Immunostimulating anti-HBSAG antibody conjugate, pharmaceutical composition, and therapeutic application

Abstract

The present invention provides immunostimulating anti-HBsAg antibody conjugates, e.g., compounds of formula (I), and pharmaceutical compositions thereof. The present invention also provides methods of using these for treating, preventing, or alleviating one or more symptoms of HBV infection.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims the benefit of priority under 35 USC 119(a) of International Application No. PCT / CN2023 / 143278 filed December 29, 2023; the entire disclosure of which is incorporated herein by reference.

[0003] Technology field

[0004] The present invention provides an immunostimulating anti-HBsAg antibody conjugate and a pharmaceutical composition thereof. The present invention also provides a method of using the same to treat, prevent, or alleviate one or more symptoms of HBV infection.

[0005] Reference to sequence list

[0006] This specification is filed together with a sequence listing titled 296A001WO01_SEQLIST_ST26.XML, which is 75,601 bytes in size and was created on December 25, 2024; the entire contents of which are incorporated herein by reference. Background Technology

[0007] Hepatitis B virus (HBV) infection remains a significant global health threat, with an estimated 296 million people worldwide chronically infected and 820,000 deaths in 2019. Chisari et al. , Pathol. Biol. (Paris) 2010 , 58 , 258-66; Martyn et al. , eLife 2023 , 12 , e81070; Forbes et al. , Expert Rev. Ant-Infect. Ther. 2023 , 21 , 847-62; Jeng et al. , Lancet 2023 , 401, 1039-52. People with chronic HBV infection have an increased risk of developing hepatic fibrosis, hepatic cirrhosis, and hepatocellular carcinoma (HCC). Chisari et al. , Pathol. Biol. (Paris) 2010 , 58 , 258-66; Martyn et al. , eLife 2023 , 12 , e81070.

[0008] To date, there is no cure for HBV infection. Chisari et al. , Pathol. Biol. (Paris) 2010 , 58 , 258-66; Martyn et al. , eLife 2023 , 12 , e81070; Forbes et al. , Expert Rev. Ant-Infect. Ther. 2023 , 21 , 847-62; Jeng et al. , Lancet 2023 , 401 , 1039-52. Current treatments, pegylated interferon (Peg-IFN) and nucleoside(iti) analogs (NA), can prevent the development of liver cirrhosis and hepatocellular carcinoma, but they do not eradicate the virus and are largely ineffective in clearing hepatitis B surface antigen (HBsAg), a serological marker for HBV infection. Forbes et al. , Expert Rev. Ant-Infect. Ther. 2023 , 21 , 847-62; Jeng et al. , Lancet 2023 , 401 , 1039-52. Therefore, there is an unmet need for effective treatments for HBV infection, particularly chronic HBV infection. Martyn et al. , eLife 2023 , 12 , e81070; Forbes et al. , Expert Rev. Ant-Infect. Ther. 2023 , 21 , 847-62.

[0009] The present invention includes compounds of formula (I):

[0010]

[0011] or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided, wherein:

[0012] Each L is independently a linker;

[0013] Each X is independently (i) bonded or -S-; or (ii) heteroarylene or heterocyclylene, each of which is optionally substituted with one or more, in one embodiment, 1, 2, 3, or 4 substituents Q;

[0014] Each R 1 is independently an immunostimulator;

[0015] R A is an antibody or its antigen-binding fragment that specifically binds to the hepatitis B surface antigen; and

[0016] m is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;

[0017] Here, each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15Aralyl, heteroaryl, and heterocyclil, each of which has one or more, in one embodiment, 1, 2, 3, or 4 substituents Q a Additionally optionally substituted with; and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a )OR d , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b Rc , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)2NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)2NR b R c Selected from, where each R a , R b , R c , and R d is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 It is an araclel, heteroaryl, or heterocyclil, each of which has one or more, in one embodiment, 1, 2, 3, or 4 substituents Q a Optionally substituted with; or (iii) R b and R c They form a heterocyclile together with the N atom to which they are attached, and this has one or more, in one embodiment, 1, 2, 3, or 4 substituents Q a Optionally replaced with;

[0018] Here, each Q aare independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 Aralkill, heteroaryl, and heterocyclil; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SRf , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)2NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)2NR f R g Selected from; where each R e , R f , R g , and R h is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 Aralyl, heteroaryl, or heterocyclil; or (iii) R f and R g They form heterocyclines together with the N atoms to which they are attached.

[0019] The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and a pharmaceutically acceptable excipient.

[0020] Additionally, the present invention provides a method for treating, preventing, or alleviating one or more symptoms of hepatitis B virus (HBV) infection in a subject, comprising the step of administering to a subject in need a therapeutically effective amount of a compound of formula (I), or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Brief explanation of the drawing

[0021] Figure 1 illustrates the SDS-PAGE analysis of anti-HBsAg antibody / CpG oligonucleotide conjugates under reducing conditions, wherein mouse anti-(mAnti)-HBsAg 1 (SEQ ID NOs 8 and 9), AOC-A1 , AOC-A2 , AOC-B1 , AOC-A3 , AOC-A4 , AOC-A5 , AOC-A6 , AOC-A7 , and markers correspond to Lanes 1 to 10, respectively. Figure 2 shows an anti-HBsAg antibody / CpG oligonucleotide conjugate AOC-A1 Illustrates the strong anion exchange chromatography (SAX-HPLC) analysis of. Figure 3 shows mouse anti-HBsAg 1 (SEQNs 8 and 9) and anti-HBsAg antibody / CpG oligonucleotide conjugates as measured by plasma HBsAg levels in an AAV-HBV mouse model. AOC-A1 It demonstrates the antiviral efficacy of. Figure 4 shows mouse anti-HBsAg 1 (SEQNs 8 and 9) and anti-HBsAg antibody / CpG oligonucleotide conjugates as measured by plasma anti-HBs levels in an AAV-HBV mouse model. AOC-A1 It demonstrates the antiviral efficacy of. Figure 5 shows mouse anti-HBsAg 1 (SEQNs 8 and 9) and anti-HBsAg antibody / CpG oligonucleotide conjugates as measured by plasma ALT levels in an AAV-HBV mouse model. AOC-A1 It demonstrates the antiviral efficacy of. Figure 6 shows mouse anti-HBsAg 1 (SEQNs 8 and 9) and anti-HBsAg antibody / CpG oligonucleotide conjugates as measured by liver HBcAg levels in an AAV-HBV mouse model. AOC-A1 It demonstrates the antiviral efficacy of. Figure 7 shows the immunostimulatory anti-HBsAg antibody conjugate as measured by plasma HBsAg levels in an AAV-HBV mouse model. AOC-A1 inside AOC-A7 , AOC-A9 , AOC-B1 , AOC-C1 , and ISAC-A1 It demonstrates the antiviral efficacy of. Figure 8 shows the immunostimulatory anti-HBsAg antibody conjugate as measured by plasma anti-HBs levels in an AAV-HBV mouse model. AOC-A1 inside AOC-A7 , AOC-A9 , AOC-B1 , AOC-C1 , and ISAC-A1 It demonstrates the antiviral efficacy of. Figure 9 shows the immunostimulatory anti-HBcAg antibody conjugate as measured by liver HBcAg levels in an AAV-HBV mouse model. AOC-A1 inside AOC-A7 , AOC-A9 , AOC-B1 , AOC-C1 , and ISAC-A1 It demonstrates the antiviral efficacy of. Figure 10 shows the anti-HBsAg antibody / CpG oligonucleotide conjugate as measured by plasma HBsAg levels in an AAV-HBV mouse model. AOC-A4 , AOC-A10 , AOC-B3 , AOC-B4 , AOC-C1 , and AOC-C2 It demonstrates the antiviral efficacy of. Figure 11 shows the anti-HBsAg antibody / CpG oligonucleotide conjugate as measured by plasma anti-HBs levels in an AAV-HBV mouse model. AOC-A4 , AOC-A10 , AOC-B3 , AOC-B4 , AOC-C1 , and AOC-C2 It demonstrates the antiviral efficacy of. Figure 12 shows the anti-HBsAg antibody / CpG oligonucleotide conjugate as measured by liver HBcAg levels in an AAV-HBV mouse model. AOC-A4 , AOC-A10 , AOC-B3 , AOC-B4 , AOC-C1 , and AOC-C2 It demonstrates the antiviral efficacy of. Figure 13 shows an immunostimulatory anti-HBsAg antibody conjugate as measured by plasma HBsAg levels in an AAV-HBV mouse model. AOC-B8 , AOC-D1 , and ISAC-A2 It demonstrates the antiviral efficacy of. Figure 14 illustrates the effects of human anti-HBsAg 1 (sequence numbers 10 and 11), human anti-HBsAg 2 (sequence numbers 21 and 22), and human anti-HBsAg 3 (sequence numbers 33 and 34) on the interaction between biotinylated human anti-(hAnti)-HBsAg 1 (sequence numbers 10 and 11) and HBsAg (sequence number 56) in a competitive ELISA. Specific details for implementing the invention

[0022] To facilitate understanding of the disclosures set forth herein, several terms are defined below.

[0023] In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, immunology, and pharmacology described herein are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by a person skilled in the art to which this disclosure pertains.

[0024] The term “subject” refers to an animal including, but not limited to, primates (e.g., humans), cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms “subject” and “patient” are used interchangeably herein to refer to mammalian subjects, such as human subjects, for example. In one embodiment, the subject is a human.

[0025] The terms "to treat," "treating," and "treatment" mean alleviating or eliminating one or more of a disorder, disease, or condition, or symptoms associated with such disorder, disease, or condition; or including alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0026] The terms "prevent," "preventing," and "prevention" mean a method of delaying and / or excluding the onset of a disorder, disease, or condition and / or associated symptoms; blocking a subject from acquiring a disorder, disease, or condition; or reducing the risk of a subject acquiring a disorder, disease, or condition.

[0027] The terms "alleviate" and "alleviating" refer to relieving or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms may also refer to reducing side effects associated with the active ingredient. In some cases, the beneficial effects obtained by a subject from a prophylactic or therapeutic agent do not result in the cure of the disorder, disease, or condition.

[0028] The term “contacting” or “contacting” means bringing together a therapeutic agent and a biological molecule (e.g., protein, enzyme, RNA, or DNA), a cell, or a tissue so that physiological and / or chemical effects occur as a result of such contact. Contacting may occur in vitro, in vitro, or in vivo. In one embodiment, the therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule. In another embodiment, the therapeutic agent is contacted with a cell in a cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In yet another embodiment, contacting the therapeutic agent with a biological molecule, cell, or tissue involves administering the therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.

[0029] The term "therapeutic effective dose" or "effective dose" means containing an amount of a compound sufficient to prevent the onset of or to alleviate to some extent one or more symptoms of the disorder, disease, or condition being treated when administered. The term "therapeutic effective dose" or "effective dose" also refers to an amount of a compound sufficient to induce a biological or medical response in a biological molecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human being sought by a researcher, veterinarian, physician, or clinician.

[0030] The term "HBsAg" refers to the hepatitis B virus envelope proteins comprising the HBV envelope proteins S, M, and L, also known as S-HBsAg, M-HBsAg, and L-HBsAg, respectively. S-HBsAg, M-HBsAg, and L-HBsAg share the same C-terminus (also known as the S domain) which is 226 amino acids long, corresponding to S-HBsAg, and is important for viral assembly and infectivity. Salisse and Sureau, J . Virol . 2009 , 83 , 9321-8.

[0031] The terms “pharmaceuticalally acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refer to pharmaceutically acceptable materials, compositions, or vehicles such as liquid or solid fillers, diluents, solvents, or encapsulating materials. In one embodiment, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of the pharmaceutical formulation and is suitable for use in contact with tissues or organs of a subject (e.g., human or animal) in accordance with a reasonable benefit / risk ratio, without excessive toxicity, irritation, allergic reaction, immunogenicity, or other problems or complications. For example, Remington: The Science and Practice of Pharmacy , 22nd edition; Allen Ed.; Pharmaceutical Press: London, 2012; Handbook of Pharmaceutical Excipients , 8th edition.; Sheskey et al. , Eds.; Pharmaceutical Press: London, 2017; Handbook of Pharmaceutical Additives , 3rd edition; Ash and Ash Eds.; Synapse Information Resources: 2007; Pharmaceutical Preformulation and Formulation See , 2nd edition; Gibson Ed.; Drugs and the Pharmaceutical Sciences 199; Informa Healthcare: New York, NY, 2009.

[0032] The term “approximately” or “roughly” means an acceptable error for a specific value determined by a person skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “approximately” or “roughly” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “approximately” or “roughly” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0033] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, alkyl has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 A linear saturated monovalent hydrocarbon radical having ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 It is a branched saturated monovalent hydrocarbon radical having a carbon atom. As used herein, linear C 1-6 and branched C 3-6Alkyl groups are also referred to as "lower alkyl." Examples of alkyl groups are methyl, ethyl, and propyl (all isomer forms, e.g., n -Including propyl and isopropyl), butyl (all isomer forms, e.g., n -Butyl, isobutyl, sec -Butyl, and t -Contains butyl), pentyl (all isomer forms, e.g., n -Pentyl, isopentyl, sec -Pentyl, neopentyl, and tert -Containing pentyl), and hexyl (all isomer forms, e.g., n - Hexyl, isohexyl, and sec - Includes, but is not limited to, hexyl.

[0034] The term "heteroalkyl" refers to a linear or branched saturated monovalent hydrocarbon radical comprising one or more heteroatoms on its main chain, each independently selected from O, S, N, and P. The heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkyl refers to a linear saturated monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, the heteroalkyl has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 A linear saturated monovalent hydrocarbon radical having ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6It is a branched saturated monovalent hydrocarbon radical having a carbon atom. As used herein, linear C 1-6 and branched C 3-6 Heteroalkyl groups are also referred to as "lower heteroalkyls." Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -CH2OCH3, -NHCH3, -ONHCH3, -NHOCH3, -SCH3, -CH2NHCH2CH3, and -NHCH2CH2CH3. Examples of substituted heteroalkyl groups include -CH2NHC(O)CH3, -NHC(O)CH2CH3, and -OP(O)(O - )OCH2CH3, -OP(S)(O - )OCH2CH3. -P(O)(O - )OCH2CH3, and -P(S)(O - Includes, but is not limited to, OCH2CH3.

[0035] The terms "alkylene" and "alkanediyl" are used interchangeably herein to refer to linear or branched saturated divalent hydrocarbon radicals, wherein the alkanediyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkanedils refer to linear saturated divalent hydrocarbon radicals having 1 to 6 carbon atoms or branched saturated divalent hydrocarbon radicals having 3 to 6 carbon atoms. In certain embodiments, alkanedils have 1 to 30 (C 1-30 ), 1 to 20 pieces (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 A linear saturated divalent hydrocarbon radical having ) carbon atoms, or 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6It is a branched saturated divalent hydrocarbon radical having a carbon atom. As used herein, linear C 1-6 and branched C 3-6 Alkandiyl is also referred to as "low-grade alkandiyl." Examples of alkanedyl groups are methanediyl, ethanediyl (including all isomer forms, e.g., ethane-1,1-diyl and ethane-1,2-diyl), propanediyl (including all isomer forms, e.g., propane-1,1-diyl, propane-1,2-diyl, and propane-1,3-diyl), butanediyl (including all isomer forms, e.g., butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, and butane-1,4-diyl), pentanediyl (including all isomer forms, e.g., pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl, and pentane-1,5-diyl), and hexanediyl (all isomer forms, e.g., hexane-1,1-diyl, Includes, but is not limited to, hexane-1,2-diyl, hexane-1,3-diyl, and hexane-1,6-diyl. Examples of substituted alkandyl groups include -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, -C(O)(CH2)4-, -C(O)(CH2)5-, -C(O)(CH2)6-, -C(O)(CH2)7-, -C(O)(CH2)8-, -C(O)(CH2)9-, -C(O)(CH2) 10 Includes, but not limited to, -, -C(O)CH2C(O)-, -C(O)(CH2)2C(O)-, -C(O)(CH2)3C(O)-, -C(O)(CH2)4C(O)-, or -C(O)(CH2)5C(O)-.

[0036] The terms "heteroalkylene" and "heteroalkanedyl" are used interchangeably herein to refer to linear or branched saturated divalent hydrocarbon radicals containing one or more heteroatoms in their main chains, each independently selected from O, S, N, and N. Heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C1-6 Heteroalkylene refers to a linear saturated divalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 A linear saturated divalent hydrocarbon radical having ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 It is a branched saturated divalent hydrocarbon radical having a carbon atom. As used herein, linear C 1-6 and branched C 3-6 Heteroalkylene groups are also referred to as "lower heteroalkylenes." Examples of heteroalkylene groups are -CH2O-, -(CH2)2O-, -(CH2)3O-, -(CH2)4O-, -(CH2)5O-, -(CH2)6O-, -(CH2)7O-, -(CH2)8O-, -(CH2)9O-, -(CH2) 10 Includes, but not limited to, O-, -CH2OCH2-, -CH2CH2O-, -(CH2CH2O)2-, -(CH2CH2O)3-, -(CH2CH2O)4-, -(CH2CH2O)5-, -CH2NH-, -CH2NHCH2-, -CH2CH2NH-, -CH2S-, -CH2SCH2-, and -CH2CH2S-. Examples of substituted heteroalkylene groups are -C(O)CH2O-, -C(O)(CH2)2O-, -C(O)(CH2)3O-, -C(O)(CH2)4O-, -C(O)(CH2)5O-, -C(O)(CH2)6O-, -C(O)(CH2)7O-, -C(O)(CH2)8O-, -C(O)(CH2)9O-, -C(O)(CH2) 10O-, -C(O)CH2OCH2CH2O-, -C(O)CH2O(CH2CH2O)2-, -C(O)CH2O(CH2CH2O)3-, -C(O)CH2O(CH2CH2O)4, -C(O)CH2O(CH2CH2O)5-, -CH2NHC(O)CH2-, -CH2CH2C(O)NH-, -CH2CH2OP(O)(O - )O-, or -CH2CH2OP(S)(O - )O-, -CH2CH2OP(O)(O - )-, and -CH2CH2OP(S)(O - Includes, but is not limited to, )-.

[0037] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical comprising one or more carbon-carbon double bond(s), in one embodiment, one, two, three, or four, and in another embodiment, one. The alkenyl is optionally substituted with one or more substituents Q as described herein. The term "alkenyl" as understood by those skilled in the art is " 시스 " or " 트랜스 " arrangement or mixture thereof, or alternatively " Z " or " E It encompasses radicals having an arrangement or a mixture thereof. For example, C 2-6 Alkenyl refers to a linear unsaturated monovalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, alkenyl has 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 A linear monovalent hydrocarbon radical having ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6It is a branched monovalent hydrocarbon radical having a carbon atom. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomer forms, e.g., propene-1-yl, propene-2-yl, and allyl), and butenyl (including all isomer forms, e.g., butene-1-yl, butene-2-yl, butene-3-yl, and 2-butene-1-yl).

[0038] The terms “alkenylene” and “alkeniyl” are used interchangeably herein to refer to linear or branched divalent hydrocarbon radicals comprising one or more carbon-carbon double bond(s), in one embodiment, one, two, three, or four, and in another embodiment, one. The alkeniyl is optionally substituted with one or more substituents Q as described herein. The term “alkeniyl” is understood by those skilled in the art as “ 시스 " or " 트랜스 " arrangement or mixture thereof, or alternatively " Z " or " E It encompasses radicals having an arrangement or a mixture thereof. For example, C 2-6 Alkenidiyl refers to a linear unsaturated divalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, the alkenidiyl has 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 A linear divalent hydrocarbon radical having ) carbon atoms, or 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6It is a branched divalent hydrocarbon radical having a carbon atom. Examples of alkenidiyl groups include ethenediyl (including all isomer forms, e.g., ethene-1,1-diyl and ethene-1,2-diyl), propenediyl (including all isomer forms, e.g., 1-propene-1,1-diyl, 1-propene-1,2-diyl, and 1-propene-1,3-diyl), butenediyl (including all isomer forms, e.g., 1-butene-1,1-diyl, 1-butene-1,2-diyl, and 1-butene-1,4-diyl), pentenediyl (including all isomer forms, e.g., 1-pentene-1,1-diyl, 1-pentene-1,2-diyl, and 1-pentene-1,5-diyl), and hexenediyl (all isomer forms, e.g., It includes, but is not limited to, 1-hexene-1,1-diyl, 1-hexene-1,2-diyl, 1-hexene-1,3-diyl, 1-hexene-1,4-diyl, 1-hexene-1,5-diyl, and 1-hexene-1,6-diyl.

[0039] The terms “heteroalkenylene” and “heteroalkenidiyl” are used interchangeably herein to refer to linear or branched divalent hydrocarbon radicals comprising one or more carbon-carbon double bond(s)—in one embodiment, one, two, three, or four; in another embodiment, one—and comprising one or more heteroatoms independently selected from O, S, and N within the hydrocarbon chain. Heteroalkenylene is optionally substituted with one or more substituents Q as described herein. The term “heteroalkenylene” is understood by those skilled in the art as “ 시스 " or " 트랜스 " arrangement or mixture thereof, or alternatively " Z " or " E It encompasses radicals having an arrangement or a mixture thereof. For example, C 2-6Heteroalkenylene refers to a linear unsaturated divalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, heteroalkenylene has 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 A linear divalent hydrocarbon radical having ) carbon atoms, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 It is a branched divalent hydrocarbon radical having a carbon atom. Examples of heteroalkenylene groups include, but are not limited to, -CH=CHO-, -CH=CHOCH2-, -CH=CHCH2O-, -CH=CHS-, -CH=CHSCH2-, -CH=CHCH2S-, or -CH=CHCH2NH-.

[0040] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical comprising one or more carbon-carbon triple bond(s), in one embodiment, one, two, three, or four, and in another embodiment, one. The alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynyl refers to a linear unsaturated monovalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical having 4 to 6 carbon atoms. In certain embodiments, alkynyl has 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 A linear monovalent hydrocarbon radical having ) carbon atoms, or 4 to 20 (C 4-20), 4 to 15 (C 4-15 ), 4 to 10 (C 4-10 ), or 4 to 6 (C 4-6 It is a branched monovalent hydrocarbon radical having a carbon atom. Examples of alkynyl groups include, but are not limited to, ethinyl (-C≡CH), propynyl (including all isomer forms, e.g., 1-propynyl (-C≡CCH3) and propargyl (-CH2C≡CH)), butynyl (including all isomer forms, e.g., 1-butyn-1-yl and 2-butyn-1-yl), fentinyl (including all isomer forms, e.g., 1-fentin-1-yl and 1-methyl-2-butyn-1-yl), and hexinyl (including all isomer forms, e.g., 1-hexine-1-yl and 2-hexine-1-yl).

[0041] The terms “alkynylene” and “alkyndiyl” are used interchangeably herein to refer to linear or branched divalent hydrocarbon radicals comprising one or more carbon-carbon triple bond(s), in one embodiment, one, two, three, or four, and in another embodiment, one. The alkyndiyl is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkyndiyl refers to a linear unsaturated divalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical having 4 to 6 carbon atoms. In certain embodiments, alkyndiyl has 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 A linear divalent hydrocarbon radical having ) carbon atoms, or 4 to 30 (C 4-30 ), 4 to 20 (C 4-20 ), 4 to 15 (C 4-15 ), 4 to 10 (C 4-10), or 4 to 6 (C 4-6 It is a branched divalent hydrocarbon radical having a carbon atom. Examples of alkindiyl groups include, but are not limited to, ethindiyl, propindiyl (including all isomer forms, e.g., 1-propin-1,3-diyl and 1-propin-3,3-diyl), buthindiyl (including all isomer forms, e.g., 1-butin-1,3-diyl, 1-butin-1,4-diyl, and 2-butin-1,1-diyl), penthindiyl (including all isomer forms, e.g., 1-penthin-1,3-diyl, 1-penthin-1,4-diyl, and 2-penthin-1,1-diyl), and hexindiyl (including all isomer forms, e.g., 1-hexin-1,3-diyl, 1-hexin-1,4-diyl, and 2-hexin-1,1-diyl).

[0042] The terms “heteroalkynylene” and “heteroalkyndiyl” are used interchangeably herein to refer to linear or branched divalent hydrocarbon radicals comprising one or more carbon-carbon triple bond(s)—in one embodiment, one, two, three, or four; in another embodiment, one—and comprising one or more heteroatoms within their main chain, each independently selected from O, S, and N. Heteroalkynylene is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Heteroalkynylene refers to a linear unsaturated divalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical having 4 to 6 carbon atoms. In certain embodiments, heteroalkynylene has 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 A linear divalent hydrocarbon radical having ) carbon atoms, or 4 to 30 (C 4-30 ), 4 to 20 (C4-20 ), 4 to 15 (C 4-15 ), 4 to 10 (C 4-10 ), or 4 to 6 (C 4-6 It is a branched divalent hydrocarbon radical having a carbon atom. Examples of heteroalkynylene groups include, but are not limited to, -C≡CCH2O-, -C≡CCH2S-, or -C≡CCH2NH-.

[0043] The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl is a saturated or unsaturated but non-aromatic, and / or cross-linked or uncross-linked, and / or fused dicyclic group. In specific embodiments, the cycloalkyl is 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 7 (C 3-7 It has a carbon atom. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In yet another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclo-butyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]-octyl, decalinyl, and adamantyl.

[0044] The terms “cycloalkylene” and “cycloalkanedil” are used interchangeably herein to refer to cyclic divalent hydrocarbon radicals, which may be optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkanedil group may be a saturated or unsaturated but non-aromatic, and / or cross-linked, and / or uncross-linked, and / or fused bicyclic group. In specific embodiments, the cycloalkanedil may have 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 7 (C 3-7 It has carbon atoms. Examples of cycloalkanedyl groups include cyclopropanediyl (including all isomer forms, e.g., cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomer forms, e.g., cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and cyclobutane-1,3-diyl), cyclopentanediyl (including all isomer forms, e.g., cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomer forms, e.g., cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, and cyclohex-1,4-diyl), and cycloheptanediyl (all isomers Forms, e.g., including cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cycloheptane-1,3-diyl, and cycloheptane-1,4-diyl), decalindiyl (all isomer forms, e.g., decalin-1,1-diyl, decalin-1,2-diyl, and decalin-1,8-diyl), and adamantdiyl (all isomer forms, e.g., adamant-1,2-diyl, adamant-1,3-diyl, and adamant-1,8-diyl), are included but not limited thereto.

[0045] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon radical and / or a monovalent polycyclic aromatic hydrocarbon radical comprising at least one aromatic carbon ring. In certain embodiments, the aryl comprises 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ), or 6 to 10 (C 6-10 It has a ring carbon atom. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to a bicyclic or tricyclic carbon ring in which one of the rings may be aromatic and the remainder may be saturated, partially unsaturated, or aromatic, e.g., dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, the aryl is monocyclic. In another embodiment, the aryl is bicyclic. In yet another embodiment, the aryl is tricyclic. In yet another embodiment, the aryl is polycyclic. In certain embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.

[0046] The terms “arylene” and “arendyl” are used interchangeably herein to refer to a divalent monocyclic aromatic hydrocarbon radical or a divalent polycyclic aromatic hydrocarbon radical comprising at least one aromatic hydrocarbon ring. In certain embodiments, the arylene comprises 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ), or 6 to 10 (C 6-10It has ring atoms of ). Examples of arylene groups are phenylene (including all isomer forms, e.g., phen-1,2-diyl, phen-1,3-diyl, and phen-1,4-diyl), naphthylene (including all isomer forms, e.g., naphth-1,2-diyl, naphth-1,3-diyl, and naphth-1,8-diyl), fluorenylene (including all isomer forms, e.g., fluoren-1,2-diyl, fluoren-1,3-diyl, and fluoren-1,8-diyl), azulenylene (including all isomer forms, e.g., azulene-1,2-diyl, azulene-1,3-diyl, and azulene-1,8-diyl), and anthrylene (including all isomer forms, e.g., anth-1,2-diyl, Includes, but is not limited to, anth-1,3-diyl and anth-1,8-diyl), phenanthrylene (all isomer forms, e.g., phenanth-1,2-diyl, phenanth-1,3-diyl, and phenanth-1,8-diyl), pyrenylene (all isomer forms, e.g., pyrene-1,2-diyl, pyrene-1,3-diyl, and pyrene-1,8-diyl), biphenylene (all isomer forms, e.g., biphen-2,3-diyl, biphen-3,4'-diyl, and biphen-4,4'-diyl), and terphenylene (all isomer forms, e.g., terpene-2,3-diyl, terpene-3,4'-diyl, and terpene-4,4'-diyl).Arrylenes are also dicyclic or tricyclic carbon rings in which one of the rings may be aromatic and the rest may be saturated, partially unsaturated, or aromatic, e.g., dihydronaphthylene (including all isomer forms, e.g., dihydronaphthylene-1,2-diyl and dihydronaphthylene-1,8-diyl), indenylene (including all isomer forms, e.g., indene-1,2-diyl, indene-1,5-diyl, and indene-1,7-diyl), indanylene (including all isomer forms, e.g., indan-1,2-diyl, indan-1,5-diyl, and indan-1,7-diyl), or tetrahydronaphthylene (tetralinylene) (all isomer forms, e.g., tetrahydronaphthylene-1,2-diyl, tetrahydronaphthylene-1,5-diyl, and Refers to tetrahydronaft-1,8-diyl). In certain embodiments, arylene is optionally substituted with one or more substituents Q as described herein.

[0047] The terms "aracleyl" or "arylalkyl" refer to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aracleyl consists of 7 to 30 (C 7-30 ), 7 to 20 (C 7-20 ), or 7 to 16 (C 7-16 It has a carbon atom of ). Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomer forms, e.g., 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomer forms, e.g., 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In certain embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.

[0048] The term "arylkylene" or "arylalkylene" refers to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the arylkylene comprises 7 to 30 (C 7-30 ), 7 to 20 (C 7-20 ), or 7 to 16 (C7-16 It has a carbon atom of ). Examples of araclelene groups include, but are not limited to, benzylene (all isomer forms, e.g., phenyl-metdiyl), phenylethylene (all isomer forms, e.g., 2-phenyl-ethane-1,1-diyl and 2-phenyl-ethane-1,2-diyl), and phenylpropylene (all isomer forms, e.g., 3-phenyl-propane-1,1-diyl, 3-phenyl-propane-1,2-diyl, and 3-phenyl-propane-1,3-diyl). In certain embodiments, the araclelene is optionally substituted with one or more substituents Q as described herein.

[0049] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group comprising at least one aromatic ring, wherein the at least one aromatic ring comprises one or more heteroatoms independently selected from O, S, and N, respectively, within the ring. The heteroaryl is bonded to the rest of the molecule through the aromatic ring. Each ring of the heteroaryl group may comprise one or two O atoms, one or two S atoms, and / or one to four N atoms; provided that the total number of heteroatoms within each ring is four or less, and each ring comprises at least one carbon atom. In certain embodiments, the heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, the heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In other embodiments, the heteroaryl is bicyclic. Examples of bicyclic heteroaryl groups include benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, and propyrindyl (all isomer forms, e.g., furo[2,3- b ]pyridinyl, furo[2,3- c ]pyridinyl, furo[3,2- b ]-pyridinyl, furo[3,2- c ]pyridinyl, furo[3,4- b ]pyridinyl, and furo[3,4- c ]including pyridinyl), imidazopyridinyl (all isomer forms, e.g., imidazo[1,2- a ]pyridinyl, imidazo[4,5- b ]pyridinyl, and imidazo[4,5- c]containing pyridinyl), imidazothiazolyl (all isomer forms, e.g., imidazo[2,1- b ]-thiazolil and imidazo[4,5- d ]including thiazolyl), indazolyl, indolizinil, indolyl, isobenzofuranil, isobenzothienyl (i.e., benzo[ c ]thienyl), isoindolyl, isoquinolinyl, naphthiridinyl (including all isomer forms, e.g., 1,5-naphthiridinyl, 1,6-naphthiridinyl, 1,7-naphthiridinyl, and 1,8-naphthiridinyl), oxazolopyridinyl (all isomer forms, e.g., oxazolo[4,5- b ]pyridinyl, oxazolo[4,5- c ]-pyridinyl, oxazolo[5,4- b ]pyridinyl, and oxazolo[5,4- c ]including pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (all isomer forms, e.g., pyrrolo[2,3- b ]pyridinyl, pyrrolo[2,3- c ]pyridinyl, pyrrolo[3,2- b ]pyridinyl, and pyrrolo[3,2- c ]including pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (all isomer forms, e.g., [1,2,5]thiadiazolo[3,4- d ]-pyrimidinyl and [1,2,3]thiadiazolo[4,5- d ]including pyrimidinyl), and thienopyridyl (all isomer forms, e.g., thieno[2,3- b ]pyridinyl, thieno[2,3- c ]pyridinyl, thieno[3,2- b ]pyridinyl, and thieno-[3,2- c]including pyridinyl) but not limited thereto. In another embodiment, the heteroaryl is tricyclic. Examples of tricyclic heteroaryl groups include, but not limited to, acridinyl, benzindolyl, carbazolyl, dibenzo-furanyl, perimidinyl, phenanthrolinyl, phenanthrolinyl, phenanthridinyl (including all isomer forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsaginyl, phenazinyl, phenothiaginyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described herein.

[0050] The terms “heteroarylene” and “heteroarendyl” are used interchangeably herein to refer to a divalent monocyclic aromatic group or a divalent polycyclic aromatic group comprising at least one aromatic ring, wherein the at least one aromatic ring comprises one or more heteroatoms independently selected from O, S, and N, respectively, within the ring. The heteroarylene group has at least one connection to the rest of the molecule through its aromatic ring(s). Each ring of the heteroarylene group may comprise one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms within each ring is four or less, and each ring comprises at least one carbon atom. In certain embodiments, the heteroarylene has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furandyl, imidazolediyl, isothiazazolediyl, isoxazazolediyl, oxazazolediyl, pyrazindiyl, pyrazoldiyl, pyridazinediyl, pyridindiyl, pyrimidindiyl, pyrroldyl, thiazazolediyl, thiazoldyl, thienediyl, tetrazoldiyl, triazinediyl, and triazoldyl. Examples of bicyclic heteroarylene groups include, but are not limited to, benzofurandyl, benzimidazolediyl, benzisoxazazolediyl, benzopyrandyl, benzothiadiazolediyl, benzothiazoldyl, benzothiendiyl, benzotriazolediyl, benzoxazoldyl, and propyridindiyl (all isomer forms, e.g., furo[2,3- b ]Pyridindiil, furo[2,3- c ]Pyridindiil, furo[3,2- b ]Pyridindiil, furo[3,2- c ]-Pyridindiil, furo[3,4- b ]pyridindiyl, and furo[3,4- c ]including pyridindiyl), imidazopyridindiyl (all isomer forms, e.g., imidazo[1,2- a ]Piridindiil, imidazo[4,5- b]pyridindiyl, and imidazo[4,5- c ]-including pyridindiyl), imidazothiazolediyl (all isomer forms, e.g., imidazo[2,1- b ]thiazoldyl and imidazo[4,5- d ]including thiazoldyl), indazoldyl, indolizindiyl, indoldiyl, isobenzofurandyl, isobenzothiendiyl (i.e., benzo[ c ]thiendiyl), isoindoldilyl, isoquinolindiyl, naftiridindiyl (including all isomer forms, e.g., 1,5-naftiridindiyl, 1,6-naftiridindiyl, 1,7-naftiridin-diyl, and 1,8-naftiridindiyl), oxazolopyridindiyl (all isomer forms, e.g., oxazolo-[4,5- b ]Pyridindiil, oxazolo[4,5- c ]Pyridindiil, oxazolo[5,4- b ]pyridindiyl, and oxazolo[5,4- c ]-including pyridindiyl), phthalazindiyl, pteridindiyl, purindiyl, pyrrolopyridindiyl (all isomer forms, e.g., pyrrolo[2,3- b ]pyridindiile, pyrrolo[2,3- c ]pyridindiil, pyrrolo[3,2- b ]pyridindiyl, and pyrrolo[3,2- c ]including pyridindiyl), quinolindiyl, quinoxalindiyl, quinazolindiyl, thiadiazolopyrimidinediyl (all isomer forms, e.g., [1,2,5]thiadiazolo[3,4- d ]pyrimidindiyl and [1,2,3]thiadiazolo-[4,5- d ]including pyrimidinediyls), and thienopyridinediyls (all isomer forms, e.g., thieno[2,3- b ]-Piridindiil, Thieno[2,3- c ]Piridindiil, Thieno[3,2- b ]Pyridindiil, and Thieno[3,2- c]including pyridindiyl) but not limited thereto. Examples of tricyclic heteroarylene groups include, but are not limited thereto, acridindiyl, benzindolediyl, carbazolediyl, dibenzofurandil, fermidindiyl, phenanthrolindiyl (including all isomer forms, e.g., 1,5-phenanthrolindiyl, 1,6-phenanthrolindiyl, 1,7-phenanthrolindiyl, 1,9-phenanthrolindiyl, and 2,10-phenanthrolindiyl), phenanthridindiyl, phenarzazinediyl, phenazinediyl, phenothiazinediyl, phenoxazinediyl, and xanthendiyl. In certain embodiments, the heteroarylene is optionally substituted with one or more substituents Q as described herein.

[0051] The term “heterocyclile” or “heterocyclic” refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system comprising at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N, respectively; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclile or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. The heterocyclile is bonded to the rest of the molecule through the non-aromatic ring. In certain embodiments, the heterocyclile is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or crosslinked, wherein the nitrogen or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, and some rings may be partially or completely saturated or aromatic. The heterocyclile may be attached to the main structure at any heteroatom or carbon atom resulting in the formation of a stable compound. Examples of heterocycliles and heterocyclic groups are azefinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (all isomer forms, e.g., 1,4-dihydrobenzo[ d ][1,3]oxazinyl, 3,4-dihydrobenzo[ c ][1,2]-oxazinyl, and 3,4-dihydrobenzo[ d ][1,2]including oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[ c]Thienyl, Dihydrofuryl, Dihydroisoindolyl, Dihydropyranil, Dihydropyrazolyl, Dihydropyrazinyl, Dihydropyridinyl, Dihydropyrimidinyl, Dihydropyrrolyl, Dioxolanil, 1,4-Dithianil, Furanonil, Imidazolidinyl, Imidazolininyl, Indolinyl, Isochromanyl, Isoindolinyl, Isothiazolidinyl, Isoxazolidinyl, Morfollinil, Octahydroindolyl, Octahydroisoindolyl, Oxazolidinonil, Oxazolidinyl, Oxiranil, Piperazinyl, Piperidinyl, 4-Piperidonyl, Pyrazolidinyl, Pyrazolininyl, Pyrrolidinyl, Pyrrolinyl, Quinuclideinyl, Tetrahydrofuryl, Includes, but is not limited to, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorfolinyl, thiazolidinyl, thiochromatinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclil is optionally substituted with one or more substituents Q as described herein.

[0052] The term “heterocyclilene” refers to a divalent monocyclic non-aromatic ring system or a divalent polycyclic ring system comprising at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. The heterocyclilene group is bonded to the rest of the molecule through the non-aromatic ring. In certain embodiments, the heterocyclilene group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, the heterocyclilene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or crosslinked, wherein the nitrogen or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, and some rings may be partially or completely saturated or aromatic. The heterocyclilene may be attached to the main structure at any heteroatom or carbon atom resulting in the formation of a stable compound. Examples of such heterocyclilene groups are azepinediyl, benzodioxanediyl, benzodioxoldiyl, benzofuranodiyl, chromandil, decahydroisoquinolindiyl, dihydrobenzofurandil, dihydrobenzisothiazoldil, dihydrobenzisosoxazinediyl (all isomer forms, e.g., 1,4-dihydrobenzo[ d ][1,3]oxazandyl, 3,4-dihydrobenzo[ c ][1,2]oxazandyl, and 3,4-dihydrobenzo[ d ][1,2]including oxazandyl), dihydrobenzothiendiyl, dihydroisobenzofurandyl, dihydrobenzo[ c] thiendiyl, dihydrofurdiyl, dihydroisoindolediyl, dihydropyrandiyl, dihydropyrazoldiyl, dihydropyrazindiyl, dihydropyridindiyl, dihydropyrimidindiyl, dihydropyrrolediyl, dioxolandiyl, 1,4-dithiandiyl, furanonediyl, imidazolidindiyl, imidazolindiyl, indolindiyl, isochromandil, isoindolindiyl, isothiazolidindiyl, isoxazolidindiyl, morpholinediyl, octahydroindolediyl, octahydroisoindolediyl, oxazolidinonediyl, oxazolidindiyl, oxirandil, piperazindiyl, piperidindiyl, 4-piperidonediyl, pyrazolidindiyl, pyrazolindiyl, Pyrrolidindiyl, pyrrolindiyl, quinuclidindiyl, tetrahydrofurdiyl, tetrahydroisoquinolinediyl, tetrahydropyrandiyl, tetrahydrothienediyl, thiamophorindiyl, thiazolidindiyl, thiochromandil, tetrahydroquinolinediyl, and 1,3,5-trithiandiyl are included, but not limited thereto. In certain embodiments, heterocyclilene is optionally substituted with one or more substituents Q as described herein.

[0053] The terms "halogen," "halide," or "halo" refer to fluoro, chloro, bromo, and / or iodo.

[0054] The term “optionally substituted” is intended to mean that a group or substituent such as an alkyl, heteroalkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclil, or heterocyclilene group may be substituted with one or more, in one embodiment, one, two, three, or four substituents Q, each of which is, for example, (a) deuterium (-D), cyano (-CN), halo, imino (=NH), nitro (-NO2), and oxo (=O); (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 Aralyl, heteroaryl, and heterocyclil, each of which has one or more, in one embodiment, 1, 2, 3, or 4 substituents Q a Additionally optionally substituted with; and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a )OR d , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR aC(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)2NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)2NR b R c Selected independently from, where each R a , R b , R c , and R d is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 It is an araclel, heteroaryl, or heterocyclil, each of which has one or more, in one embodiment, 1, 2, 3, or 4 substituents Q a Optionally substituted with; or (iii) R b and R c They form a heterocyclile together with the N atom to which they are attached, and this has one or more, in one embodiment, 1, 2, 3, or 4 substituents Q aIt is optionally substituted with. As used herein, all groups that can be substituted are "optionally substituted".

[0055] In one embodiment, each Q a are independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 Aralkill, heteroaryl, and heterocyclil; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NRe C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)2NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)2NR f R g Selected from; where each R e , R f , R g , and R h is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 Aralyl, heteroaryl, or heterocyclil; or (iii) R f and R g They form heterocyclines together with the N atoms to which they are attached.

[0056] In certain embodiments, “optically active” and “enantiomerically active” refer to a set of molecules having an excess of enantiomers of about 80% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In certain embodiments, the optically active compound comprises about 95% or more of one enantiomer and about 5% or less of another enantiomer based on the total weight of the enantiomer mixture. In certain embodiments, the optically active compound comprises about 98% or more of one enantiomer and about 2% or less of another enantiomer based on the total weight of the enantiomer mixture. In a specific embodiment, the optically active compound comprises about 99% or more of one enantiomer and about 1% or less of another enantiomer based on the total weight of the enantiomer mixture.

[0057] When describing optically active compounds, prefix R and S is used to indicate the absolute configuration of the compound with respect to its chiral center(s). (+) and (-) are used to indicate the optical rotation of the compound, that is, the direction in which the plane of polarization is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, meaning that the compound rotates the plane of polarization to the left or counterclockwise. The (+) prefix indicates that the compound is levorotatory, meaning that the compound rotates the plane of polarization to the right or clockwise. However, the signs of optical rotation, (+) and (-), are the absolute configuration of the compound R and S It is not related to.

[0058] The terms “substantially pure” and “substantially homogeneous” when referring to a substance mean that it is sufficiently homogeneous to be found to be free of easily detectable impurities as determined by standard analytical methods used by a person skilled in the art, including but not limited to thin-layer chromatography (TLC), gel electrophoresis, high-performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or that it is sufficiently pure so that further purification does not detectably alter the physical, chemical, biological, and / or pharmacological properties of the substance, such as enzymatic and biological activity. In certain embodiments, “substantially pure” or “substantially homogeneous” refers to a set of molecules, wherein, as determined by standard analytical methods, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules is a single compound comprising a single enantiomer, a racemic mixture, or a mixture of enantiomers. As used herein, where an atom at a specific position of an isotope-enriched molecule is designated to a specific less common isotope, a molecule containing anything other than the designated isotope at the designated position is an impurity to the isotope-enriched compound. Thus, in the case of a deuterium compound where an atom at a specific position is designated to deuterium, a compound containing light hydrogen at the same position is an impurity.

[0059] The term "solvent" refers to a complex or aggregate formed by one or more molecules of a solute, for example, a compound provided herein, and one or more molecules of a solvent present in stoichiometric or non-stoichiometric amounts. Suitable solvents include water, methanol, ethanol, n- Includes, but is not limited to, propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in an amorphous form. If the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, and pentahydrates.

[0060] For the divalent groups described herein, no orientation is implied by the direction in which the divalent group is presented. For example, unless a specific orientation is specified, the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)-.

[0061] The phrase “its diastereomer, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or its pharmaceutically acceptable salt, solvate, or hydrate” has the same meaning as the phrase “(i) a diastereomer of the compound mentioned therein, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; (ii) a pharmaceutically acceptable salt, solvate, or hydrate of the compound mentioned therein; or (iii) a diastereomer of the compound mentioned therein, a mixture of two or more diastereomers, a tautomer, or a pharmaceutically acceptable salt, solvate, or hydrate of a mixture of two or more tautomers.”

[0062] compound

[0063] In one embodiment, the compound of formula (I) herein:

[0064]

[0065] or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided, wherein:

[0066] Each L is independently a linker;

[0067] Each X is independently (i) bonded or -S-; or (ii) heteroarylene or heterocyclylene, each of which is optionally substituted with one or more, in one embodiment, 1, 2, 3, or 4 substituents Q;

[0068] Each R 1 is independently an immunostimulant;

[0069] R A is an antibody or its antigen-binding fragment that specifically binds to the hepatitis B surface antigen; and

[0070] m is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;

[0071] Here, each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 Aralyl, heteroaryl, and heterocyclil, each of which has one or more, in one embodiment, 1, 2, 3, or 4 substituents Q a Additionally optionally substituted with; and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b Rc , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a )OR d , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b Rc , -NR a S(O)2NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)2NR b R c Selected from, where each R a , R b , R c , and R d is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 It is an araclel, heteroaryl, or heterocyclil, each of which has one or more, in one embodiment, 1, 2, 3, or 4 substituents Q a Optionally substituted with; or (iii) R b and R c They form a heterocyclile together with the N atom to which they are attached, and this has one or more, in one embodiment, 1, 2, 3, or 4 substituents Q a Optionally replaced with;

[0072] Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 Aralkill, heteroaryl, and heterocyclil; and (c) -C(O)R e , -C(O)OR e , -C(O)NR fR g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NRe S(O)NR f R g , -NR e S(O)2NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)2NR f R g Selected from; where each R e , R f , R g , and R h is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 Aralyl, heteroaryl, or heterocyclil; or (iii) R f and R g They form heterocyclines together with the N atoms to which they are attached.

[0073] In a specific embodiment, each X is a bond. In a specific embodiment, each X is -S-. In a specific embodiment, each X is independently a heteroarylene and optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a monocyclic heteroarylene and optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a 5-membered heteroarylene and optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a 6-membered heteroarylene and optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a bicyclic heteroarylene and optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a 5,5-, 5,6-, or 6,6-membered heteroarylene, and each is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a 5,5-membered heteroarylene and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a 5,6-membered heteroarylene and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a 6,6-membered heteroarylene and is optionally substituted with one or more substituents Q.

[0074] In a specific embodiment, each X is independently a heterocyclilene and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a unicyclic heterocyclilene and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a 3-, 4-, 5-, 6-, or 7-membered heterocyclilene, each optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a 3-membered heterocyclilene and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a 4-membered heterocyclilene and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a 5-membered heterocyclilene and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently a pyrrolidindiyl and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently pyrrolidine 1,3-diyl and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is 2,5-deoxy-pyrrolidin-1,3-diyl. In a specific embodiment, each X is independently 6-membered heterocyclilene and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently 7-membered heterocyclilene and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently bicyclic heterocyclilene and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently cross-linked, fused, or spiro heterocyclilene, each of which is optionally substituted with one or more substituents Q. In a specific embodiment, each X is independently cross-linked heterocyclilene and is optionally substituted with one or more substituents Q. In a specific embodiment, each X is an independently fused heterocyclylene and is optionally substituted with one or more substituents Q.In a specific embodiment, each X is independently a spiroheterocyclilene and is optionally substituted with one or more substituents Q.

[0075] In another embodiment, the compound of formula (II):

[0076]

[0077] or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided, wherein each L independently R through a disulfide bond A Covalently connected to the thiol group of the cysteine ​​residue; where each R 1 , R A , L, and m are as defined herein.

[0078] In another embodiment, the compound of formula (III):

[0079]

[0080] or its diastereomers, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided, wherein each L independently R through a 2,5-deoxypyrrolidin-1,3-diyl group A Covalently connected to the thiol group of the cysteine ​​residue; where each R 1 , R A , L, and m are as defined herein.

[0081] In one embodiment, each L is an independently cleavable linker. In another embodiment, each L is an independently non-cleavable linker.

[0082] In a specific embodiment, each L is independently a cleavable linker sensitive to acidic pH. In a specific embodiment, each L is independently a cleavable linker containing a reducible disulfide. In a specific embodiment, each L is independently a linker cleavable by glutathione. In a specific embodiment, each L is independently a linker cleavable by an enzyme. In a specific embodiment, each L is independently a linker cleavable by a protease. In a specific embodiment, each L is independently a linker cleavable by a lysosomal protease. In a specific embodiment, each L is independently a linker cleavable by cathepsin B. In a specific embodiment, each L is independently a linker cleavable by glycosidase. In a specific embodiment, each L is independently a linker cleavable by β-glycosidase. In a specific embodiment, each L is independently a linker cleavable by galactosidase. In a specific embodiment, each L is independently a linker cleavable by β-galactosidase. In certain embodiments, each L is a linker independently cleaved by glucuronidase. In certain embodiments, each L is a linker independently cleaved by β-glucuronidase. In certain embodiments, each L is a linker independently cleaved by phosphatase. An exemplary linker suitable for the compounds provided herein is Beck et al. , Nat. Rev. Drug Discov. 2017 , 16 , 317-37; Bargh et al. , Chem. Soc. Rev. 2019 , 48 Includes, but not limited to, those disclosed in 4361-74; each of these disclosures is incorporated herein by reference in its entirety.

[0083] In a specific embodiment, each L is independently C 1-50 Alkylene, C 1-50 Heteroalkylene, C 2-50 Alkenylene, C 2-50 Heteroalkenylene, C2-50 alkynylene, C 2-50 Heteroalkynylene, C 3-10 Cycloalkylene, C 6-14 It is an arylene, a heteroarylene, or a heterocyclilene, each of which is optionally substituted with one or more substituents Q. In a specific embodiment, each L is independently C 1-50 Alkylene, C 1-50 Heteroalkylene, C 2-50 Alkenylene, C 2-50 Heteroalkenylene, C 2-50 alkynylene, or C 2-50 They are heteroalkynylenes, each of which is optionally substituted with one or more substituents Q. In a specific embodiment, each L is independently C 1-50 Alkylene or C 1-50 They are heteroalkylenes, each of which is optionally substituted with one or more substituents Q.

[0084] In a specific embodiment, each L is independently C 1-50 It is an alkylene and is optionally substituted with one or a substituent Q. In certain embodiments, each L is independently C 1-40 It is an alkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-30 It is an alkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is an alkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 2-16 It is an alkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 2-12 It is an alkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 2-6 It is an alkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20It is an alkylene and is optionally substituted with one or two oxos. In certain embodiments, each L is independently C 2-16 It is an alkylene and is optionally substituted with one or two oxos. In certain embodiments, each L is independently C 2-12 It is an alkylene and is optionally substituted with one or two oxos. In certain embodiments, each L is independently C 2-6 It is an alkylene and is optionally substituted with one or two oxos. In certain embodiments, each L is independently -(CH2) p - and optionally substituted with one or two oxos; where p is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In a specific embodiment, each L is independently -(CH2) p - and optionally substituted with one or two oxos; where p is an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In a specific embodiment, each L is independently -(CH2) p - and optionally substituted with 1 or 2 oxos; where p is an integer of 2, 3, 4, 5, or 6.

[0085] In a specific embodiment, each L is independently C 1-50 It is heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-40 It is heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-30 It is heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 2-16It is heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 2-12 It is heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 2-6 It is heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is heteroalkylene and is optionally substituted with one, two, or three ioxons. In certain embodiments, each L is independently C 2-16 It is heteroalkylene and is optionally substituted with one, two, or three ioxons. In certain embodiments, each L is independently C 2-12 It is heteroalkylene and is optionally substituted with one, two, or three ioxons. In certain embodiments, each L is independently C 2-6 It is a heteroalkylene and is optionally substituted with one, two, or three iodines.

[0086] In a specific embodiment, each L is independently a C containing an ethyleneoxy(-CH2CH2O-) group. 2-50 It is a heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently a C containing an ethyleneoxy group. 2-40 It is a heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently a C containing an ethyleneoxy group. 2-30 It is a heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently a C containing an ethyleneoxy group. 2-20 It is a heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently a C containing an ethyleneoxy group. 2-14 It is a heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently a C containing an ethyleneoxy group. 2-10It is a heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently a C containing an ethyleneoxy group. 2-6 It is a heteroalkylene and is optionally substituted with one or more substituents Q.

[0087] In a specific embodiment, each L is independently a C containing a propyleneoxy(-CH2CH2CH2O-) group. 3-50 It is heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L independently contains a propyleneoxy group C. 3-40 It is heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L independently contains a propyleneoxy group C. 3-30 It is heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L independently contains a propyleneoxy group C. 3-20 It is heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L independently contains a propyleneoxy group C. 3-14 It is heteroalkylene and is optionally substituted with one or more substituents Q. In certain embodiments, each L independently contains a propyleneoxy group C. 3-10 It is a heteroalkylene and is optionally substituted with one or more substituents Q.

[0088] In a specific embodiment, each L is independently C 1-50 Alkylene, C 1-50 Heteroalkylene, C 2-50 Alkenylene, C 2-50 Heteroalkenylene, C 2-50 alkynylene, or C 2-50 It is a heteroalkynylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14arylene, heteroarylene, or heterocyclylene; wherein alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-50 Alkylene or C 1-50 It is a heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; where alkylene, heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q.

[0089] In a specific embodiment, each L is independently C 1-50 It is an alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-40 It is an alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-30 It is an alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is an alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; where alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q.

[0090] In a specific embodiment, each L is independently C 1-50 It is an alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-40 It is an alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-30 It is an alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is an alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is an alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phendiyl, triazolediyl, 2,5-dioxopyrrolidinediyl, or piperazinediyl. In certain embodiments, each L is independently C 1-20 It is an alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phendiyl, triazolediyl, or 2,5-dioxopyrrolidinediyl. In certain embodiments, each L is independently C 1-20 It is an alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxopyrrolidine-1,3-diyl, or piperazine-1,4-diyl. In certain embodiments, each L is independently C 1-20It is an alkylene, where one, two, three, or four methylene groups are each independently replaced by a divalent group; where each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0091] In a specific embodiment, each L is independently C 1-20 It is an alkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is an alkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phendiyl, triazolediyl, 2,5-dioxopyrrolidinediyl, or piperazinediyl. In certain embodiments, each L is independently C 1-20 It is an alkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phendiyl, triazolediyl, or 2,5-dioxopyrrolidinediyl. In certain embodiments, each L is independently C 1-20 It is an alkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxopyrrolidine-1,3-diyl, or piperazine-1,4-diyl. In certain embodiments, each L is independently C 1-20It is an alkylene, where one or two methylene groups are each independently replaced by a divalent group; where each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0092] In a specific embodiment, each L is independently C 1-20 It is an alkylene, where the methylene group is replaced by a divalent group; where the divalent group is C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is an alkylene, wherein the methylene group is replaced by a divalent group; wherein the divalent group is cyclohexanediyl, phendiyl, triazolediyl, 2,5-dioxopyrrolidinediyl, or piperazinediyl. In certain embodiments, each L is independently C 1-20 It is an alkylene, wherein the methylene group is replaced by a divalent group; wherein the divalent group is cyclohexanediyl, phendiyl, triazolediyl, or 2,5-dioxopyrrolidinediyl. In certain embodiments, each L is independently C 1-20 It is an alkylene, wherein the methylene group is replaced by a divalent group; wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxopyrrolidine-1,3-diyl, or piperazine-1,4-diyl. In certain embodiments, each L is independently C 1-20 It is an alkylene, where the methylene group is replaced by a divalent group; where each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0093] In a specific embodiment, each L is independently C 1-50 It is a heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-40 It is a heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-30 It is a heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is a heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q.

[0094] In a specific embodiment, each L is independently C 1-50 It is a heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-40 It is a heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-30 It is a heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; wherein heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is a heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14arylene, heteroarylene, or heterocyclylene; wherein heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phendiyl, triazolediyl, 2,5-dioxopyrrolidinediyl, or piperazinediyl. In certain embodiments, each L is independently C 1-20 It is heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phendiyl, triazolediyl, or 2,5-dioxopyrrolidinediyl. In certain embodiments, each L is independently C 1-20 It is heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxopyrrolidine-1,3-diyl, or piperazine-1,4-diyl. In certain embodiments, each L is independently C 1-20 It is heteroalkylene, where one, two, three, or four methylene groups are each independently replaced by a divalent group; where each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0095] In a specific embodiment, each L is independently C 1-20 It is a heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C 3-10 Cycloalkylene, C 6-14arylene, heteroarylene, or heterocyclylene; wherein heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is a heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phendiyl, triazolediyl, 2,5-dioxopyrrolidinediyl, or piperazinediyl. In certain embodiments, each L is independently C 1-20 It is a heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phendiyl, triazolediyl, or 2,5-dioxopyrrolidinediyl. In certain embodiments, each L is independently C 1-20 It is heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxopyrrolidine-1,3-diyl, or piperazine-1,4-diyl. In certain embodiments, each L is independently C 1-20 It is heteroalkylene, where one or two methylene groups are each independently replaced by a divalent group; where each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0096] In a specific embodiment, each L is independently C 1-20 It is a heteroalkylene, where the methylene group is replaced by a divalent group; where the divalent group is C 3-10 Cycloalkylene, C 6-14arylene, heteroarylene, or heterocyclylene; wherein heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C 1-20 It is heteroalkylene, wherein the methylene group is replaced by a divalent group; wherein the divalent group is cyclohexanediyl, phendiyl, triazolediyl, 2,5-dioxopyrrolidinediyl, or piperazinediyl. In certain embodiments, each L is independently C 1-20 It is heteroalkylene, wherein the methylene group is replaced by a divalent group; wherein the divalent group is cyclohexanediyl, phendiyl, triazolediyl, or 2,5-dioxopyrrolidinediyl. In certain embodiments, each L is independently C 1-20 It is heteroalkylene, wherein the methylene group is replaced by a divalent group; wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl. In certain embodiments, each L is independently C 1-20 It is heteroalkylene, where the methylene group is replaced by a divalent group; where each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, dioxopyrrolidine-1,3-diyl, or piperazine-1,4-diyl.

[0097] In a specific embodiment, each L is independently:

[0098] , , or am.

[0099] In a specific embodiment, each L is independently:

[0100] , or am.

[0101] In a specific embodiment, each L is independently:

[0102]

[0103] or am.

[0104] In a specific embodiment, each L is independently:

[0105] or am.

[0106] In a specific embodiment, each L is independently:

[0107] or am.

[0108] In a specific embodiment, each L is independently:

[0109] , or am.

[0110] In a specific embodiment, each L is independently:

[0111]

[0112] or am.

[0113] In a specific embodiment, each L is independently:

[0114] or am.

[0115] In a specific embodiment, each XL moiety independently:

[0116] or am.

[0117] In a specific embodiment, each XL moiety independently:

[0118] or am.

[0119] In a specific embodiment, each XL moiety independently:

[0120] or am.

[0121] In a specific embodiment, each XL moiety independently:

[0122] or am.

[0123] In one embodiment, the present invention includes a compound of formula (IV):

[0124]

[0125] or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided, wherein each R 1 , R A , and m are as defined herein. In a specific embodiment, each linker independently R through a 2,5-dioxopyrrolidine-1,3-diyl group. A It is covalently linked to the thiol group of the cysteine ​​residue. R 1 In the case of this immunostimulating oligonucleotide, in a specific embodiment, each linker is independently R 1 Covalently connected to the 3'- or 5'- ends; in a specific embodiment, each linker independently R 1 It is covalently connected to the 3'-terminus; in a specific embodiment, each linker independently R 1 It is sharedly connected to the 5'-end of.

[0126] In another embodiment, the present invention includes a compound of formula (V):

[0127]

[0128] or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided, wherein each R 1 , R A , and m are as defined herein. In a specific embodiment, each linker independently R through a 2,5-dioxopyrrolidine-1,3-diyl group. A It is covalently linked to the thiol group of the cysteine ​​residue. R 1 In the case of this immunostimulating oligonucleotide, in a specific embodiment, each linker is independently R 1 Covalently connected to the 3'- or 5'- ends; in a specific embodiment, each linker independently R 1 It is covalently connected to the 3'-terminus; in a specific embodiment, each linker independently R 1 It is sharedly connected to the 5'-end of.

[0129] In another embodiment, the present invention relates to a compound of formula (VI):

[0130]

[0131] or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided, wherein each R 1 , R A , and m are as defined herein. In a specific embodiment, each linker independently R through a 2,5-dioxopyrrolidine-1,3-diyl group. A It is covalently linked to the thiol group of the cysteine ​​residue. R 1 In the case of this immunostimulating oligonucleotide, in a specific embodiment, each linker is independently R 1 Covalently connected to the 3'- or 5'- ends; in a specific embodiment, each linker independently R1 It is covalently connected to the 3'-terminus; in a specific embodiment, each linker independently R 1 It is sharedly connected to the 5'-end of.

[0132] In another embodiment, the present invention relates to a compound of formula (VII):

[0133]

[0134] or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided, wherein each R 1 , R A , and m are as defined herein. In a specific embodiment, each linker independently R through a disulfide bond. A It is covalently linked to the thiol group of the cysteine ​​residue. R 1 In the case of this immunostimulating oligonucleotide, in a specific embodiment, each linker is independently R 1 Covalently connected to the 3'- or 5'- ends; in a specific embodiment, each linker independently R 1 It is covalently connected to the 3'-terminus; in a specific embodiment, each linker independently R 1 It is sharedly connected to the 5'-end of.

[0135] In another embodiment, the present invention relates to a compound of formula (VIII):

[0136]

[0137] or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided, wherein each R 1 , R A, and m are as defined herein. In a specific embodiment, each linker independently R through a 2,5-dioxopyrrolidine-1,3-diyl group. A It is covalently linked to the thiol group of the cysteine ​​residue. R 1 In the case of this immunostimulating oligonucleotide, in a specific embodiment, each linker is independently R 1 Covalently connected to the 3'- or 5'- ends; in a specific embodiment, each linker independently R 1 It is covalently connected to the 3'-terminus; in a specific embodiment, each linker independently R 1 It is sharedly connected to the 5'-end of.

[0138] In another embodiment, the present invention relates to a compound of formula (IX):

[0139]

[0140] or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided; where R A and m are each as defined herein. In a specific embodiment, each linker independently R through a 2,5-dioxopyrrolidine-1,3-diyl group. A It is covalently linked to the thiol group of the cysteine ​​residue.

[0141] In another embodiment, the present invention relates to a compound of formula (X):

[0142]

[0143] or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided; where R Aand m are each as defined herein. In a specific embodiment, each linker independently R through a 2,5-dioxopyrrolidine-1,3-diyl group. A It is covalently linked to the thiol group of the cysteine ​​residue.

[0144] In another embodiment, the present invention relates to a compound of formula (XI):

[0145]

[0146] or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof is provided; where R A and m are each as defined herein. In a specific embodiment, each linker independently R through a 2,5-dioxopyrrolidine-1,3-diyl group. A It is covalently linked to the thiol group of the cysteine ​​residue.

[0147] In a specific implementation, R A is an antibody or an antigen-binding fragment thereof that specifically binds to S-HBsAg, M-HBsAg, or L-HBsAg. In certain embodiments, R A is an antibody that specifically binds to S-HBsAg or an antigen-binding fragment thereof. In a specific embodiment, R A is an antibody that specifically binds to M-HBsAg or an antigen-binding fragment thereof. In a specific embodiment, R A is an antibody that specifically binds to L-HBsAg or an antigen-binding fragment thereof. In a specific embodiment, R A is an antibody or its antigen-binding fragment that specifically binds to the S domain. In a specific embodiment, R A is an antibody or an antigen-binding fragment thereof that specifically binds to a hepatitis B surface antigen comprising the amino acid sequence of SEQ ID NO. 56. In a specific embodiment, R Ais an antibody or its antigen-binding fragment that specifically binds to a hepatitis B surface antigen comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 56.

[0148] In a specific implementation, R A is a full-length or intact monoclonal antibody. In certain embodiments, R A is a single-chain variable fragment (scFv), Fab, Fab', F(ab)2, F(ab')2, Fv, diabadi, triabadi, tetrabadi, or minibadi. In certain embodiments, R A is scFv. In a specific implementation, R A is Fab. In a specific implementation, R A is Fab'. In a specific implementation, R A is F(ab)2. In a specific implementation, R A is F(ab')2. In a specific implementation, R A is Fv. In a specific implementation, R A is a diabody. In a specific implementation, R A is a triabadi. In a specific implementation, R A is a tetrabody. In a specific embodiment, R A is a mini body.

[0149] In a specific implementation, R A is a monoclonal antibody or an antigen-binding fragment thereof. In certain embodiments, R A is an afucosylated antibody or an antigen-binding fragment thereof. In certain embodiments, R A is a human, humanized, or chimeric antibody, or an antigen-binding fragment thereof. In certain embodiments, R A is a human antibody or an antigen-binding fragment thereof. In certain embodiments, R Ais a humanized antibody or an antigen-binding fragment thereof. In certain embodiments, R A is a chimeric antibody or its antigen-binding fragment.

[0150] In one embodiment, R A is an IgA, IgD, IgE, IgG, or IgM antibody, or an antigen-binding fragment thereof. In other embodiments, R A is an IgA antibody or its antigen-binding fragment. In another embodiment, R A is an IgD antibody or its antigen-binding fragment. In another embodiment, R A is an IgE antibody or its antigen-binding fragment. In another embodiment, R A is an IgG antibody or an antigen-binding fragment thereof. In another embodiment, R A is an IgM antibody or its antigen-binding fragment.

[0151] In one embodiment, R A is an IgA1, IgA2, IgG1, IgG2, IgG3, or IgG4 antibody, or an antigen-binding fragment thereof. In other embodiments, R A is IgA1 or IgA2, or an antigen-binding fragment thereof. In another embodiment, R A is IgA1 or its antigen-binding fragment. In another embodiment, R A is IgA2 or its antigen-binding fragment. In another embodiment, R A is an IgG1, IgG2, IgG3, or IgG4 antibody, or an antigen-binding fragment thereof. In another embodiment, R A is an IgG1 antibody or an antigen-binding fragment thereof. In another embodiment, R A is an IgG2 antibody or an antigen-binding fragment thereof. In another embodiment, R A is an IgG3 antibody or its antigen-binding fragment. In another embodiment, R A is an IgG4 antibody or its antigen-binding fragment.

[0152] In one embodiment, R A is a recombinant antibody or its antigen-binding fragment. In other embodiments, R A is a purified antibody or an antigen-binding fragment thereof. In another embodiment, R A is an isolated antibody or its antigen-binding fragment.

[0153] In one embodiment, R A is an antibody or an antigen-binding fragment thereof comprising (i) a light chain complementarity determining region 1 (CDRL1) having the amino acid sequence of SEQ ID NO. 1; (ii) a light chain complementarity determining region 2 (CDRL2) having the amino acid sequence of AAS; (iii) a light chain complementarity determining region 3 (CDRL3) having the amino acid sequence of SEQ ID NO. 2; (iv) a heavy chain complementarity determining region 1 (CDRH1) having the amino acid sequence of SEQ ID NO. 3; (v) a heavy chain complementarity determining region 2 (CDRH2) having the amino acid sequence of SEQ ID NO. 4; and (vi) a heavy chain complementarity determining region 3 (CDRH3) having the amino acid sequence of SEQ ID NO. 5. In another embodiment, R ACDRL1 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 1; (ii) CDRL2 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of AAS; (iii) CDRL3 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 2; (iv) CDRH1 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 3; (v) CDRH2 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 4; and (vi) CDRH3 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 5, and is an antibody or an antigen-binding fragment thereof comprising CDRH3. In certain embodiments, the CDRs described herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs described herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs described herein are defined according to the Kabat numbering system.

[0154] In another implementation, R Ais an antibody or an antigen-binding fragment thereof comprising (i) a light chain variable region having the amino acid sequence of SEQ ID NO. 6; and (ii) a heavy chain variable region having the amino acid sequence of SEQ ID NO. 7. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 6. In a specific embodiment, R A is an antibody comprising a heavy chain variable region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 7.

[0155] In a specific implementation, R A is an antibody comprising a light chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 6; and a heavy chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 7. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 6; and a heavy chain variable region having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 7. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 6; and a heavy chain variable region having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 7. In a specific embodiment, R Ais an antibody comprising a light chain variable region having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 6; and a heavy chain variable region having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 7. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 6; and a heavy chain variable region having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 7. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 6; and a heavy chain variable region having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 7. In a specific embodiment, R A The antibody comprises a light chain variable region having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 6; and a heavy chain variable region having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 7.

[0156] In another implementation example, R A is an antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain having the amino acid sequence of SEQ ID NO. 10; and (ii) a heavy chain having the amino acid sequence of SEQ ID NO. 11. In a specific embodiment, R A is an antibody comprising a light chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 10. In a specific embodiment, R Ais an antibody comprising a heavy chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 11.

[0157] In a specific implementation, R A is an antibody comprising a light chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 10; and a heavy chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 11. In a specific embodiment, R A is an antibody comprising a light chain having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 10; and a heavy chain having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 11. In a specific embodiment, R A is an antibody comprising a light chain having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 10; and a heavy chain having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 11. In a specific embodiment, R A is an antibody comprising a light chain having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 10; and a heavy chain having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 11. In a specific embodiment, R A is an antibody comprising a light chain having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 10; and a heavy chain having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 11. In a specific embodiment, R A is an antibody comprising a light chain having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 10; and a heavy chain having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 11. In a specific embodiment, R AThe antibody comprises a light chain having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 10; and a heavy chain having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 11.

[0158] In one embodiment, R A is an antibody or an antigen-binding fragment thereof comprising (i) CDRL1 having the amino acid sequence of SEQ ID NO. 12; (ii) EVK or CDRL2 having the amino acid sequence of SEQ ID NO. 13; (iii) CDRL3 having the amino acid sequence of SEQ ID NO. 14; (iv) CDRH1 having the amino acid sequence of SEQ ID NO. 15; (v) CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and (vi) CDRH3 having the amino acid sequence of SEQ ID NO. 18. In another embodiment, R ACDRL1 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 12; (ii) CDRL2 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of EVK or SEQ ID NO. 13; (iii) CDRL3 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 14; (iv) CDRH1 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 15; (v) CDRH2 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 16 or 17; and (vi) CDRH3 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 18, and is an antibody or an antigen-binding fragment thereof comprising CDRH3. In certain embodiments, the CDRs described herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs described herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs described herein are defined according to the Kabat numbering system.

[0159] In another implementation, R Ais an antibody or an antigen-binding fragment thereof comprising (i) a light chain variable region having the amino acid sequence of SEQ ID NO. 19; and (ii) a heavy chain variable region having the amino acid sequence of SEQ ID NO. 20. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 19. In a specific embodiment, R A is an antibody comprising a heavy chain variable region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 20.

[0160] In a specific implementation, R A is an antibody comprising a light chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 19; and a heavy chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 20. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 19; and a heavy chain variable region having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 20. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 19; and a heavy chain variable region having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 20. In a specific embodiment, R Ais an antibody comprising a light chain variable region having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 19; and a heavy chain variable region having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 20. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 19; and a heavy chain variable region having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 20. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 19; and a heavy chain variable region having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 20. In a specific embodiment, R A The antibody comprises a light chain variable region having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 19; and a heavy chain variable region having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 20.

[0161] In another implementation example, R A is an antibody or an antigen-binding fragment thereof comprising (i) a light chain having the amino acid sequence of SEQ ID NO. 21; and (ii) a heavy chain having the amino acid sequence of SEQ ID NO. 22. In certain embodiments, R A is an antibody comprising a light chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 21. In a specific embodiment, R A is an antibody comprising a heavy chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 22.

[0162] In a specific implementation, R A is an antibody comprising a light chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 21; and a heavy chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 22. In a specific embodiment, R A is an antibody comprising a light chain having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 21; and a heavy chain having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 22. In a specific embodiment, R A is an antibody comprising a light chain having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 21; and a heavy chain having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 22. In a specific embodiment, R A is an antibody comprising a light chain having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 21; and a heavy chain having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 22. In a specific embodiment, R A is an antibody comprising a light chain having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 21; and a heavy chain having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 22. In a specific embodiment, R A is an antibody comprising a light chain having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 21; and a heavy chain having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 22. In a specific embodiment, R A The antibody comprises a light chain having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 21; and a heavy chain having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 22.

[0163] In one embodiment, R Ais an antibody or an antigen-binding fragment thereof comprising (i) CDRL1 having the amino acid sequence of SEQ ID NO. 23; (ii) CDRL2 having the amino acid sequence of SEQ ID NO. 24; (iii) CDRL3 having the amino acid sequence of SEQ ID NO. 25; (iv) CDRH1 having the amino acid sequence of SEQ ID NO. 26; (v) CDRH2 having the amino acid sequence of SEQ ID NO. 27; and (vi) CDRH3 having the amino acid sequence of SEQ ID NO. 28. In another embodiment, R ACDRL1 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 23; (ii) CDRL2 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 24; (iii) CDRL3 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 25; (iv) CDRH1 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 26; (v) CDRH2 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 27; and (vi) CDRH3 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 28, and is an antibody or an antigen-binding fragment thereof comprising CDRH3. In certain embodiments, the CDRs described herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs described herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs described herein are defined according to the Kabat numbering system.

[0164] In another implementation, R Ais an antibody or an antigen-binding fragment thereof comprising (i) a light chain variable region having the amino acid sequence of SEQ ID NO. 29; and (ii) a heavy chain variable region having the amino acid sequence of SEQ ID NO. 30. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 29. In a specific embodiment, R A is an antibody comprising a heavy chain variable region having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 30.

[0165] In a specific implementation, R A is an antibody comprising a light chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 29; and a heavy chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 30. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 29; and a heavy chain variable region having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 30. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 29; and a heavy chain variable region having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 30. In a specific embodiment, R Ais an antibody comprising a light chain variable region having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 29; and a heavy chain variable region having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 30. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 29; and a heavy chain variable region having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 30. In a specific embodiment, R A is an antibody comprising a light chain variable region having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 29; and a heavy chain variable region having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 30. In a specific embodiment, R A The antibody comprises a light chain variable region having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 29; and a heavy chain variable region having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 30.

[0166] In another implementation example, R A is an antibody or an antigen-binding fragment thereof comprising (i) a light chain having the amino acid sequence of SEQ ID NO. 33; and (ii) a heavy chain having the amino acid sequence of SEQ ID NO. 34. In certain embodiments, R A is an antibody comprising a light chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 33. In a specific embodiment, R A is an antibody comprising a heavy chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 34.

[0167] In a specific implementation, R A is an antibody comprising a light chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 33; and a heavy chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 34. In a specific embodiment, R A is an antibody comprising a light chain having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 33; and a heavy chain having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 34. In a specific embodiment, R A is an antibody comprising a light chain having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 33; and a heavy chain having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 34. In a specific embodiment, R A is an antibody comprising a light chain having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 33; and a heavy chain having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 34. In a specific embodiment, R A is an antibody comprising a light chain having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 33; and a heavy chain having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 34. In a specific embodiment, R A is an antibody comprising a light chain having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 33; and a heavy chain having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 34. In a specific embodiment, R A The antibody comprises a light chain having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 33; and a heavy chain having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 34.

[0168] In one embodiment, R Ais an antibody or an antigen-binding fragment thereof comprising (i) CDRL1 having the amino acid sequence of SEQ ID NO. 35; (ii) CDRL2 having the amino acid sequence of AAS; (iii) CDRL3 having the amino acid sequence of SEQ ID NO. 36; (iv) CDRH1 having the amino acid sequence of SEQ ID NO. 37; (v) CDRH2 having the amino acid sequence of SEQ ID NO. 38; and (vi) CDRH3 having the amino acid sequence of SEQ ID NO. 39. In another embodiment, R ACDRL1 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 35; (ii) CDRL2 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of AAS; (iii) CDRL3 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 36; (iv) CDRH1 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 37; (v) CDRH2 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 38; and (vi) CDRH3 having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 39, and is an antibody or an antigen-binding fragment thereof comprising CDRH3. In certain embodiments, the CDRs described herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs described herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs described herein are defined according to the Kabat numbering system.

[0169] In another implementation example, R Ais an antibody or an antigen-binding fragment thereof, and the antibody comprises (i) a light chain having the amino acid sequence of SEQ ID NO. 40; and (ii) a heavy chain having the amino acid sequence of SEQ ID NO. 41. In a specific embodiment, R A is an antibody comprising a light chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 40. In a specific embodiment, R A is an antibody comprising a heavy chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 41.

[0170] In a specific implementation, R A is an antibody comprising a light chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 40; and a heavy chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 41. In a specific embodiment, R A is an antibody comprising a light chain having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 40; and a heavy chain having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 41. In a specific embodiment, R A is an antibody comprising a light chain having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 40; and a heavy chain having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 41. In a specific embodiment, R A is an antibody comprising a light chain having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 40; and a heavy chain having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 41. In a specific embodiment, R Ais an antibody comprising a light chain having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 40; and a heavy chain having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 41. In a specific embodiment, R A is an antibody comprising a light chain having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 40; and a heavy chain having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 41. In a specific embodiment, R A The antibody comprises a light chain having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 40; and a heavy chain having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 41.

[0171] In another implementation example, R A is an antibody or an antigen-binding fragment thereof comprising (i) a light chain having the amino acid sequence of SEQ ID NO. 42; and (ii) a heavy chain having the amino acid sequence of SEQ ID NO. 43. In a specific embodiment, R A is an antibody comprising a light chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 42. In a specific embodiment, R A is an antibody comprising a heavy chain having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 43.

[0172] In a specific implementation, R A is an antibody comprising a light chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 42; and a heavy chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 43. In a specific embodiment, R Ais an antibody comprising a light chain having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 42; and a heavy chain having at least about 85% sequence identity with respect to the amino acid sequence of SEQ ID NO. 43. In a specific embodiment, R A is an antibody comprising a light chain having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 42; and a heavy chain having at least about 90% sequence identity with respect to the amino acid sequence of SEQ ID NO. 43. In a specific embodiment, R A is an antibody comprising a light chain having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 42; and a heavy chain having at least about 95% sequence identity with respect to the amino acid sequence of SEQ ID NO. 43. In a specific embodiment, R A is an antibody comprising a light chain having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 42; and a heavy chain having at least about 97% sequence identity with respect to the amino acid sequence of SEQ ID NO. 43. In a specific embodiment, R A is an antibody comprising a light chain having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 42; and a heavy chain having at least about 98% sequence identity with respect to the amino acid sequence of SEQ ID NO. 43. In a specific embodiment, R A The antibody comprises a light chain having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 42; and a heavy chain having at least about 99% sequence identity with respect to the amino acid sequence of SEQ ID NO. 43.

[0173] Additional exemplary antibodies and antigen-binding fragments suitable for the compounds provided herein include, but are not limited to, those disclosed in WO 2021 / 042000 A1 and US 10,689,434 B2, each of which is incorporated herein by reference in its entirety.

[0174] In a specific implementation, R 1is a retinoic acid-inducible gene 1 (RIG-I) agonist, a stimulator of interferon gene (STING) agonist, or a toll-like receptor (TLR) agonist. In certain embodiments, R 1 is a RIG-I agonist. In certain embodiments, R 1 It is a STING agent.

[0175] In a specific implementation, R 1 is a TLR agonist. In certain embodiments, R 1 TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, It is a TLR11, TLR12, or TLR13 agonist. In certain embodiments, R 1 is a TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, or TLR10 agonist. In certain embodiments, R 1 is a TLR3, TLR7, TLR8, or TLR9 agonist. In certain embodiments, R 1 is a TLR3 agonist. In a specific embodiment, R 1 is a TLR7 agonist. In certain embodiments, R 1 is a TLR8 agonist. In certain embodiments, R 1 It is a TLR9 agonist.

[0176] In a specific implementation, R 1 is a synthetic TLR agonist. In a specific embodiment, R 1 Silver synthesizes TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, It is a TLR11, TLR12, or TLR13 agonist. In certain embodiments, R 1is a synthetic TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, or TLR10 agonist. In certain embodiments, R 1 is a synthetic TLR3, TLR7, TLR8, or TLR9 agonist. In certain embodiments, R 1 is a synthetic TLR3 agonist. In a specific embodiment, R 1 is a synthetic TLR7 agonist. In a specific embodiment, R 1 is a synthetic TLR8 agonist. In a specific embodiment, R 1 It is a synthetic TLR9 agonist.

[0177] In a specific implementation, R 1 is an immunostimulating oligonucleotide. In a specific embodiment, R 1 is a single-stranded oligonucleotide. In a specific embodiment, each R 1 is a single-stranded oligonucleotide comprising about 10 to about 50, about 15 to about 40, or about 15 to about 30 nucleotides independently. In certain embodiments, each R 1 is a single-stranded oligonucleotide comprising about 10 to about 50 nucleotides independently. In a specific embodiment, each R 1 is a single-stranded oligonucleotide comprising about 15 to about 40 nucleotides independently. In a specific embodiment, each R 1 is a single-stranded oligonucleotide comprising about 15 to about 30 nucleotides independently. In a specific embodiment, each R 1 It is a single-stranded oligonucleotide containing about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 nucleotides independently.

[0178] In a specific implementation, R1 is a single-stranded CpG oligodeoxynucleotide. In a specific embodiment, each R 1 is a single-stranded CpG oligodeoxynucleotide comprising about 10 to about 50, about 15 to about 40, about 15 to about 30, or about 20 to about 30 deoxyribonucleotides independently. In certain embodiments, each R 1 is a single-stranded oligodeoxynucleotide comprising about 10 to about 50 deoxyribonucleotides independently. In a specific embodiment, each R 1 is a single-stranded oligodeoxynucleotide comprising about 15 to about 40 deoxyribonucleotides independently. In a specific embodiment, each R 1 is a single-stranded oligodeoxynucleotide comprising about 15 to about 30 deoxyribonucleotides independently. In a specific embodiment, each R 1 is a single-stranded oligodeoxynucleotide comprising about 20 to about 30 deoxyribonucleotides independently. In a specific embodiment, each R 1 It is a single-stranded oligodeoxynucleotide containing about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 deoxyribonucleotides independently.

[0179] In a specific implementation, R 1 is a single-stranded oligodeoxynucleotide comprising one or more nonmethylated CpG dideoxynucleotide motifs. In certain embodiments, R 1 It comprises about 1 to about 20 or about 1 to about 10 nonmethylated CpG dideoxynucleotide motifs. In a specific embodiment, R 1 It comprises about 1 to about 20 unmethylated CpG dideoxynucleotide motifs. In a specific embodiment, R 1It comprises about 1 to about 10 unmethylated CpG dideoxynucleotide motifs. In a specific embodiment, R 1 It contains about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 unmethylated CpG dideoxynucleotide motifs.

[0180] In certain embodiments, each deoxynucleotide in a single-stranded oligodeoxynucleotide is independently a natural deoxynucleotide or a modified deoxynucleotide. In certain embodiments, the natural nucleotides include deoxyadenosine (dA), deoxycitidine (dC), deoxyguanosine (dG), and deoxythimine (dT). In certain embodiments, the modified deoxynucleotide is a deoxynucleotide having a modification on its nucleobase, a modification on its sugar, and / or a modification on its phosphate linker. Examples of modified deoxynucleotides are 2'-fluoroadenosine (fA), 2'-fluorocitidine (fC), 2'-fluoroguanosine (fG), 2'-fluorouridine (fU), 2'- O -methyladenosine (mA), 2'- O -Methyl-cytidine (mC), 2'- O -methylguanosine (mG), or 2'- O - Methyluridine (mU) is included, but is not limited thereto. In certain embodiments, each deoxynucleotide in the single-stranded oligodeoxynucleotide is independently adenosine, cytidine, guanosine, inosine, uridine, deoxyadenosine, deoxycytidine, deoxyguanosine, deoxyinosine, deoxythymine, 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluoro-guanosine, 2'-fluorouridine, 2'-deoxyadenosine, 2'-deoxycytidine, 2'-deoxyguanosine, 2'-deoxyinosine, 2'-deoxythymidine, 2'- O -methyladenosine, 2'- O -methylcytidine, 2'- O -methyl-guanosine, 2'- O- methyluridine, 2'-deoxy-5-bromouridine, or 5-methyl-2'-methoxyuridine. In certain embodiments, each deoxynucleotide in the single-stranded oligodeoxynucleotide is independently adenosine, cytidine, guanosine, uridine, deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymine, 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluorogunaosin, 2'-fluorouridine, 2'-deoxyadenosine, 2'-deoxycytidine, 2'-deoxygunaosin, 2'-deoxythymidine, 2'- O -methyladenosine, 2'- O -methylcytidine, 2'- O -methylguanosine, or 2'- O -methyluridine. In certain embodiments, each deoxynucleotide in the single-stranded oligodeoxynucleotide is independently deoxyadenosine, deoxycytidine, deoxyguanosine, deoxyinosine, deoxythymine, 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluorogunaosin, 2'-fluorouridine, 2'-deoxyadenosine, 2'-deoxycytidine, 2'-deoxygunaosin, 2'-deoxythymidine, 2'- O -methyladenosine, 2'- O -methylcytidine, 2'- O -methylguanosine, 2'- O -methyluridine, 2'-deoxy-5-bromouridine, or 5-methyl-2'-methoxyuridine. In certain embodiments, each deoxynucleotide in the single-stranded oligodeoxynucleotide is independently deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymine, 2'-fluoroadenosine, 2'-fluorocytidine, 2'-fluorogunaosin, 2'-fluorouridine, 2'-deoxy-adenosine, 2'-deoxycytidine, 2'-deoxygunaosin, 2'-deoxythymidine, 2'- O -methyladenosine, 2'- O -methylcytidine, 2'- O -methylguanosine, or 2'- O - It is methyluridine.

[0181] In a specific embodiment, the single-stranded oligonucleotide is in which one or more phosphate linkers are replaced with methylphosphate, phosphoramidate, phosphorothioate, phosphorodithioate, phosphotriester, or diphosphate. In a specific embodiment, the single-stranded oligonucleotide is in which one or more phosphate linkers are replaced with phosphorothioate or phosphorodithioate. In a specific embodiment, the single-stranded oligonucleotide is in which all phosphate linkers are replaced with phosphorothioate or phosphorodithioate. In a specific embodiment, the single-stranded oligonucleotide is in which all phosphate linkers are replaced with phosphorothioate.

[0182] In a specific implementation, R 1 is a TLR9 agonist of class A. In a specific implementation, R 1 is a Class B TLR9 agonist. In a specific implementation, R 1 is a TLR9 agonist of class C. In a specific implementation, R 1 It is a Class P TLR9 agonist.

[0183] In a specific implementation, R 1 is a TLR9 agonist comprising any one of the nucleotide sequences of SEQ ID NOs 44 to 55. In a specific embodiment, R 1 is a TLR9 agonist comprising any one of the nucleotide sequences of SEQ ID NOs 44 to 54. In a specific embodiment, R 1 is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 44. In a specific embodiment, R 1 is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 45. In a specific embodiment, R 1 is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 46. In a specific embodiment, R 1 is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 47. In a specific embodiment, R 1is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 48. In a specific embodiment, R 1 is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 49. In a specific embodiment, R 1 is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 50. In a specific embodiment, R 1 is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 51. In a specific embodiment, R 1 is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 52. In a specific embodiment, R 1 is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 53. In a specific embodiment, R 1 is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 54. In a specific embodiment, R 1 is a TLR9 agonist containing the nucleotide sequence of SEQ ID NO. 55.

[0184] In a specific implementation, R 1 is CpG 1018, CpG 1826, CpG 2006 / 7909, CpG 2007, CpG 2216, CpG 2336, CpG 2395, CpG BW006, CpG D-SL01, CpG D-SL03, CpG M362, or T-CpG. In a specific embodiment, R 1 is CpG 1018, CpG 1826, CpG 2006 / 7909, CpG 2007, CpG 2216, CpG 2336, CpG 2395, CpG BW006, CpG D-SL01, CpG D-SL03, or CpG M362. In a specific embodiment, R 1 is CpG 1018. In a specific implementation, R 1 is CpG 1826. In a specific implementation, R 1 is CpG 2006. In a specific implementation, R 1 is CpG 2007. In a specific implementation, R 1is CpG 2216. In a specific implementation, R 1 is CpG 2336. In a specific implementation, R 1 is CpG 2395. In a specific implementation, R 1 is CpG BW006. In a specific embodiment, R 1 is CpG D-SL01. In a specific embodiment, R 1 is CpG D-SL03. In a specific embodiment, R 1 is CpG M362. In a specific implementation, R 1 It is T-CpG.

[0185] In a specific implementation, R 1 is a TLR7 agonist. In certain embodiments, R 1 silver , , or It is a TLR7 agonist having the structure of. In a specific embodiment, R 1 is a TLR7 agonist. In certain embodiments, R 1 silver or It is a TLR7 agonist having the structure of. In a specific embodiment, R 1 silver It is a TLR7 agonist having the structure of. In a specific embodiment, R 1 silver It is a TLR7 agonist having the structure of. In a specific embodiment, R 1 silver It is a TLR7 agonist comprising the structure of. In a specific embodiment, R 1 silver It is a TLR7 agonist having the structure of

[0186] In a specific implementation, R 1 is a TLR8 agonist. In certain embodiments, R 1 silver It is a TLR8 agonist comprising the structure of. In a specific embodiment, R 1 is a TLR8 agonist. In certain embodiments, R 1 silver It is a TLR8 agonist having the structure of

[0187] In a specific embodiment, m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In a specific embodiment, m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In a specific embodiment, m is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In a specific embodiment, m is an integer of 1. In a specific embodiment, m is an integer of 2. In a specific embodiment, m is an integer of 3. In a specific embodiment, m is an integer of 4. In a specific embodiment, m is an integer of 5. In a specific embodiment, m is an integer of 6. In a specific embodiment, m is an integer of 7. In a specific embodiment, m is an integer of 8. In a specific embodiment, m is an integer of 9. In a specific embodiment, m is an integer of 10. In a specific embodiment, m is an integer of 11. In a specific embodiment, m is an integer of 12. In a specific embodiment, m is an integer of 13. In a specific embodiment, m is an integer of 14. In a specific embodiment, m is an integer of 15. In a specific embodiment, m is an integer of 16.

[0188] In a specific embodiment, the compound provided herein in the composition (e.g., pharmaceutical composition) has a drug-antibody ratio (DAR) in the range of about 0.5 to about 12, about 1 to about 10, or about 2 to about 8. In a specific embodiment, the compound provided herein in the composition (e.g., pharmaceutical composition) has a DAR in the range of about 0.5 to about 12. In a specific embodiment, the compound provided herein in the composition (e.g., pharmaceutical composition) has a DAR in the range of about 1 to about 10. In a specific embodiment, the compound provided herein in the composition (e.g., pharmaceutical composition) has a DAR in the range of about 2 to about 8. In certain embodiments, the compound provided herein in a composition (e.g., a pharmaceutical composition) has a DAR of about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, or about 8.

[0189] The group within the formulas described herein, including formulas (I) to (XI), R 1 , R A All combinations of the embodiments provided herein for , L, X, and m are within the scope of the present disclosure.

[0190] In one embodiment, the present invention provides an antibody-oligonucleotide conjugate of any one of formulas (I) to (VIII); wherein each R 1 Its 3'- or 5'-terminus independently R through the XL moiety A It is a single-stranded CpG oligonucleotide of any one of SEQ ID NOs 44 to 55 linked to; R A is an antibody containing the following:

[0191] (i) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0192] (ii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 12; (b) CDRL2 having EVK or the amino acid sequence of SEQ ID NO. 13; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 14; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 15; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 18;

[0193] (iii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 23; (b) CDRL2 having the amino acid sequence of SEQ ID NO. 24; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 25; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 26; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 27; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 28; or

[0194] (iv) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 35; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 36; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 37; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 38; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 39.

[0195] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of any one of formulas (I) to (VIII); wherein each R 1Its 3'- or 5'-terminus independently R through the XL moiety A It is a single-stranded CpG oligonucleotide of any one of SEQ ID NOs 44 to 55 linked to; R A is an antibody containing the following:

[0196] (i) light chain variable region of SEQ ID NO. 6 and heavy chain variable region of SEQ ID NO. 7;

[0197] (ii) light chain variable region of SEQ ID NO. 19 and heavy chain variable region of SEQ ID NO. 20;

[0198] (iii) the light chain variable region of SEQ ID NO. 29 and the heavy chain variable region of SEQ ID NO. 30; or

[0199] (iv) light chain variable region of SEQ ID NO 40 and heavy chain variable region of SEQ ID NO 41.

[0200] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of any one of formulas (I) to (VIII); wherein each R 1 Its 3'- or 5'-terminus independently R through the XL moiety A It is a single-stranded CpG oligonucleotide of any one of SEQ ID NOs 44 to 55 linked to; R A is an antibody containing the following:

[0201] (i) light chain of sequence number 10 and heavy chain of sequence number 11;

[0202] (ii) light chain of sequence number 21 and heavy chain of sequence number 22;

[0203] (iii) the light chain of SEQ ID NO. 33 and the heavy chain of SEQ ID NO. 34; or

[0204] (iv) light chain of sequence number 42 and heavy chain of sequence number 43.

[0205] In one embodiment, the present invention provides an antibody-oligonucleotide conjugate of any one of formulas (IV) to (VIII); wherein each R 1Its 3'- or 5'-terminus independently R through the XL moiety A It is a single-stranded CpG oligonucleotide of sequence number 44, 45, 46, 53, or 55 linked to; R A is an antibody containing the following:

[0206] (i) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0207] (ii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 12; (b) CDRL2 having EVK or the amino acid sequence of SEQ ID NO. 13; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 14; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 15; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 18;

[0208] (iii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 23; (b) CDRL2 having the amino acid sequence of SEQ ID NO. 24; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 25; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 26; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 27; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 28; or

[0209] (iv) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 35; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 36; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 37; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 38; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 39.

[0210] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of any one of formulas (IV) to (VIII); wherein each R 1 Its 3'- or 5'-terminus independently R through the XL moiety A It is a single-stranded CpG oligonucleotide of sequence number 44, 45, 46, 53, or 55 linked to; R A is an antibody containing the following:

[0211] (i) light chain variable region of SEQ ID NO. 6 and heavy chain variable region of SEQ ID NO. 7;

[0212] (ii) light chain variable region of SEQ ID NO. 19 and heavy chain variable region of SEQ ID NO. 20;

[0213] (iii) the light chain variable region of SEQ ID NO. 29 and the heavy chain variable region of SEQ ID NO. 30; or

[0214] (iv) light chain variable region of SEQ ID NO 40 and heavy chain variable region of SEQ ID NO 41.

[0215] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of any one of formulas (IV) to (VIII); wherein each R 1 Its 3'- or 5'-terminus independently R through the XL moiety A It is a single-stranded CpG oligonucleotide of sequence number 44, 45, 46, 53, or 55 linked to; R A is an antibody containing the following:

[0216] (i) light chain of sequence number 10 and heavy chain of sequence number 11;

[0217] (ii) light chain of sequence number 21 and heavy chain of sequence number 22;

[0218] (iii) the light chain of SEQ ID NO. 33 and the heavy chain of SEQ ID NO. 34; or

[0219] (iv) light chain of sequence number 42 and heavy chain of sequence number 43.

[0220] In one embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (IV); wherein each R 1 The 3'- or 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of sequence number 44, 45, 46, 53, or 55 linked to; R A is an antibody containing the following:

[0221] (i) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0222] (ii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 12; (b) CDRL2 having EVK or the amino acid sequence of SEQ ID NO. 13; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 14; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 15; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 18;

[0223] (iii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 23; (b) CDRL2 having the amino acid sequence of SEQ ID NO. 24; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 25; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 26; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 27; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 28; or

[0224] (iv) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 35; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 36; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 37; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 38; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 39.

[0225] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (IV); wherein each R 1 The 3'- or 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of sequence number 44, 45, 46, or 53 linked to; R A is an antibody containing the following:

[0226] (i) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0227] (ii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 12; (b) EVK or CDRL2 having the amino acid sequence of SEQ ID NO. 13; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 14; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 15; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 18; or

[0228] (iii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 23; (b) CDRL2 having the amino acid sequence of SEQ ID NO. 24; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 25; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 26; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 27; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 28.

[0229] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (IV); where:

[0230] (i) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0231] (ii) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R Ais an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0232] (iii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 44 linked to; R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0233] (iv) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0234] (v) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 53 linked to; RA is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0235] (vi) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 12; (b) EVK or CDRL2 having the amino acid sequence of SEQ ID NO. 13; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 14; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 15; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 18;

[0236] (vii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 23; (b) CDRL2 having the amino acid sequence of SEQ ID NO. 24; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 25; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 26; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 27; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 28; or

[0237] (viii) Each R 1 The 5'-terminus of the tooth is R through the XL moiety AIt is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A The antibody comprises (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5.

[0238] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (IV); where:

[0239] (i) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0240] (ii) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0241] (iii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 44 linked to; R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0242] (iv) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0243] (v) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 53 linked to; R Ais an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0244] (vi) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 12; (b) EVK or CDRL2 having the amino acid sequence of SEQ ID NO. 13; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 14; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 15; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 18; or

[0245] (vii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A The antibody comprises (a) CDRL1 having the amino acid sequence of SEQ ID NO. 23; (b) CDRL2 having the amino acid sequence of SEQ ID NO. 24; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 25; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 26; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 27; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 28.

[0246] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (IV); where:

[0247] (i) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0248] (ii) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0249] (iii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 44 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0250] (iv) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0251] (v) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 53 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0252] (vi) Each R 1 The 3'-terminus of the tooth is R through the XL moietyA It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 19 and the heavy chain variable region of SEQ ID NO. 20;

[0253] (vii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 29 and the heavy chain variable region of SEQ ID NO. 30; or

[0254] (viii) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7.

[0255] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (IV); where:

[0256] (i) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0257] (ii) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0258] (iii) Each R 1The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 44 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0259] (iv) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0260] (v) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 53 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0261] (vi) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 19 and the heavy chain variable region of SEQ ID NO. 20; or

[0262] (vii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 29 and the heavy chain variable region of SEQ ID NO. 30.

[0263] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (IV); where:

[0264] (i) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 8 and the heavy chain of SEQ ID NO. 9;

[0265] (ii) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 8 and the heavy chain of SEQ ID NO. 9;

[0266] (iii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 44 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 8 and the heavy chain of SEQ ID NO. 9;

[0267] (iv) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 8 and the heavy chain of SEQ ID NO. 9;

[0268] (v) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 53 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 8 and the heavy chain of SEQ ID NO. 9;

[0269] (vi) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R Ais an antibody comprising the light chain of SEQ ID NO. 21 and the heavy chain of SEQ ID NO. 22;

[0270] (vii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 31 and the heavy chain of SEQ ID NO. 32;

[0271] (viii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11; or

[0272] (ix) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11.

[0273] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (IV); wherein each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of sequence number 8 and the heavy chain of sequence number 9.

[0274] In one embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VI); wherein each R 1 The 3'- or 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of sequence number 45 or 46 linked to; R Ais an antibody containing the following:

[0275] (i) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0276] (ii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 12; (b) CDRL2 having EVK or the amino acid sequence of SEQ ID NO. 13; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 14; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 15; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 18;

[0277] (iii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 23; (b) CDRL2 having the amino acid sequence of SEQ ID NO. 24; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 25; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 26; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 27; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 28; or

[0278] (iv) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 35; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 36; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 37; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 38; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 39.

[0279] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VI); wherein each R1 The 3'- or 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of sequence number 45 or 46 linked to; R A The antibody comprises (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5.

[0280] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VI); wherein each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of sequence number 45 or 46 linked to; R A The antibody comprises (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5.

[0281] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VI); wherein each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of sequence number 45 or 46 linked to; R AThe antibody comprises (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5.

[0282] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VI); where:

[0283] (i) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0284] (ii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0285] (iii) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7;

[0286] (iv) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R Ais an antibody comprising the light chain variable region of SEQ ID NO. 19 and the heavy chain variable region of SEQ ID NO. 20; or.

[0287] (v) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 29 and the heavy chain variable region of SEQ ID NO. 30.

[0288] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VI); where:

[0289] (i) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7; or

[0290] (ii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7.

[0291] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VI); where:

[0292] (i) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 8 and the heavy chain of SEQ ID NO. 9;

[0293] (ii) Each R 1The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 8 and the heavy chain of SEQ ID NO. 9;

[0294] (iii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11;

[0295] (iv) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 8 and the heavy chain of SEQ ID NO. 9;

[0296] (v) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11;

[0297] (vi) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 21 and the heavy chain of SEQ ID NO. 22;

[0298] (vii) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R Ais an antibody comprising the light chain of SEQ ID NO. 33 and the heavy chain of SEQ ID NO. 34; or

[0299] (viii) Each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of sequence number 42 and the heavy chain of sequence number 43.

[0300] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VI); where:

[0301] (i) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 46 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 8 and the heavy chain of SEQ ID NO. 9; or

[0302] (ii) Each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11.

[0303] In one embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VII); wherein each R 1 The 3'- or 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of sequence number 45 or 46 linked to; R A is an antibody containing the following:

[0304] (i) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0305] (ii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 12; (b) CDRL2 having EVK or the amino acid sequence of SEQ ID NO. 13; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 14; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 15; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 18;

[0306] (iii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 23; (b) CDRL2 having the amino acid sequence of SEQ ID NO. 24; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 25; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 26; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 27; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 28; or

[0307] (iv) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 35; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 36; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 37; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 38; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 39.

[0308] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VII); wherein each R 1 The 3'- or 5'-terminus of the tooth is R through the XL moietyA It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A The antibody comprises (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5.

[0309] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VII); wherein each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A The antibody comprises (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5.

[0310] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VII); wherein each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R AThe antibody comprises (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5.

[0311] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VII); wherein each R 1 The 3'- or 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7.

[0312] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VII); wherein each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7.

[0313] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VII); wherein each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7.

[0314] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VII); wherein each R1 The 3'- or 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11.

[0315] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VII); wherein each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11.

[0316] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VII); wherein each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 45 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11.

[0317] In one embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VIII); wherein each R 1 The 3'- or 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of sequence number 45 or 55 linked to; R A is an antibody containing the following:

[0318] (i) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0319] (ii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 12; (b) CDRL2 having EVK or the amino acid sequence of SEQ ID NO. 13; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 14; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 15; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 18;

[0320] (iii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 23; (b) CDRL2 having the amino acid sequence of SEQ ID NO. 24; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 25; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 26; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 27; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 28; or

[0321] (iv) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 35; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 36; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 37; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 38; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 39.

[0322] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VIII); wherein each R 1 The 3'- or 5'-terminus of the tooth is R through the XL moietyA It is a single-stranded CpG oligonucleotide of SEQ ID NO. 55 linked to; R A The antibody comprises (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5.

[0323] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VIII); wherein each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 55 linked to; R A The antibody comprises (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5.

[0324] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VIII); wherein each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 55 linked to; R AThe antibody comprises (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5.

[0325] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VIII); wherein each R 1 The 3'- or 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 55 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7.

[0326] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VIII); wherein each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 55 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7.

[0327] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VIII); wherein each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 55 linked to; R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7.

[0328] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VIII); wherein each R1 The 3'- or 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 55 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11.

[0329] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VIII); wherein each R 1 The 3'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 55 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11.

[0330] In another embodiment, the present invention provides an antibody-oligonucleotide conjugate of formula (VIII); wherein each R 1 The 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of SEQ ID NO. 55 linked to; R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11.

[0331] In one embodiment, the present invention provides an antibody-immunostimulator conjugate of any one of formulas (I) to (III) and (IX) to (XI); wherein R A is an antibody containing the following:

[0332] (i) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5;

[0333] (ii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 12; (b) CDRL2 having EVK or the amino acid sequence of SEQ ID NO. 13; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 14; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 15; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 18;

[0334] (iii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 23; (b) CDRL2 having the amino acid sequence of SEQ ID NO. 24; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 25; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 26; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 27; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 28; or

[0335] (iv) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 35; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 36; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 37; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 38; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 39.

[0336] In one embodiment, the present invention provides an antibody-immunostimulator conjugate of formula (IX); wherein R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5. In another embodiment, the present invention provides an antibody-immunostimulator conjugate of formula (IX); wherein RA is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7. In another embodiment, the present invention provides an antibody-immunostimulator conjugate of formula (IX); wherein R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11.

[0337] In one embodiment, the present invention provides an antibody-immunostimulator conjugate of formula (X); wherein R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5. In another embodiment, the present invention provides an antibody-immunostimulator conjugate of formula (X); wherein R A is an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7. In another embodiment, the present invention provides an antibody-immunostimulator conjugate of formula (X); wherein R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11.

[0338] In one embodiment, the present invention provides an antibody-immunostimulator conjugate of formula (XI); wherein R A is an antibody comprising (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5. In another embodiment, the present invention provides an antibody-immunostimulator conjugate of formula (XI); wherein R Ais an antibody comprising the light chain variable region of SEQ ID NO. 6 and the heavy chain variable region of SEQ ID NO. 7. In another embodiment, the present invention provides an antibody-immunostimulator conjugate of formula (X); wherein R A is an antibody comprising the light chain of SEQ ID NO. 10 and the heavy chain of SEQ ID NO. 11.

[0339] In one embodiment, the present invention relates to an antibody-immunostimulator conjugate AOC-A1 inside AOC-A10 , AOC-B1 inside AOC-B8 , AOC-C1 , AOC-C2 , AOC-D1 , and ISAC-A1 inside ISAC-A3 One of them is provided.

[0340] In certain embodiments, the compound provided herein is isolated or purified. In certain embodiments, the compound provided herein has a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.

[0341] The compounds provided herein are intended to encompass all possible stereoisomers unless a specific stereochemistry is specified. If a compound provided herein contains an alkenyl group, the compound is geometric 시스 / 트랜스 (or Z / E It may exist as one of the isomers or as a mixture. If the structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This may take the form, for example, proton tautomerism in compounds containing imino, keto, or oxime groups; or so-called valence tautomerism in compounds containing aromatic moiety. Thus, a single compound may exhibit more than one type of isomerism.

[0342] The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or may be a mixture of enantiomers, for example, a racemic mixture of two enantiomers; or a mixture of stereoisomers, such as a mixture of two or more diastereomers. As such, in the case of a compound undergoing epimerization in vivo, ( R Administration of the compound in the form of ( S It will be recognized that this is equivalent to administering a compound in the form of ). Conventional techniques for the preparation / isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from an achiral starting material, or separation of an enantiomer mixture, e.g., chiral chromatography, recrystallization, separation, formation of a diastereomer salt, or derivatization into a diastereomer adduct followed by separation.

[0343] If the compounds provided herein contain an acidic or basic moiety, they may also be provided as pharmaceutically acceptable salts. Berge et al. , J. Pharm. Sci. 1977 , 66 , 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use See , 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011. In certain embodiments, the pharmaceutically acceptable salt of the compound provided herein is a solvate. In certain embodiments, the pharmaceutically acceptable salt of the compound provided herein is a hydrate.

[0344] Acids suitable for use in the preparation of pharmaceutically acceptable salts of the compounds provided herein are acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-campforic acid, camphorsulfonic acid, (+)-(1 S)-Camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromide, hydrochloric acid, hydroiodonic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, Naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, parmoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanate, p - Includes, but is not limited to, toluenesulfonic acid, undecylenic acid, and valeric acid.

[0345] Bases suitable for use in the preparation of pharmaceutically acceptable salts of the compounds provided herein are inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and L-arginine, benetamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N -Methyl-glucarmine, hydravamin, 1 H -Imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N- It includes, but is not limited to, organic bases such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including but not limited to methyl-D-glucarmine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

[0346] Pharmaceutical composition

[0347] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound provided herein, e.g., a compound of formula (I), or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and a pharmaceutically acceptable excipient.

[0348] In one embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration. In another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for subcutaneous administration.

[0349] The pharmaceutical compositions provided herein may be provided in a unit-dosage form or a multiple-dosage form. As used herein, a unit-dosage form refers to physically distinct units that are suitable for administration to a subject and are individually packaged as known in the art. Each unit-dosage contains a predetermined quantity of active ingredient(s) (e.g., compounds provided herein) sufficient to produce a desired therapeutic effect, along with the necessary pharmaceutical excipient(s). Examples of unit-dosage forms include, but are not limited to, ampoules and syringes. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered as separate unit-dosage forms. Examples of multiple-dosage forms include, but are not limited to, vials or bottles in pint or gallon units.

[0350] The pharmaceutical composition provided herein may be administered at once or multiple times at time intervals. It is understood that the exact dosage and duration of treatment may vary depending on the age, weight, and condition of the subject being treated and may be determined empirically using known test protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any specific individual, the specific administration regimen must be adjusted over time according to the subject's needs and the professional judgment of the person administering or supervising the pharmaceutical composition.

[0351] How to use

[0352] In one embodiment, the present invention provides a method for treating, preventing, or alleviating one or more symptoms of HBV infection in a subject, comprising the step of administering to a subject in need a therapeutically effective amount of a compound of formula (I), or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0353] In a specific embodiment, the HBV infection is an acute HBV infection. In a specific embodiment, the HBV infection is a chronic HBV infection.

[0354] In a specific embodiment, the object is a mammal. In a specific embodiment, the object is a human.

[0355] In certain embodiments, the therapeutically effective amount of the compound provided herein is in the range of about 0.1 mg / kg every 4 weeks to about 20 mg / kg every week, about 0.2 mg / kg every 4 weeks to about 10 mg / kg every week, about 0.5 mg / kg every 4 weeks to about 5 mg / kg every week, or about 1 mg / kg every 4 weeks to about 2 mg / kg every week.

[0356] In one embodiment, the therapeutic effective dose of the compound provided herein is in the range of about 0.1 mg / kg every 4 weeks to about 20 mg / kg every week. In another embodiment, the therapeutic effective dose of the compound provided herein is in the range of about 0.2 mg / kg every 4 weeks to about 10 mg / kg every week. In yet another embodiment, the therapeutic effective dose of the compound provided herein is in the range of about 0.5 mg / kg every 4 weeks to about 5 mg / kg every week. In yet another embodiment, the therapeutic effective dose of the compound provided herein is in the range of about 1 mg / kg every 4 weeks to about 2 mg / kg every week. In yet another embodiment, the therapeutic effective dose of the compound provided herein is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5 mg / kg every 3 weeks.

[0357] Depending on the disorder, disease, or condition to be treated and the state of the subject, the compounds provided herein may be administered by a parenteral route of administration (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracerebral injection or infusion, subcutaneous injection, or implant). The compounds provided herein may be formulated in suitable dosage units with pharmaceutically acceptable excipients, carriers, adjuvants, or vehicles appropriate for the route of administration.

[0358] In one embodiment, the compound provided herein is administered parenterally. In another embodiment, the compound provided herein is administered intravenously. In yet another embodiment, the compound provided herein is administered intramuscularly. In yet another embodiment, the compound provided herein is administered subcutaneously.

[0359] The compounds provided herein may be delivered as a single dose, for example, as a single bolus injection, or over time, for example, as a continuous infusion over time or as divided bolus doses over time. The compounds provided herein may be administered repeatedly if necessary, for example, until the subject experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity.

[0360] The compound provided herein may be administered once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In one embodiment, the compound provided herein is administered once every 1 week. In another embodiment, the compound provided herein is administered once every 2 weeks. In yet another embodiment, the compound provided herein is administered once every 2 weeks. In yet another embodiment, the compound provided herein is administered once every 3 weeks. In yet another embodiment, the compound provided herein is administered once every 4 weeks. In yet another embodiment, the compound provided herein is administered once every 5 weeks. In yet another embodiment, the compound provided herein is administered once every 6 weeks.

[0361] The compounds provided herein may also be provided as manufactured articles using packaging materials well known to those skilled in the art. For example, see U.S. Patents No. 5,525,907; No. 5,052,558; and No. 5,055,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for selected formulations and intended modes of administration and treatment.

[0362] In a specific embodiment, the present invention provides a kit that can simplify the administration of an appropriate amount of the compound provided herein as an active ingredient to a subject when used by a medical professional. In a specific embodiment, the kit provided herein includes a container and a form of administration of the compound provided herein.

[0363] The kit provided herein may further comprise a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may comprise a sealed container of a suitable vehicle in which the active ingredient is dissolved to form a particle-free sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include: aqueous vehicles comprising, but not limited to, water for injection USP, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles comprising, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and includes, but is not limited to, non-aqueous vehicles including corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

[0364] The present disclosure may be further understood by the following non-limiting embodiments.

[0365] Examples

[0366] As used herein, the symbols and conventions used in these processes, reaction schemes, and examples are consistent with those used in modern scientific literature, e.g., the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry, regardless of whether specific abbreviations are specifically defined. Specifically, but without limitation, the following abbreviations may be used throughout the examples and specifications: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimole); μM (micromolar); mmol (millimole); h (hour); min (minute); Su (succinimido); TCEP (tris(2-carboxyethyl)phosphine); TEAA (triethyl-ammonium acetate); HPLC (High Performance Liquid Chromatography); prep-HPLC (Preparative HPLC); SDS-PAGE (Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis); and SAX-HPLC (Strong Anion Exchange Chromatography HPLC).

[0367] For all of the following examples, standard post-treatment and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in °C (degrees). Unless otherwise specified, all reactions are carried out at room temperature. The synthesis methodologies illustrated herein are intended to illustrate applicable chemistry through the use of specific examples and do not represent the scope of this disclosure.

[0368] Example 1

[0369] Functionalized CpG oligodeoxynucleotide A1 manufacturing

[0370]

[0371] compound A1 was synthesized as shown in Reaction Scheme 1, where R 1is a CpG oligodeoxynucleotide having the nucleotide sequence of SEQ ID NO. 44, 45, 46, or 53; wherein the CpG oligodeoxynucleotide 1.2 It was prepared by solid-phase oligonucleotide synthesis.

[0372] Compound in pH 8 phosphate buffer (50 mL) 1.1 (5 mmol) and oligodeoxynucleotide 1.2 A mixture of (1 mmol) was stirred at 35°C for 120 minutes. Subsequently, the reaction mixture was diluted with TEAA. The resulting precipitate was collected and purified by reverse-phase preparative HPLC, followed by ultrafiltration and freeze-drying to obtain the compound A1 obtained.

[0373]

[0374] Functionalized CpG oligodeoxynucleotide A2 is manufactured similarly, where R 1 is a CpG oligodeoxynucleotide having the nucleotide sequence of sequence number 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55.

[0375]

[0376] Functionalized CpG oligodeoxynucleotide A3 is manufactured similarly, where R 1 is a CpG oligodeoxynucleotide having the nucleotide sequence of SEQ ID NO. 45 or 46.

[0377]

[0378] Example 2

[0379] Functionalized CpG oligodeoxynucleotide A4 manufacturing

[0380]

[0381] compound A4was synthesized as shown in Reaction Scheme 2, where R 1 is a CpG oligodeoxynucleotide having the nucleotide sequence of SEQ ID NO. 45.

[0382]

[0383] Oligodeoxynucleotides in pH 8 phosphate buffer (50 mL) 1.2 (1 mmol) and compound 2.1 A mixture of (5 mmol) was stirred at 35°C for 120 minutes. Subsequently, the reaction mixture was diluted with TEAA. The resulting precipitate was collected and purified by reverse-phase preparative HPLC, followed by ultrafiltration and freeze-drying to obtain the compound. A4 obtained.

[0384] Example 3

[0385] Functionalized CpG oligodeoxynucleotide A5 manufacturing

[0386]

[0387] compound A5 was synthesized as shown in Reaction Scheme 3, where R 1 is a CpG oligodeoxynucleotide having the nucleotide sequence of SEQ ID NO. 55.

[0388] Oligodeoxynucleotides in PBS buffer (pH 8) 3.2 Compound in an equal volume of DMF in a solution of (0.1 g / mL) 3.1 (3-5 equivalents) was added. After incubation at 35°C for 2 hours, the reaction mixture was precipitated and purified by preparative HPLC (TEAA system). The fraction was freeze-dried, salt-exchanged, desalted by ultrafiltration, and freeze-dried to obtain the compound. A5 obtained.

[0389]

[0390] Example 4

[0391] Preparation of anti-HBsAg / CpG oligonucleotide conjugates

[0392] The monoclonal anti-HBsAg antibody was buffered with 20 mM sodium phosphate-buffered saline solution and further diluted to 2–10 mg / mL in the same buffer. 8 molar equivalents of TCEP were added to reduce the interchain disulfide bonds of the anti-HBsAg antibody at pH 4–6. 6 molar equivalents of functionalized CpG oligodeoxynucleotides (e.g., A1 , A3 or A5 )(10 mg / mL) was added to the reduced anti-HBsAg antibody solution and incubated at room temperature for 1–12 hours. Excess TCEP and functionalized CpG oligodeoxynucleotides were removed via gel filtration chromatography or ultrafiltration to obtain the anti-HBsAg / CpG oligonucleotide conjugate, which was analyzed by SDS-PAGE (Fig. 1) to determine its drug-to-antibody ratio (DAR). The anti-HBsAg / CpG oligonucleotide conjugate was prepared as shown in Fig. 2. AOC-A1 It was analyzed by SAX-HPLC. The results are summarized in Tables 1 to 3, where each anti-HBsAg / CpG oligonucleotide conjugate was determined to have a DAR of about 4.

[0393]

[0394]

[0395]

[0396] Example 5

[0397] Preparation of anti-HBsAg / CpG oligonucleotide conjugates

[0398] The monoclonal anti-HBsAg antibody was buffered with 20 mM sodium phosphate-buffered saline solution and further diluted to 2–10 mg / mL in the same buffer. 8 molar equivalents of TCEP were added to reduce the interchain disulfide bonds of the anti-HBsAg antibody at pH 4–6. Subsequently, excess TCEP was removed via gel filtration chromatography or ultrafiltration. 6 molar equivalents of functionalized CpG oligodeoxynucleotides (e.g., A4 )(10 mg / mL) was added to the reduced antibody solution and incubated at room temperature for 1–12 hours. Excess functionalized CpG oligodeoxynucleotides were removed by gel filtration chromatography or ultrafiltration to obtain anti-HBsAg / CpG oligonucleotide conjugates, which were analyzed by SDS-PAGE to determine their drug-to-antibody ratio (DAR). The results are summarized in Table 4, where each anti-HBsAg / CpG oligonucleotide conjugate was determined to have a DAR of approximately 4.

[0399]

[0400] Example 6

[0401] Anti-HBsAg / TLR-7 agonist conjugate ISAC-A1 manufacturing

[0402]

[0403] Monoclonal anti-HBsAg 1 (SEQ NOs. 8 and 9) was buffered with 20 mM sodium phosphate and 0.5 M EDTA-buffered saline solution and further diluted to 2–10 mg / mL in the same buffer. 6 molar equivalents of TCEP were added to reduce the interchain disulfide bonds of anti-HBsAg at pH 4–6. 6 molar equivalents of functionalized TLR-7 agonist, ( S )- N -(16-(4-amino-2-butyl-1 H -Imidajo[4,5- c]quinoline-1-yl)-7-benzyl-2,5,8,11-tetraoxo-3,6,9,12-tetraazahexadecyl)-6-(2,5-dioxo-2,5-dihydro-1 H ε-pyrrole-1-yl)hexanamide (10 mg / mL) was added to the reduced anti-HBsAg solution and incubated at room temperature for 1–12 hours. Excess TCEP and functionalized TLR-7 agonists were removed by gel filtration chromatography or ultrafiltration to obtain the anti-HBsAg / TLR-7 agonist conjugate. ISAC-A1 (m = approximately 4) was obtained, which was determined to have a DAR of approximately 4 by HIC-HPLC or mass spectrometry.

[0404] Example 7

[0405] Anti-HBsAg / TLR-7 agonist conjugate ISAC-A2 manufacturing

[0406]

[0407] Anti-HBsAg / TLR-7 agonist conjugate ISAC-A2 (m is about 4) is a monoclonal anti-HBsAg 1 (SEQ NOs 10 and 11) and a functionalized TLR-7 agonist, 1-((4-(4-(4-((2-amino-4-(pentylamino)-5 as described in Example 6 H -pyrrolo[3,2- d ]pyrimidine-5-yl)methyl)-3-methoxy-benzyl)piperazine-1-carbonyl)cyclohexyl)methyl)-1 H - Prepared from pyrrole-2,5-dione. Anti-HBsAg / TLR-7 agonist conjugate ISAC-A2 It was determined to have a DAR of about 4 by HIC-HPLC or mass spectrometry.

[0408] Example 8

[0409] Anti-HBsAg / TLR-8 agonist conjugate ISAC-A3 manufacturing

[0410]

[0411] Monoclonal anti-HBsAg 1 (SEQ NOs 10 and 11) was buffered with 20 mM sodium phosphate and 0.5 M EDTA-buffered saline solution and further diluted to 2–10 mg / mL in the same buffer. 6 molar equivalents of TCEP were added to reduce the interchain disulfide bonds of anti-HBsAg at pH 4–6. 6 molar equivalents of functionalized TLR-8 agonist, 4-(( S )-2-(( S )-2-(6-(2,5-dioxo-2,5-dihydro-1 H -pyrrole-1-yl)-hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl ((5-(2-amino-4-(dipropyl-carbamoyl)-3 H -Benzo[ b ]azepine-8-carboxamido)pyridine-3-yl)methyl)carbamate (10 mg / mL) was added to the reduced anti-HBsAg solution and incubated at room temperature for 1–12 hours. Excess TCEP and functionalized TLR-8 agonists were removed by gel filtration chromatography or ultrafiltration to obtain the anti-HBsAg / TLR-8 agonist conjugate. ISAC-A3 (m = approximately 4) was obtained, which was determined to have a DAR of approximately 4 by HIC-HPLC or mass spectrometry.

[0412] Example 9

[0413] Determination of the binding affinity of anti-HBsAg / CpG oligonucleotide conjugates to human HBsAg

[0414] Human anti-HBsAg 1 and human anti-HBsAg / CpG oligonucleotide conjugates AOC-A8 and AOC-B2 The binding affinity of to human HBsAg (SEQ No. 56) was determined using ELISA. Briefly, human HBsAg was coated onto the wells of ELISA plates overnight at 4°C. Human human anti-HBsAg 1 (Human hAnti-HBsAg 1), AOC-A8 , and AOC-B2[The substance] was added at a predetermined concentration. After incubating the ELISA plate at 25°C for 1 hour, horseradish (HRP) solution was added to each well, and the plate was incubated at 25°C for an additional 1 hour. TMB substrate was added. After adding the termination solution, the ELISA plate was read at 450 nm using an ELISA plate reader. Binding affinities were calculated, and the results are summarized in Table 5.

[0415]

[0416] Example 10

[0417] Antiviral effect of anti-HBsAg antibody / TLR conjugate in HBV-infected cells

[0418] Hepatocellular carcinoma cells HepG2.2.15 with stable HBsAg expression were seeded into 96-well cell culture plates at a cell density of 8,000 cells per well and cultured overnight at 37°C under 5% CO2. On Day 1, the medium was discarded and PBMCs were added to the 96-well plates containing the HepG2.2.15 cells. Anti-HBsAg / TLR agonist conjugate AOC-B5 , AOC-B6 , AOC-B7 , ISAC-A2 , ISAC-A3 , and TL9 agonist 2 (SEQ No. 45) were each added in an amount of 100 μL, and a commercial human CD3 / CD28 T cell activator as a positive control was added in an amount of 2 μL to each well of a 96-well plate. Each AOC-B5 , AOC-B6 , AOC-B7 , and ISAC-A2 The final concentrations were 120 μg / mL (A), 12 μg / mL (B), and 1.2 μg / mL (C). ISAC-A3The final concentrations of were 780 μg / mL (A), 78 μg / mL (B), and 7.8 μg / mL (C). The final concentrations of TLR9 agonist 2 were 38 μg / mL (A), 3.8 μg / mL (B), and 0.38 μg / mL (A). Medium (100 μL) was added to each well of a 96-well plate. On day 7, the culture supernatant was collected and analyzed for HBsAg. The results are summarized in Table 6.

[0419]

[0420] Example 11

[0421] Anti-HBV effect of anti-HBsAg / TLR agonist conjugate in AAV-HBV mouse model

[0422] AAV8-HBV (genotype D) (1 x 10⁶) in PBS (200 μL) to C57BL / 6 male mice 10 The viral genome was injected into the tail vein of each mouse. On day 28 (Day 0) after viral injection, mice were randomized into three groups of four mice per group. Mouse anti-HBsAg 1 and mouse anti-HBsAg / TLR agonist conjugates AOC-A1 15 mg / kg was administered intravenously to mice in groups 1 and 2 on days 0, 21, 42, 62, and 84, respectively. PBS (control) was administered intravenously to mice in group 3. Blood samples were collected from mice in each group and analyzed for HBsAg, anti-HBs, ALT, and cytokine levels. On day 128, mice were euthanized, liver samples were collected, and liver HBcAg levels were analyzed using the IHC method. The results are shown in Figures 3 to 6 and summarized in Table 7.

[0423]

[0424] Anti-HBsAg / TLR agonist conjugate AOC-A1 , AOC-A2 , AOC-A3 , AOC-A4 , AOC-A5 , AOC-A6 , AOC-A7 , AOC-A9 , AOC-B1 , AOC-C1 , and ISAC-A1 Its anti-HBV activity was also evaluated. On days 0, 21, 42, and 63, an anti-HBsAg conjugate was administered intravenously at a dose of 15 mg / kg to each mouse in the treatment group. PBS was administered intravenously to each mouse in the control group. Blood samples were collected from the mice and analyzed for HBsAg and anti-HBs levels. On day 106, the mice were euthanized, and liver samples were collected and analyzed for liver HBcAg levels using the IHC method. The results are summarized in Figures 7 to 9.

[0425] Additionally, anti-HBsAg / TLR agonist conjugate AOC-A4 , AOC-A10 , AOC-B3 , AOC-B4 , AOC-C1 , and AOC-C2 Its anti-HBV activity was evaluated. On days 0, 21, 42, and 63, an anti-HBsAg / TLR agonist conjugate was administered intravenously at a dose of 15 mg / kg to each mouse in the treatment group. PBS was administered intravenously to each mouse in the control group. Blood samples were collected from the mice and analyzed for HBsAg and anti-HBs levels. On day 84, the mice were euthanized, and liver samples were collected and analyzed for liver HBcAg levels using the IHC method. The results are summarized in Figures 10 to 12.

[0426] In addition, anti-HBsAg / TLR agonist conjugate AOC-B8 , AOC-D1 , and ISAC-A2 In addition, the CpG oligonucleotide (SEQ No. 45) was evaluated for its anti-HBV activity. On days 0, 21, and 42, the anti-HBsAg / TLR agonist conjugate AOC-B8 and ISAC-A2was administered intravenously at 15 mg / kg, and the anti-HBsAg / TLR agonist conjugate AOC-D1 5 mg / kg was administered intravenously, and CpG oligonucleotides were administered subcutaneously at 2.5 mg / kg. PBS was administered intravenously to each control mouse. Blood samples were collected from the mice and analyzed for HBsAg. The results are summarized in Figure 13.

[0427] Example 12

[0428] Epitope-based competitive ELISA

[0429] Anti-HBsAg antibodies, human anti-HBsAg 1, human anti-HBsAg 2, and human anti-HBsAg 3 were evaluated in an epitope-based competitive ELISA. In the assay, each well of the ELISA plate was coated with 1 μg / mL of HBsAg. 2 μg / mL of biotinylated human anti-HBsAg 1 and a mixture of human anti-HBsAg 1, human anti-HBsAg 2, or human anti-HBsAg 3 at a predetermined concentration were subsequently added, followed by the addition of streptavidin and a secondary streptavidin antibody. The results are shown in Fig. 14, which indicate no competition between human anti-HBsAg 1 and human anti-HBsAg 2, indicating that the two antibodies bind to two different epitopes on HBsAg; There is competition between human anti-HBsAg 1 and human anti-HBsAg 3, which suggests that their epitopes may overlap. The competitive ELISA results shown in Fig. 14, along with the anti-HBV efficacy results shown in Figs. 7 through 9, demonstrate that anti-HBsAg / CpG oligonucleotide conjugates targeting different HBsAg epitopes are effective in treating HBV infection.

[0430] The sequences described herein are provided in the sequence table below.

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437] * * * * *

[0438] The embodiments presented above are provided to provide those skilled in the art with a complete disclosure and description of how to manufacture and use the claimed embodiments and should not be construed as limiting the scope of the contents disclosed herein. Variations obvious to those skilled in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited herein are incorporated by reference as specifically and individually specified herein, each of which is incorporated by reference herein.

Claims

Claim 1 Compound of Formula (I): or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein: each L is independently a linker; each X is independently (i) bonded or -S-; or (ii) heteroarylene or heterocyclylene, each optionally substituted with one or more, in one embodiment, 1, 2, 3, or 4 substituents Q; and each R 1 is independently an immunostimulator and;R A is an antibody or its antigen-binding fragment that specifically binds to hepatitis B surface antigen (HBsAg); and m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; where each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 Aralyl, heteroaryl, and heterocyclil, each of which has one or more, in one embodiment, 1, 2, 3, or 4 substituents Q a Additionally optionally substituted with; and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a )OR d , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)2NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)2NR b R c Selected from, where each R a , R b , R c , and R d is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 It is an araclel, heteroaryl, or heterocyclil, each of which has one or more, in one embodiment, 1, 2, 3, or 4 substituents Q a Optionally substituted with; or (iii) R b and R c They form a heterocyclile together with the N atom to which they are attached, and this has one or more, in one embodiment, 1, 2, 3, or 4 substituents Q a Optionally substituted as; where each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 Aralkill, heteroaryl, and heterocyclil; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)2NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)2NR f R g Selected from; where each R e , R f , R g , and R h is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-14 Aril, C 7-15 Aralyl, heteroaryl, or heterocyclil; or (iii) R f and R g A compound that forms a heterocyclile together with the N atom to which they are attached. Claim 2 In paragraph 1, each X is a compound that is a bond. Claim 3 A compound according to claim 1, wherein each X is independently a heterocyclylene and is optionally substituted with one or more substituents Q. Claim 4 A compound according to claim 1 or 3, wherein each X is independently a monocyclic heterocyclylene and is optionally substituted with one or more substituents Q. Claim 5 A compound according to claim 1, 3, or 4, wherein each X is independently a 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each of which is optionally substituted with one or more substituents Q. Claim 6 A compound according to any one of claims 1 and 3 to 5, wherein each X is independently a 5-membered heterocyclylene and is optionally substituted with one or more substituents Q. Claim 7 In claim 1 or 2, a compound having the structure of formula (II): or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 8 A compound having the structure of formula (III) in any one of claims 1 to 6: or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 9 In any one of paragraphs 1 through 8, each L is independently C 1-50 It is a heteroalkylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent group, and each divalent group is independently C 6-14 A compound that is an arylene, a heteroarylene, or a heterocyclylene; and wherein each heteroalkylene, arylene, heteroarylene, and heterocyclylene is optionally substituted with one or more substituents Q. Claim 10 In any one of paragraphs 1 through 9, each L is independently C 1-30 A compound that is heteroalkylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent group, and each divalent group is independently cyclohexanediyl, phendiyl, triazolediyl, 2,5-dioxopyrrolidinediyl, or piperazinediyl. Claim 11 In any one of paragraphs 1 through 10, each L is independently C 1-30 A compound that is heteroalkylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent group, and each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, 2,5-dioxopyrrolidine-1,3-diyl, or piperazine-1,4-diyl. Claim 12 In any one of paragraphs 1 through 11, each L is independently: or Phosphorus, compound. Claim 13 In any one of paragraphs 1 through 11, each L is independently: or Phosphorus, compound. Claim 14 In any one of paragraphs 1 through 11, each L moiety is independently: or Phosphorus, compound. Claim 15 In any one of paragraphs 1 through 11, each XL moiety is independently: , or Phosphorus, compound. Claim 16 In any one of paragraphs 1 and 9 through 11, each XL moiety is independently: or Phosphorus, compound. Claim 17 A compound having the structure of formula (IV) in any one of claims 1 to 6, 8 to 11, 14 and 16: or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 18 A compound having the structure of formula (V) in any one of claims 1 to 6, 8 to 11, 14 and 16: or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 19 A compound having the structure of formula (VI) in any one of claims 1 to 6, 8 to 11, 14 and 16: , or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 20 A compound having the structure of formula (VII) in any one of claims 1, 2, 7, 9 through 11, 14 and 16: , or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 21 A compound having the structure of formula (VIII) in any one of claims 1 to 6, 8 to 11, 14 and 16: , or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 22 A compound having the structure of formula (IX) in any one of claims 1 to 6, 8 to 11, 14 and 16: , or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 23 A compound having the structure of formula (X) in any one of claims 1 to 6, 8 to 11, 14 and 16: , or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 24 A compound having the structure of formula (XI) in any one of claims 1 to 6, 8 to 11, 14 and 16: , or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Claim 25 In any one of paragraphs 1 through 24, R A A compound comprising an antibody or an antigen-binding fragment thereof, comprising CDRL1 having the amino acid sequence of SEQ ID NO. 1; CDRL2 having the amino acid sequence of AAS; CDRL3 having the amino acid sequence of SEQ ID NO. 2; CDRH1 having the amino acid sequence of SEQ ID NO. 3; CDRH2 having the amino acid sequence of SEQ ID NO. 4; and CDRH3 having the amino acid sequence of SEQ ID NO.

5. Claim 26 In any one of paragraphs 1 through 25, R A A compound comprising an antibody or an antigen-binding fragment thereof, comprising: a light chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 6; and a heavy chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO.

7. Claim 27 In any one of paragraphs 1 through 26, R A A compound that is an antibody or an antigen-binding fragment thereof, comprising a light chain variable region having the amino acid sequence of SEQ ID NO. 6 and a heavy chain variable region having the amino acid sequence of SEQ ID NO.

7. Claim 28 In any one of paragraphs 1 through 27, R A A compound comprising an antibody having a light chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 10; and a heavy chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO.

11. Claim 29 In any one of paragraphs 1 through 28, R A A compound that is an antibody comprising a light chain having the amino acid sequence of SEQ ID NO. 10 and a heavy chain having the amino acid sequence of SEQ ID NO.

11. Claim 30 In any one of paragraphs 1 through 24, R A A compound comprising an antibody or an antigen-binding fragment thereof, comprising CDRL1 having the amino acid sequence of SEQ ID NO. 12; EVK or CDRL2 having the amino acid sequence of SEQ ID NO. 13; CDRL3 having the amino acid sequence of SEQ ID NO. 14; CDRH1 having the amino acid sequence of SEQ ID NO. 15; CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and CDRH3 having the amino acid sequence of SEQ ID NO.

18. Claim 31 In any one of paragraphs 1 through 24 and 30, R A A compound comprising an antibody or an antigen-binding fragment thereof, comprising: a light chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 19; and a heavy chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO.

20. Claim 32 In any one of paragraphs 1 through 24, 30 and 31, R A A compound that is an antibody or an antigen-binding fragment thereof, comprising a light chain variable region having the amino acid sequence of SEQ ID NO. 19 and a heavy chain variable region having the amino acid sequence of SEQ ID NO.

20. Claim 33 In any one of paragraphs 1 through 24 and paragraphs 30 through 32, R A A compound comprising an antibody having a light chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 21; and a heavy chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO.

22. Claim 34 In any one of paragraphs 1 through 24 and paragraphs 30 through 33, R A A compound that is an antibody comprising a light chain having the amino acid sequence of SEQ ID NO. 21 and a heavy chain having the amino acid sequence of SEQ ID NO.

22. Claim 35 In any one of paragraphs 1 through 24, R A A compound comprising an antibody or an antigen-binding fragment thereof, comprising CDRL1 having the amino acid sequence of SEQ ID NO. 23; CDRL2 having the amino acid sequence of SEQ ID NO. 24; CDRL3 having the amino acid sequence of SEQ ID NO. 25; CDRH1 having the amino acid sequence of SEQ ID NO. 26; CDRH2 having the amino acid sequence of SEQ ID NO. 27; and CDRH3 having the amino acid sequence of SEQ ID NO.

28. Claim 36 In any one of paragraphs 1 through 24 and 35, R A A compound comprising an antibody or an antigen-binding fragment thereof, comprising: a light chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 29; and a heavy chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO.

30. Claim 37 In any one of paragraphs 1 through 24, 35 and 36, R A A compound that is an antibody or an antigen-binding fragment thereof, comprising a light chain variable region having the amino acid sequence of SEQ ID NO. 29 and a heavy chain variable region having the amino acid sequence of SEQ ID NO.

30. Claim 38 In any one of paragraphs 1 through 24 and paragraphs 35 through 37, R A A compound comprising an antibody having a light chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 33; and a heavy chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO.

34. Claim 39 In any one of paragraphs 1 through 24 and paragraphs 35 through 38, R A A compound that is an antibody or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO. 33 and a heavy chain having the amino acid sequence of SEQ ID NO.

34. Claim 40 In any one of paragraphs 1 through 24, R A A compound comprising an antibody or an antigen-binding fragment thereof, comprising CDRL1 having the amino acid sequence of SEQ ID NO. 35; CDRL2 having the amino acid sequence of AAS; CDRL3 having the amino acid sequence of SEQ ID NO. 36; CDRH1 having the amino acid sequence of SEQ ID NO. 37; CDRH2 having the amino acid sequence of SEQ ID NO. 38; and CDRH3 having the amino acid sequence of SEQ ID NO.

39. Claim 41 In any one of paragraphs 1 through 24 and 40, R A A compound comprising an antibody or an antigen-binding fragment thereof, comprising: a light chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 40; and a heavy chain variable region having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO.

41. Claim 42 In any one of paragraphs 1 through 24, paragraph 40 and paragraph 41, R A A compound that is an antibody or an antigen-binding fragment thereof, comprising a light chain variable region having the amino acid sequence of SEQ ID NO. 40 and a heavy chain variable region having the amino acid sequence of SEQ ID NO.

41. Claim 43 In any one of paragraphs 1 through 24 and paragraphs 40 through 42, R A A compound comprising an antibody having a light chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO. 42; and a heavy chain having at least about 80% sequence identity with respect to the amino acid sequence of SEQ ID NO.

43. Claim 44 In any one of paragraphs 1 through 24 and paragraphs 40 through 43, R A A compound that is an antibody comprising a light chain having the amino acid sequence of SEQ ID NO. 42 and a heavy chain having the amino acid sequence of SEQ ID NO.

43. Claim 45 In any one of paragraphs 1 through 44, R A A compound that is a human antibody, a humanized antibody, or a chimeric antibody, or an antigen-binding fragment thereof. Claim 46 In any one of paragraphs 1 through 45, R A is a compound that is an IgG1, IgG2, IgG3, or IgG4 antibody, or an antigen-binding fragment thereof. Claim 47 In any one of paragraphs 1 through 46, R A is a compound that is a monoclonal antibody or its antigen-binding fragment. Claim 48 In any one of paragraphs 1 through 21 and paragraphs 25 through 47, R 1 A compound that is a toll-like receptor 9 (TLR9) agonist. Claim 49 In any one of paragraphs 1 through 21 and paragraphs 25 through 48, R 1 is a compound that is a single-stranded oligonucleotide. Claim 50 In any one of paragraphs 1 through 21 and paragraphs 25 through 49, R 1 is a compound that is a single-stranded CpG oligodeoxynucleotide. Claim 51 In claim 50, the single-stranded CpG oligodeoxynucleotide is a compound comprising about 15 to about 30 deoxynucleotides. Claim 52 A compound according to claim 50 or 51, wherein the single-stranded CpG oligodeoxynucleotide comprises about 1 to about 20 unmethylated CpG dideoxynucleotide motifs. Claim 53 In any one of claims 50 to 52, the single-stranded CpG oligodeoxynucleotide is a compound in which one or more phosphate linkage groups are replaced with phosphorothioate or phosphorodithioate. Claim 54 In any one of claims 50 to 53, the single-stranded CpG oligodeoxynucleotide is a compound in which all phosphate linkers are replaced with phosphorothioates. Claim 55 In any one of paragraphs 1 through 21 and paragraphs 25 through 54, R 1 A compound that is a TLR9 agonist of class A, B, C, or P. Claim 56 In any one of paragraphs 1 through 21 and paragraphs 25 through 55, R 1 A compound that is a class B TLR9 agonist. Claim 57 In any one of paragraphs 1 through 21 and paragraphs 25 through 56, R 1 A compound that is a TLR9 agonist comprising any one of the nucleotide sequences of SEQ ID NOs 44 to 49 and 55. Claim 58 In any one of paragraphs 1 through 21 and paragraphs 25 through 57, R 1 A compound that is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NOs 44, 45, 46, or 55. Claim 59 In any one of paragraphs 1 through 21 and paragraphs 25 through 55, R 1 A compound that is a class A TLR9 agonist. Claim 60 In any one of paragraphs 1 through 21, 25 through 55 and 59, R 1 A compound that is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 50 or 51. Claim 61 In any one of paragraphs 1 through 21 and paragraphs 25 through 55, R 1 A compound that is a class C TLR9 agonist. Claim 62 In any one of paragraphs 1 through 21, 25 through 55 and 61, R 1 A compound that is a TLR9 agonist comprising the nucleotide sequence of SEQ ID NO. 52, 53, or 54. Claim 63 In any one of paragraphs 1 through 21 and paragraphs 25 through 47, R 1 is a compound that is a TLR7 agonist. Claim 64 In any one of paragraphs 1 through 21, 25 through 47 and 63, R 1 silver , or A compound that is a TLR7 agonist having the structure of Claim 65 In any one of paragraphs 1 through 21 and paragraphs 25 through 47, R 1 is a compound that is a TLR8 agonist. Claim 66 In any one of paragraphs 1 through 21, 25 through 47 and 65, R 1 silver A compound that is a TLR8 agonist containing the structure of Claim 67 A compound according to any one of claims 1 to 66, wherein m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. Claim 68 A compound according to any one of claims 1 to 67, wherein m is an integer of 4, 5, 6, 7, or 8. Claim 69 In any one of paragraphs 17 through 21, each R 1 The 3'- or 5'-terminus of the tooth is R through the XL moiety A It is a single-stranded CpG oligonucleotide of sequence number 44, 45, 46, 53, or 55 linked to; R A Compounds comprising antibodies including: (i) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 1; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 2; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 3; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 4; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 5; (ii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 12; (b) CDRL2 having the amino acid sequence of EVK or SEQ ID NO. 13; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 14; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 15; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 16 or 17; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 18; (iii) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 23; (b) CDRL2 having the amino acid sequence of SEQ ID NO. 24; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 25; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 26; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 27; and (f) CDRH3 having the amino acid sequence of SEQ ID NO. 28; or (iv) (a) CDRL1 having the amino acid sequence of SEQ ID NO. 35; (b) CDRL2 having the amino acid sequence of AAS; (c) CDRL3 having the amino acid sequence of SEQ ID NO. 36; (d) CDRH1 having the amino acid sequence of SEQ ID NO. 37; (e) CDRH2 having the amino acid sequence of SEQ ID NO. 38; and (f) CDRH3 having the amino acid sequence of SEQ ID NO.

39. Claim 70 In paragraph 1, the compound is an antibody-immunostimulator conjugate AOC-A1 inside AOC-A10 , AOC-B1 inside AOC-B8, AOC-C1 , AOC-C2 , AOC-D1 , and ISAC-A1 inside ISAC-A3 One of the compounds. Claim 71 A pharmaceutical composition comprising a compound of any one of claims 1 to 70, or a diastereomer thereof, a mixture of two or more diastereomers, a tautomer, or a mixture of two or more tautomers; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and a pharmaceutically acceptable excipient. Claim 72 In paragraph 71, the composition is a pharmaceutical composition in a single dosage form. Claim 73 A pharmaceutical composition according to claim 71 or 72, wherein the composition is in the form of parenteral or intravenous administration. Claim 74 In paragraph 73, the composition is a pharmaceutical composition formulated for intravenous administration. Claim 75 A method for treating, preventing, or alleviating one or more symptoms of HBV infection in a subject, comprising the step of administering a therapeutically effective amount of a compound of any one of claims 1 to 70 or a pharmaceutical composition of any one of claims 71 to 74 to a subject in need thereof. Claim 76 In paragraph 75, HBV infection is acute, method. Claim 77 In paragraph 75, the HBV infection is chronic, method.

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