On day zero, cells were washed several times with PBS and treated with a tetracycline-free culture medium containing a test drug or a vehicle control group. Each test compound was screened in triplicate at one concentration. On the 3rd, 6th and 9th days, the culture medium was removed and replaced with a fresh culture medium containing the compound. After 24 hours, the culture medium was collected and clarified by centrifugation (SorvallRT-6000D centrifuge, 1,000rpm, 5 minutes). The culture medium of HepAD38 cell culture was harvested 3, 6 and 9 days after HBV infection, and the levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) in the culture medium were measured using the AXSYM system kit (Abbott Diagnostics). Whether there is HBV DNA in the supernatant was detected with RT-PCR.

[0304] [In vivo Materials and Methods]

[0305] For in vivo experiments, male C3H / HeN mice were purchased from the International Laboratory Animal Center (Taipei, Taiwan, China). The animals were housed at the Laboratory Animal Center, School of Medicine, Yang-Ming Chiao Tung University, Taiwan, under specific pathogen-free conditions. All mice were used in accordance with the guidelines for the use of experimental animals specified by the School of Medicine, Yang-Ming Chiao Tung University, Taiwan. Four mice per cage were fed normal chow and housed in a temperature-controlled room (21 ± 3 °C) with a 12 / 12 h day / night cycle (lights on from 06:00 am to 06:00 pm), which included a 30-min twilight period.

[0306] [Fluid dynamic injection and serum collection]

[0307] For in vivo experiments, HBV expression plasmid pAAV / HBV1.2 (genotype A) was used according to the method of Huang et al. (Proc Natl Acad Sci USA 2006; 103: 17862-17867). All animals were anesthetized with intramuscular ketamine (0.75 g / kg; Merial) and xylazine (60 μg / kg; Bayer) before hydrodynamic injection (HDI). 10 μg pAAV / HBV1.2 dissolved in 8% body weight PBS was injected into the tail vein of the mice. The injection time was controlled between 5 and 8 s. About 150 μL of serum was collected on the second day, and about 150 μL of serum was collected every week after HDI until the end of the experiment. Serum HBsAg, HBeAg and anti-HBs were measured using the AXSYM system kit (Abbott Diagnostika). Anti-HBs measurements are absolute values, while HBsAg measurements are relative values. The HBsAg positivity threshold was set at a signal-to-noise ratio of 10(1). Statistics were calculated using GraphPad Prism and Microsoft Excel.

[0308] [DNA extraction]

[0309] Nucleic acids were extracted from the cell supernatant using the QIAamp DNA Blood Kit (QIAGEN, 51106, Hilden, Germany). First, 100 μl of cell supernatant was added to a microcentrifuge tube, followed by 200 μl of ALbuffer, shaken and mixed thoroughly. Add 20 μl of Protease K and shake well, place the sample in a 56°C incubator for 10 minutes, remove the sample, shake well, and then add 200 μl of 100% alcohol and shake well. Transfer the liquid to the QIAamp Spin Column and centrifuge at 8000 rpm for 1 minute. Discard the liquid and add 500 μl of AW1 buffer to wash the QIAamp Spin Column. Centrifuge at 8000 rpm for 1 minute. Centrifuge at maximum speed for three minutes and dispose of any remaining liquid. Transfer the QIAamp Spin Column to a new microcentrifuge tube, add 100 μl of AE buffer to the QIAamp Spin Column membrane, and centrifuge at 8000 rpm for 1 minute to obtain the extracted nucleic acid sample.

[0310] Experimental Example 1: In vitro cell line evaluation of entecavir-based compounds

[0311] In Experimental Example 1, 5 hepatitis treatment groups were prepared and added to HepG22.2.15 cells for evaluation. Group 1 was a control group containing only culture medium (PBS), to which no drug compound was added. Group 2 was the conventional drug Entecavir (100mM) alone. Group 3 (CPD-0148) involved a compound of formula (IA2) (100mM). Group 4 (CPD-0150) involved a compound of formula (IA3) (100mM). Group 5 (CPD-0147) involved a compound of formula (IA4) (100mM). After incubation of the above-mentioned treatment groups for 6 to 9 days, the hepatitis B surface antigen (HBsAg) level was determined using the AXSYM system kit (Abbott Diagnostika), and the results are as follows: Fig.10 shown.

[0312] like Fig.10 As shown, it can be seen that the conventional drug Entecavir (Group 2) can reduce HBsAg levels compared to the control group. In addition, it was found that when the conventional drug Entecavir was modified with the linker and sugar described in the present disclosure, such as when the compound of formula (IA2) (CPD-0148; Group 3) or when the compound of formula (IA3) (CPD-0150; Group 4), HBsAg levels were further reduced compared to the unmodified drug Entecavir (Group 2). It is worth noting that not all types of linkers and sugars can be used to effectively reduce HBsAg levels. For example, Fig.10As shown, when the compound of formula (IA4) (CPD-0147; Group 5) was used, the HBsAg level seemed to be similar to that of the unmodified drug Entecavir (Group 2), and the HBsAg level could not be significantly reduced. These results show that the carbamate bond of the linker to the sugar (>NC(=O)-O-; Group 3) or the carbonate bond of the linker (-OC(=O)-O-; Group 4) to the sugar seems to be better than the ester bond (-RC(=O)-O-); Group 5) to further reduce the HBsAg level.

[0313] Experimental Example 2: In vitro cell line evaluation of birinapant-based compounds

[0314] In Experimental Example 2, 8 hepatitis treatment groups were prepared and added to HepG22.2.15 cells for evaluation. Group 1 was a control group containing only culture medium (PBS), in which no drug compound was added. Group 2 was a conventional drug Birinapant (500 mM) used alone. Group 3 (CPD-0004) involved a compound of formula (IB1) (500 mM). Group 4 (CPD-0030) involved a compound of formula (IB7) (500 mM). Group 5 (CPD-0036) involved a compound of formula (IB2) (500 mM). Group 6 (CPD-0133) involved a compound of formula (IB3) (500 mM). Group 7 (CPD-0142) involved a compound of formula (IB4) (500 mM). Group 8 (CPD-0186) involved a compound of formula (IB5) (500 mM). After 6 to 9 days of incubation in the above treatment groups, the hepatitis B surface antigen (HBsAg) level was measured using the AXSYM system kit (Abbott Diagnostika). Fig.11 shown.

[0315] like Fig.11As shown, it can be seen that the conventional drug Birinapant (Group 2) is able to reduce HBsAg levels compared to the control group. In addition, it was found that when the conventional drug Birinapant was modified with the linkers and sugars described in the present disclosure, for example, when using the compound of formula (IB1) (CPD-0004; Group 3), the compound of formula (IB2) (CPD-0036; Group 5), the compound of formula (IB3) (CPD-0133; Group 6), the compound of formula (IB4) (CPD-0142; Group 7), and the compound of formula (IB5) (CPD-0186; Group 8), the HBsAg levels were further reduced compared to the unmodified drug Birinapant (Group 2). It is also worth noting that when the monomeric Birinapant (Formula (IB7); CPD-0030) was modified in the same manner as the compound of formula (IB1) (CPD-0004; Group 3), the same reduction in HBsAg levels could not be observed. These results suggest that the reduction in HBsAg levels appears to be more pronounced when two sugar chains (double chain) are attached to the drug via a linker.

[0316] Experimental Example 3: In vitro cell line evaluation of tenofovir-based compounds

[0317] In Experimental Example 3, 13 hepatitis treatment groups were prepared and added to HepG22.2.15 cells for evaluation. Group 1 was a control group containing only culture medium (PBS) without adding drug compounds. Group 2 (Teno-Int) was a control group using conventional drug Tenofovir (100 mM; structure as Figure 3The first step is shown in Figure 1. The third group (CPD-0134) is related to the compound of formula (IC1) (100mM). The fourth group (CPD-0136) is related to the compound of formula (IC2) (100mM). The fifth group (CPD-0137) is related to the compound of formula (IC3) (510mM). The sixth group (CPD-0138) is related to the compound of formula (IC4) (100mM). The seventh group (CPD-0139) is related to the compound of formula (IC5) (100mM). The eighth group (CPD-0143) is related to the compound of formula (IC6) (100mM). The ninth group (CPD-0144) is related to the compound of formula (IC7) (100mM). The tenth group (CPD-0149) is related to the compound of formula (IC8) (100mM). The eleventh group (CPD-0158) is related to the compound of formula (IC9) (100mM). Group 12 (CPD-0169) involves the compound of formula (IC10) (100 mM). Group 12 (CPD-0170) involves the compound of formula (IC11) (100 mM). After 6 to 9 days of incubation in the above treatment groups, the hepatitis B surface antigen (HBsAg) level was measured using the AXSYM system kit (Abbott Diagnostika). The results are as follows Fig.12 shown.

[0318] like Fig.12 As shown, it can be seen that when the Tenofovir intermediate (Teno-Int) is used alone, the HBsAg level can be slightly reduced compared to the control group. In addition, when the conventional Tenofovir intermediate is modified with the linker and sugar described in the present disclosure, for example, when the compound of formula (IC1) (CPD-0134; Group 3), the compound of formula (IC2) (CPD-0136; Group 4), the compound of formula (IC3) (CPD-0137; Group 5), the compound of formula (IC4) (CPD-0138; Group 6), the compound of formula (IC5) (CPD-0139; Group 7), the compound of formula (IC6) (CPD-0140; Group 8), the compound of formula (IC7) (CPD-0141; Group 9), the compound of formula (IC8) (CPD-0142; Group 10), the compound of formula (IC9) (CPD-0143; Group 11), the compound of formula (IC10) (CPD-0144; Group 12), the compound of formula (IC11) (CPD-0145; Group 13), the compound of formula (IC11) (CPD-0146; Group 14), the compound of formula (IC11) (CPD-0147; Group 15), the compound of formula (IC11) (CPD-0148; Group 16), the compound of formula (IC11) (CPD-0149; Group 17), the compound of formula (IC11) (CPD-0140; Group 18), the compound of formula (IC11) (CPD-0141; Group 19), the compound of formula (IC11) (CPD-0142; Group 11), the compound of formula (IC11) (CPD-0143; Group 12), the compound of formula (IC11) (CPD-0144; 143; Group 8), compound of formula (IC7) (CPD-0144; Group 9), compound of formula (IC8) (CPD-0149; Group 10), compound of formula (IC9) (CPD-0158; Group 11), compound of formula (IC10) (CPD-0169; Group 12), and compound of formula (IC11) (CPD-0170; Group 13), HBsAg levels were further reduced compared to the unmodified Tenofovir intermediate (Group 2).

[0319] In addition, it can be seen that the HBsAg level was lowest when the compounds of formula (IC2), formula (IC7) and formula (IC9) were used. These results suggest that the presence of a carbamate bond (>NC(=O)-O-) connecting the linker and the sugar chain and the presence of a triazole group in the linker may be responsible for further reducing the HBsAg level.

[0320] Experimental Example 4: In vitro cell line evaluation of LCL161 compounds

[0321] In Experimental Example 4, 6 hepatitis treatment groups were prepared and added to HepG22.2.15 cells for evaluation. Group 1 was a control group containing only culture medium (PBS), to which no drug compound was added. Group 2 was the conventional drug LCL161 (500mM) alone. Group 3 (CPD-0033) involved a compound of formula (ID1) (500mM). Group 4 (CPD-0130) involved a compound of formula (ID2) (500mM). Group 5 (CPD-0156) involved a compound of formula (ID3) (500mM). Group 6 (CPD-0171) involved a compound of formula (ID4) (500mM). After incubation of the above-mentioned treatment groups for 6 to 9 days, the hepatitis B surface antigen (HBsAg) level was determined using the AXSYM system kit (Abbott Diagnostika), and the results are as follows. Fig.13 shown.

[0322] like Fig.13 As shown, it can be seen that the conventional drug LCL161 (Group 2) is able to reduce HBsAg levels compared to the control group. In addition, it was found that when the conventional drug LCL161 was modified with the linker and sugar described in the present disclosure, for example, when the compound of formula (ID1) (CPD-0033; Group 3), the compound of formula (ID2) (CPD-0130; Group 4), the compound of formula (ID3) (CPD-0156; Group 5) and the compound of formula (ID4) (CPD-0171; Group 6), the HBsAg level was further reduced compared to the unmodified drug LCL161 (Group 2). In addition, it can be seen that when the compounds of formula (ID3) and formula (ID4) were used, the HBsAg level was the lowest. These results indicate that the presence of a carbamate bond (>NC(=O)-O-) connecting the linker and the sugar chain, the presence of a triazole group in the linker, and the control of the number of sugars and the number of sugar chains may be the reason for further reducing the HBsAg level.

[0323] Experimental Example 5: In vitro cell line evaluation of Telbivudine-based compounds and Adefovir-based compounds

[0324] In Experimental Example 5, five hepatitis treatment groups were prepared and added to HepG22.2.15 cells for evaluation. Group 1 was a control group containing only culture medium (PBS) without adding drug compounds. Group 2 was a conventional drug Telbivudine (200 mM) alone. Group 3 (CPD-0117) involved a compound of formula (IE1) (200 mM). Group 4 (Ade-Int) was a conventional drug Adefovir (100 mM; structure as Figure 6 The fourth group (CPD-0146) involves the compound of formula (IF1) (200 mM). After 6 to 9 days of incubation in the above treatment groups, the hepatitis B surface antigen (HBsAg) level was measured using the AXSYM system kit (Abbott Diagnostika). The results are as follows Fig.14 shown.

[0325] like Fig.14 As shown, it can be seen that when the conventional drug Telbivudine (Group 2) is further modified with the linkers and sugars described in the present disclosure, such as when the compound of formula (IE1) (CPD-0117; Group 3) is used, the HBsAg level can be further reduced. Similarly, when the conventional Adefovir intermediate (Group 4) is further modified with the linkers and sugars described in the present disclosure, such as when the compound of formula (IF1) (CPD-0146; Group 5) is used, the HBsAg level can be further reduced.

[0326] Experimental Example 6: In vitro cell line evaluation of drug complexes

[0327] In Experimental Example 6, three hepatitis treatment groups were prepared and added to HepG22.2.15 cells for evaluation. Group 1 was a control group containing only culture medium (PBS), to which no drug compound was added. Group 2 used the conventional drug Entecavir (100mM) alone. Group 3 (CPD-0005CPD-0004) involved the combined use of the compound of formula (IA1) (100mM) and the compound of formula (IB1) (100mM). After incubation of the above treatment groups for 6 to 9 days, the levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were determined using the AXSYM system kit (Abbott Diagnostika), and the results are as follows: Fig.15 as shown.

[0328] like Fig.15As shown, it can be seen that the conventional drug Entecavir can effectively reduce HBsAg and HBeAg levels compared with the control group. However, when the drug complex of formula (IA1) and the drug complex of formula (IB1) are used in combination, it can be seen that HBsAg and HBeAg levels are further reduced. These results show that when the drug complexes of the present disclosure are used in combination, they are more effective than conventional drugs in reducing HBsAg and HBeAg levels.

[0329] Experimental Example 7: In vitro cell line evaluation of drug complexes

[0330] In Experimental Example 7, three hepatitis treatment groups were prepared and added to HepAD38 cells for evaluation. Group 1 was a control group containing only culture medium (PBS), to which no drug compound was added. Group 2 was a combination of conventional drugs Entecavir (25nM) and Birinapant (25nM). Group 3 (CPD-0005CPD-0004) involved the combined use of a compound of formula (IA1) (25nM) and a compound of formula (IB1) (25nM). After incubation of the above treatment groups for 6 to 9 days, the levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were determined using the AXSYM system kit (Abbott Diagnostika), and the presence of HBV DNA in the supernatant was determined by RT-PCR. The results are as follows Fig.16A and Fig. 16B shown.

[0331] like Fig.16A As shown, it can be seen that when the conventional drugs Entecavir and Birinapant are used in combination, they can effectively reduce the levels of HBsAg and HBeAg compared to the control group. However, when the drug complex of formula (IA1) and the drug complex of formula (IB1) are used in combination, it can be seen that the levels of HBsAg and HBeAg are further reduced. These results show that when the drug complexes of the present disclosure are used in combination, they are more effective than conventional drugs in reducing the levels of HBsAg and HBeAg. In addition, as Fig. 16B As shown, it was also found that the combined use of the drug complexes of formula (IA1) and formula (IB1) disclosed in the present invention seemed to have a better effect of reducing HBV DNA levels than the combined use of the conventional drugs Entecavir and Birinapant.

[0332] Experimental Example 8: In vivo evaluation of combined use of drug complexes

[0333] In Experimental Example 8, three hepatitis treatment groups were prepared and administered to C3H mice (intraperitoneal (ip) administration). Group 1 was a control group without drug compounds (PBS as a control). Group 2 was a combination of the conventional drug Entecavir (1.5 mg / kg, ip) and the conventional drug Birinapant (10 mg / kg, ip). Group 3 was a combination of the drug complex of formula (IA1) disclosed herein (3.8 mg / kg, ip) and the drug complex of formula (IB1) (16.6 mg / kg, ip) (CPD-0005CPD-0004). The HBsAg, HBeAg and HBV DNA levels of mice were measured on day 2 (after HDI), day 14, day 21, day 63, day 77, day 105, day 133 and day 151. The results are as shown in FIG. FIG. 17A to FIG. 19B In addition, the hair loss of C3H mice was also evaluated, and the hair loss observation results were shown in Fig. 20 The anti-HBsAg levels of mice were also measured on day 151, and the results were shown in Fig.21 shown.

[0334] like Fig.17A , Fig. 17B as well as Fig.18A and Fig.18B As shown, it can be seen that when the drug complex of formula (IA1) is used in combination with the drug complex of formula (IB1), the levels of HBsAg and HBeAg are further reduced compared with conventional drugs (Entecavir and Birinapant used in combination). The decrease in HBsAg and HBeAg levels is more obvious after day 63. In addition, Fig.19A and Fig.19B As shown, it was also found that the drug complexes of formula (IA1) and formula (IB1) disclosed herein, when used in combination, had a significantly better effect of reducing HBV DNA levels than when used alone. These results demonstrate that when the drug complexes disclosed herein are used in combination in vivo, a synergistic effect can be achieved, whereby the combined use of the drug complexes is more effective in reducing HBsAg and HBeAg levels than conventional drugs. This result is consistent with the results obtained in the in vitro cell line study.

[0335] In addition, if Fig. 20As shown, it is noteworthy that although conventional drugs Entecavir and Birinapant can effectively reduce HBeAg and HBV DNA levels, significant hair loss was also observed in C3H mice. In contrast, the drug complexes of formula (IA1) and (IB1) of the present application did not show hair loss in C3H mice even after 95 days. These results indicate that the drug complexes of the present application are more effective in reducing HBsAg, HBeAg and HBV DNA levels, while achieving fewer side effects.

[0336] In addition, if Fig.21 As shown, it was found that even when conventional drugs Entecavir and Birinapant were used in combination, the anti-HBsAg level obtained was similar to that of the control group. In contrast, when the drug complex of formula (IA1) and the drug complex of formula (IB1) (CPD-0005CPD-0004) were used in combination, significantly higher anti-HBsAg levels were observed. These results indicate that the composition comprising the drug complex of formula (IA1) and formula (IB1) can effectively induce an immune response against hepatitis B virus, while this effect was not observed in conventional drugs.

[0337] Experimental Example 9: In vivo evaluation of the compound of formula (IA1)

[0338] In Experimental Example 9, three hepatitis treatment groups were prepared and administered to C3H mice (intraperitoneal (ip) administration). Group 1 was a control group without drug compound (PBS as control). Group 2 was a conventional drug Entecavir (1.5 mg / kg, intraperitoneal injection) alone. Group 3 was a drug complex of formula (IA1) (3.8 mg / kg, ip). The HBsAg, HBeAg and HBVDNA levels of mice were measured on day 2 (after HDI), day 14, day 21, day 28, day 35, day 42, day 49 and day 56. The results are shown in Table 1. FIG. 22A to FIG. 24B shown.

[0339] like Fig.22A , Fig. 22B as well as Fig.23A and Fig. 23B As shown in the figure, it can be seen that when the conventional drug Entecavir is modified to form the drug complex (CPD-0005) of the disclosed formula (IA1), the HBsAg and HBeAg levels are further reduced compared with the conventional drug. The decrease in HBsAg and HBeAg levels is more obvious after day 49. In addition, Fig.24A and Fig. 24BAs shown, it was also found that the drug complex of formula (IA1) disclosed herein has a better effect of reducing HBV DNA levels than the conventional drug Entecavir. These results demonstrate that when the drug complex of the present disclosure is used in animals (in vivo), they are more effective than conventional drugs in reducing HBsAg, HBeAg and HBV DNA levels. This result is consistent with the results obtained in the in vitro cell line study.

[0340] Experimental Example 10: In vivo evaluation of the compound of formula (IB1)

[0341] In Experimental Example 10, three hepatitis treatment groups were prepared and administered to C3H mice (intraperitoneal (ip) administration). Group 1 was a control group without drug compound (PBS as control). Group 2 was a conventional drug Birinapant (10 mg / kg, intraperitoneal injection) alone. Group 3 was a drug complex of formula (IB1) (16.6 mg / kg, ip). The HBsAg, HBeAg and HBVDNA levels of mice were measured on day 2 (after HDI), day 14, day 21, day 28, day 35, day 56, day 63 and day 70. The results are shown in Table 1. FIG. 25A to FIG. 27B shown.

[0342] like Fig.25A , Fig.25B as well as Fig.26A and Fig.26B As shown in the figure, it can be seen that when the conventional drug Birinapant is modified to form the drug complex (CPD-0004) of the disclosed formula (IB1), the HBsAg and HBeAg levels are further reduced compared with the conventional drug. The reduction in HBsAg and HBeAg levels is more obvious after day 56. In addition, as Fig.27A and Fig.27B As shown, it was also found that the drug complex of formula (IB1) disclosed in the present invention has a better effect of reducing HBV DNA levels than the conventional drug Birinapant. These results demonstrate that when the drug complexes disclosed in the present invention are used in animals (in vivo), they are more effective than conventional drugs in reducing HBsAg, HBeAg and HBV DNA levels. This result is consistent with the results obtained in the in vitro cell line study.

[0343] According to exemplary embodiments of the present disclosure, the drug complex or drug composition of the present disclosure is more effective than conventional drugs in treating hepatitis, such as hepatitis B. Compared with conventional hepatitis B treatment methods, the drug complex or drug composition of the present disclosure can further reduce the level of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and HBV DNA, while increasing the level of hepatitis B surface antibody (anti-HBsAg). In addition, in the drug composition, when the first drug complex (including HBV drug) and the second drug complex (including IAP antagonist) are used in combination, at least the same or lower HBsAg, HBeAg and HBV DNA levels can be achieved, while the side effects (hair loss) are less. In some embodiments, when any of the first drug complex (including HBV drug) or the second drug complex (including IAP antagonist) is used in combination with a conventional drug (unmodified drug compound), the levels of HBsAg, HBeAg and HBV DNA can be further reduced compared to the use of conventional drugs alone.

[0344] It will be apparent to those skilled in the art that various modifications and variations may be made to the disclosed embodiments without departing from the scope or spirit of the present disclosure. In view of the foregoing, the present disclosure is intended to cover modifications and variations that fall within the scope of the appended claims and their equivalents.

Claims

1. A drug complex having a structure shown in formula (I): Z-(Linker-[R] m ) n Formula (I) in, In formula (I), Z is a pharmaceutical compound, R is a sugar, and m and n are independently integers of 1 to 6.

2. The drug complex according to claim 1, wherein the drug compound Z is a hepatitis virus targeted drug, a hepatitis B virus (HBV) drug, a hepatitis C virus (HCV) drug, an inhibitor of apoptosis protein (IAP) antagonist, a multidrug resistance (MDR) inhibitor, or an analog, precursor, prodrug, or derivative thereof.

3. The drug complex according to claim 1, wherein the drug compound Z is selected from the group consisting of: tenofovir, tenofovir diisoproxil, tenofovir alafenamide, entecavir, telbivudine, adefovir, adefovir dipivoxil, lamivudine, interferon-α-2A, interferon-α-2B, birinapant, monomer birinapant, Birinapant), LCL161, GDC-0152, GDC-0917, CUDC-427, APG-1387, DeBio-1143, Selgantolimod, BI-82, Zosuquidar, Glecaprevir, Pibrentasvir, Ombitasvir, Paritaprevir, Ritonavir, Sofosbuvir, Velpatasvir, Ledipasvir, Voxilaprevir, Daclatasvir, Asunaprevir, Telaprevir, Elbasvir, Grazoprevir, Ribavarin, Telaprevir, EDP-239, Alisporivir, Filibuvir, Mericitabine, Danoprevir, Velpatasvir, and analogs, precursors, prodrugs, and derivatives thereof.

4. The drug complex according to claim 1, wherein the sugar R is a monosaccharide, a disaccharide, a trisaccharide, a tetrasaccharide, an oligosaccharide, a polysaccharide or a derivative thereof.

5. The drug conjugate according to claim 1, wherein the linker is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, heterocyclo, cycloalkyl, cycloalkenyl, alkarylalkyl, alkarylalkenyl, alkarylalkynyl, alkenarylalkyl, alkenarylalkenyl, alkenarylalkynyl, alkynearalkyl, alkynearalkenyl , alkynylarylalkynyl, alkanheteroarylalkyl, alkanheteroarylalkenyl, alkanheteroarylalkynyl, alkenheteroarylalkyl, alkenheteroarylalkenyl, alkenheteroarylalkynyl, alkyneheteroarylalkyl, alkenheteroarylalkenyl, alkenheteroarylalkynyl, alkyneheteroarylalkyl, alkenheteroarylalkenyl, alkenheteroarylalkynyl, alkanheterocycloalkyl, alkanheterocycloalkenyl, alkanheterocycloalkynyl, alkenheterocycloalkyl, alkenheterocycloalkenyl, alkenheterocycloalkynyl, alkyneheterocycloalkyl, alkenheterocycloalkenyl, alkenheterocycloalkynyl, alkaryl, alkenaryl, alkarylaryl, alkanheteroaryl, alkenheteroaryl, and alkyneheteroaryl, wherein one or more methylene groups may be replaced by O, S, S(O), SO2, N(R 8 ), C(O), substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic group; wherein R 8 is hydrogen, acyl, aliphatic or substituted aliphatic.

6. The drug complex according to claim 1, wherein the linker in formula (I) comprises L 1 (L 2 ) p Group, wherein said L 1 The group is connected to the drug compound Z, the L 2 The group will be said L 1 The group is connected to the sugar R, wherein p is an integer from 1 to 4, and the L 1 The group is selected from the group consisting of carbamate, amide, ester, amidine, carboxylic acid imide ester, sulfonic acid, sulfuric acid, sulfonated amide, thioether, ether, imine, imide, thioamide, carbonic acid, thiourea, urea, triazole, amine, oxime, thiocarbonic acid, thioester and thiocarbamate, and wherein said L 2 The group is selected from the group consisting of a single bond, an alkyl group containing 1 to 50 carbon atoms, an alkoxy group containing 1 to 50 carbon atoms, an alkenyl group containing 2 to 50 carbon atoms, and an alkenyloxy group containing 2 to 50 carbon atoms, wherein the alkyl group, the alkoxy group, the alkenyl group, and the alkenyloxy group in the above group may be straight chain or branched chain, at least one -CH2- may be substituted by -CO-, -COO-, -OCO-, -S-, -O-, or -NH-, and at least one -CH2CH2- may be substituted by -CH=CH- or -C =C-substituted, and at least one hydrogen in the above-mentioned -CH2-, -CH= or -NH- can be replaced by halogen, trifluoromethyl, alkyl containing 1 to 20 carbons, alkoxy containing 1 to 20 carbons or alkanoyl containing 1 to 20 carbons, and at least one of the above-mentioned -O- can be replaced by phosphoric acid, phosphonic acid, phosphinic acid, phosphine oxide, phosphoramide, aminophosphoric acid, phosphorous acid, phosphinic acid, phosphine, aminophosphine, iminophosphate, phosphonic acid imide, phosphonamide, diphenylphosphamide, or phosphorous acid diamide group.

7. The drug complex according to claim 1, wherein the linker is selected from any one of the group consisting of formula (LX1) to formula (LX30): in, In Formula (LX1) to Formula (LX30), Z is the position where the linker bonds to the drug compound, and R is the position where the linker bonds to the sugar.

8. The drug complex according to claim 7, wherein the sugar R is selected from the group consisting of monosaccharides, disaccharides and trisaccharides, wherein the monosaccharides, the disaccharides and the trisaccharides are independently unsubstituted or substituted with acetyl or N-acetyl groups, and The drug compound Z is selected from the group consisting of: Entecavir, Adefovir, Telbivudine, Lamivudine, Tenofovir, GDC-0152, DeBio-1143, LCL161, Birinapant, and analogs, precursors, prodrugs, and derivatives thereof.

9. The drug complex according to claim 1, wherein in the drug complex, the drug compound Z is coupled to the linker to form a carbamate bond (>NC(=O)-O-), an amide bond (RC(=O)-N<), a carbonate bond (RO-C(=O)-OR') or an ester bond (RC(=O)-OR').

10. The drug complex according to claim 9, wherein in the drug complex, the drug compound Z is coupled to the linker to form a carbamate bond (>NC(=O)-O-) or an ester bond (RC(=O)-OR'). The drug complex according to claim 1 , wherein the linker comprises at least triazole.

12. The drug complex according to claim 1, wherein the structure represented by formula (I) is further represented by formula (II): Z-(Linker-[R] m )2 Formula (II) in, In formula (II), Z is the drug compound, R is the sugar, and m is independently an integer of 1 to 3.

13. The drug complex according to claim 1, wherein the structure represented by formula (I) is further represented by any one of formulas (IA1) to (IA4):

14. The drug complex according to claim 1, wherein the structure represented by formula (I) is further represented by any one of formulas (IB1) to (IB11):

15. The drug complex according to claim 1, wherein the structure represented by formula (I) is further represented by any one of formulas (IC1) to (IC11): Formula (IC11).

16. The drug complex according to claim 1, wherein the structure represented by formula (I) is further represented by any one of formulas (ID1) to (ID5):

17. The drug complex according to claim 1, wherein the structure represented by formula (I) is further represented by formula (IE1):

18. The drug complex according to claim 1, wherein the structure represented by formula (I) is further represented by formula (IF1) or formula (IF2):

19. The drug complex according to claim 1, wherein the structure represented by formula (I) is further represented by formula (IG1):

20. The drug complex according to claim 1, wherein the structure represented by formula (I) is further represented by any one of formula (IH1) to formula (IH3):

21. The drug complex according to claim 1, wherein the structure represented by formula (I) is further represented by formula (IJ1) or formula (IJ2):

22. A pharmaceutical composition comprising: Active ingredient, wherein the active ingredient comprises a drug complex having a structure shown in formula (I): Z-(Linker-[R] m ) n Formula (I) wherein, in formula (I), Z is a drug compound, R is a sugar, and m and n are independently integers from 1 to 6; and At least one or more pharmaceutically acceptable excipients.

23. The pharmaceutical composition according to claim 22, wherein the drug complex comprises a first drug complex represented by formula (I), and wherein in formula (I), drug compound Z is a first drug compound X, and the first drug compound X is selected from the group consisting of: tenofovir, tenofovir diisoproxil, tenofovir alafenamide, entecavir, telbivudine, adefovir, adefovir dipivoxil, lamivudine, interferon-α-2A, interferon-α-2B, selgantolimod, BI-82 and zosuquidar, and analogs, precursors, prodrugs, and derivatives thereof.

24. The pharmaceutical composition according to claim 23, wherein the first drug complex represented by formula (I) is further represented by any one of formulas (IA1) to (IA4), any one of formulas (IC1) to (IC11), formula (IE1), formula (IF1), formula (IF2), or formula (IG1):

25. The pharmaceutical composition according to claim 24, wherein the drug complex further comprises a second drug complex of formula (I), and wherein in formula (I), the drug compound Z is a second drug compound Y, and the second drug compound Y is selected from the group consisting of: Birinapant, monomer Birinapant, Xevinapant, LCL161, GDC-0152, GDC-0917, CUDC-427, APG-1387, DeBio-1143 and analogs, precursors, prodrugs, and derivatives thereof.

26. The pharmaceutical composition according to claim 25, wherein the second drug complex represented by formula (I) is further represented by any one of formulas (IB1) to (IB11), any one of formulas (ID1) to (ID5), any one of formulas (IH1) to (IH3), formula (IJ1) or formula (IJ2):

27. The pharmaceutical composition according to claim 26, wherein the first drug complex is a compound represented by formula (IA1), and the second drug complex is a compound represented by formula (IB1):

28. The pharmaceutical composition according to claim 27, wherein the first drug complex and the second drug complex are administered at a dose of 0.1 mg / kg to 100 mg / kg, respectively.

29. The pharmaceutical composition according to claim 22, wherein the sugar R is a monosaccharide, a disaccharide, a trisaccharide, a tetrasaccharide, an oligosaccharide, a polysaccharide or a derivative thereof.

30. The pharmaceutical composition of claim 22, wherein the linker is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, heterocyclo, cycloalkyl, cycloalkenyl, alkarylalkyl, alkarylalkenyl, alkarylalkynyl, alkenarylalkyl, alkenarylalkenyl, alkenarylalkynyl, alkynearalkyl, alkynear ...kenaryl The invention also provides a plurality of radicals, for example, alkyl, alkynyl, arylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkyneheteroarylalkyl, alkyneheteroarylalkenyl, alkyneheteroarylalkynyl, alkylheterocycloalkyl, alkylheterocycloalkenyl, alkylheterocycloalkynyl, alkenylheterocycloalkyl, alkenylheterocycloalkenyl, alkenylheterocycloalkynyl, alkyneheterocycloalkyl, alkenylheterocycloalkenyl, alkenylheterocycloalkynyl, alkaryl, alkenaryl, alkaryl, alkenaryl, alkenylheteroaryl, and alkyneheteroaryl, wherein one or more methylene radicals may be replaced by O, S, S(O), SO2, N(R2), SO2, N(R3), SO3, N(R4), SO4, N(R5), SO5, N(R6), SO6, N(R7), SO7, N(R8), SO8, SO9, SO10, SO11, SO12, SO13, SO14, SO15, SO16, SO17, SO18, SO19, SO21 8 ), C(O), substituted or unsubstituted aromatic group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclic group; wherein R 8 is hydrogen, acyl, aliphatic or substituted aliphatic.

31. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition is prepared into tablets, capsules, granules, powders, solutions, syrups, sprays, injections or inhalants.

32. The pharmaceutical composition of claim 22, wherein the at least one or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, extenders, binders, admixtures, surfactants, emulsifiers, dispersants, defoamers, lubricants, non-stick agents, blends, coating materials, glidants, anti-sticking agents, diluents, dyes, pigments, dispersants, wetting agents, and combinations thereof.

33. Use of the drug complex according to claim 1 in preparing a medicine for treating hepatitis.

34. Use of the pharmaceutical composition according to claim 22 in the preparation of a medicament for treating hepatitis.

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