Therapeutic agents and conjugates thereof

Abstract

The present disclosure provides a class of conjugates, a class of TLR9 agonist derivatives (such as Formula (I), (XX), and (XXI)), certain diastereomers of STING agonists, a class of STING agonist derivatives (such as Formula (XXVIV)), a class of heterocyclic compounds having the general formula (II), a class of heterocyclic compounds having the general formula (III), as defined herein. A 1 , A 2 , T, Z 1 , Z 2 , Z 3 , b1 and b2 are defined herein. The conjugates provide unique properties based on the properties of the therapeutic agent that is part of the conjugate. Methods of synthesis and uses of the compounds are also provided.[A 2 -Z 2 -T-Z 3 ] b2 -A 1 -[Z 1 -T-Z 2 -A 2 ] b1 (X).

Description

[0001] Citation of relevant applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 986,223, filed March 6, 2020, and U.S. Provisional Application No. 63 / 062,503, filed August 7, 2020, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0003] sequence list

[0004] This application was filed electronically via EFS-Web and includes a sequence list filed electronically in txt format. The txt file contains a sequence list named “CSPL_011_02WO_SeqList_ST25.txt”, created on March 2, 2021, and approximately 1.87 kilobytes in size. The sequence list contained in this txt file is part of the specification and is incorporated herein by reference in its entirety. Background Technology

[0005] Cancer researchers have long recognized that the phenotypic heterogeneity and progressive evolution of malignant tumors minimize the chances of any agent targeting a single molecular pathway being effective in treating advanced cancer. Indeed, not only do given cancer cells typically disrupt additional normal growth and anti-apoptotic mechanisms to avoid death, but they also employ mechanisms to evade elimination by the immune system and coordinate changes in the tumor microenvironment (TME) to ensure their survival (Nature. 2017; 541:321-30). Despite recent breakthroughs in cancer immunotherapy, combination therapies to improve efficacy remain needed for patients whose tumors do not respond to current and emerging treatment standards.

[0006] Activation of the immune system is a key component of an effective and durable anti-tumor response. Pathogen-associated molecular patterns (PAMPs) have attracted considerable attention as immunotherapies due to their known mechanisms and ability to elicit Th1 immune responses. PAMPs consist of one or more structures sensed by pattern recognition receptors (PRRs) on host cells and can activate immune responses mediated by one or more signaling pathways. Three common classes of PRRs are Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), and stimulators of interferon genes (STINGs).

[0007] STING agonist

[0008] Detection of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) via pattern recognition receptors (PRRs) triggers innate immunity, leading to the production of type I and III IFNs, pro-inflammatory cytokines, and chemokines.

[0009] STING (stimulator of the interferon gene) is an endoplasmic reticulum (ER) membrane signaling protein involved in the innate immune response to cytoplasmic nucleic acids, including self-derived and exogenously derived double-stranded DNA and bacterial circular dinucleotides.

[0010] STING is activated by cyclic dinucleotides (such as 2'3'-cGAMP) produced by cGAS in response to cytoplasmic double-stranded DNA. STING activation induces its relocation from the endoplasmic reticulum to the Golgi apparatus. In this process, STING recruits TBK1, which is phosphorylated by STING, thereby generating a platform for IRF3 recruitment and phosphorylation by TBK1. STING also activates NF-κB. Phosphorylated IRF3 and NF-κB then translocate to the nucleus to induce the expression of type I IFN and inflammatory genes. In dendritic cells (DCs), STING activation further induces the expression of co-stimulatory molecules, leading to cellular maturation and the initiation of adaptive immunity.

[0011] Recent publications suggest that lower doses of STING agonists are optimal for generating systemic tumor-specific T-cell responses and durable anti-tumor immunity, and that combining low-immunogenic dosing regimens of STING agonists with other immunotherapies may be beneficial for achieving good efficacy.

[0012] TLR agonists

[0013] Toll-like receptors (TLRs) comprise a family of highly conserved germline-encoded pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPs) expressed by a variety of infectious microorganisms. The ability of TLRs to trigger the innate immune system and enhance adaptive immunity against antigens expressed by pathogens and tumors is well-established. At least 13 distinct TLRs have been identified in mammals, among which TLR 7, TLR 8, and TLR 9 are similar in their recognition of nucleic acid motifs and expression within endosomal compartments.

[0014] Studies show that TLR7 is primarily expressed by plasmacytoid dendritic cells (pDCs), TLR8 by monocytes, monocyte-derived (m)DCs, macrophages, and Langerhans cells, and TLR9 by DCs, B cells, monocytes, and mast cells. Designed synthetic agonist analogs (such as imiquimod (R837), remiquimod (R848), and loxorebin) to stimulate TLR7 often also trigger TLR8 and induce the secretion of IL-12 and TNFα by mDCs and / or pDCs. Many TLR7 / 8 agonists also enhance the expression of co-stimulatory molecules and DC migration, thereby promoting the induction of Th1 immune responses. Synthetic oligonucleotides expressing CpG motifs (such as PF-3512676, SD-101, CMP-001, MGN-1703, and IMO-2125) trigger TLR9 and elicit a Th1-dominated immune response characterized by the production and co-stimulation of pro-inflammatory cytokines (including IL-12, IFNα, and TNFα) and CD80 and CD86, as well as the upregulation of MHC class I and II molecules. The antitumor activity of TLR agonists targeting TLR7, 8, and 9 is typically explored through systemic or intratumoral delivery to the tumor. Increasing evidence suggests that the efficacy of TLR agonists can be improved through combination therapy.

[0015] Co-delivery of STING, TLR9, and TLR7 / 8 agonists

[0016] PAMPs (such as STING, TLR9, and TLR7 / 8 agonists) are located on the cell membrane or in the cytosol and require intracellular delivery. These cytoplasmic PRRs primarily coordinate Th1-biased humoral and cellular immunity. Their activity can be further enhanced by combining two or more PAMPs, especially those that activate multiple immune signaling pathways. A method to induce a broader and more protective cytokine response is co-delivery of PAMPs to simultaneously activate PRRs (Mol. Pharmaceutics 2018, 15, 11, 4933-4946).

[0017] Experiments have shown that delivery of PAMP in the same microparticle (MP) induces superior responses both in vitro and in vivo compared to delivery of the same dose of PAMP in a single MP. One possible explanation for this observation is that co-encapsulated agonists always bind their corresponding PRRs in the same cell (cis-binding), thus allowing PRR crosstalk and enhanced immune activation. Conversely, when PAMP is delivered in a single particle, both particle types require intracellular delivery for PRR crosstalk to occur (trans-binding). The likelihood of this occurring depends on the particle location and the cell's phagocytic capacity, resulting in a more variable response. Less research has been conducted on this cis-trans binding of the receptor in the context of innate immunity, but it may be important for optimal biological responses, as PRR crosstalk plays a central role in innate immunity and allows for the generation of a pathogen-specific immune response (Int. Rev. Immunol. 2014, 33(6), 443-53). Furthermore, it has been shown that co-encapsulated PAMP combinations have stronger adjuvant delivery than individually encapsulated PAMPs (Nature 2011, 470(7335), 543-7, Sci.Rep.2017, 7(1), 2530). These works strongly support the ability of co-conjugating multiple PRRs to generate effective humoral and cellular responses.

[0018] While many forms of immunotherapy are effective against tumors, the pharmacokinetic parameters of many drugs are adversely affected, limiting their effectiveness. Rapid clearance of such drugs from physiological compartments via metabolism or excretion can lead to short lifespans and reduced exposure to the target. Many therapeutic agonists are attractive immunomodulators; however, they are not ideal agents due to poor pharmacokinetics (PK), poor tolerability, and pleiotropic activity that can be exacerbated by frequent dose administration.

[0019] We envision drug-drug conjugates with releaseable connectors linking drugs to deliver active drugs to simultaneously activate multiple immune signaling pathways. Drug delivery in this manner can activate receptor cis-binding and may be important for optimal biological response. Furthermore, drug-drug conjugates will optimize the pharmacokinetic (PK) properties of the drugs and exhibit advantages over the co-administration of each individual drug. Summary of the Invention

[0020] This application partially provides: a conjugate of formula (X), a STING agonist, a compound of formula (III) comprising a releasable linker portion covalently attached to a therapeutic agent A, a compound of formula (XXII) comprising a linker portion covalently attached to a STING agonist, a compound of formula (V), (VI), (VII), (VIII) or (IX), a STING agonist derivative of formula (XXVIV), a TLR9 agonist derivative of formula (XX) or (XXI), a TLR9 agonist of formula (I), a releasable linker of formula (II), and compositions and methods thereof.

[0021] On one hand, this application provides combinations of formula (X):

[0022] [A 2 -Z 2 -TZ 3 ] b2 -A 1 -[Z 1 -TZ 2 -A 2 ] b1

[0023] (X)

[0024] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, regioisomers, mixtures of two or more regioisomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs;

[0025] in:

[0026] b1 is an integer that is either 0 or 1;

[0027] b2 is an integer that is either 0 or 1;

[0028] Where b1+b2 is 1 or 2;

[0029] Each T is independently a triazole functional group;

[0030] Z 1 Z 2 and Z 3 Each is an independent spacer group; and

[0031] A 1 and A 2 Each is independently a therapeutic agent or an active portion of a therapeutic agent; or a compound that can be decomposed into a therapeutic agent; wherein one or more atoms or chemical groups in the therapeutic agent or the compound that can be decomposed into a therapeutic agent are independently replaced by covalent bonds to be connected to the aforementioned spacer groups.

[0032] In some implementations, A 1 and A 2 Each can be independently a STING agonist, a TLR9 agonist, or a TLR7 / 8 agonist.

[0033] In some embodiments, this application provides STING agonists represented by the following:

[0034]

[0035] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof.

[0036] In some embodiments, this application relates to formulas (X), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XH), (XXIV), (XXV), (X-1), (XI), (XI-A), (XI-B), (XXVI), (XXVI-A), (XXVI-B), (XII), (XII-A), (XII-B), (XXVII), (XXVII-A), (XXVII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A) (XV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII-A), (XVII-B), (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XXVIII) or enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, regioisomers, mixtures of two or more regioisomers or combinations of their isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof.

[0037] In some embodiments, this application provides compounds comprising a releasable connector portion covalently attached to a therapeutic agent, wherein the compound has a structure according to formula (III):

[0038] [Connector] b -A (III);

[0039] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0040] in,

[0041] A is a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent;

[0042] b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to A; and

[0043] Each joint has an independent structure according to formula (III-L):

[0044]

[0045] in:

[0046] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0047] X is the spacer group portion;

[0048] R 1 and R 2 Each is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aryl; or R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0049] Y 1 Is it O or S?

[0050] Y 2 It is O, NH or S;

[0051] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0052] This indicates a bond attached to A; wherein one or more atoms in each therapeutic agent or compound that can be broken down into a therapeutic agent are independently replaced by covalent bonds to attach to the connector, or chemical groups to attach the therapeutic agent or compound that can be broken down into a therapeutic agent to the connector.

[0053] In some embodiments, this application provides compounds comprising a linker portion covalently attached to a STING agonist, wherein the compound has a structure according to formula (XXII):

[0054]

[0055] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0056] in:

[0057] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0058] X is the spacer group portion;

[0059] R 1 and R 2 Each is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aryl; or

[0060] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0061] FG 1 It is a functional group that can undergo chemical reactions through click;

[0062] b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to A; and

[0063] A is a STING agonist; wherein one or more atoms in the STING agonist are independently replaced by covalent bonds to connect to the linker.

[0064] In some embodiments, this application provides compounds of formula (VI):

[0065] CpG-X-FG 1

[0066] (VI)

[0067] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0068] in:

[0069] X is the spacer group portion;

[0070] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0071] CpG is a TLR9 agonist oligodeoxynucleotide in which CpG is covalently bonded to X via a 3'-O or 5'-O terminal nucleotide.

[0072] In some embodiments, this application provides compounds of formula (V):

[0073]

[0074] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0075] in:

[0076] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0077] X 1 and X 2 Each is an independent spacer group portion;

[0078] R 1 and R 2 Each is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aryl; or

[0079] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0080] Y 1 It is O, NH or S;

[0081] Y 2 It is O, NH or S;

[0082] Y 3 It is O, NH or S;

[0083] Y 4 It is O, NH or S;

[0084] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0085] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist, wherein the CpG is covalently bonded to X via a 3'-O or 5'-O terminal nucleotide. 1 .

[0086] In some embodiments, this application provides compounds of formula (VII):

[0087]

[0088] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0089] in:

[0090] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0091] X 1 X 2 and X 3 Each is an independent spacer group portion;

[0092] R 1 and R 2 Each is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aryl; or

[0093] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0094] Y 1 It is O, NH or S;

[0095] Y 2 It is O, NH or S;

[0096] Y 3 It is O, NH or S;

[0097] Y 4 It is O, NH or S;

[0098] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0099] CpG is a TLR9 agonist oligodeoxynucleotide, in which either X 1 It is covalently bonded to the 5'-O of the terminal nucleotide of CpG, and X 3 Covalently bonded to the 3'-O of the terminal nucleotide of CpG; or X 1 It is covalently bonded to the 3'-O of the terminal nucleotide of CpG, and X 3 It is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[0100] In some embodiments, this application provides compounds of formula (VIII):

[0101] FG 1 -X 2 -CpG-X 1 -FG 1

[0102] (VIII)

[0103] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0104] in:

[0105] X 1 and X 2 Each is an independent spacer group portion;

[0106] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0107] CpG is a TLR9 agonist oligodeoxynucleotide, in which either X 1 It is covalently bonded to the 3'-O of the terminal nucleotide of CpG, and X 2 Covalently bonded to the 5'-O of the terminal nucleotide of CpG; or X 1 It is covalently bonded to the 5'-O of the terminal nucleotide of CpG, and X 2 It is covalently bonded to the 3'-O of the terminal nucleotide of CpG.

[0108] In some embodiments, this application provides compounds of formula (IX):

[0109]

[0110] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0111] in:

[0112] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0113] X is the spacer group portion;

[0114] R 1 and R 2 Each is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl; or

[0115] R 1 and R2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0116] Y 1 Is it O or S?

[0117] Y 2 It is O, NH or S;

[0118] Y 3 Is it O or S?

[0119] Y 4 It is O or S; and

[0120] FG 1 It is a functional group that can undergo chemical reactions through click.

[0121] In some embodiments, this application provides a STING agonist derivative released from the conjugate of this application, wherein the STING agonist derivative has a structure according to formula (XXVIV):

[0122]

[0123] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, regioisomers, mixtures of two or more regioisomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs;

[0124] in:

[0125] Ar 1 It is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0126] X 1 and X 2 Each is an independent spacer group portion;

[0127] R 1 and R 2 Each is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or

[0128] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0129] Y 3 and Y 4Each can be either O or S independently;

[0130] b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to A;

[0131] Each T is independently a triazole functional group; and

[0132] A is a STING agonist; wherein one or more atoms in the STING agonist are independently replaced by covalent bonds to be attached to a spacer group.

[0133] In some embodiments, this application provides a TLR9 agonist derivative released from the conjugate of this application, wherein the released TLR9 agonist has a structure according to formula (XX):

[0134]

[0135] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, regioisomers, mixtures of two or more regioisomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs;

[0136] in:

[0137] X 1 and X 2 Each is an independent spacer group portion;

[0138] Y 1 and Y 2 Each can be either O or S independently.

[0139] T is a triazole functional group; and

[0140] CpG is a TLR9 agonist oligodeoxynucleotide; wherein one or more atoms in the CpG are independently covalently substituted to be linked to X. 2 .

[0141] In some embodiments, this application provides a TLR9 agonist derivative released from the conjugate of this application, wherein the released TLR9 agonist has a structure according to formula (XXI):

[0142]

[0143] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, regioisomers, mixtures of two or more regioisomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs;

[0144] in:

[0145] X 1 X 2 and X 3 Each is an independent spacer group portion;

[0146] Y 1 and Y 2 Each can be either O or S independently;

[0147] Each T is independently a triazole functional group; and

[0148] CpG is a TLR9 agonist oligodeoxynucleotide; wherein one or more atoms in the CpG are independently covalently substituted to be linked to X. 2 and X 3 .

[0149] In some embodiments, this application provides a TLR9 agonist having the structure according to formula (I):

[0150]

[0151] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof;

[0152] in:

[0153] X 1 X 2 Each is an independent spacer group portion;

[0154] a1 is an integer that is either 0 or 1;

[0155] a2 is an integer that is either 0 or 1;

[0156] Where a1+a2 is 1 or 2; and

[0157] CpG is a TLR9 agonist oligodeoxynucleotide; in which one or more atoms in CpG are independently replaced by covalent bonds to be linked to X. 1 and / or X 2 .

[0158] In some embodiments, this application provides a releasable connector having a structure according to formula (II):

[0159]

[0160] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0161] in:

[0162] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0163] X is the spacer group portion;

[0164] R 1 It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aryl;

[0165] R 2 It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aryl; or

[0166] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings that can contain one or two heteroatoms;

[0167] Y 1 It is O, NH or S;

[0168] Y 2 It is O, NH or S;

[0169] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0170] FG 3 Functional groups – OH, SH, LG 1 (Leaving group 1), which includes, but is not limited to, -Cl, -Br, -I, Among them, Y 3 Is it O or S; Y 4 Is it O or S; LG 2 It is a leaving group

[0171] In some embodiments, this application provides a method for preparing drug-drug conjugates (e.g., according to scheme (II)).

[0172] In some embodiments, according to scheme (I), this application provides a method for chiral synthesis of STING agonists. Attached Figure Description

[0173] Figure 1 Tumor growth curves are shown in an MC38 mouse colon cancer model after treatment with compounds A5-I, A5-II, A6-I, and A6-II.

[0174] Figure 2 Tumor growth curves in an MC38 mouse colon cancer model are shown after treatment with compounds A1, A11, A1 and A11 and their conjugate A16.

[0175] Figure 3 Tumor growth curves are shown in an MC38 mouse colon cancer model after treatment with compounds A11, A12, A13, and A26.

[0176] Figure 4 Tumor growth curves in an MC38 mouse colon cancer model are shown after treatment with compounds A16, A17, A19, A23, A24, A25, and A30.

[0177] Figure 5 Tumor growth curves are shown in an MC38 mouse colon cancer model after treatment with compounds A5-I, A19, A33, A34, A38, A69, A71 and A85.

[0178] Figure 6 Tumor growth curves are shown in an MC38 mouse colon cancer model after treatment with compounds A19, A73, A74, and A75.

[0179] Figure 7 The tumor growth curves in the MC38 mouse colon cancer model are shown after treatment with compound A68.

[0180] Figure 8 The structure of equation (XVIII) is shown.

[0181] Figure 9 The structure of formula (XVIII-A) is shown.

[0182] Figure 10 The structure of formula (XVIII-B) is shown.

[0183] Figure 11 The structure of A57 is shown. A57 is a mixture of regioisomers as shown.

[0184] Figure 12 The structure of A47 is shown, and A57 is a mixture of regioisomers as shown.

[0185] Figure 13 The structure of A65 is shown. A65 is a mixture of structural isomers as shown.

[0186] Figure 14 The structure of A58 is shown. A58 is a mixture of regioisomers as shown.

[0187] Figure 15 The structure of A50 is shown. A50 is a mixture of regioisomers as shown.

[0188] Figure 16 The structure of A66 is shown. A66 is a mixture of regioisomers as shown. Detailed Implementation

[0189] limited

[0190] It should be understood that the terminology used herein is for the purpose of describing particular implementations only and is not intended to be limiting.

[0191] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. Although any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this application, representative methods and materials are described herein.

[0192] Under the long-standing Patent Law Convention, when used in this application, including the claims, the terms “a,” “an,” and “the” refer to “one or more.” Thus, for example, reference to “carrier” includes one or more carriers, a mixture of two or more carriers, etc.

[0193] Unless otherwise stated, all figures used in the specification and claims to indicate the amount of ingredients, reaction conditions, etc., should be understood to be modified by the term "about" in all cases. Therefore, unless stated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary depending on the desired characteristics sought to be obtained in this application.

[0194] The terms “one or more compounds of the present invention” or “one or more compounds of the present application” refer to compounds having the formula disclosed herein or any subgenus thereof, or pharmaceutically acceptable salts, stereoisomers, solvates or hydrates as disclosed herein.

[0195] In some embodiments, the intermediate is envisioned to be a compound of this application.

[0196] The compounds of this application, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and are therefore capable of producing enantiomers, diastereomers, and other stereoisomers, which may be defined according to absolute stereochemistry as (R)-, (S)-, (D)-, or (L)-amino acids. This application is intended to include all such possible isomers, as well as their racemic and optically pure forms, whether or not they are specifically described herein. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise specified, it is intended that these compounds include both E and Z geometric isomers. Similarly, it aims to include all tautomer forms.

[0197] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This application envisions different stereoisomers and mixtures thereof, and includes "enantiomers," and mixtures of such isomers are often referred to as enantiomer mixtures.

[0198] "Enantiomers" refer to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0199] A 50:50 mixture of enantiomers refers to a racemic mixture or racemate that may occur where there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that is not optically active. This invention includes all stereoisomers of the compounds described herein. A "diastereomer" is a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Mixtures of diastereomers can be separated under high-resolution analytical steps (such as electrophoresis and chromatography).

[0200] The term "regioisomer" is widely accepted and refers to compounds with the same molecular formula but different degrees of atomic connectivity. Therefore, a "regioselective process" is a process in which the formation of a particular regioisomer is superior to that of other regioisomers; for example, the reaction significantly increases the yield of the particular regioisomer. And so on.

[0201] "Tautomer" refers to a proton that has moved from one atom of a molecule to another atom of the same molecule. This application includes tautomers of any of the compounds described.

[0202] As used herein, the terms “drug combination,” “treatment combination,” or “combination” refer to a single dosage form containing at least two therapeutic agents, or a single dosage form containing at least two therapeutic agents, used together or alone in a combination therapy. For example, one therapeutic agent may be formulated into one dosage form, and other therapeutic agents may be formulated into single or different dosage forms. For example, one therapeutic agent may be formulated into a solid oral dosage form, while a second therapeutic agent may be formulated into a solution dosage form for parenteral administration.

[0203] The chemical nomenclature and structural diagrams used in this paper are the modified forms of IUPAC. The nomenclature system was implemented using ACD / Name Version 9.07, ChemDraw Ultra Version 11.0.1, and / or ChemDraw UltraVersion 14.0 software (CambridgeSoft). For complex chemical names used herein, substituents are named before the groups they are linked to. For example, cyclopropylethyl comprises an ethyl backbone with cyclopropyl substituents. Except as described below, all bonds are identified in the chemical structural diagrams herein, except for a few carbon atoms which are considered to be bonded to a sufficient number of hydrogen atoms to complete the valence.

[0204] The terms "composition" or "formulation" refer to one or more substances in physical form, such as solid, liquid, gas, or mixtures thereof. One example of a composition is a pharmaceutical composition, i.e., a composition relating to medical treatment, prepared for medical treatment, or used for medical treatment.

[0205] As used herein, "pharmaceutically acceptable" means suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, etc., and is effective for its intended use within the bounds of reasonable medical judgment.

[0206] "Salt" includes derivatives of an active agent, wherein the active agent is modified by preparing an acid or base addition salt. Preferably, these salts are pharmaceutically acceptable salts. Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts, and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as salts of organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, etc. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonyl aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthalates, glycerophosphates, ketoglutarate, etc. Base addition salts include, but are not limited to, ethylenediamine, N-methylglucosamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenylethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydrorosinamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, and basic amino acids (e.g., lysine and arginine dicyclohexylamine). Examples of metal salts include lithium, sodium, potassium, and magnesium salts. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, and tetramethylammonium salts. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, and choline. Standard methods for preparing pharmaceutically acceptable salts and their formulations are well known in the art and are disclosed in various references, including "Remington: The Science and Practice of Pharmacy", A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

[0207] As used herein, "solvent" refers to a complex formed by solvation (a combination of solvent molecules and molecules or ions of the active agent of this application), or an aggregate composed of solute ions or molecules (the active agent of this application) and one or more solvent molecules. In this application, the preferred solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, hexahydrates, etc. Those skilled in the art will understand that pharmaceutically acceptable salts of the compounds of this invention may also be present in solvate form. Solvents are typically formed via hydration, which is either part of the preparation of the compounds of this invention or through the natural absorption of water by the anhydrous compounds of this application. Solvents comprising hydrates may be composed in stoichiometric proportions, for example, each solvate or hydrate molecule having two, three, or four salt molecules. Another possibility is, for example, two salt molecules stoichiometrically associated with three, five, or seven solvent or hydrate molecules. Solvents used for crystallization (such as alcohols, especially methanol and ethanol; aldehydes; ketones, especially acetone; esters, such as ethyl acetate) can be embedded in the crystal grating. Pharmaceutically acceptable solvents are preferred.

[0208] The terms “excipient,” “carrier,” and “transporter” are used interchangeably throughout this application and refer to substances given to the compounds of this application.

[0209] "Therapeutic effective amount" refers to the amount of a compound or therapeutic active agent that, when administered to a patient for the treatment of a disease or other undesirable medical condition, is sufficient to have a beneficial effect relative to that disease or condition. Therapeutic effective amounts will vary depending on the type of compound or therapeutic active agent selected, the disease or condition and its severity, and the age, weight, etc., of the patient to be treated. Determining the therapeutic effective amount of a given compound or therapeutic active agent is within the general technical scope of this art and requires only routine experiments.

[0210] As used herein, “treating” or “treatment” encompasses treating a disease or condition of interest in a mammal (preferably a human) and includes: suppressing the disease or condition, i.e., preventing its development; alleviating the disease or condition, i.e. causing its remission; or relieving symptoms caused by the disease or condition, i.e. relieving pain without resolving the underlying disease or condition.

[0211] As used herein, the terms “disease” and “symptom” may be used interchangeably or differently, because a particular disease or symptom cannot have a known pathogen (thus the etiology has not yet been determined), and therefore it has not been identified as a disease but only as an undesirable symptom or syndrome in which a clinician has identified a more or less specific set of symptoms.

[0212] This application also aims to cover the in vivo metabolites of the disclosed compounds. Such products can arise from, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc., of the compounds administered primarily by enzymatic processes. Therefore, this application includes compounds produced by a method comprising administering the compound of this application to a mammal for a period of time sufficient to produce its metabolites. Such products are typically identified by administering the radiolabeled compound of this application to animals (e.g., rats, mice, guinea pigs, monkeys) or humans at detectable doses, allowing sufficient time for metabolism, and separating the metabolites from urine, blood, or other biological samples.

[0213] As used herein, “subject” can refer to a human, a non-human primate, a mammal, a rat, a mouse, a cow, a horse, a pig, a sheep, a goat, a dog, a cat, etc. The terms “subject” and “patient” are used interchangeably herein, for example, with reference to mammalian subjects (such as human subjects).

[0214] Subjects may be suspected of or at risk of having cancer (such as prostate cancer, breast cancer, ovarian cancer, salivary gland cancer, or endometrial cancer), or suspected of having acne or at risk of having acne, hirsutism, hair loss, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome, precocious puberty, spinal bulbar muscular atrophy, or age-related macular degeneration. Diagnostic methods for various cancers (such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, salivary gland cancer, or endometrial cancer), as well as diagnostic methods for acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome, precocious puberty, spinal bulbar muscular atrophy, or age-related macular degeneration, and clinical descriptions of cancers (such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, salivary gland cancer, or endometrial cancer), and diagnostic and clinical descriptions of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome, precocious puberty, spinal bulbar muscular atrophy, or age-related macular degeneration, are known to those skilled in the art.

[0215] "Mammals" include humans and livestock, such as laboratory animals and domesticated pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), as well as non-livestock animals, such as wild animals.

[0216] "Optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes examples in which the described event or condition occurs as well as examples in which it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0217] Unless otherwise stated, the following terms as used herein have the following meanings:

[0218] "Acyl" refers to –C(=O)-alkyl.

[0219] "Amino" refers to the -NH2 group.

[0220] "Cyano" refers to the -CN group.

[0221] "Halogen", "halogenated" or "halogen" refers to a group consisting of bromine, chlorine, fluorine or iodine.

[0222] "Hydroxyl" or "hydroxyl group" refers to the -OH group.

[0223] "Imine" refers to the =NH substituent.

[0224] "Nitro" refers to the -NO2 group.

[0225] "Oxyto" refers to the =O substituent.

[0226] "Thio" refers to the =S substituent.

[0227] "Mercapto" and "thiol" refer to the -SH group.

[0228] "alkyl" or "alkyl group" refers to a fully saturated, straight-chain (linear) or branched hydrocarbon chain group having 1 to 20 carbon atoms, attached to the rest of the molecule by a single bond. This includes alkyl groups containing any number of carbon atoms from 1 to 20. Alkyl groups containing up to 20 carbon atoms are C1-C2. 20 Alkyl groups, which contain up to 10 carbon atoms, are C1-C6. 10 Alkyl groups are categorized as follows: alkyl groups containing a maximum of 6 carbon atoms are C1-C6 alkyl groups, and alkyl groups containing a maximum of 5 carbon atoms are C1-C5 alkyl groups. C1-C5 alkyl groups include C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl groups include all the aforementioned C1-C5 alkyl groups, but also include C6 alkyl groups. C1-C 10 Alkyl groups include all the portions of C1-C5 and C1-C6 alkyl groups mentioned above, but also include C7, C8, C9 and C6 alkyl groups. 10 Alkyl group. Similarly, C1-C 12 Alkyl groups include all the foregoing portions, but also include C. 11 and C 12 Alkyl group. C1-C 12Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specifically stated in the specification, alkyl groups may optionally be substituted. The term "lower alkyl" refers to C1-C6 alkyl groups, which can be straight-chain or branched, such as branched C3-C6 alkyl groups.

[0229] "alkylene", "alkyl-", or "alkylene chain" refers to a fully saturated, straight-chain or branched divalent hydrocarbon chain group having 1 to 20 carbon atoms. C1-C 20 Non-limiting examples of alkylene groups include methylene, ethylene, propylene, n-butylene, vinylene, propenylene, n-butynylene, n-butynylene, etc. The alkylene chain is connected to the remainder of the molecule and to a group via single bonds. The connection points between the alkylene chain and the remainder of the molecule and to the group can be one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, the alkylene chain may optionally be substituted.

[0230] "Alkenyl" or "alkenyl group" refers to a straight-chain or branched hydrocarbon chain group having 2 to 20 carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is connected to the rest of the molecule by a single bond. This includes alkenyl groups containing any number of carbon atoms from 2 to 20. Alkenyl groups containing up to 20 carbon atoms are C2-C. 20 Alkenyl groups, which contain up to 10 carbon atoms, are C2-C. 10 Alkenyl groups, with a maximum of 6 carbon atoms, are C2-C6 alkenyl groups, and with a maximum of 5 carbon atoms, are C2-C5 alkenyl groups. C2-C5 alkenyl groups include C5, C4, C3, and C2 alkenyl groups. C2-C6 alkenyl groups include all the aforementioned C2-C5 alkenyl groups, but also include C6 alkenyl groups. C2-C... 10 Alkenyl groups include all the C2-C5 and C2-C6 alkenyl groups mentioned above, but also include C7, C8, C9, and C6 alkenyl groups. 10 Alkenyl groups. Similarly, C2-C 12 The alkenyl group includes all the aforementioned parts, but also includes C. 11 and C 12 Alkenyl. C2-C 12Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl. 6-Nonenyl, 7-Nonenyl, 8-Nonenyl, 1-Decenyl, 2-Decenyl, 3-Decenyl, 4-Decenyl, 5-Decenyl, 6-Decenyl, 7-Decenyl, 8-Decenyl, 9-Decenyl, 1-Undecenyl, 2-Undecenyl, 3-Undecenyl, 4-Undecenyl, 5-Undecenyl, 6-Undecenyl, 7-Undecenyl, 8-Undecenyl, 9-Undecenyl, 10-Undecenyl, 1-Dodecenyl, 2-Dodecenyl, 3-Dodecenyl, 4-Dodecenyl, 5-Dodecenyl, 6-Dodecenyl, 7-Dodecenyl, 8-Dodecenyl, 9-Dodecenyl, 10-Dodecenyl, and 11-Dodecenyl. Unless otherwise specified in the specification, alkyl groups may optionally be substituted.

[0231] "Alkenyl" or "alkenyl chain" refers to a straight-chain or branched divalent hydrocarbon chain group having 2 to 20 carbon atoms and one or more carbon-carbon double bonds. (C2-C) 20 Non-limiting examples of alkenyl groups include ethylene, propylene, butene, etc. The alkylene chain is connected to the rest of the molecule and to a group via a single bond. The connection points between the alkylene chain and the rest of the molecule and to the group can be one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, the alkenyl chain may optionally be substituted.

[0232] "Alynyl" or "alkynyl group" refers to a straight-chain or branched hydrocarbon chain group having 2 to 20 carbon atoms and one or more carbon-carbon triple bonds. Each alkynyl group is connected to the rest of the molecule by a single bond. This includes alkynyl groups containing any number of carbon atoms from 2 to 20. Alynyl groups containing up to 20 carbon atoms are C2-C. 20 The alkynyl group, which contains up to 10 carbon atoms, is C2-C. 10The ynyl group has a maximum of 6 carbon atoms, which are C2-C6 ynyl groups, and a maximum of 5 carbon atoms, which are C2-C5 ynyl groups. C2-C5 ynyl groups include C5, C4, C3, and C2 ynyl groups. C2-C6 ynyl groups include all the aforementioned C2-C5 ynyl groups, but also include C6 ynyl groups. 10 The alkynyl group includes all the C2-C5 and C2-C6 alkynyl groups mentioned above, but also includes C7, C8, C9, and C6 alkynyl groups. 10 Alkyne group. Similarly, C2-C 12 The alkynyl group includes all the aforementioned parts, but also includes C. 11 and C 12 Alkyne group. C2-C 12 Non-limiting examples of alkenyl groups include ethynyl, propynyl, butynyl, pentyynyl, etc. Unless otherwise specifically stated in the specification, alkyl groups may optionally be substituted.

[0233] "Imyynyl" or "Imyynyl chain" refers to a divalent hydrocarbon chain group having 2 to 20 carbon atoms and one or more carbon-carbon triple bonds, either straight-chain or branched. (C2-C) 20 Non-limiting examples of ynylene groups include ethynylene, propynylene, etc. The ynylene chain is connected to the rest of the molecule and to a group via single bonds. The connection points between the ynylene chain and the rest of the molecule, and with the group, can be one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, the ynylene chain may optionally be substituted.

[0234] "Alkoxy" or "-O-alkyl" refers to a compound with the formula -OR a The group, wherein R a It is an alkyl, alkenyl, or alkynyl group containing one to twenty carbon atoms as defined above. Unless otherwise specified in the specification, the alkoxy group may optionally be substituted.

[0235] "Alkylamino" refers to a compound with the formula -NHR a or -NR a R a The groups, wherein each R a Independently, it is an alkyl, alkenyl, or ynyl group comprising one to twelve carbon atoms as defined above. Unless otherwise specifically stated in the specification, alkylamino groups may optionally be substituted.

[0236] "alkyl carbonyl" refers to –C(=O)R a Part of it, of which R a It is an alkyl, alkenyl, or alkynyl group as defined above. A non-limiting example of an alkyl carbonyl group is a methyl carbonyl (“acetal”) moiety. An alkyl carbonyl group can also be referred to as a “Cw-Cz acyl”, where w and z depict the R group as defined above. aThe range of the number of carbon atoms in the carbon. For example, "C1-C 10 "Acyl" refers to the alkyl carbonyl group as defined above, wherein R a It is C1-C as defined above. 10 Alkyl, C1-C 10 alkenyl or C1-C 10 Alkyne group. Unless otherwise specified in the specification, the alkyl carbonyl group may optionally be substituted.

[0237] The term "aminoalkyl" refers to an alkyl group substituted with one or more -NH2 groups. In some embodiments, the aminoalkyl group is substituted with one, two, three, four, five, or more -NH2 groups. The aminoalkyl group may optionally be substituted with one or more additional substituents as described herein.

[0238] "Aryl" refers to a hydrocarbon ring system group containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For the purposes of this application, an aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from: anthracene, acenaphthene, acephenanthrylene, anthracene, azurite, benzene, etc. Fluoranthracene, fluorene, as-indoanthracene, s-indoanthracene, indane, indene, naphthalene, phenylalanine, phenanthrene, pleiadene, pyrene, and benzo[a]phenanthrene. Unless otherwise expressly stated in the specification, the term "aryl" is intended to include optionally substituted aryl groups.

[0239] "Aryl", "aryl", or "-alkylaryl" refers to the formula -R b -R c The group, wherein R b It is an alkylene, alkenylene, or ynylene group as defined above, and R c It is one or more aryl groups as defined above, such as benzyl, diphenylmethyl, etc. Unless otherwise specified in the specification, the aryl group may optionally be substituted.

[0240] "Carbocyclic group," "carbocyclic," or simply "carbocyclic" refers to a ring structure in which each of the atoms forming the ring is carbon. A carbocyclic ring can contain from 3 to 20 carbon atoms. Carbocyclic rings include aryl and cycloalkyl groups, as defined herein, cycloalkenyl and cycloynyl groups. Unless otherwise specifically stated in the specification, the carbocyclic group may optionally be substituted.

[0241] “Cycloalkyl” refers to a stable, non-aromatic, fully saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms. It may include fused or bridged ring systems having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and is attached to the remainder of the molecule by a single bond. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethylbicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexane, octahydrocyclopentene, bicyclo[1.1.1]pentane, cubane, etc. Unless otherwise specified in the specification, cycloalkyl groups may optionally be substituted.

[0242] "Cycloalkenyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which may include fused or bridged ring systems, having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and attached to the rest of the molecule by single bonds. Monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyl groups include, for example, bicyclic [2.2.1]hept-2-enyl, etc. Unless otherwise specifically stated in the specification, cycloalkenyl groups may optionally be substituted.

[0243] "Cycloynyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which may include fused or bridged ring systems, having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and attached to the rest of the molecule by single bonds. Monocyclic cycloynyl groups include, for example, cycloheptyneyl, cyclooctyneyl, etc. Unless otherwise specifically stated in the specification, the cycloynyl group may optionally be substituted.

[0244] "Cycloalkyl" or "-alkylcycloalkyl" refers to the formula -R b -R d The group, wherein R b It is an alkylene, alkenylene, or ynylene group as defined above, and R d It refers to cycloalkyl, cycloalkenyl, and cycloynyl groups as defined above. Unless otherwise specified in the specification, cycloalkyl groups may optionally be substituted.

[0245] As defined above, "haloalkyl" refers to an alkyl group substituted with one, two, three, four, five, six or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specifically stated in the specification, haloalkyl groups may optionally be substituted.

[0246] As defined above, "haloalkenyl" refers to an alkenyl group substituted with one, two, three, four, five, six or more halogen groups as defined above, such as 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless otherwise specified in the specification, the haloalkenyl group may be optionally substituted.

[0247] As defined above, "haloalkynyl" refers to an alkynyl group substituted with one, two, three, four, five, six or more halogen groups as defined above, such as 1-fluoropropynyl, 1-fluorobutynyl, etc. Unless otherwise specified in the specification, the haloalkynyl group may be optionally substituted.

[0248] "Heterocyclic group," "heterocycle," or "heterocyclic" refers to a stable 3- to 20-membered non-aromatic ring group consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclic groups include heteroaryl groups as defined below. Unless otherwise specified in the specification, a heterocyclic group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to: dioxolane, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Unless otherwise specifically stated in the specification, the heterocyclic group may optionally be substituted.

[0249] The term "hydroxyalkyl" or "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxyl (-OH) groups. In some embodiments, the hydroxyalkyl group is substituted with one, two, three, four, five, or more -OH groups. The hydroxyalkyl group may optionally be substituted with one or more additional substituents as described herein.

[0250] The term "hydrocarbon group" refers to a monovalent hydrocarbon group, whether aliphatic, partially or fully unsaturated, acyclic, cyclic, or aromatic, or any combination thereof. In some embodiments, the hydrocarbon group has 1 to 40 or more, 1 to 30 or more, 1 to 20 or more, or 1 to 10 or more carbon atoms. The term "hydrocarbon group" refers to a divalent hydrocarbon group. The hydrocarbon group or hydrocarbon group may optionally be substituted by one or more substituents as described herein.

[0251] The term "heteroalkyl group" refers to a hydrocarbon group in which one or more carbon atoms are independently substituted by heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heteroalkyl group has 1 to 40 or more, 1 to 30 or more, 1 to 20 or more, or 1 to 10 or more carbon atoms and 1 to 10 or more, or 1 to 5 or more heteroatoms. The term "heteroalkylene group" refers to a divalent hydrocarbon group. Examples of heteroalkyl groups and heteroalkylene groups include, but are not limited to, ethylene glycol and polyethylene glycol moieties (such as (-CH2CH2O-)). n H (monovalent heteroalkyl group) and (-CH2CH2O-) n (divalent heteroalkylene groups), where n is an integer from 1 to 12 or greater) and propylene glycol and polypropylene glycol moieties (such as, (-CH2CH2CH2O-). n H and (-CH2CH(CH3)O-) n H (monovalent heteroalkyl group) and (-CH2CH2CH2O-) n and (-CH2CH(CH3)O) n (divalent heteroalkylene group), where n is an integer from 1 to 12 or greater. The heteroalkylene group or heteroalkylene group may optionally be substituted by one or more substituents as described herein.

[0252] "N-Heterocyclic group" means a heterocyclic group as defined above containing at least one nitrogen atom, wherein the attachment point of the heterocyclic group to the rest of the molecule is through the nitrogen atom in the heterocyclic group. Unless otherwise specified in the specification, the N-heterocyclic group may optionally be substituted.

[0253] "Heterocyclic alkyl" or "-alkyl heterocyclic" refers to the formula -R b -R e The group, wherein R b It is an alkylene, alkenyl, or ynylene chain as defined above, and R e It is a heterocyclic group as defined above, and if the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group may be attached to an alkyl, alkenyl, or alkynyl group at the nitrogen atom. Unless otherwise specifically stated in the specification, the heterocyclic alkyl group may optionally be substituted.

[0254] "Heteroaryl" refers to a 5- to 20-membered ring system group comprising a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For the purposes of this application, the heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Examples include, but are not limited to, azepinyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxazolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazolyl, 1,4-benzodioxylalkyl, benzonaphthofuranyl, benzooxazolyl, benzodioxazolyl, benzodioxinyl, benzopyranyl, benzopyrannonyl, benzofuranyl, benzofuranoneyl, benzothiopheneyl (benzophenylthio), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenyl, dibenzofuranyl, dibenzothiopheneyl, furanyl, furanoneyl, Isothiazolyl, imidazolyl, indazole, indoleyl, indazole, isoindoleyl, dihydroindoleyl, isodihydroindoleyl, isoquinolinyl, inazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxozazironeyl, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purineyl, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiopheneyl (i.e., thiophene). Unless otherwise specified in the specification, heteroaryl groups may be optionally substituted.

[0255] "N-Heteroaryl" means a heteroaryl group as defined above that contains at least one nitrogen atom, wherein the attachment point of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. Unless otherwise specified in the specification, the N-heteroaryl group may optionally be substituted.

[0256] "Heteroarylalkyl" or "-alkylheteroaryl" refers to the formula -R b -R f The group, wherein R b It is an alkylene, alkenylene, or ynylene chain as defined above, and R f It is a heteroaryl group as defined above. Unless otherwise specified in the specification, the heteroaryl alkyl group may optionally be substituted.

[0257] "Thioalkyl" refers to a compound with the formula -SR a The group, wherein Ra It is an alkyl, alkenyl, or alkynyl group containing 1 to 12 carbon atoms as defined above. Unless otherwise specified in the specification, thioalkyl groups may optionally be substituted.

[0258] As used herein, the term “substituted” means any of the above groups (i.e., alkyl, alkylene, alkenyl, alynyl, alynyl, alkyne, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloynyl, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl), wherein, using the list provided herein, at least one hydrogen atom is replaced by a non-hydrogen atom bond. If no list of substituents is included, substituents may be, but are not limited to: halogen atoms (such as F, Cl, Br, and I); oxygen atoms in groups (such as hydroxyl, alkoxy, and ester groups); sulfur atoms in groups (such as thiols, thioalkyls, sulfones, sulfonyls, and sulfoxides); nitrogen atoms in groups (such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines); silicon atoms in groups (such as trialkylsilyls, dialkylarylsilyls, alkyldiarylsilyls, and triarylsilyls); and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double or triple bond) of a heteroatom (such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles). For example, "substituted" includes any of the above groups, wherein one or more hydrogen atoms are replaced by: halide, cyano, nitro, hydroxyl, mercapto, amino, -OR g -SR g -NR h R i Alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(=O)R g -C(=NR) j )R g -S(=O)R g -S(=O)2R g -S(=O)2OR k -C(=O)OR k -OC(=O)R g -C(=O)NR h R i -NR g C(=O)R g -S(=O)2NR h Ri -NR g S(=O)2R g -OC(=O)OR g -OC(=O)NR h R i -NR g C(=O)OR g -NR g C(=O)NR h R i -NR g C(=NR j )NR h R i -P(=O)(R g )2、-P(=O)(OR k )R g -P(=O)(OR) k )2、-OP(=O)(R g )2、-OP(=O)(OR k )R g and -OP(=O)(OR) k )2, where: each occurrence of R g Independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, cycloalkyl, heterocyclic, aryl, or heteroaryl; each occurrence of R h and R i Independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, cycloalkyl, heterocyclic, aryl or heteroaryl, or R h and R i Together with the nitrogen atoms they are attached to, they form heterocycles or heteroaryl rings; each occurrence of R j Independently, it is hydrogen, -OR g Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, cycloalkyl, heterocyclic, aryl or heteroaryl; and R k Each occurrence of is independently hydrogen, W, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcycloalkyl, alkylheterocyclic, alkylaryl, alkylheteroaryl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein each occurrence of W is independently H. + Li + Na + K + Cs + Mg +2 Ca +2 or- + N(Rg )2R h R i .

[0259] As used in this article, when BH(OR) 7 2. BH(R) b When the BH2 or BH3 group forms a single bond with the P(=O) group (for example, BH(OR)), 7 2. BH(R) b BH2 or BH3 has a negative charge. 7 )2 - BH(R) b )2 - and BH3 - The "-" in the figure indicates that the B group has a single negative charge.

[0260] As used here, the symbol (Hereinafter referred to as a "point bond") indicates a bond that serves as a point of attachment between two chemical entities, one of which is described as being attached to a point bond, while the other is not described as being attached to a point bond. For example, This indicates that chemical entities "XY" are bonded to another chemical entity via attachment site bonds. Furthermore, specific attachment sites with undescribed chemical entities can be specified through inference. For example, the compound CH3-R 3 , where R 3 Is it H or Inferring when R 3 When it is "XY", the auxiliary contact key is the same as R. 3 The same bond that is bonded to CH3.

[0261] "Fused" means any ring structure fused with an existing ring structure in the compounds of this application as described herein. When the fused ring is a heterocyclic or heteroaryl ring, any carbon atom that becomes part of the fused heterocyclic or heteroaryl ring in the existing ring structure may be replaced by a nitrogen atom.

[0262] As used herein, when a sulfur atom replaces a non-bridging oxygen in the phosphate backbone of an oligodeoxynucleotide, the terms "phosphothiophosphate bond," "phosphothiophosphate bond," or "phosphothiophosphate-linked nucleotide" appear. As used herein, an asterisk (*) between two nucleotides indicates that the two nucleotides are linked by a phosphothiophosphate bond. For example, the sequence 5'-T*C*G*A-3' indicates that all nucleotides are linked by a phosphothiophosphate bond, while the sequence 5'-TC*GA-3' indicates that C and G are linked by a phosphothiophosphate bond. As used herein, a phosphothiophosphate bond "*" indicates its two stereoisomers.

[0263] As used herein, the term "immunomodulatory sequence" or "IRS" refers to a nucleic acid sequence having immunomodulatory activity as measured in vitro, in vivo, and / or ex vivo.

[0264] As used herein, the term "immunomodulatory compound" or "IRC" refers to a molecule having immunomodulatory activity and comprising a nucleic acid moiety having an immunomodulatory sequence (IRS). The IRCs provided herein comprise one or more nucleic acid moieties and one or more non-nucleotide spacer moieties. For example, an IRC may comprise a non-nucleotide spacer group bound to a nucleic acid moiety. An IRC may comprise more than one IRS or at least one IRS. An IRC may comprise modified and / or unmodified IRSs. Modified IRSs may comprise modifications to sugars, bases, or the backbone. Thus, the term IRC encompasses a compound incorporating one or more nucleic acid moieties covalently bonded to a non-nucleotide spacer moiety, wherein at least one of these nucleic acid moieties comprises an IRS. In some embodiments, the non-nucleotide spacer group is covalently bonded to the nucleic acid moiety via a 3'-O or 5'-O terminal nucleotide. In IRCs comprising more than one spacer moiety, these spacer groups may be the same or different.

[0265] As used herein, the term "nucleic acid moiety" refers to a nucleotide monomer (i.e., a mononucleotide) or a polymer (i.e., comprising at least two consecutive nucleotides). As used herein, a nucleotide comprises (1) a purine or pyrimidine base linked to a sugar ester connected to a phosphate group or (2) an analog wherein the base and / or sugar and / or phosphate ester is replaced by an analog as described herein. In an IRC comprising more than one nucleic acid moiety moiety, these nucleic acid moieties may be identical or different. Thus, in various variations, an IRC incorporated into an immunomodulatory composition comprises (a) nucleic acid moieties having the same sequence, (b) more than one repeating sequence, or (c) two or more different nucleic acid moieties. Additionally, a single nucleic acid moiety moiety may comprise more than one IRS, which may be adjacent, overlapping, or separated by additional nucleotide bases within the nucleic acid moiety moiety.

[0266] The nucleic acid moiety used in the IRC incorporated into the immunomodulatory composition may contain any IRS sequence disclosed herein, and may additionally be a sequence of 6 base pairs or fewer. In IRCs containing multiple nucleic acid moieties, these moieties may be of the same or different lengths. In some variants of the IRC containing more than one nucleic acid moieties, only one of these moieties needs to contain an IRS. In some variants, the IRS is a modified IRS. In some variants, the IRS is an unmodified IRS.

[0267] As used herein, the term "immunomodulatory polynucleotide" or "IRP" refers to a polynucleotide containing at least one IRS that has immunomodulatory activity as measured in vitro, in vivo, and / or ex vivo.

[0268] The term "conjugate" refers to a compound in which two or more identical or different therapeutic agents are linked together by one or more identical or different linker sites. The therapeutic agents can be IRPs and / or IRCs. The linker sites of such conjugates can be metabolically or chemically stable or unstable.

[0269] As used herein, the symbol 3' typically refers to a region or position within a polynucleotide or oligonucleotide that is 3' (downstream) from another region or position within the same polynucleotide or oligonucleotide. The term "3' end" refers to the 3' end of a polynucleotide.

[0270] As used herein, the symbol 5' generally refers to a region or position within a polynucleotide or oligonucleotide that is 5' (upstream) of another region or position within the same polynucleotide or oligonucleotide. The term "5' end" refers to the 5' end of a polynucleotide.

[0271] As used herein, the terms “oligonucleotide” or “polynucleotide” refer to a nucleic acid sequence comprising two or more nucleotides, generally consisting of at least about 6 nucleotides to about 100,000 nucleotides, or about 6 to about 2,000 nucleotides, or about 6 to about 300 nucleotides, or about 20 to about 300 nucleotides, or about 20 to about 100 nucleotides. The terms “oligonucleotide” or “oligomer” also refer to nucleic acid sequences comprising more than 100 to about 2,000 nucleotides, or more than 100 to about 1,000 nucleotides, or more than 100 to about 500 nucleotides. The term “oligonucleotide” also generally refers to any polynucleotide or polydeoxynucleotide, which may be unmodified RNA or DNA or modified RNA or DNA.

[0272] "Oligonucleotides" include, but are not limited to, single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA), modified polynucleotides and polynucleotides, or combinations thereof. Polynucleotides can be linear or circular in configuration, or can contain both linear and circular segments. Polynucleotides are polymers of nucleosides typically linked by phosphodiester bonds, although alternative bonds, such as thiophosphates, can also be used in polynucleotides. Nucleosides consist of purine (adenine (A) or guanine (G) or derivatives thereof) or pyrimidine (thymine (T), cytosine (C) or uracil (U) or derivatives thereof) bases bonded to sugars. The four nucleoside units (or bases) in DNA are called deoxyadenosine, deoxyguanosine, deoxythymidine, and deoxycytidine. Nucleotides are phosphate esters of nucleosides.

[0273] As used herein, the term “oligodeoxynucleotide” refers to an oligonucleotide whose nucleotides contain deoxyribose.

[0274] As used herein, the term 5'-O refers to the oxygen atom attached to the 5' carbon of a deoxyribonucleotide or ribonucleotide. As used herein, the term 3'-O refers to the oxygen atom attached to the 3' carbon of a deoxyribonucleotide or ribonucleotide. For example, as shown below, 5'-O of a deoxyribonucleotide is the oxygen atom attached to the 5' carbon of the deoxyribonucleotide, and 3'-O is the oxygen atom attached to the 3' carbon of the deoxyribonucleotide:

[0275]

[0276] As used herein, "immunostimulatory nucleic acid" refers to a nucleic acid capable of inducing and / or enhancing an immune response. As used herein, immunostimulatory nucleic acid comprises ribonucleic acid, particularly deoxyribonucleic acid. Preferably, the immunostimulatory nucleic acid contains at least one CpG motif, such as a CG dinucleotide, wherein the C is unmethylated. The CG dinucleotide may be part of a palindromic sequence or may be encompassed within a non-palindromic sequence. As used herein, the term "immunostimulatory nucleic acid" should also refer to nucleic acids containing modified bases, such as 4-bromocytosine.

[0277] As used herein, the term "CpG oligonucleotide" (or CpG ODN) refers to a short, single-stranded synthetic DNA molecule containing cytosine phosphate deoxynucleotide ("C") followed by guanine phosphate deoxynucleotide ("G"). "p" refers to the phosphodiester chain between consecutive nucleotides, although some ODNs have a modified phosphate thioester (PS) backbone. In some embodiments, one or more nucleotide bonds in a CpG ODN are modified bonds. In some embodiments, one or more nucleotide bonds in a CpG ODN are phosphate thioester (PS) bonds. In some embodiments, all nucleotide bonds in a CpG ODN are phosphate thioester (PS) bonds. A phosphate thioester backbone means that all nucleotide bonds in a CpG ODN are phosphate thioester (PS) bonds. Based on the structural characteristics and activity of human peripheral blood mononuclear cells (PBMCs), particularly B cells and plasmacytoid dendritic cells (pDCs), three major classes of stimulatory CpG ODNs have been identified. These three classes are class A (type D), class B (type K), and class C. Synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs (CpG-ODNs) act as potent immunostimulants. The CpGs described herein can stimulate / activate (e.g., promote mitosis in vertebrate bone marrow-derived cells) or induce and / or increase their cytokine expression. For example, CpGs can be used to activate B cells, NK cells, and antigen-presenting cells, such as monocytes, dendritic cells, and macrophages, as well as T cells. CpGs may include nucleotide modifications / analogs (such as phosphate thioester modifications) and can be double-stranded or single-stranded. Generally, double-stranded molecules are more stable in vivo, while single-stranded molecules have increased immunomodulatory activity.

[0278] As used herein, the term “functional group” or any of its synonyms means including both its protected and unprotected forms.

[0279] As used herein, the term "electron-modifying group" is intended to include any atom or functional group that modifies the electron density of the portion to which it is attached. Electron-modifying groups include electron-donating groups that contribute electron density (e.g., amines, hydroxyl groups, alkoxy groups, alkyl groups) and electron-withdrawing groups that withdraw electron density (e.g., nitro groups, cyano groups, trifluoromethyl groups).

[0280] The terms “spacer group,” “spacer group moiety,” “non-nucleotide spacer group,” “non-nucleotide spacer group moiety,” “intercalary bond,” and “connector” are used herein to refer to a bond or set of atoms optionally used to connect interconnected portions, such as the terminal portion of a macromolecular fragment (e.g., the 5'-terminus of a CpG oligodeoxynucleotide) and a second segment (e.g., a cyclic dinucleotide and a protein or an electrophile or nucleophile of a protein). The spacer group moiety may be hydrolyzed stable or may include physiologically hydrolyzable or enzymatically degradable indirect portions. Unless the context otherwise clearly indicates, the spacer group moiety is optionally present between any two elements of a compound (e.g., the provided conjugate comprising a CpG moiety and a cyclic dinucleotide moiety, which are directly or indirectly connected by the spacer group moiety).

[0281] Suitable spacer groups in this application include spacer groups containing a linker, which may include one or more of a carbon atom, nitrogen atom, sulfur atom, phosphorus atom, oxygen atom, and combinations thereof. Suitable spacer group portions may include amides, secondary amines, carbamates, thioethers, phosphate esters, thiophosphate esters, disulfide groups, and / or click chemical product groups. Non-limiting examples of specific spacer group portions include those selected from the group consisting of: -O-, -S-, -SS-, -C(O)-, -C(O)-NH-, -NH-C(O)-NH-, -OC(O)-NH-, -OP(O)(OH)-, -OP(S)(OH)-, -C(S)-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-, -O-CH2-, -CH2-O-, -O-CH2-CH2- , -CH2-O-CH2-, -CH2-CH2-O-, -O-CH2-CH2-CH2-, -CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-CH2-O-, -O-CH2-CH2-CH2-CH2 -, -CH2-O-CH2-CH2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-CH2-CH2-O-CH2-, -CH2-CH2-CH2-CH2-O-, -C(O)-NH-CH2-, -C(O)-NH-CH2 -CH2-, -CH2-C(O)-NH-CH2-, -CH2-CH2-C(O)-NH-, -C(O)-NH-CH2-CH2-CH2-, -CH2-C(O)-NH-CH2-CH2-, -CH2-CH2-C(O)-NH-CH2- , -CH2-CH2-CH2-C(O)-NH-, -C(O)-NH-CH2-CH2-CH2-CH2-, -CH2-C(O)-NH-CH2-CH2-CH2-, -CH2-CH2-C(O)-NH-CH2-CH2-, -CH2-CH 2-CH2-C(O)-NH-CH2-, -CH2-CH2-CH2-C(O)-NH-CH2-CH2-, -CH2-CH2-CH2-CH2-C(O)-NH-, -C(O)-O-CH2-, -CH2-C(O)-O-CH2-, -C H2-CH2-C(O)-O-CH2-, -C(O)-O-CH2-CH2-, -NH-C(O)-CH2-, -CH2-NH-C(O)-CH2-, -CH2-CH2-NH-C(O)-CH2-, -NH-C(O)-CH2-CH2-,-CH2-NH-C(O)-CH2-CH2-, -CH2-CH2-NH-C(O)-CH2-CH2-, -C(O)-NH-CH2-, -C(O)-NH-CH2-CH2-, -OC(O)-NH-CH2-, -OC(O)-NH-CH2- CH2-, -NH-CH2-, -NH-CH2-CH2-, -CH2-NH-CH2-, -CH2-CH2-NH-CH2-, -C(O)-CH2-, -C(O)-CH2-CH2-, -CH2-C(O)-CH2-, -CH2-CH2-C(O )-CH2-, -CH2-CH2-C(O)-CH2-CH2-, -CH2-CH2-C(O)-, -CH2-CH2-CH2-C(O)-NH-CH2-CH2-NH-, -CH2-CH2-CH2-C(O)-NH-CH2-CH2-NH- C(O)-, -CH2-CH2-CH2-C(O)-NH-CH2-CH2-NH-C(O)-CH2-, -CH2-CH2-CH2-C(O)-NH-CH2-CH2-NH-C(O)-CH2-CH2-, -OC(O)-NH-[CH2], l -(OCH2CH2) m -, divalent cycloalkyl, divalent aryl, -O-, -S-, divalent amino acid residues and -N(R 3 - or a combination of two or more of the aforementioned, wherein R 3 It is an organic group consisting of H or selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl, (1) being 0 to 6, and (m) being 0 to 20. Other specific spacer groups have the following structure: C(O)-NH-(CH2) 1-6 -NH-C(O)-、-NH-C(O)-NH-(CH2) 1-6 -NH-C(O)- and -OC(O)-NH-(CH2) 1-6 -NH-C(O)-, where the subscript value after each methylene group indicates the number of methylene groups contained in the structure, for example, (CH2). 1-6 The structure can contain 1, 2, 3, 4, 5 or 6 methylene groups.

[0282] The term "organic group" as used in this article should include alkyl, substituted alkyl, aryl, and substituted aryl groups.

[0283] "Physiologically cleavable," "hydrolyzable," or "degradable" bonds are those that react with water (i.e., are hydrolyzed) under physiological conditions. The tendency of a bond to hydrolyze in water will depend not only on the general type of inter-atom bond connecting the two central atoms but also on the substituents attached to those central atoms. Suitable hydrolytically unstable or weakly linked bonds include, but are not limited to, urethanes, carboxylates, phosphates, acid anhydrides, acetals, ketals, acyloxyalkyl ethers, imines, orthoesters, peptides, and oligonucleotides.

[0284] A "releasable connector" is a connector that links different therapeutic agents in a conjugate. The therapeutic agent is released through hydrolysis, enzymatic processes, catalytic processes, or other means, resulting in an unbound portion. In some embodiments, the releasable connector releases the therapeutic agent through the aforementioned processes occurring in vivo.

[0285] "Optional" or "optionally" means that the situation described below may or may not occur, such that the description includes both the scenario in which the situation occurs and the scenario in which the situation does not occur.

[0286] This application includes all pharmaceutically acceptable isotopically labeled compounds of this application, wherein one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from those commonly found in nature. Examples of isotopes suitable for inclusion in compounds of this application include hydrogen (such as...). 2 H and 3 H), carbon (such as, 11 C 13 C and 14 C), chlorine (such as, 36 Cl), fluorine (such as, 18 F), iodine (such as, 123 I and 125 I) Nitrogen (such as, 13 N and 15 N), oxygen (such as, 15 O、 17 O and 18 O), phosphorus (such as, 32 P) and sulfur (such as, 35 Isotopes of S).

[0287] Certain isotope-labeled compounds of this application (e.g., those doped with radioactive isotopes) are useful in studies of drug and / or substrate tissue distribution. Radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) It is particularly suitable for this purpose due to its ease of incorporation and easy detection.

[0288] Use heavier isotopes (e.g., deuterium, i.e., 2H) substitution can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and is therefore preferred in some cases.

[0289] Using positron emission to emit isotopes (such as, 11 C 18 F, 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0290] The isotope-labeled compounds of this application can generally be prepared using conventional techniques known to those skilled in the art.

[0291] The phrase “enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, regioisomer, mixture of two or more regioisomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof” has the same meaning as the phrase “(i) enantiomer, mixture of enantiomers, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, regioisomer”. (i) a mixture of two or more regioisomers or isotopic variants; (ii) a pharmaceutically acceptable salt, solvate, hydrate or prodrug of the compound mentioned herein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate or prodrug of an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, a regioisomer, a mixture of two or more regioisomers or an isotopic variant of the compound cited herein, having the same meaning.

[0292] In some embodiments, this application provides STING agonists selected from the group consisting of:

[0293] as well as

[0294] Or a mixture of its enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug.

[0295] In some embodiments, methods for synthesizing optically pure STING agonists are provided herein, as shown in Scheme 1.

[0296] In some embodiments, this application provides large-scale quantities of optically pure STING agonists. In some embodiments, the STING agonist is the STING agonist disclosed in WO 2019 / 043634, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0297] In one respect, this application provides a TLR9 agonist of formula (I):

[0298]

[0299] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof;

[0300] in:

[0301] X 1 and X 2 Each is an independent spacer group moiety; wherein, X 1 Linked to the 3'-terminal nucleotide of CpG, and X 2 The 5'-terminal nucleotide linked to the CpG moiety;

[0302] a1 is an integer that is either 0 or 1;

[0303] a2 is an integer that is either 0 or 1;

[0304] The condition is that a1 + a2 is 1 or 2; and

[0305] CpG is the oligodeoxynucleotide moiety of a TLR9 agonist; wherein one or more atoms in CpG are independently coupled with X. 1 and / or X 2 The covalent bond substitution.

[0306] In some embodiments of the TLR9 agonist of formula (I), CpG is an oligodeoxynucleotide moiety comprising a cytosine deoxynucleotide (“C”) followed by a guanine deoxynucleotide (“G”). In some embodiments, at least one phosphate thioester bond exists between the two nucleotides in CpG.

[0307] In some embodiments of the TLR9 agonist of formula (I), CpG is a TLR9 agonist ODN (oligodeoxynucleotide). In some embodiments, the ODN is a short, synthetic, single-stranded DNA molecule containing an unmethylated CpG motif.

[0308] In some implementations, CpG includes the following formula:

[0309] 5'X1X2CGX3X43'

[0310] Where X1, X2, X3, and X4 are any nucleotides, and

[0311] CpG is attached to a spacer group at the 5'-O and / or 3'-O position of the terminal nucleotide.

[0312] In some implementations, CpG includes the following formula:

[0313] 5'N1X1CGX2N2 3'

[0314] In this sequence, at least one nucleotide isolates a continuous CpG; X1 is adenine, guanine, or thymine; X2 is cytosine or thymine; N is any nucleotide, and N1+N2 is approximately 0 to 26 bases, provided that N1 and N2 do not contain a CCGG tetramer or more than one CCG or CGG trimer; the nucleic acid sequence length is approximately 8 to 30 bases; and

[0315] CpG is attached to a spacer group at the 5'-O and / or 3'-O position of the terminal nucleotide.

[0316] In some implementations, CpG comprises the following formula:

[0317] a)5'-N x (TCG(N q )) y N w (X1X2CGX2'X1'(CG) p ) z

[0318] Where N is a nucleotide, x = 0, y = 1, w = 0, p = 0 or 1, q = 0, 1 or 2, and z = 1-20, X1 and X1' are self-complementary nucleotides, X2 and X2' are self-complementary nucleotides, and (TCG(N) q )) y The 5'T of the sequence is located at the 5' end of the polynucleotide; and

[0319] b) A palindromic sequence of at least 8 bases, wherein the palindromic sequence contains (X1X2CGX2'X1'(CG)). p ) z The first part of the sequence (X1X2CGX2'X1'), wherein the polynucleotide length is at least 15 bases; and

[0320] CpG is attached to a spacer group at the 5'-O and / or 3'-O position of the terminal nucleotide.

[0321] In some implementations, CpG comprises at least two oligonucleotides, internucleotide bonds, or non-nucleotide linker-functionalized nucleobases or sugars linked to their 3' ends;

[0322] At least one of the oligonucleotides is an immunostimulatory oligonucleotide having an accessible 5' end and comprising an immunostimulatory dinucleotide selected from the group consisting of: CG, C # G, CG # and C # G # ;

[0323] Wherein, C is cytidine or 2'-deoxycytidine, C # It is 2'-deoxythymidine, cytarabine, 2'-deoxy-2'-substituted cytarabine, 2'-O-substituted cytarabine, 2'-deoxy-5-hydroxycytidine, 2'-deoxy-N4-alkyl-cytosine nucleoside, 2'-deoxy-4-thiouridine, or other non-natural pyrimidine nucleoside. G is guanosine or 2'-deoxyguanosine. # It is 2'-deoxy-7-denitroguanosine, 2'-deoxy-6-thioguanosine, vidarabine, 2'-deoxy-2'-substituted vidarabine, 2'-O-substituted vidarabine or other non-natural purine nucleosides;

[0324] p is a nucleoside internucleotide bond selected from the group consisting of: phosphate diesters, thiophosphates, and dithiophosphates; and

[0325] CpG is attached to a spacer group at one or both 5'-O positions of the terminal nucleotide and / or internucleotide bond.

[0326] In some embodiments of the TLR9 agonist of formula (I), CpG is a phosphate-thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*T*C*G*A*A*T–3' (SD-101; SEQ ID NO: 1), with a spacer group at the 5'-O and / or 3'-O of the terminal nucleotide; a phosphate-thioester-linked 5'-T*C*G1*A*A*C*G1*T*T*C*G1*-X-*G1*C*T*T*G1*C*A*A*G1*C*T*-5', where X is a glycerol linker and G1 is 2'-deoxy-7-deazonoguanosine (IMO-2125; SEQ ID NO: 1). NO: 2), with a spacer group attached to one or both 5'-O positions and / or glycerol positions of the terminal nucleotide; 5'-GGGGGGGGGGGACGATCGTCGGGGGGGGGG-3' (CMP-001; SEQ ID NO: 3), with a spacer group attached to the 5'-O and / or 3'-O positions of the terminal nucleotide; or 5'-T*C*G*T*C*G*T*T*T*T*T*T*T*T*T*T*T*T*T*T*T*T*T*T*T*T*T*T*T*T*T-3' (PF-3512676; SEQ ID NO: 4), with a spacer group attached to the 5'-O and / or 3'-O positions of the terminal nucleotide.

[0327] Table A.

[0328]

[0329]

[0330] In some embodiments of the TLR9 agonist of formula (I), X 1 and X 2 Each independently is: C3-C 12 alkyl;

[0331] or

[0332] Where * indicates an attachment point connected to CpG and ** indicates an attachment point connected to –NH2.

[0333] In some embodiments of the TLR9 agonist of formula (I), X 1 and X 2 Each independently is: **-C3-C 12 Alkylene-L 1 -*;

[0334]

[0335]

[0336] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; * indicates a 3'-O or 5'-O attachment site of the terminal nucleotide linked to CpG, and ** indicates an attachment site linked to –NH2.

[0337] In some embodiments of the TLR9 agonist of formula (I), X 2 It is **-C3-C 12 Alkylene-L 1 -*; where L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates an attachment site at the 5'-O of the terminal nucleotide of the CpG; and ** indicates an attachment site at the amino group; and X 1 It is selected from spacer group B3 as described herein, wherein L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates an attachment site at the 3'-O of the terminal nucleotide of the CpG; ** indicates an attachment site to an amino group. In some embodiments, the CpG is a phosphate-thioester-linked oligodeoxynucleotide having the sequence 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*T*C*G*A*A*T–3' (SD-101), with spacer groups attached at the 5'-O and / or 3'-O of the terminal nucleotide.

[0338] In some embodiments of the TLR9 agonist of formula (I), the TLR9 agonist is:

[0339] or

[0340] CpG is a phosphate thioester-linked oligodeoxynucleotide with the sequence 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101), with a spacer group attached to the 5'-O and / or 3'-O of the terminal nucleotide.

[0341] In some embodiments, this application provides a releasable connector having formula (II):

[0342]

[0343] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0344] in:

[0345] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0346] X is the spacer group portion;

[0347] R 1 and R 2 Independently, it is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl, or R 1 and R 2 Together with the atoms they are attached to, they form 3-8 membered rings that can contain one or two heteroatoms;

[0348] Y 1 It is O, NH or S;

[0349] Y 2 It is O, NH or S;

[0350] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0351] FG 3 It is selected from –OH, SH, LG 1 Functional groups of (leaving group 1), including but not limited to -Cl, -Br, -I, Among them, Y 3 Is it O or S; Y 4 It is O or S; and LG 2 It is a leaving group, including but not limited to In some implementations, FG 3 It is selected from –OH, -Cl, -Br, -I, as well as . group.

[0352] In some embodiments of the releasable connector of formula (II), the releasable connector has a structure according to formula (II-A):

[0353]

[0354] in:

[0355] X is:

[0356]

[0357]

[0358]

[0359]

[0360] Wherein, R is methyl or

[0361] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates a connection to FG. 1 The attachment point, ** indicates an attachment point connected to a carbonyl or thiocarbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. 1 Either carbonyl or thiocarbonyl;

[0362] R 1 and R 2 Each is independently hydrogen or C1-C6 alkyl;

[0363] Or R 1 and R 2 Together with the atoms they are attached to, they can form 3-8 membered rings that may optionally contain one or more of O, NMe, NAc, NSO2Me, S or SO2;

[0364] a is an integer from 0 to 4;

[0365] Each R e It is independently selected from nitro, cyano, halogen, amide, substituted amide, sulfone, substituted sulfone, sulfonamide, substituted sulfonamide, alkoxy, substituted alkoxy, alkyl or cycloalkyl, substituted alkyl or cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or heteroaryl and substituted aryl or heteroaryl.

[0366] Y 1 It is O, NH or S;

[0367] Y 2 It is O, NH or S;

[0368] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0369] FG 3 The functional groups selected are those that can be composed of the following groups: –OH, -Cl, -Br, -I, as well as

[0370] In some implementations, R 1 and R2 Together with the atoms they are attached to, they can be linked together to form 3-6 membered rings that may optionally contain one or more O, NMe, NAc, NSO2Me, S or SO2.

[0371] In some embodiments of the releasable connector of formula (II), the releasable connector has a structure according to formula (II-B):

[0372]

[0373] in:

[0374] X is selected from spacer groups C1 to C1 as described herein. 17 ;

[0375] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates a connection to the selected FG. l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl;

[0376] R 1 It is hydrogen, Me, or Et;

[0377] R 2 It is hydrogen, Me, or Et;

[0378] a is an integer from 0 to 2;

[0379] R e Each is independently selected from the following groups: nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me, and -OCF3.

[0380] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0381] FG 3 It is a functional group selected from the following groups:

[0382] -OH, -Cl, -Br, -I as well as

[0383] In some embodiments, the releasable connector has a structure according to formula (II-C):

[0384]

[0385] in:

[0386] As described herein, X is selected from spacer groups C1, C3, C8, C10, C13, C18, or C19;

[0387]

[0388] Where * indicates connection to the selected FG l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl;

[0389] FG 1 It is an azide, dibenzocyclooctylene (DBCO), or alkynyl; and

[0390] FG 3 It is a functional group selected from the following groups:

[0391] -OH, -Cl, -Br, -I as well as

[0392] In some embodiments of compounds of formula (II-C), X is selected from spacer groups C3, C10, C13, C18, or C19 as described herein.

[0393] In some embodiments, the releasable connector having formula (II) is:

[0394] (i)

[0395] (ii)

[0396] (iii)

[0397] (iv)

[0398] (v) or

[0399] (vi)

[0400] Among them, each FG 3 Independently, -OH, -Cl, -I, or

[0401] In some embodiments, the releasable connector of formula (II) has the following structure:

[0402]

[0403]

[0404]

[0405] or

[0406] In some embodiments, this application provides a connector having the following structure:

[0407] i)

[0408] ii)

[0409] iii) or

[0410] iv)

[0411] v)

[0412] vi) or

[0413] vii) R is methyl or

[0414] Among them, FG 3 Independently, they are –OH, -Cl, -I,

[0415] In some implementations, the connector has the following structure:

[0416]

[0417] or

[0418]

[0419] In some embodiments, this application provides a compound comprising a releasable connector portion covalently attached to a therapeutic agent, wherein the compound has a structure according to formula (III):

[0420] [Connector] b -A;

[0421] (III)

[0422] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0423] in,

[0424] A is a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent;

[0425] b is an integer of 1 or 2; where, when b = 2, the two groups (in parentheses, for example, the linker) are directly bonded to A; and

[0426] Each joint has an independent structure according to formula (III-L):

[0427]

[0428]

[0429] in:

[0430] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0431] X is the spacer group portion;

[0432] R 1 and R 2 Each is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl; or

[0433] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0434] Y 1 Is it O or S?

[0435] Y 2 It is O, NH or S;

[0436] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0437] This indicates a bond attached to A; wherein one or more atoms in each therapeutic agent or compound that can be broken down into a therapeutic agent are independently replaced by covalent bonds to attach to the connector, or chemical groups to attach the therapeutic agent or compound that can be broken down into a therapeutic agent to the connector.

[0438] In some embodiments, in formula (III-L), R 1 and R 2 Together with the atoms they are attached to, they can be linked together to form 3-8 membered rings, NR, which may optionally contain one or more O atoms. XA (where R) XAIt is an alkyl group, -C(O)-alkyl group, or -S(O). 0-2 -alkyl) or S(O) w (where w is 0, 1, or 2). In some implementations, R 1 and R 2 Together with the atoms they are attached to, they can be linked together to form 3-8 membered rings that may optionally contain one or more O, NMe, NAc, NSO2Me, S or SO2.

[0439] The active portion of a therapeutic agent refers to a specific part of the therapeutic agent responsible for its characteristic activity. For example, and not limited to this particular embodiment, in one implementation, CpG is the active portion of a therapeutic agent TLR9 agonist having formula (I): Compounds that can be broken down into therapeutic agents refer to chemical structures that can be readily converted into therapeutic agents. For example, and not limited to this particular embodiment, in one implementation, in formula (III), if A is RNH2 is a therapeutic agent.

[0440] In some embodiments, the compound of formula (III) is a compound of formula (III-A):

[0441]

[0442] in:

[0443] Each X is independently selected from spacer groups C1 to C17 or C20 to C22 as described herein:

[0444] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates a connection to the selected FG. l The attachment point, ** indicates an attachment point connected to a carbonyl or thiocarbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Either carbonyl or thiocarbonyl;

[0445] R 1 and R 2 Each is independently hydrogen or C1-C6 alkyl; or

[0446] R 1 and R 2 They can connect with the atoms to which they are attached to form 3-6 membered rings that can optionally contain one or more of O, NMe, NAc, NSO2Me, S or SO2;

[0447] a is an integer from 0 to 4;

[0448] b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to A;

[0449] Each R e It is independently selected from nitro, cyano, halogen, amide, substituted amide, sulfone, substituted sulfone, sulfonamide, substituted sulfonamide, alkoxy, substituted alkoxy, alkyl or cycloalkyl, substituted alkyl or cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or heteroaryl and substituted aryl or heteroaryl.

[0450] Y 1 Is it O or S?

[0451] Y 2 It is O, NH or S;

[0452] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0453] A is a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[0454] In some embodiments of the compound of formula (III), the compound is a compound of (III-B):

[0455]

[0456] in:

[0457] Each X is independently selected from spacer groups C1 to C1 as described herein. 17 ;

[0458] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates a connection to the selected FG. l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl;

[0459] R 1 and R 2 Each is independently hydrogen, Me, or Et;

[0460] a is an integer from 0 to 2;

[0461] b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to A;

[0462] R e Each is independently selected from the following groups: nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me, and -OCF3;

[0463] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0464] A is a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[0465] In some embodiments of the compound of formula (III), the compound is a compound of formula (III-C):

[0466]

[0467] in:

[0468] Each X is independently selected from the spacer groups C1, C3, C8, C10, C13, C18, and C19 as described herein:

[0469] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates a connection to the selected FG. l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl;

[0470] b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to A;

[0471] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0472] A is a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[0473] In some embodiments of compounds of formula (III-C), each X is independently selected from spacer groups C3, C10, C13, C18 and C19 as described herein.

[0474] In some embodiments, this application provides compounds comprising a connector portion covalently attached to a therapeutic agent, wherein the compound has a structure according to formula (XXII):

[0475]

[0476] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0477] in:

[0478] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0479] X is the spacer group portion;

[0480] R 1 and R 2 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or

[0481] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0482] FG 1 It is a functional group that can undergo chemical reactions through click;

[0483] b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to A; and

[0484] A is a STING agonist; wherein one or more atoms in the STING agonist are independently replaced by covalent bonds to connect to the linker.

[0485] In some embodiments of the compound of formula (III), the therapeutic agent is a TLR9 agonist.

[0486] In some embodiments of the compound of formula (III), the therapeutic agent is a TLR7 / 8 agonist.

[0487] In some embodiments of compounds of formula (III) or (XXII), the therapeutic agent is a STING agonist. Suitable STING agonists include those disclosed in WO 2019 / 043634, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the STING agonist is the agonist disclosed in WO 2019 / 043634, ADU-S100, MK-1454, BMS-986301, GSK3745417, E7766, SB11285, etc.

[0488]

[0489]

[0490] Or its stereoisomers.

[0491] In some embodiments, this application provides compounds of formula (IV):

[0492] [Connector] b-CDN;

[0493] (IV)

[0494] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0495] in,

[0496] CDN is a cyclic dinucleotide that acts as a STING agonist;

[0497] b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to the CDN; and

[0498] Each joint has an independent structure according to formula (IV-L):

[0499]

[0500] in:

[0501] X is the spacer group portion;

[0502] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0503] R 1 and R 2 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or

[0504] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0505] Y 1 Is it O or S?

[0506] Y 2 It is O, NH or S;

[0507] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0508] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[0509] In some embodiments of formula (IV), the linker is covalently bonded to the thiol group (-SH) of the cyclic dinucleotide STING agonist (i.e., the H of the thiol is covalently replaced). In some embodiments of formula (IV), the linker is covalently bonded to the nitrogen of the cyclic dinucleotide STING agonist (by replacing the amino group H with a covalent bond).

[0510] In some embodiments of the (IV-L) type connector, R 1 and R 2 Together with the atoms they are attached to, they can be linked together to form a structure that may optionally contain one or more O, NR atoms. XA 3-8 member rings, (where R XA It is an alkyl group, -C(O)-alkyl group, or -S(O). 0-2 -alkyl) or S(O) w -(where w is 0, 1, or 2). In some embodiments, the R of the connector of formula (IV-L) 1 and R 2 The atoms connected to them can link together to form 3-8 membered rings that may optionally contain one or more O, NMe, NAc, NSO2Me, S or SO2.

[0511] In some embodiments of the compound of formula (IV), the compound is a compound having formula (IV-A):

[0512]

[0513] in:

[0514] Each X is independently selected from spacer groups C1 to C1 as described herein. 17 :

[0515] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates a connection to the selected FG. l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl;

[0516] R 1 and R 2 Each is independently hydrogen, Me, or Et;

[0517] a is an integer from 0 to 2;

[0518] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[0519] R eEach is independently selected from the following groups: nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me, and -OCF3;

[0520] FG 1 It is a functional group that can undergo chemical reactions through click;

[0521] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[0522] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[0523] In some embodiments of formula (IV-A), the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments of formula (IV-A), the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[0524] In some embodiments of the compound of formula (IV), the compound is a compound of formula (IV-B):

[0525]

[0526] in:

[0527] X is selected from the spacer groups C1, C3, C8, C10, C13, C18, and C19 as described herein:

[0528] Where * indicates connection to the selected FG l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl;

[0529] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[0530] FG 1 It is an azide, dibenzocyclooctylene (DBCO), or alkynyl group;

[0531] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[0532] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[0533] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[0534] In some embodiments of compounds of formula (IV-A) or (IV-B), X is selected from spacer groups C1, C3, C8, and C10 as described herein; and * indicates a connection to FG. 1 The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that the attachment point can connect to FG. 1 Or carbonyl; b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to CDN; FG 1 It is an azide; CDN is a cyclic dinucleotide that acts as a STING agonist; and the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, X is C3 or C10. In some embodiments, n is 1 or 2.

[0535] In some embodiments, this application provides compounds of formula (XXIII):

[0536]

[0537] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0538] in:

[0539] X is the spacer group portion;

[0540] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0541] R 1 and R 2 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or

[0542] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0543] FG 1 It is a functional group that can undergo chemical reactions through click;

[0544] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[0545] The linker is covalently bonded to an atom or a group of the cyclic dinucleotide STING agonist.

[0546] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[0547] In some embodiments of the compound of formula (XXIII), the compound is a compound having formula (XXIII-A):

[0548]

[0549] in:

[0550] X is:

[0551]

[0552]

[0553] Among them, AA 1 -[AA 2 ] m Includes groups selected from the following: Gly, Lys, Val-Ala, Val-Lys, Val-Cit, Ala-Lys, Phe-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Arg, Phe-Leu, Ala-Phe, Met-Lys, Asn-Lys, Ile-Pro, Ile-Val, Asp-Val, His-Val, Met-(D)Lys, Asn-(D)Lys, Val-(D)Asp, NorVal-(D)Asp, Ala-(D)Asp, Me3Lys-Pro, PhenylGly-(D)Lys, Pro-(D)Lys, Met-Cit-Val, Gly-Cit-Val, Phe-Phe-Lys, ( D)Phe-Phe-Lys, (D)Ala-Phe-Lys, Gly-Phe-Lys, Glu-Val-Cit, Ser-Val-Cit, Gly-Phe-Leu-Gly and Ala-Leu-Ala-Leu;

[0554] * indicates connection to FG 1 The attachment site, ** indicates an attachment site connected to the phenyl group, and the absence of a spacer group (* or **) indicates that the attachment site can connect to FG. 1 Or phenyl;

[0555] R 1 and R 2 Each is independently hydrogen, Me, or Et;

[0556] a is an integer from 0 to 2;

[0557] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[0558] R e Each is independently selected from the following groups: nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me, and -OCF3;

[0559] FG 1 It is a functional group that can undergo chemical reactions through click;

[0560] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[0561] The linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist.

[0562] As used in this article, the amino acid “Cit” refers to citrulline, and the amino acid “NorVal” refers to valine.

[0563] In some embodiments of the compound of formula (XXIII), the compound is a compound of formula (XXIII-B):

[0564]

[0565] in:

[0566] X is selected from spacer groups D1, D5, D6, or D9, or D13, as described herein: D13; where R is a methyl group or

[0567] Where * indicates connection to FG 1 The attachment point, ** indicates the attachment point connected to the phenyl group;

[0568] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[0569] FG 1 It is an azide;

[0570] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[0571] The linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist.

[0572] In some embodiments of compounds having the formula (XXIII-B), R is methyl for the spacer group D13 as described herein.

[0573] In some embodiments of compounds having formulas (III), (XXII), (IV), and (XXIII), the cyclic dinucleotide STING agonist is:

[0574]

[0575] Or its stereoisomers;

[0576] Wherein, * represents the thiol group of the cyclic dinucleotide linked to the linker; when only the linker is linked to the STING agonist shown above, the remaining S* is SH.

[0577] In some embodiments of compounds having formulas (III), (IV), (XXII), and (XXIII), the cyclic dinucleotide STING agonist is: Or its stereoisomers, wherein any atom or group of the STING agonist is replaced to form a covalent bond connected to the rest of the compound, including the H of –SH and –NH2.

[0578] In some embodiments of compounds having formulas (III), (XXII), (IV), and (XXIII), b is 1. In some embodiments of compounds having formulas (III), (XXII), (IV), and (XXIII), b is 2.

[0579] In some embodiments of compounds having formulas (III), (XXII), (IV), and (XXIII), when b is 1, the cyclic dinucleotide STING agonist is:

[0580]

[0581]

[0582]

[0583] Or its stereoisomers;

[0584] Wherein, * represents the thiol group of the cyclic dinucleotide linked to the linker;

[0585] In some embodiments of compounds of formulas (III), (IV), (XXII), and (XXIII), FG 1 It is an azide.

[0586] In some embodiments of compounds of formula (IV) and (XXIII), n is 2.

[0587] In some embodiments of compounds having formulas (IV), (IV-A), (IV-B), (XXIII), (XXIII-A), and (XXIII-B), the compounds are selected from:

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599] or

[0600] Or its stereoisomers.

[0601] In some embodiments, this application provides compounds of formula (V):

[0602]

[0603] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0604] in:

[0605] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0606] X 1 and X 2 Each is an independent spacer group portion;

[0607] R 1 and R 2Each is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl; or

[0608] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0609] Y 1 It is O, NH or S;

[0610] Y 2 It is O, NH or S;

[0611] Y 3 It is O, NH or S;

[0612] Y 4 It is O, NH or S;

[0613] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0614] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist, wherein the CpG is formed by the 3'-O or 5'-O of the terminal nucleotide with X. 1 Covalent bonding;

[0615] In some embodiments of the compound of formula (V), R 1 and R 2 They can be linked together with the atoms they are attached to form a structure that may optionally contain one or more O, NR atoms. XA 3-8 member ring (where R XA It is an alkyl group, -C(O)-alkyl group, or -S(O). 0-2 -alkyl) or S(O) w -(where w is 0, 1, or 2). In some embodiments of the compound of formula (V), R 1 and R 2 Together with the atoms they are attached to, they can be linked together to form 3-8 membered rings that may optionally contain one or more O, NMe, NAc, NSO2Me, S or SO2.

[0616] In some embodiments of compounds having formula (V), the compound is a compound of formula (VA):

[0617]

[0618] in:

[0619] X 1 It is **-C3-C 12Alkylene-L 1 -*; and spacer groups B1 to B5 as described herein:

[0620] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; ** indicates an attachment site to an amino group;

[0621] X 2 Selected from the spacer groups C1 to C17 described herein:

[0622] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates a connection to the selected FG. l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl group.

[0623] R 1 and R 2 Each is independently hydrogen, Me, or Et;

[0624] a is an integer from 0 to 2;

[0625] R e Each is independently selected from the following groups: nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me, and -OCF3;

[0626] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0627] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist, wherein the CpG is covalently bonded to X via a 3'-O or 5'-O terminal nucleotide. 1 .

[0628] In some embodiments of the compound of formula (V), the compound is a compound of formula (VB):

[0629]

[0630] in:

[0631] X 1 Selected from **-C3-C 12 Alkylene-L 1 -*; or as described herein, spacer groups B1 to B5:

[0632] Among them, L 1Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; ** indicates an attachment site to an amino group;

[0633] X 2 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[0634] Where * indicates connection to the selected FG l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can be connected to either FGl or the carbonyl group.

[0635] FG 1 It is an azide, dibenzocyclooctylene (DBCO), or alkynyl; and

[0636] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist, wherein the CpG is covalently bonded to X via a 3'-O or 5'-O terminal nucleotide. 1 .

[0637] In some embodiments of compounds having formula (VB), wherein X 1 It is the spacer group B3 as described in this article: wherein, L 1 Independently -OP(O)(OH)- or -OP(S)(OH)-; * indicates an attachment site at the 3'-O of the terminal nucleotide of the CpG; and ** indicates an attachment site to an amino group; X 2 It is the spacer group C19 as described in this article: where * indicates that it is attached to FG 1 The attachment point, and ** indicates the attachment point connected to the carbonyl group; and FG 1 It is dibenzocyclooctyne (DBCO). In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101); wherein, CpG is covalently bonded to X via the 3'-O of the CpG terminal nucleotide. 1 .

[0638] In some embodiments of compounds of formula (V), (VA), or (VB), X 1 It is B3 and o is 1. In some embodiments of compounds of formula (V), (VA), or (VB), X 2 It is C19; q is 1; and r is 2.

[0639] In some embodiments of the compound of formula (V), (VA), or (VB), the compound is

[0640]

[0641] CpG is an oligodeoxynucleotide linked to a phosphate thioester, having the sequence 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101), with a spacer group attached to the 3'-O position of the terminal nucleotide.

[0642] In some embodiments, this application provides compounds of formula (VI):

[0643] CpG-X-FG 1

[0644] (VI)

[0645] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0646] in:

[0647] X is the spacer group portion;

[0648] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0649] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist. CpG is covalently bonded to the X-linked nucleotide via a 3'-O or 5'-O bond at its terminal nucleotide. 1 .

[0650] In some embodiments of the compound of formula (VI), X is -X 1 -NH-CO-X 2 -, where: X 1 It is **-C3-C 12 Alkylene-L 1 -*; or spacer groups B1 to B5 or B6 or B7 as described herein:

[0651]

[0652] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; and ** indicates an attachment site to an amino group;

[0653] X 2 The spacer groups selected are C1, C3, C8, C10, C13, C18, and C19 as described herein: where * indicates attachment to the selected FG. l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl;

[0654] FG 1 It is an azide, dibenzocyclooctylene (DBCO), or alkynyl.

[0655] In some embodiments of compounds having formula (VI), X is -X 1 -NH-CO-X 2 -, where: X 1 Selected from spacer groups B3 and B6 as described herein: wherein, L 1 Independently -OP(O)(OH)- or -OP(S)(OH)-; * indicates an attachment site at the 3'-O of the terminal nucleotide of the CpG; and ** indicates an attachment site to an amino group; or X 1 It is: **-C3-C 12 Alkylene-L1-*, or B7 as described herein, wherein L 1 Independently -OP(O)(OH)- or -OP(S)(OH)-; * indicates an attachment site at the 5'-O of the terminal nucleotide of the CpG; and ** indicates an attachment site to an amino group; X 2 The spacer groups C1, C3, C13, and C18 described herein are selected: where * indicates attachment to the selected FG. l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl; FG 1 It is an azide or dibenzocyclooctylene (DBCO). In some embodiments, CpG is a phosphate-thioester-linked oligodeoxynucleotide having the sequence 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*T*C*G*A*A*T–3' (SD-101), with a spacer group attached at the 3'-O or 5'-O position of the terminal nucleotide.

[0656] In some embodiments of the compound of formula (VI), X 1 It is either B3 or B6. In the implementation, X 1 It is either B3 or B6, and o is 1. In the implementation, X 2It is C3 or C13. In the implementation, X 2 It is C3 or C13; n is 4; and p is 4. In the implementation, X 2 It is C18. In the implementation method, X 2 It is C18; q is 3; and r is 2.

[0657] In some embodiments of the compound of formula (VI), X 1 It is B7, where * indicates the 5'-O attachment site of the terminal nucleotide of CpG; and ** indicates the attachment site of the amino group.

[0658] In some embodiments of the compound of formula (VI), the compound is represented by the following:

[0659] or

[0660] CpG is a phosphate-thioester-linked oligodeoxynucleotide with the sequence 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101), with a spacer group attached to the 3'-O position of the terminal nucleotide; or or

[0661] CpG is an oligodeoxynucleotide linked to a phosphate thioester, having the sequence 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101), with a spacer group linked to the 5'-O position of the terminal nucleotide.

[0662] In some embodiments of this application, compounds having formula (VII) are provided:

[0663]

[0664] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0665] in:

[0666] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0667] X1 X 2 and X 3 Each is an independent spacer group portion;

[0668] R 1 and R 2 Each is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl; or

[0669] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0670] Y 1 It is O, NH or S;

[0671] Y 2 It is O, NH or S;

[0672] Y 3 It is O, NH or S;

[0673] Y 4 It is O, NH or S;

[0674] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0675] CpG is a TLR9 agonist oligodeoxynucleotide, in which either X 1 It is covalently bonded to the 5'-O of the terminal nucleotide of CpG, and X 3 The 3'-O covalent bond of the terminal nucleotide of CpG; or X 1 It is covalently bonded to the 3'-O of the terminal nucleotide of CpG, and X 3 It is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[0676] In some embodiments of the compound of formula (VII), R 1 and R 2 They can be attached together with the atoms they are connected to form a structure that may optionally contain one or more O, NR atoms. XA 3-8 member ring (where R XA It is an alkyl group, -C(O)-alkyl group, or -S(O). 0-2 -alkyl) or S(O) w -(where w is 0, 1 or 2).

[0677] In some embodiments of the compound of formula (VII), the compound is a compound having formula (VII-A):

[0678]

[0679] in:

[0680] X 1 and X 3 Each is independently selected from **-C3-C 12 alkylene-L1-*; and spacer groups B1 to B5 as described herein:

[0681] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; ** indicates an attachment site to an amino group;

[0682] X 2 Selected from the spacer groups C1 to C17 described herein:

[0683] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates a connection to the selected FG. l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl;

[0684] R 1 and R 2 Each is independently hydrogen, Me, or Et;

[0685] a is an integer from 0 to 2;

[0686] Each R e Independently selected from nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me, and -OCF3; and

[0687] FG 1 It is a functional group that can undergo chemical reactions through click, and

[0688] CpG is a TLR9 agonist oligodeoxynucleotide, in which either X 1 It is covalently bonded to the 5'-O of the terminal nucleotide of CpG, and X 3 The 3'-O covalent bond of the terminal nucleotide of CpG; or X 1 It is covalently bonded to the 3'-O of the terminal nucleotide of CpG, and X 3 It is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[0689] In some embodiments of the compound of formula (VII), the compound is a compound having formula (VII-B):

[0690]

[0691] in:

[0692] X 1 and X 3 Each is independently selected from **-C3-C 12 alkylene-L1-*; and spacer groups B1 to B5 as described herein:

[0693] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; ** indicates an attachment site to an amino group;

[0694] X 2 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[0695] Where * indicates connection to the selected FG l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl;

[0696] FG 1 It is an azide, dibenzocyclooctylene (DBCO), or alkynyl; and

[0697] CpG is a TLR9 agonist oligodeoxynucleotide, in which either X 1 It is covalently bonded to the 5'-O of the terminal nucleotide of CpG, and X 3 The 3'-O covalent bond of the terminal nucleotide of CpG; or X 1 It is covalently bonded to the 3'-O of the terminal nucleotide of CpG, and X 3 It is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[0698] In some embodiments of the compound of formula (VII-B), X 3 It is **-C3-C 12 Alkylene-L 1 -*; where L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates the 5'-O attachment site of the terminal nucleotide linked to CpG; and ** indicates the attachment site linked to an amino group; and X 1It is the spacer group B3 as described herein: wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to the 3'-O of the CpG-terminal nucleotide; and ** indicates an attachment site to an amino group; X 2 It is the spacer group C19 as described herein: where * indicates attachment to the selected FG l The attachment point, and ** indicates the attachment point connected to the carbonyl group; FG 1 It is dibenzocyclooctyne (DBCO). In some embodiments, CpG is a thiophosphate-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101); wherein, X 1 Covalently bonded to the 3'-O of the CpG-terminal nucleotide; and X 3 It is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[0699] In some embodiments, this application provides compounds of formula (VIII):

[0700] FG 1 -X 2 -CpG-X 1 -FG 1

[0701] (VIII)

[0702] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0703] in:

[0704] X 1 and X 2 Each is an independent spacer group portion;

[0705] FG 1 It is a functional group capable of undergoing a click chemical reaction; and

[0706] CpG is a TLR9 agonist oligodeoxynucleotide, in which either X 1 It is covalently bonded to the 3'-O of the terminal nucleotide of CpG, and X 2 Covalently bonded to the 5'-O of the terminal nucleotide of CpG; or X 1 It is covalently bonded to the 5'-O of the terminal nucleotide of CpG, and X 2 It is covalently bonded to the 3'-O of the terminal nucleotide of CpG.

[0707] In some embodiments of the compound of formula (VIII), X 1 and X 2 Each is X independently 3 -NH-CO-X 4 - where X 3 Selected from **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B5 as described herein:

[0708] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; ** indicates an attachment site to an amino group;

[0709] X 4 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[0710] Where * indicates connection to the selected FG l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl group.

[0711] In some embodiments of the compound of formula (VIII), X 1 and X 2 Each is X independently 3 -NH-CO-X 4 -, where X 3 It is **-C3-C 12 Alkylene-L 1 -*, where L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates the 5'-O attachment site of the terminal nucleotide linked to CpG; and ** indicates the attachment site linked to an amino group; or X 3 It is the spacer group B3 as described herein; wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates the 3'-O attachment site of the terminal nucleotide linked to CpG; and ** indicates the attachment site linked to an amino group; and

[0712] X 4 Selected from spacer group C13 as described herein: where * indicates attachment to the selected FG l The attachment point, ** indicates the attachment point connected to the carbonyl group;

[0713] And FG 1 It is dibenzocyclooctylene (DBCO).

[0714] In some embodiments, CpG is a thiophosphate-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101).

[0715] In some embodiments, this application provides compounds of formula (IX):

[0716]

[0717] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants;

[0718] in:

[0719] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0720] X is the spacer group portion;

[0721] R 1 and R 2 Each is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl; or

[0722] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0723] Y 1 Is it O or S?

[0724] Y 2 It is O, NH or S;

[0725] Y 3 Is it O or S?

[0726] Y 4 It is O or S; and

[0727] FG 1 It is a functional group that can undergo chemical reactions through click.

[0728] In some embodiments of the compound of formula (IX), R 1 and R 2They can be attached together with the atoms they are connected to form a structure that may optionally contain one or more O, NR atoms. XA 3-8 member ring (where R XA It is an alkyl group, -C(O)-alkyl group, or -S(O). 0-2 -alkyl) or S(O) w -(where w is 0, 1 or 2).

[0729] In some embodiments of the compound of formula (IX), the compound is a compound having formula (IX-A):

[0730]

[0731] in:

[0732] X is selected from spacer groups C1 to C17 as described herein:

[0733] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates a connection to the selected FG. l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl;

[0734] R 1 and R 2 Each is independently hydrogen, Me, or Et;

[0735] a is an integer from 0 to 2;

[0736] R e Each group is independently selected from the following groups: nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me, and -OCF3. Furthermore...

[0737] FG 1 It is a functional group that can undergo chemical reactions through click.

[0738] In some embodiments of the compound of formula (IX), the compound is a compound of formula (IX-B):

[0739]

[0740] in:

[0741] X is selected from the spacer groups C1, C3, C8, C10, C13, C18, and C19 as described herein.

[0742] Where * indicates connection to the selected FG lThe attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl; and

[0743] FG 1 It is an azide, dibenzocyclooctylene (DBCO), or alkynyl.

[0744] In some embodiments of the compounds of formula (IX-B), X is selected from spacer groups C1, C3, C13, and C18 as described herein: where * indicates attachment to the selected FG. l The attachment point, ** indicates an attachment point connected to the carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can connect to FG. l Or carbonyl; and FG 1 It is an azide or dibenzocyclooctylene (DBCO).

[0745] In some embodiments of compounds of formula (IX), (IX-A), or (IX-B), X is C3, C13, or C18. In one embodiment, X is C3 and n is 3. In one embodiment, X is C13 and p is 4. In one embodiment, X is C18; q is 3, and r is 2.

[0746] In some embodiments of the compounds of formula (IX), (IX-A), or (IX-B), the compounds have the following structure:

[0747]

[0748] or

[0749]

[0750] In some embodiments of formulas (II), (II-A), (II-B), (II-C), (III), (III-A), (III-B), (III-C), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VII), (VII-A), (VII-B), (VIII), (IX), (IX-A), (IX-B), (XXII), (XXIII), (XXIII-A), and (XXIII-B), FG 1 It is an azide, alkynyl, or cycloalkynyl. In some embodiments, the cycloalkynyl group is dibenzocyclooctyne (DBCO) or bicyclic [6.1.0]nonyne (BCN).

[0751] In some embodiments, this application provides a combination having formula (X):

[0752] [A 2 -Z 2 -TZ 3 ] b2 -A 1 -[Z 1 -TZ 2 -A 2 ] b1

[0753] (X)

[0754] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, regioisomers, mixtures of two or more regioisomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof;

[0755] in:

[0756] b1 is an integer that is either 0 or 1;

[0757] b2 is an integer that is either 0 or 1;

[0758] The condition is that b1 + b2 is 1 or 2;

[0759] Each T is independently a triazole functional group;

[0760] Z 1 Z 2 and Z 3 Each is an independent spacer group; and

[0761] A 1 and A 2 Each is independently a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[0762] In some embodiments of the combination having formula (X), one or more atoms or chemical groups in each therapeutic agent or compound decomposable into a therapeutic agent are independently substituted to form a covalent bond linked to a spacer group. In some embodiments, one or more atoms in each therapeutic agent or compound decomposable into a therapeutic agent are substituted by a covalent bond of a spacer group. In some embodiments, one or more chemical groups in each therapeutic agent or compound decomposable into a therapeutic agent are substituted by a covalent bond of a spacer group. In some embodiments, one or more atoms in each therapeutic agent or compound decomposable into a therapeutic agent are substituted by a chemical group that links the therapeutic agent or compound to a spacer group. In some embodiments, one or more chemical groups in each therapeutic agent or compound decomposable into a therapeutic agent are substituted by a chemical group that links the therapeutic agent or compound to a spacer group. In some embodiments, one or more hydrogen atoms (e.g., CH, NH, OH, or SH) in each therapeutic agent or compound decomposable into a therapeutic agent are substituted to form a covalent bond of a spacer group. In some embodiments, A 1 and A 2 Each is independently a STING agonist, a TLR9 agonist, or a TLR7 / 8 agonist. In some embodiments, A 1 It is a TLR9 agonist, and A 2 It is a TLR7 / 8 agonist. In some implementations, A 1 It is a TLR9 agonist, and A 2 It is a STING agonist.

[0763] In some implementations, A 2 It is a STING agonist. In some embodiments, one or more hydrogens in the STING agonist (e.g., one or more hydrogens in the SH moiety) are replaced by covalent bonds in the spacer groups. In some embodiments, the STING agonist is a cyclic dinucleotide (CDN).

[0764] In some implementations, A 2 It is a TLR7 / 8 agonist or a derivative thereof. In some embodiments, A is a TLR7 / 8 agonist or a derivative thereof. In some embodiments, the TLR7 / 8 agonist is R848.

[0765] In some embodiments, the hydrogen (e.g., NH) in the TLR7 / 8 agonist (e.g., R848) is replaced by a *–C(O)-O-** that links the TLR7 / 8 agonist to a spacer group; where * indicates the attachment point to the TLR7 / 8 agonist and ** indicates the attachment point to the spacer group. In some embodiments, the hydrogen (e.g., NH) in the TLR7 / 8 agonist (e.g., R848) is replaced by a covalent bond in the spacer group.

[0766] In some embodiments of the combination of formula (X),

[0767] Z 1 yes Among them, Z 1 Through X 3 Connect to A 1 And through X 2 Connect to T;

[0768] Z 2 yes Among them, Z 2 Through X 1 Connect to T; and

[0769] Z 3 yes Among them, Z 3 Through X 4 Connect to A 1 And through X 2 Connect to T.

[0770] In some embodiments, the combination of formula (X) is a combination having formula (XA).

[0771]

[0772] in:

[0773] b1 is an integer that is either 0 or 1;

[0774] b2 is an integer that is either 0 or 1;

[0775] The condition is that b1 + b2 is 1 or 2;

[0776] Each T is independently a triazole functional group;

[0777] Ar 1 and Ar 2 Each is independently either a substituted or unsubstituted aryl or heteroaryl group;

[0778] X 1 X 2 X 3 and X 4 Each is an independent spacer group;

[0779] R 1 R 2 R 3 and R 4 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl;

[0780] R 1 and R2 Or R 3 and R 4 Together with the atoms to which they are attached, they can link together to form substituted or unsubstituted 3-8 membered rings that can optionally contain one or two heteroatoms;

[0781] Y 1 Y 2 Y 3 Y 4 Y 5 and Y 6 Each is independently O, NH, or S; and

[0782] A 1 and A 2 Each is independently a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[0783] In some embodiments, the combination of formula (X) has a structure according to formula (XB):

[0784]

[0785] in:

[0786] b1 is an integer that is either 0 or 1;

[0787] b2 is an integer that is either 0 or 1;

[0788] The condition is that b1 + b2 is 1 or 2;

[0789] a1 and a2 are each independent integers from 0 to 4;

[0790] Each R e1 and R e2 Each is independently selected from nitro, cyano, halogen, amide, substituted amide, sulfone, substituted sulfone, sulfonamide, substituted sulfonamide, alkoxy, substituted alkoxy, alkyl or cycloalkyl, substituted alkyl or cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or heteroaryl and substituted aryl or heteroaryl.

[0791] Each T is independently a triazole functional group;

[0792] X 1 X 2 The spacer groups are selected from C1 to C17 or C20 to C22 as described herein, and each oxygen is independently and optionally surrounded by NH, NMe, NAc, S or SO. 2 Alternatives; * indicates an attachment point connected to T, and ** indicates an attachment point connected to a carbonyl or thiocarbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can be connected to T or a carbonyl or thiocarbonyl group.

[0793] X 3 and X 4 Each is independently selected from **-C3-C 12 alkylene-L1-*; and spacer groups B1 to B5 as described herein:

[0794] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; * indicates a connection to A. 1 The attachment point; and ** indicates the attachment point connected to the amino group;

[0795] R 1 R 2 R 3 and R 4 Each is independently hydrogen or C1-C6 alkyl; or

[0796] R 1 and R 2 Together with the carbon atoms to which they are attached, they can be linked together to form 3-6 membered rings that may optionally contain one or more O, NMe, NAc, NSO2Me, S or SO2;

[0797] R 3 and R 4 Together with the carbon atoms to which they are attached, they can be linked together to form 3-6 membered rings that may optionally contain one or more O, NMe, NAc, NSO2Me, S or SO2;

[0798] Y 1 Y 2 Y 3 Y 4 Y 5 and Y 6 Each is independently O, NH, or S; and

[0799] A 1 and A 2 Each is independently a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[0800] In some embodiments, the combination of formula (X) has a structure according to formula (XC):

[0801]

[0802] in:

[0803] b1 is an integer that is either 0 or 1;

[0804] b2 is an integer that is either 0 or 1;

[0805] The condition is that b1 + b2 is 1 or 2;

[0806] a1 and a2 are each independent integers from 0 to 2;

[0807] R e1 and R e2 Each is independently selected from nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me and -OCF3;

[0808] Each T is independently a triazole functional group;

[0809] X 1 X 2 The spacer groups are selected from C1 to C17 as described herein, each oxygen being independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group; and the absence of a * or ** spacer group indicates that the attachment site can be connected to either T or a carbonyl group.

[0810] X 3 and X 4 Each is independently selected from **-C3-C 12 alkylene-L1-*; and spacer groups B1 to B5 as described herein:

[0811] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; * indicates a connection to A. 1 The attachment point; and ** indicates the attachment point connected to the amino group;

[0812] R 1 R 2 R 3 and R 4 Each is independently hydrogen, Me, or Et; and

[0813] A 1 and A 2 Each is independently a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[0814] In some embodiments, the combination of formula (X) has a structure according to formula (XD):

[0815]

[0816] in:

[0817] b1 is an integer that is either 0 or 1;

[0818] b2 is an integer that is either 0 or 1;

[0819] The condition is that b1 + b2 is 1 or 2;

[0820] Each T is independently a triazole functional group;

[0821] X 1 X 2 Each is independently selected from the spacer groups C1, C3, C8, C10, C13, C18, and C19 described herein:

[0822] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[0823] X 3 and X 4 Each is independently selected from **-C3-C 12 alkylene-L1-* and spacer group B3 as described herein: wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates connection to A 1 The attachment point; and ** indicates the attachment point connected to the amino group; and

[0824] A 1 and A 2 Each is independently a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[0825] In some embodiments, the combination of formula (X) has a structure according to formula (XE):

[0826]

[0827] in:

[0828] b1 is an integer that is either 0 or 1;

[0829] b2 is an integer that is either 0 or 1;

[0830] The condition is that b1 + b2 is 1 or 2;

[0831] Each T is independently a triazole functional group;

[0832] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0833] X 1 X 2 and X 3 Each is an independent spacer group;

[0834] R 1 and R 2Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or

[0835] R 1 and R 2 Together with the atoms they are attached to, they can attach together to form 3-8 membered rings that can optionally contain one or two heteroatoms;

[0836] Y 1 and Y 2 Each is independently O, NH, or S; and

[0837] A 1 and A 2 Each is independently a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[0838] In some embodiments, the combination of formula (X) has a structure according to formula (XF):

[0839]

[0840] in:

[0841] b1 is an integer that is either 0 or 1;

[0842] b2 is an integer that is either 0 or 1;

[0843] The condition is that b1 + b2 is 1 or 2;

[0844] a1 and a2 are each independent integers from 0 to 4;

[0845] Each R e1 Independently, it is nitro, cyano, halogen, amide, substituted amide, sulfone, substituted sulfone, sulfonamide, substituted sulfonamide, alkoxy, substituted alkoxy, alkyl or cycloalkyl, substituted alkyl or cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or heteroaryl and substituted aryl or heteroaryl.

[0846] Each T is independently a triazole functional group;

[0847] X 1 The spacer group is selected from C1 to C17 or C20 to C22 as described herein, each oxygen being independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, and ** indicates an attachment site connected to a carbonyl or thiocarbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to T or a carbonyl or thiocarbonyl group.

[0848] X 2 and X 3Each is independently -X 4 -NH-CO-X 5 - where X 4 Selected from **-C3-C 12 Alkylene-L 1-* ; and spacer groups B1 to B7 as described herein: wherein, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; * indicates a connection to A. 1 The attachment point; and ** indicates the attachment point connected to the amino group;

[0849] X 5 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[0850] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[0851] R 1 and R 2 Each is independently hydrogen or C1-C6 alkyl; or

[0852] R 1 and R 2 Together with the carbon atoms to which they are attached, they can be linked together to form 3-6 membered rings that may optionally contain one or more of O, NMe, NAc, NSO2Me, S or SO2;

[0853] Y 1 and Y 2 Each is independently O, NH, or S; and

[0854] A 1 and A 2 Each is independently a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[0855] In some embodiments, the combination of formula (X) has a structure according to formula (XG):

[0856]

[0857] in:

[0858] b1 is an integer that is either 0 or 1;

[0859] b2 is an integer that is either 0 or 1;

[0860] The condition is that b1 + b2 is 1 or 2;

[0861] a1 is an integer from 0 to 2;

[0862] R e1 and R e2 Each is independently selected from nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me and -OCF3;

[0863] Each T is independently a triazole functional group;

[0864] X 1 Selected from the spacer groups C1 to C17 described herein:

[0865] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[0866] X 2 and X 3 Each is independently -X 4 -NH-CO-X 5 - where X 4 Selected from **-C3-C 12 Alkylene-L 1-* ; and spacer groups B1 to B7 as described herein: wherein, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; * indicates a connection to A. 1 The attachment point; and ** indicates the attachment point connected to the amino group;

[0867] X 5 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[0868] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[0869] R 1 and R 2 Each is independently hydrogen, Me, or Et; and

[0870] A 1 and A 2 Each is independently a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[0871] In some embodiments, the combination having formula (X) has a structure according to formula (XH):

[0872]

[0873] in:

[0874] b1 is an integer that is either 0 or 1;

[0875] b2 is an integer that is either 0 or 1;

[0876] The condition is that b1 + b2 is 1 or 2;

[0877] Each T is independently a triazole functional group;

[0878] X 1 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[0879] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[0880] X 2 and X 3 Each is independently -X 4 -NH-CO-X 5 -, where X 4 Selected from **-C3-C 12 Alkylene-L 1-* ; such as the spacer groups B3, B6 or B7 described herein: wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates connection to A 1 The attachment point; and ** indicates the attachment point connected to the amino group;

[0881] X 5 Selected from the spacer groups C13 and C18 described in this article:

[0882] Where * indicates an attachment point connected to T, and ** indicates an attachment point connected to a carbonyl group; and

[0883] A 1 and A 2 Each is independently a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[0884] In some embodiments of the combination of this application, X 4 It is B3 or B6 and L 1It is -OP(O)(OH)-.

[0885] In some embodiments of the combination of this application, X 4 It is **-C3-C 12 Alkylene-L 1-* ;and L 1 It is -OP(S)(OH)-.

[0886] In some combinations of this application, X 5 It is C13 or C18. In some implementations, X 5 It is C13. In some implementations, X 5 It's C18.

[0887] In some embodiments of the combination of formula (X), the therapeutic agent is a STING agonist, a TLR9 agonist, or a TLR7 / 8 agonist.

[0888] In some embodiments of the complex of formula (X), the complex comprises a STING agonist, described in OncoImmunology, 9:1, 1777624; Theranostics. 2019; 9(25):7759–7771; US ​​20140341976; WO 2016145102; WO 2019232392; WO2017027645; WO 2017027646; WO 2017123657; WO2017123669; WO2018098203; WO 2017161349; WO 2018009652; WO 2019069275; or WO2019069270, the contents of which are incorporated herein by reference.

[0889] In some embodiments of the (X) conjugate, the conjugate comprises a TLR9 agonist, as described in Nat Rev DrugDiscov 2010 Apr; 9(4): 293-307; Front Immunol 2019 Oct 22; 10: 2388; Immunotherapy 2009 Nov; 1(6): 949-64; Oncogene 2008 Jan 7; 27(2): 161-7; J Clin Invest 2007 May; 117(5): 1184-94; J Leukoc Biol 2013 June; 93(6): 847-63; WO 2004 / 058179 A1; WO 2018 / 053242A1; WO 1998018810A1; WO The contents of 2003024480A2; WO2015013673A1; and WO2017050806A1 are incorporated herein by reference.

[0890] In some embodiments of the combination of formula (X), A 1 It is a TLR9 agonist. In some embodiments of the formula (X) complex, A 2 It is a TLR7 / 8 agonist or a derivative thereof. In some embodiments of the complex of formula (X), A 2 It is a STING agonist. In some embodiments of the formula (X) complex, A 1 It is a TLR9 agonist, and A 2 It is a STING agonist. In some embodiments of the formula (X) complex, A 1 It is a TLR9 agonist, and A 2 It is a TLR7 / 8 agonist or a derivative thereof. In some embodiments of the complex of formula (X), the STING agonist is CDN. In some embodiments of the complex of formula (X), the TLR7 / 8 agonist is R848 or a derivative thereof. In some embodiments of the complex of formula (X), A 1 It is CpG of CpG ODN (oligodeoxynucleotide) that acts as a TLR9 agonist. CpG ODN is a short synthetic single-stranded DNA molecule containing an unmethylated CpG motif.

[0891] In some implementations, CpG includes the following formula:

[0892] 5'X1X2CGX3X43'

[0893] Where X1, X2, X3, and X4 are any nucleotides, and

[0894] CpG is attached to a spacer group at the 5'-O and / or 3'-O position of the terminal nucleotide.

[0895] In some implementations, CpG is:

[0896] 5'-GGGGGGGGGGACGATCGTCGGGGGGGGGG-3'(CMP-001); ligated at the 5'-O and / or 3'-O of the terminal nucleotide.

[0897] In some implementations, CpG includes the following formula:

[0898] 5'N1X1CGX2N2 3'

[0899] In this sequence, at least one nucleotide isolates a continuous CpG; X1 is adenine, guanine, or thymine; X2 is cytosine or thymine; N is any nucleotide, and N1+N2 is approximately 0 to 26 bases long, provided that N1 and N2 do not contain a CCGG tetramer or more than one CCG or CGG trimer; the length of the above nucleic acid sequence is approximately 8 to 30 bases; and

[0900] CpG is attached to a spacer group at the 5'-O and / or 3'-O position of the terminal nucleotide.

[0901] In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*T*C*G*T*T*T*T*T*T*T*C*G*T*T*T*T-3' (PF-3512676); with a spacer group attached at the 5'-O and / or 3'-O of the terminal nucleotide.

[0902] In some implementations, CpG comprises the following formula:

[0903] a)5'-N x (TCG(N q )) y N w (X1X2CGX2'X1'(CG) p ) z

[0904] Where N is a nucleotide, x = 0, y = 1, w = 0, p = 0 or 1, q = 0, 1 or 2, and z = 1-20, X1 and X1' are self-complementary nucleotides, X2 and X2' are self-complementary nucleotides, and (TCG(N) q )) y The 5'T of the sequence is located at the 5' end of the polynucleotide; and

[0905] b) A palindromic sequence of at least 8 bases, wherein the palindromic sequence contains (X1X2CGX2'X1'(CG)). p ) zThe first part of the sequence (X1X2CGX2'X1'), wherein the length of the above polynucleotide sequence is at least 15 bases; and

[0906] CpG is attached to a spacer group at the 5'-O and / or 3'-O position of the terminal nucleotide.

[0907] In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101); linked at the 5'-O and / or 3'-O of the terminal nucleotide.

[0908] In some embodiments, CpG comprises at least two oligonucleotides, internucleotide bonds, or nucleobases or sugars functionalized by non-nucleotide linkers linked together at their 3' ends, wherein at least one of these oligonucleotides is an immunostimulatory oligonucleotide having an accessible 5' end and comprising an immunostimulatory dinucleotide selected from the group consisting of: CG, C # G, CG # and C # G # Where C is cytidine or 2'-deoxycytidine, C # It is 2'-deoxythymidine, cytarabine, 2'-deoxy-2'-substituted cytarabine, 2'-O-substituted cytarabine, 2'-deoxy-5-hydroxycytidine, 2'-deoxy-N4-alkyl-cytidine, 2'-deoxy-4-thiouridine, or other non-natural pyrimidine nucleosides. G is guanosine or 2'-deoxyguanosine. # It is 2'-deoxy-7-denitroguanosine, 2'-deoxy-6-thioguanosine, vidarabine, 2'-deoxy-2'-substituted vidarabine, 2'-O-substituted vidarabine, or other non-natural purine nucleosides, where p is a nucleoside internucleotide selected from the group consisting of phosphate diesters, thiophosphates, and dithiophosphates; and

[0909] CpG is attached to a spacer group at one or both 5'-O positions of the terminal nucleotide and / or internucleotide bond.

[0910] In some embodiments, CpG is a phosphate-thioester linked 5'-T*C*G1*A*A*C*G1*T*T*C*G1*-X-*G1*C*T*T*G1*C*A*A*G1*C*T*-5', where X is a glycerol linker and G1 is 2'-deoxy-7-dezoguanosine (IMO-2125); at one or both 5'-O sites of the terminal nucleotide and / or the glycerol is linked to a spacer group.

[0911] In some embodiments of compounds having formula (X), (XA), (XB), (XC), (XD), (XE), (XF), (XG), or (XH), A 1 It is CpG and * indicates that the attachment site is connected to A via i) the 5'-O of the terminal nucleotide of CpG and / or ii) the 3'-O of the terminal nucleotide of CpG. 1 .

[0912] In some embodiments of formulas (X), (XA), (XB), (XC), (XD), (XE), (XF), (XG), or (XH), A 1 It is a CpG having the following sequence: 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101); or 5'-T*C*G1*A*A*C*G1*T*T*C*G1*-X-*G1*C*T*T*G1*C*A*A*G1*C*T*-5', where X is a glycerol linker and G1 is 2'-deoxy-7-dezoguanosine (IMO-2125); or 5'-GGGGGGGGGGGACGATCGTCGGGGGGGGGG-3' (CMP-001) or 5'-T*C*G*T*C*G*T*T*T*T*T*T*T*C*G*T*T*T*T*T*T*T*C*G*T*T-3' (PF-3512676), where the 5'-O and / or 3'-O of the CpG-terminal nucleotide is linked to a spacer group.

[0913] In some embodiments of the combination having formula (X), the combination has a structure according to formula (X-1):

[0914] [A 2 -Z 2 -TZ 3 ] b2 -CpG-[Z 1 -TZ 2 -A 2 ] b1

[0915] (X-1)

[0916] in:

[0917] CpG is a TLR9 agonist oligodeoxynucleotide;

[0918] A 2 It is a STING agonist;

[0919] Z1 and Z 3 Each person independently chooses from the following groups:

[0920] Where * represents the attachment site of T and ** represents the 3'-O or 5'-O attachment site of the terminal nucleotide of CpG;

[0921] Z 2 Choose from the following groups:

[0922] Where * represents the attachment point with T and *** represents the attachment point with the STING agonist;

[0923] Ar 1 and Ar 2 Each is independently a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0924] X 1 X 2 X 3 and X 4 Each is an independent spacer group;

[0925] R 1 R 2 R 3 and R 4 Each is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aryl; or

[0926] R 1 and R 2 Or R 3 and R 4 Together with the atoms to which they are attached, they can link together to form substituted or unsubstituted 3-8 membered rings that can optionally contain one or two heteroatoms; and

[0927] Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 and Y 7 Each can be either O or S independently.

[0928] In some embodiments having a combination of formulas (X) and (X-1), Z 1 -TZ 2 and / or Z 2 -TZ 3 Choose from the following groups:

[0929] as well as Wherein, ** represents the 3'-O or 5'-O attachment site of the terminal nucleotide of the CpG and *** represents the attachment site of the STING agonist;

[0930] in:

[0931] a1 and a2 are each independent integers from 0 to 4; and

[0932] R e1 and R e2 Each time it appears, it is independently selected from nitro, cyano, halogen, substituted or unsubstituted amide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfonamide, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0933] In some implementations, X 1 X 2 and X 4 Choose from the following groups:

[0934] as well as in,

[0935] X 11 Independently selected from the following groups: -O-, -NC(O)R C -、-NR C -, -S-, SO2- and CR D R E ;

[0936] X 12 Independently, O and NR C Or S;

[0937] R C It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

[0938] R D and R E Each of them is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0939] Wherein, * indicates an attachment point connected to T, and ** indicates an attachment point connected to a carbonyl or thiocarbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment points can be connected to T or a carbonyl or thiocarbonyl group.

[0940] In some embodiments of the combination of formulas (X) and (X-1), X 1 X 2 and X 4 Choose independently from the following groups:

[0941] as well as Among them, AA 1 -[AA 2 ] m Includes groups selected from the following: Gly, Lys, Val-Ala, Val-Lys, Val-Cit, Ala-Lys, Phe-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Arg, Phe-Leu, Ala-Phe, Met-Lys, Asn-Lys, Ile-Pro, Ile-Val, Asp-Val, His-Val, Met-(D)Lys, Asn-(D)Lys, Val-(D)Asp, NorVal-(D)Asp, Ala-(D)Asp, Me3Lys-Pro, PhenylGly-(D)Lys, Pro-(D)Lys, Met-Cit-Val, Gly-Cit-Val, Phe-Phe-Lys, ( D) Phe-Phe-Lys, (D) Ala-Phe-Lys, Gly-Phe-Lys, Glu-Val-Cit, Ser-Val-Cit, Gly-Phe-Leu-Gly and Ala-Leu-Ala-Leu.

[0942] In some embodiments of the combination of formulas (X) and (X-1), X 1 X 2 and X 4 Choose independently from the following groups:

[0943] as well as Wherein, R is methyl or

[0944] In some embodiments of the combination of formulas (X) and (X-1), X 1 X 2 and X 4Each independently is:

[0945]

[0946]

[0947] In some embodiments of the combination of formulas (X) and (X-1), X 1 X 2 and X 4 Each independently is:

[0948]

[0949] In some embodiments of the combination of formulas (X) and (X-1), X 3 Independently: **-C3-C 12 Alkylene-L 1 -*;

[0950] or

[0951] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; * indicates a 3'-O or 5'-O attachment site to the terminal nucleotide of the CpG; ** indicates an attachment site to an amino group. In some embodiments, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-. In some embodiments, L 1 It is -OP(O)(OH)-.

[0952] In some implementations, X 3 Independently: **-C3-C 12 Alkylene-L 1 -*;

[0953] or

[0954] Among them, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates a 3'-O or 5'-O attachment site of the terminal nucleotide of CpG; ** indicates an attachment site of an amino group.

[0955] In some embodiments of the combination of formulas (X) and (X-1), X 1 Selected from: as well as Among them, AA 1-[AA 2 ] m Includes groups selected from the following: Gly, Lys, Val-Ala, Val-Lys, Val-Cit, Ala-Lys, Phe-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Arg, Phe-Leu, Ala-Phe, Met-Lys, Asn-Lys, Ile-Pro, Ile-Val, Asp-Val, His-Val, Met-(D)Lys, Asn-(D)Lys, Val-(D)Asp, NorVal-(D)Asp, Ala-(D)Asp, Me3Lys-Pro, PhenylGly-(D)Lys, Pro-(D)Lys, Met-Cit-Val, Gly-Cit-Val, Phe-Phe-Lys, ( D)Phe-Phe-Lys, (D)Ala-Phe-Lys, Gly-Phe-Lys, Glu-Val-Cit, Ser-Val-Cit, Gly-Phe-Leu-Gly and Ala-Leu-Ala-Leu;

[0956] Where * indicates an attachment point connected to the selected T, and ** indicates a connection point connected to Ar. 1 Attachment point.

[0957] In some embodiments of the combination of formulas (X) and (X-1), X 1 Choose from the following groups:

[0958] as well as Wherein, R is methyl or * indicates connection to the attachment point of the selected T, ** indicates connection to Ar 1 Attachment point.

[0959] In some embodiments of the combination of formulas (X) and (X-1), R 1 R 2 R 3 and R 4 It is hydrogen; and / or Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 and Y 7 Each is O.

[0960] In some embodiments of the combination of formulas (X) and (X-1), X 3 yes In some implementations, X 3 yes In some implementations, X 3 yes In some implementations, X 3 yes In some implementations, X 3 yes

[0961] In some embodiments having the combination of (X) and (X-1):

[0962] X 1 yes: and / or

[0963] X 2 yes and / or

[0964] X 4 yes

[0965] In some implementations, X 1 yes: In some implementations, X 1 yes: In some implementations, X 1 yes: In some implementations, X 1 yes: In some implementations, X 1 yes:

[0966] In some embodiments, X 4 yes: In some implementations, X 4 yes

[0967] In some implementations, b1 is 1 and b2 is 0, or b1 is 1 and b2 is 1. In some implementations, b1 is 1 and b2 is 0. In some implementations, b1 is 1 and b2 is 1. In some implementations, b2 is 1 and b1 is 0. In some implementations, when b1 is 0 or b2 is 0, X... 3 One end is attached to the 3'-O of the terminal nucleotide of CpG. In some embodiments, X is 0 when b1 is 0 or b2 is 0. 3 One end is attached to the 5'-O of the terminal nucleotide of CpG.

[0968] In some embodiments, the triazole functional group is selected from the group consisting of:

[0969] as well as

[0970] In some embodiments, the triazole functional group is selected from the group consisting of:

[0971] as well as In some implementations, T is connected to -Z via *. 2 -A 2 And T is connected to -Z via **. 1 -or-Z 3 -; In some implementations, T is connected to -Z via **. 2 -A 2 And T is connected to -Z via * 1 -or-Z 3 -;

[0972] In some embodiments, the triazole functional group is

[0973]

[0974] In some embodiments, the triazole functional group is

[0975]

[0976] In some implementations, T is connected to -Z via *. 2 -A 2 And T is connected to -Z via **. 1 -or-Z 3 -; In some implementations, T is connected to -Z via **. 2 -A 2 And T is connected to -Z via * 1 -or-Z 3 -

[0977] In some embodiments of the combination of formula (X), the combination has a structure according to formula (XXIV):

[0978]

[0979] in:

[0980] Ar 1 and Ar 2 Each is independently a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0981] X 1 X2 and X 3 Each is an independent spacer group portion;

[0982] R 1 R 2 R 3 and R 4 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl; or

[0983] R 1 and R 2 Or R 3 and R 4 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0984] Y 3 Y 4 Y 5 and Y 6 Each can be independently O, NH, or S;

[0985] b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to A;

[0986] Each T is independently a triazole functional group;

[0987] CpG is a TLR9 agonist oligodeoxynucleotide; and

[0988] A is a STING agonist.

[0989] In some embodiments, the spacer group is covalently bonded to the 3'-O of the terminal nucleotide of CpG. In some embodiments, the spacer group is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[0990] In some embodiments of the combination of formula (X), the combination has a structure according to formula (XXV):

[0991]

[0992] in:

[0993] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[0994] X 1 and X 2 Each is an independent spacer group portion;

[0995] R 1 and R 2Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[0996] b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to A;

[0997] Each T is independently a triazole functional group;

[0998] CpG is a TLR9 agonist oligodeoxynucleotide; and

[0999] A is a STING agonist.

[1000] In some embodiments of formula (XXV), X 2 It is -X 3 -NH-CO-X 4 -, and X 1 X 3 X 4 Each is an independent spacer group portion.

[1001] In some embodiments, the spacer group is covalently bonded to the 3'-O of the terminal nucleotide of CpG. In some embodiments, the spacer group is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[1002] In certain embodiments of the combinations of formulas (X), (X-1), (XXIV), and (XXV), the STING agonist is disclosed in U.S. Patent Application Nos. 16 / 643,127, ADU-S100, MK-1454, BMS-986301, GSK3745417, E7766, and SB11285.

[1003]

[1004] Or its stereoisomers.

[1005] In some embodiments, the combination of formula (X) has a structure according to formula (XI):

[1006]

[1007] in:

[1008] Ar 1 and Ar 2 Each is independently a substituted or unsubstituted aryl or heteroaryl group;

[1009] X 1 X 2 and X 3 Each is an independent spacer group portion;

[1010] R 1 R 2 R 3 and R 4 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl; or

[1011] R 1 and R 2 Or R 3 and R 4 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[1012] Y 1 Y 2 Y 3 Y 4 Y 5 and Y 6 Each can be independently O, NH, or S;

[1013] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1014] Each T is independently a triazole functional group;

[1015] CpG is a TLR9 agonist oligodeoxynucleotide; and

[1016] CDN is a cyclic dinucleotide that acts as a STING agonist; and the aforementioned linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1017] In some embodiments, the spacer group is covalently bonded to the 3'-O of the terminal nucleotide of CpG. In some embodiments, the spacer group is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[1018] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1019] In some embodiments, the combination of formula (X) has a structure according to formula (XI-A):

[1020]

[1021] in:

[1022] X 1 and X 2 Each is independently selected from the spacer groups C1 to C17 described herein;

[1023] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[1024] X 3 Selected from **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B5 as described herein:

[1025] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; ** indicates an attachment site to an amino group;

[1026] R 1 R 2 R 3 and R 4 Each is independently hydrogen, Me, or Et;

[1027] Each T is independently a triazole functional group;

[1028] a1 and a2 are each independent integers from 0 to 2;

[1029] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1030] R e1 and R e2 Each is independently selected from nitro, cyano, halogen, -OMe, and -OCF3.

[1031] CpG is a TLR9 agonist oligodeoxynucleotide;

[1032] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1033] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1034] In some embodiments, the spacer group is covalently bonded to the 3'-O of the terminal nucleotide of CpG. In some embodiments, the spacer group is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[1035] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1036] In some embodiments, the combination of formula (X) has a structure according to formula (X-IB):

[1037]

[1038] in:

[1039] X 1 and X 2 Each is independently selected from the spacer groups C1, C3, C8, C10, C13, C18 and C19 described herein;

[1040] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1041] X 3 Selected from **-C3-C 12 Alkylene-L 1 -*; or as described herein, spacer groups B1 to B5:

[1042] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates a 3'-O or 5'-O attachment site of the terminal nucleotide linked to CpG; ** indicates an attachment site linked to an amino group;

[1043] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1044] Each T is independently a triazole functional group;

[1045] CpG is a TLR9 agonist oligodeoxynucleotide;

[1046] CDN is a cyclic dinucleotide that acts as a STING agonist; and the linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1047] In some embodiments, the spacer group is covalently bonded to the 3'-O of the terminal nucleotide of CpG. In some embodiments, the spacer group is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[1048] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1049] In some embodiments of the combination of formula (XI-B), wherein X 1 Selected from the spacer groups C8 and C10 described in this article; X 2 Selected from the spacer group C19 described herein: where * indicates an attachment site to T, and ** indicates an attachment site to a carbonyl group; X 3 Selected from the spacer group B3 described in this article: where L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to the 3'-O terminal nucleotide of CpG; and ** indicates an attachment site to an amino group; b is an integer of 1 or 2; wherein, when b = 2, both groups are directly bonded to CDN; each T is independently a triazole functional group; CDN is a cyclic dinucleotide acting as a STING agonist; and the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*T*C*G*A*A*T–3' (SD-101), with a spacer group attached at the 3'-O terminal nucleotide of CpG.

[1050] In some embodiments of the (XI-B) combination, X 1 It is the spacer group C10 described in this article.

[1051] In some embodiments, the combination of formula (X) has a structure according to formula (XXVI):

[1052]

[1053] in:

[1054] Ar 1 and Ar 2 Each is independently a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1055] X 1 X 2 and X 3 Each is an independent spacer group portion;

[1056] R 1 R 2 R 3 and R 4Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl; or

[1057] R 1 and R 2 Or R 3 and R 4 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[1058] Y 3 Y 4 Y 5 and Y 6 Each can be independently O, NH, or S;

[1059] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1060] Each T is independently a triazole functional group;

[1061] CpG is a TLR9 agonist oligodeoxynucleotide;

[1062] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1063] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1064] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1065] In some embodiments, the spacer group is covalently bonded to the 3'-O of the terminal nucleotide of CpG. In some embodiments, the spacer group is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[1066] In some embodiments, the combination of formula (X) has a structure according to formula (XXVI-A):

[1067]

[1068] in:

[1069] X 1 The spacer group is selected from D1 to D12 as described herein; wherein * indicates an attachment site connected to the selected T, ** indicates an attachment site connected to the phenyl, and the absence of a * or ** spacer group indicates that the attachment site can be connected to T or the phenyl.

[1070] X 2The spacer group is selected from C13 to C17 as described herein: wherein oxygen can optionally be replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site to T, and ** indicates an attachment site to carbonyl group;

[1071] X 3 Selected from: **-C3-C 12 Alkylene-L 1 -*and spacer groups B1 to B5 as described herein: wherein, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-, * indicates a 3'-O or 5'-O attachment site of the terminal nucleotide of CpG; and ** indicates an attachment site of an amino group.

[1072] R 1 R 2 R 3 and R 4 Each is independently hydrogen, Me, or Et;

[1073] Each T is independently a triazole functional group;

[1074] a1 and a2 are each independent integers from 0 to 2;

[1075] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1076] R e1 and R e2 Each is independently selected from nitro, cyano, halogen, -OMe, and -OCF3.

[1077] CpG is a TLR9 agonist oligodeoxynucleotide;

[1078] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1079] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1080] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1081] In some embodiments, the combination of formula (X) has a structure according to formula (XXVI-B):

[1082]

[1083] in:

[1084] X 1The spacer groups D1, D5, D6, D9, and D13 described herein are selected: where * indicates an attachment site to the selected T, and ** indicates an attachment site to a phenyl group;

[1085] X 2 Selected from the spacer group C19 described herein; wherein, * denotes an attachment site connected to T, and ** denotes an attachment site connected to a carbonyl group;

[1086] X 3 Selected from spacer group B3 as described herein: wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-, * indicates the 3'-O attachment site of the terminal nucleotide of CpG; ** indicates the attachment site of the amino group;

[1087] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1088] Each T is independently a triazole functional group;

[1089] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1090] The linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist.

[1091] In some embodiments of the combination of formula (XXVI-B), X 1 The spacer groups D9 and D13 are selected from those described herein. In some embodiments of the complex of formula (XXVI-B), R in spacer group D13 is a methyl group.

[1092] In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*T*C*G*A*A*T–3' (SD-101), located at the 3'-O position of the terminal nucleotide and linked to a spacer group.

[1093] In some embodiments, the combination of formula (X) has a structure according to formula (XII):

[1094]

[1095] in:

[1096] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1097] X 1 and X 2 Each is an independent spacer group portion;

[1098] R 1 and R 2 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[1099] Y 1 and Y 2 Each can be O, NH, or S independently.

[1100] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1101] Each T is independently a triazole functional group;

[1102] CpG is a TLR9 agonist oligodeoxynucleotide;

[1103] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1104] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1105] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1106] In some embodiments, the spacer group is covalently bonded to the 3'-O of the terminal nucleotide of CpG. In some embodiments, the spacer group is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[1107] In some embodiments, the combination of formula (X) has a structure according to formula (XII-A):

[1108]

[1109] in:

[1110] X 1 Selected from the spacer groups C1 to C17 described herein:

[1111] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[1112] X 2 It is -X 3 -NH-CO-X 4 -, where X 3 Selected from **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B6 as described herein:

[1113] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; and ** indicates an attachment site to an amino group;

[1114] X 4 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[1115] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[1116] R 1 and R 2 Each is independently hydrogen, Me, or Et;

[1117] Each T is independently a triazole functional group;

[1118] a is an integer from 0 to 2;

[1119] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1120] R e1 and R e2 Each is independently selected from nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me and -OCF3;

[1121] CpG is a TLR9 agonist oligodeoxynucleotide;

[1122] CDN is a cyclic dinucleotide that acts as a STING agonist; and the linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1123] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1124] In some embodiments, the spacer group is covalently bonded to the 3'-O of the terminal nucleotide of CpG. In some embodiments, the spacer group is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[1125] In some embodiments, the combination of formula (X) has a structure according to formula (XII-B):

[1126]

[1127] in:

[1128] X 1 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[1129] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1130] X 2 It is -X 3 -NH-CO-X 4 -, where X 3 Selected from **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B6 as described herein:

[1131] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates a 3'-O or 5'-O attachment site of the terminal nucleotide connected to CpG; and ** indicates an attachment site connected to an amino group;

[1132] X 4 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[1133] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1134] Each T is independently a triazole functional group;

[1135] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1136] CpG is a TLR9 agonist oligodeoxynucleotide;

[1137] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1138] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1139] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1140] In some embodiments, the spacer group is covalently bonded to the 3'-O of the terminal nucleotide of CpG. In some embodiments, the spacer group is covalently bonded to the 5'-O of the terminal nucleotide of CpG.

[1141] In some embodiments of the combination of formula (XII-B), wherein: X 1 Selected from spacer groups C8 and C10 as described herein: where * denotes an attachment site to T, and ** denotes an attachment site to a carbonyl group; X 2 It is -X 3 -NH-CO-X 4 -, where X 3 Selected from the spacer groups B3 and B6 described herein: wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to the 3'-O of the CpG-terminal nucleotide; and ** indicates an attachment site to an amino group; or X 3 It is: **-C3-C 12 Alkylene-L 1 -*; where L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates the 5'-O attachment site of the terminal nucleotide linked to CpG; and ** indicates the attachment site linked to an amino group; X 4 The spacer groups C13 and C18 described herein are selected: where * indicates an attachment site to T, and ** indicates an attachment site to a carbonyl group; each T is independently a triazole functional group; b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to CDN; CDN is a cyclic dinucleotide acting as a STING agonist; and the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101); a spacer group is attached at the 3'-O or 5'-O of the terminal nucleotide of CpG.

[1142] In some embodiments of the combination of formula (XII-B), wherein: X 1 It is the spacer group C10 as described in this article.

[1143] In some embodiments, the combination of formula (X) has a structure according to formula (XXVII):

[1144]

[1145] in:

[1146] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1147] X 1 and X 2 Each is an independent spacer group portion;

[1148] R 1 and R 2 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[1149] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1150] Each T is independently a triazole functional group;

[1151] CpG is a TLR9 agonist oligodeoxynucleotide;

[1152] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1153] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1154] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1155] In some embodiments, the combination of formula (X) has a structure according to formula (XXVII-A):

[1156]

[1157] in:

[1158] X 1The spacer groups D1 to D12 described herein are selected: where * indicates an attachment site connected to a selected T, ** indicates an attachment site connected to a phenyl group, and the absence of a * or ** spacer group indicates that the attachment site can be connected to either T or a phenyl group.

[1159] X 2 It is -X 3 -NH-CO-X 4 -, where X 3 Selected from: **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B7 as described herein: wherein, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-, * indicates a 3'-O or 5'-O attachment site of the terminal nucleotide of CpG; and ** indicates an attachment site of an amino group.

[1160] X 4 The spacer groups are selected from C13, C18, and C19 as described herein: wherein oxygen can optionally be replaced by NH, NMe, NAc, S, or SO2; * indicates an attachment site to T, and ** indicates an attachment site to a carbonyl group;

[1161] R 1 and R 2 Each is independently hydrogen, Me, or Et;

[1162] Each T is independently a triazole functional group;

[1163] a is an integer from 0 to 2;

[1164] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1165] R e1 and R e2 Each is independently selected from nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me and -OCF3;

[1166] CpG is a TLR9 agonist oligodeoxynucleotide;

[1167] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1168] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1169] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1170] In some embodiments, the combination of formula (X) has a structure according to formula (XXVII-B):

[1171]

[1172] in:

[1173] X 1 The spacer groups D1, D5, D6, D9, and D13 described herein are selected; where * indicates an attachment site connected to T, and ** indicates an attachment site connected to a phenyl group.

[1174] X 2 It is -X 3 -NH-CO-X 4 -, where X 3 Selected from the spacer groups B3 and B6 described herein: wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-, * indicates the 3'-O attachment site of the terminal nucleotide of CpG; and ** indicates the attachment site of an amino group; or X 3 It is: **-C3-C 12 Alkylene-L1-*, or B7 as described herein, wherein L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates the 5'-O attachment site of the terminal nucleotide of CpG; and ** indicates the attachment site of the amino group.

[1175] X 4 The spacer groups C13 and C18 described herein are selected: where * indicates an attachment point to T, and ** indicates an attachment point to a carbonyl group;

[1176] Each T is independently a triazole functional group;

[1177] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1178] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1179] The linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist.

[1180] In some embodiments of the combination of formula (XXVII-B), X 1 The spacer groups D9 and D13 are selected from those described herein. In some embodiments of the complex of formula (XXVII-B), R in spacer group D13 is a methyl group.

[1181] In some embodiments, CpG is a phosphate-thioester linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*T*C*G*A*A*T–3' (SD-101), with a spacer group attached to the 3'-O or 5'-O of the terminal nucleotide of CpG.

[1182] In some embodiments, the combination of formula (X) has a structure according to formula (XIII):

[1183]

[1184] in:

[1185] Ar 1 and Ar 2 Each is independently either a substituted or unsubstituted aryl or heteroaryl group;

[1186] X 1 X 2 X 3 and X 4 Each is an independent spacer group portion;

[1187] R 1 R 2 R 3 and R 4 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl; or

[1188] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms; or

[1189] Or R 3 and R 4 Together with the atoms they are attached to, they can be linked together to form 3-8 membered rings that may optionally contain one or two heteroatoms;

[1190] Y 1 Y 2 Y 3 Y 4 Y 5 and Y 6 Each can be independently O, NH, or S;

[1191] Each T is independently a triazole functional group;

[1192] CpG is a TLR9 agonist oligodeoxynucleotide;

[1193] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1194] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1195] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1196] In some embodiments, the combination of formula (X) has a structure according to formula (XIII-A):

[1197]

[1198] in:

[1199] X 1 and X 2 Each is independently selected from the spacer groups C1 to C17 described herein;

[1200] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[1201] X 3 and X 4 Each is independently selected from **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B5 as described herein:

[1202] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; and ** indicates an attachment site to an amino group;

[1203] R 1 R 2 R 3 and R 4 Each is independently hydrogen, Me, or Et;

[1204] Each T is independently a triazole functional group;

[1205] a1 and a2 are each independent integers from 0 to 2;

[1206] R e1 and R e2Each is independently selected from nitro, cyano, halogen, -OMe, and -OCF3;

[1207] CpG is a TLR9 agonist oligodeoxynucleotide;

[1208] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1209] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1210] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1211] In some embodiments, the combination of formula (X) has a structure according to formula (XIII-B):

[1212]

[1213] in:

[1214] X 1 and X 2 Each is independently selected from the spacer groups C1, C3, C8, C10, C13, C18 and C19 described herein;

[1215] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1216] X 3 and X 4 Each is independently selected from **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B5 as described herein:

[1217] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates a 3'-O or 5'-O attachment site of the terminal nucleotide connected to CpG; and ** indicates an attachment site connected to an amino group;

[1218] Each T is independently a triazole functional group;

[1219] CpG is a TLR9 agonist oligodeoxynucleotide;

[1220] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1221] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1222] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1223] In some embodiments of the combination of formula (XIII-B), wherein X 1 Selected from the spacer groups C8 and C10 described herein, and X 2 Selected from the spacer group C19 described herein; wherein, * indicates an attachment site to T, and ** indicates an attachment site to a carbonyl group; X 4 Selected from **-C3-C 12 Alkylene-L 1-* Among them, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates the 5'-O attachment site of the terminal nucleotide linked to CpG; and ** indicates the attachment site linked to an amino group; and X 3 It is selected from spacer group B3 as described herein: wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to the 3'-O of the CpG terminal nucleotide; ** indicates an attachment site to an amino group; each T is independently a triazole functional group; CDN is a cyclic dinucleotide acting as a STING agonist; and the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101), where X 4 Covalently bonded to the 5'-O of the CpG-terminal nucleotide, and X 3 It is covalently bonded to the 3'-O of the CpG terminal nucleotide.

[1224] In some embodiments, the combination of formula (X) has a structure according to formula (XIV):

[1225]

[1226] in:

[1227] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1228] X 1 X 2 and X 3Each is an independent spacer group portion;

[1229] R 1 and R 2 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or

[1230] R 1 and R 2 Together with the atoms they are attached to, they can attach together to form 3-8 membered rings that can optionally contain one or two heteroatoms;

[1231] Y 1 and Y 2 Each can be O, NH, or S independently.

[1232] Each T is independently a triazole functional group;

[1233] CpG is a TLR9 agonist oligodeoxynucleotide;

[1234] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1235] The linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1236] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1237] In some embodiments, the combination of formula (X) has a structure according to formula (XIV-A):

[1238]

[1239] in:

[1240] X 1 Selected from the spacer groups C1 to C17 described herein:

[1241] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[1242] X 2 and X 3 Each is independently -X 4 -NH-CO-X 5 -, where X 4 Selected from **-C3-C12 Alkylene-L 1-* ; and spacer groups B1 to B5 as described herein: wherein, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; ** indicates an attachment site to an amino group;

[1243] X 5 The spacer groups are selected from the C1, C3, C8, C10, C13, C18 and C19 described herein: wherein each oxygen is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group;

[1244] R 1 and R 2 Each is independently hydrogen, Me, or Et;

[1245] Each T is independently a triazole functional group;

[1246] a is an integer from 0 to 2;

[1247] Each R e Independently selected from nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me and -OCF3;

[1248] CpG is a TLR9 agonist oligodeoxynucleotide;

[1249] CDN is a cyclic dinucleotide that acts as a STING agonist; and the linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1250] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1251] In some embodiments, the combination of formula (X) has a structure according to formula (XIV-B):

[1252]

[1253] in:

[1254] X 1 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[1255] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1256] X 2 and X 3 Each is independently -X 4 -NH-CO-X 5 - where X 4 Selected from **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B5 as described herein:

[1257] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; ** indicates an attachment site to an amino group;

[1258] X 5 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[1259] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1260] Each T is independently a triazole functional group;

[1261] CpG is a TLR9 agonist oligodeoxynucleotide;

[1262] CDN is a cyclic dinucleotide that acts as a STING agonist; and the linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1263] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1264] In some embodiments of the combination of formula (XIV-B), wherein X 1 Selected from the spacer groups C8 and C10 described herein: where * indicates an attachment site to T, and ** indicates an attachment site to a carbonyl group; X 2 and X 3 Each is independently -X 4 -NH-CO-X 5 - where X 4 It is **-C3-C 12Alkylene-L 1-* ; among which, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates an attachment site at the 5'-O of the terminal nucleotide of CpG; and ** indicates an attachment site to an amino group; or X 4 It is the spacer group B3 as described in this article: wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to the 3'-O of the CpG-terminal nucleotide; ** indicates an attachment site to an amino group; X 5 The spacer group C13 is as described herein: where * denotes an attachment site to T, and ** denotes an attachment site to a carbonyl group; each T is independently a triazole functional group; CDN is a cyclic dinucleotide acting as a STING agonist; and the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101).

[1265] In some embodiments, the combination of formula (X) has a structure according to formula (XV):

[1266]

[1267] in:

[1268] Ar 1 and Ar 2 Each is independently a substituted or unsubstituted aryl or heteroaryl group;

[1269] X 1 and X 2 Each is an independent spacer group portion;

[1270] R 1 R 2 R 3 and R 4 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl; or

[1271] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings that can contain one or two heteroatoms; or

[1272] R 3 and R 4Together with the atoms they are attached to, they can link together to form 3-8 membered rings that can contain one or two heteroatoms;

[1273] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1274] Y 1 Y 2 Y 3 Y 4 Y 5 and Y 6 Each can be either O or S independently;

[1275] Each T is independently a triazole functional group;

[1276] CDN is a cyclic dinucleotide that acts as a STING agonist; and the linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1277] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1278] In some embodiments, the combination of formula (X) has a structure according to formula (XV-A):

[1279]

[1280] in:

[1281] X 1 and X 2 Each is independently selected from the spacer groups C1 to C17 described herein:

[1282] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[1283] R 1 R 2 R 3 and R 4 Each is independently hydrogen, Me, or Et;

[1284] Each T is independently a triazole functional group;

[1285] a1 and a2 are each independent integers from 0 to 2;

[1286] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1287] R e1 and R e2 Each is independently selected from nitro, cyano, halogen, -OMe, and -OCF3;

[1288] CDN is a cyclic dinucleotide that acts as a STING agonist; and the linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1289] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1290] In some embodiments, the combination of formula (X) has a structure according to formula (XV-B):

[1291]

[1292] in:

[1293] X 1 and X 2 Each is independently selected from the spacer groups C1, C3, C8, C10, C13, C18 and C19 described herein;

[1294] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1295] Each T is independently a triazole functional group;

[1296] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1297] CDN is a cyclic dinucleotide that acts as a STING agonist; and the linker is covalently bonded to the cyclic dinucleotide STING agonist.

[1298] In some embodiments, the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments, the linker is covalently bonded to the nitrogen group of the cyclic dinucleotide STING agonist.

[1299] In some embodiments of the combination of formula (XV-B), X 1 Selected from the spacer groups C8 and C10 described herein; and X 2The spacer group is selected from C13 as described herein: wherein * denotes an attachment site to T, and ** denotes an attachment site to a carbonyl group; each T is independently a triazole functional group; b is an integer of 1 or 2; wherein, when b = 2, both groups are directly bonded to CDN; CDN is a cyclic dinucleotide acting as a STING agonist; and the linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist. In some embodiments of the complex of formula (XV-B), X 1 It is C10.

[1300] In certain embodiments of the therapeutic agents of formulas (III), (III-A), (III-B), (III-C), (IV), (IV-A), (IV-B), (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XH), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), and (XXVII-B), the cyclic dinucleotide is

[1301]

[1302]

[1303] Or its pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate.

[1304] In certain embodiments of the therapeutic agents of formulas (III), (III-A), (III-B), (II-C), (IV), (IV-A), (IV-B), (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XH), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), and (XXVII-B), the cyclic dinucleotide is:

[1305]

[1306]

[1307]

[1308]

[1309] Or its stereoisomers.

[1310] In some embodiments of the conjugates of formulas (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), and (XXVII-B), the cyclic dinucleotide is:

[1311] or Or its stereoisomers;

[1312] Wherein, * represents the S of the thiol group (-SH, H not shown, where * appears) of the cyclic dinucleotide linked to the linker. In some embodiments, when b is 1, one S* of the cyclic dinucleotide is linked to the linker and the other S* is linked to hydrogen. In some embodiments, when b is 2, both S* of the cyclic dinucleotide are linked to the linker.

[1313] In some implementations, the binder is selected from the group consisting of:

[1314]

[1315]

[1316]

[1317]

[1318]

[1319]

[1320]

[1321]

[1322]

[1323]

[1324]

[1325]

[1326]

[1327]

[1328]

[1329]

[1330]

[1331]

[1332]

[1333]

[1334]

[1335]

[1336]

[1337]

[1338]

[1339]

[1340] as well as

[1341]

[1342] Wherein, CpG is a thiophosphate-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101); or a thiophosphate-linked 5'-T*C*G1*A*A*C*G1*T*T*C*G1*-X-*G1*C*T*T*G1*C*A*A*G1*C*T*-5', where X is a glycerol linker and G 1 is 2'-deoxy-7-dezoguanosine (IMO-2125); or 5'-GGGGGGGGGGGACGATCGTCGGGGGGGGGG-3' (CMP-001) or 5'-T*C*G*T*C*G*T*T*T*T*T*T*T*T*C*G*T*T*T*T*T*T*T*T*T*T*T-3' (PF-3512676) linked to a spacer group at the 3'-O or 5'-O position of the terminal nucleotide.

[1343] In some embodiments of the conjugates of formulas (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XV), (XV-A), (XV-B), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), and (XXVII-B), CpG is linked at the 3'-O position of the terminal nucleotide. In some embodiments, CpG is linked at the 5'-O position of the terminal nucleotide.

[1344] In some embodiments, the CpG is a phosphate-thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*T*C*G*A*A*C*G*T*T*T*C*G*A*A*T–3' (SD-101), with a spacer group attached to the 3'-O position of the terminal nucleotide.

[1345] In some embodiments of the combinations of formulas (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XV), (XV-A), (XV-B), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), and (XXVII-B), b is 1.

[1346] In some embodiments of the combinations of formulas (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XV), (XV-A), (XV-B), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), and (XXVII-B), b is 2.

[1347] In some embodiments of the complexes of formulas (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), and (XXVII-B), wherein b is 1 and the cyclic dinucleotide is selected from:

[1348]

[1349] as well as

[1350] In this context, * indicates that the S of the thiol group is linked to the cyclic dinucleotide (-SH, where the position of H where * appears is not shown).

[1351] In some embodiments, the combination has the following structure:

[1352]

[1353]

[1354]

[1355]

[1356]

[1357]

[1358]

[1359]

[1360]

[1361]

[1362]

[1363]

[1364]

[1365]

[1366]

[1367]

[1368]

[1369]

[1370]

[1371]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379]

[1380]

[1381]

[1382]

[1383]

[1384]

[1385]

[1386]

[1387]

[1388]

[1389]

[1390]

[1391] or Or its stereoisomers;

[1392] CpG is a phosphate-thioester-linked oligodeoxynucleotide with the sequence 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101), with a spacer group attached to the 3'-O position of the terminal nucleotide; and

[1393]

[1394]

[1395]

[1396]

[1397]

[1398]

[1399]

[1400]

[1401]

[1402] or

[1403]

[1404] CpG is an oligodeoxynucleotide linked to a phosphate thioester, having the sequence 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101), with a spacer group attached to the 5'-O position of the terminal nucleotide;

[1405] In some embodiments, this application provides a combination having formula (XVI-1):

[1406]

[1407] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, regioisomers, mixtures of two or more regioisomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof;

[1408] Among them, Z 1 and X 1 Each is an independent spacer group portion;

[1409] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1410] R 1 and R 2 Each is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aryl; or

[1411] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings that can contain one or two heteroatoms;

[1412] Y 2 It is O, NH or S;

[1413] Y 1 Y 3 and Y 4 Each is independently O or S; and

[1414] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1415] In some embodiments, this application provides an assembly having a structure according to formula (XVI):

[1416]

[1417] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, regioisomers, mixtures of two or more regioisomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof;

[1418] in:

[1419] Ar 1 and Ar 2 Each is independently either a substituted or unsubstituted aryl or heteroaryl group;

[1420] X 1 X 2 and X 3 Each is an independent spacer group portion;

[1421] R 1 R 2 R 3 and R 4 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl; or

[1422] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings that can contain one or two heteroatoms; or

[1423] R 3 and R 4 Together with the atoms they are attached to, they can link together to form 3-8 membered rings that can contain one or two heteroatoms;

[1424] Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Each can be either O or S independently;

[1425] T is a triazole functional group; and

[1426] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1427] In some embodiments, the combination of formula (XVI) has a structure according to formula (XVI-A):

[1428]

[1429] in:

[1430] X 1 and X 2 Each spacer group is independently selected from the spacers described herein, C1 to C17; wherein each oxygen is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[1431] X 3 Selected from **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B5 as described herein: wherein, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; and ** indicates an attachment site to an amino group;

[1432] R 1 R 2 R 3 and R 4 Each is independently hydrogen, Me, or Et;

[1433] a1 and a2 are each independent integers from 0 to 2;

[1434] R e1 and R e2 Each is independently selected from nitro, cyano, halogen, -OMe, and -OCF3;

[1435] T is a triazole functional group; and

[1436] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1437] In some embodiments, the combination of formula (XVI) has a structure according to formula (XVI-B):

[1438]

[1439] in:

[1440] X 1 and X 2 Each is independently selected from the spacer groups C1, C3, C8, C10, C13, C18 and C19 described herein;

[1441] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1442] X 3 Selected from **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B5 as described herein:

[1443] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; and ** indicates an attachment site to an amino group;

[1444] T is a triazole functional group; and

[1445] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1446] In some embodiments of the combination of formula (XVI-B), wherein: X 1 Selected from the spacer groups C1 and C3 described in this article; X 2 Selected from spacer group C19 as described herein: where * indicates an attachment site to T, ** indicates an attachment site to carbonyl, and the absence of * or ** spacer groups indicates that each of the two attachment sites can be attached to either T or carbonyl; X 3 Selected from spacer group B3 as described herein: wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to the 3'-O of the CpG terminal nucleotide; and ** indicates an attachment site to an amino group; and T is a triazole functional group. In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*T*C*G*A*A*T–3' (SD-101), linked to a spacer group at the 3'-O of the terminal nucleotide. In some embodiments of the conjugate of formula (XVI-B), wherein: X 1 It's C3.

[1447] In some embodiments, combinations of formula (XVI) are represented by the following:

[1448]

[1449] and / or

[1450]

[1451] CpG is an oligodeoxynucleotide linked to a phosphate thioester, having the sequence 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101), with a spacer group attached to the 3'-O position of the terminal nucleotide.

[1452] In some embodiments, the combination of formula (X) has a structure according to formula (XVII):

[1453]

[1454] in:

[1455] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1456] X 1 and X 2 Each is an independent spacer group portion;

[1457] R 1 and R 2 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or

[1458] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings that can contain one or two heteroatoms;

[1459] Y 1 Y 2 Y 3 and Y 4 Each can be either O or S independently;

[1460] T is a triazole functional group; and

[1461] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1462] In some embodiments, the combination is a combination of formula (XVII-A):

[1463]

[1464]

[1465] in:

[1466] X 1 Selected from the spacer groups C1 to C17 described herein:

[1467] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[1468] X 2 It is -X 3 -NH-CO-X 4 -, where X 3 Selected from **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B5 as described herein: wherein, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; and ** indicates an attachment site to an amino group;

[1469] X 4 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[1470] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[1471] R 1 and R 2 Each is independently hydrogen, Me, or Et;

[1472] T is a triazole functional group;

[1473] a is an integer between 0 and 2;

[1474] Each R e Independently selected from nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me and -OCF3; and

[1475] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1476] In some embodiments, the combination of formula (XVII-A) has a structure according to formula (XVII-B):

[1477]

[1478] in:

[1479] X 1The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[1480] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1481] X 2 It is -X 3 -NH-CO-X 4 -, where X 3 Selected from **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B5 as described herein: wherein, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates a 3'-O or 5'-O attachment site of the terminal nucleotide connected to CpG; and ** indicates an attachment site connected to an amino group;

[1482] X 4 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[1483] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1484] T is a triazole functional group; and

[1485] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1486] In some embodiments of the combination of formula (XVII-B), X 1 The spacer groups C1, C3, and C13 described herein are selected: where * indicates an attachment site to T, ** indicates an attachment site to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be attached to either T or a carbonyl group; X 2 It is -X 3 -NH-CO-X 4 -, where X 3 It is the spacer group B3 as described in this article: wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates the 3'-O attachment site of the terminal nucleotide linked to CpG; and ** indicates the attachment site linked to an amino group; X 4The spacer groups C1, C3, and C13 described herein are selected: where * indicates an attachment site to T, ** indicates an attachment site to a carbonyl group, and the absence of * or ** indicates that each of the two attachment sites can be attached to either T or a carbonyl group; T is a triazole functional group. In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*T*C*G*A*A*T–3' (SD-101), with the spacer group attached at the 3'-O position of the terminal nucleotide.

[1487] In some embodiments of the combination of formula (XVII-B), X 1 Selected from the spacer groups C3 and C13 described herein, and X 4 The spacer groups C3 and C13 described herein are selected.

[1488] In some implementations, the combination is represented by the following:

[1489]

[1490] and / or

[1491]

[1492] CpG is an oligodeoxynucleotide linked to a phosphate thioester, having the sequence 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101), with a spacer group attached to the 3'-O position of the terminal nucleotide.

[1493] In some embodiments, the combination of formula (X) has a structure according to formula (XVIII):

[1494]

[1495] in:

[1496] Ar 1 and Ar 2 Each is independently a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1497] X 1 X 2 X 3 and X 4 Each is an independent spacer group portion;

[1498] R 1 R 2 R3 and R 4 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl or substituted aryl; or

[1499] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms; or

[1500] R 3 and R 4 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[1501] Y 2 and Y 6 Each can be independently O, NH, or S;

[1502] Y 1 Y 3 Y 4 Y 5 Y 7 and Y 8 Each can be either O or S independently;

[1503] Each T is independently a triazole functional group; and

[1504] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1505] In some embodiments, the combination of formula (X) has a structure according to formula (XVIII-A):

[1506]

[1507] in:

[1508] X 1 and X 2 Each is independently selected from the spacer groups C1 to C17 described herein;

[1509] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[1510] X 3 and X 4 Each is independently selected from **-C3-C 12 Alkylene-L 1-*; and spacer groups B1 to B5 as described herein:

[1511] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; and ** indicates an attachment site to an amino group;

[1512] R 1 R 2 R 3 and R 4 Each is independently hydrogen, Me, or Et;

[1513] Each T is independently a triazole functional group;

[1514] a1 and a2 are each independent integers from 0 to 2;

[1515] R e1 and R e2 Each is independently selected from nitro, cyano, halogen, -OMe, and -OCF3; and

[1516] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1517] In some embodiments, the combination of formula (X) has formula (XVIII-B):

[1518]

[1519] in:

[1520] X 1 and X 2 Each is independently selected from the spacer groups C1, C3, C8, C10, C13, C18 and C19 described herein;

[1521] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1522] X 3 and X 4 Each is independently selected from **-C3-C 12 Alkylene-L 1 -*; and spacer groups B1 to B5 as described herein:

[1523] Among them, L 1Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; and ** indicates an attachment site to an amino group;

[1524] Each T is independently a triazole functional group; and

[1525] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1526] In some embodiments of the combination of formula (XVIII-B), X 1 Selected from the spacer groups C1 and C3 described herein, and X 2 Selected from the spacer group C19 described herein: where * indicates an attachment site to T, ** indicates an attachment site to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be attached to either T or a carbonyl group; X 4 It is **-C3-C 12 Alkylene-L 1-* ; among which, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates the 5'-O attachment site of the terminal nucleotide linked to CpG; and ** indicates the attachment site linked to an amino group; and X 3 It is the spacer group B3 as described herein: wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to the 3'-O of the CpG terminal nucleotide; and ** indicates an attachment site to an amino group; each T is independently a triazole functional group. In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T–3' (SD-101), where X 4 Covalently bonded to the 5'-O of the CpG-terminal nucleotide, and X 3 It is covalently bonded to the 3'-O of the CpG terminal nucleotide.

[1527] In some embodiments, the combination of formula (X) has a structure according to formula (XIX):

[1528]

[1529] in:

[1530] Ar is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1531] X 1 X2 and X 3 Each is an independent spacer group portion;

[1532] R 1 and R 2 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or

[1533] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings that can contain one or two heteroatoms;

[1534] Y 2 It is O, NH or S;

[1535] Y 1 Y 3 and Y 4 Each can be either O or S independently;

[1536] Each T is independently a triazole functional group; and

[1537] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1538] In some embodiments, the combination of formula (X) has a structure according to formula (XIX-A):

[1539]

[1540] in:

[1541] X 1 Selected from the spacer groups C1 to C17 described herein:

[1542] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[1543] X 2 and X 3 Each is independently -X 4 -NH-CO-X 5 -, where X 4 Selected from **-C3-C 12 Alkylene-L 1-* ; and spacer groups B1 to B5 as described herein:

[1544] Among them, L 1Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; and ** indicates an attachment site to an amino group;

[1545] X 5 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[1546] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group.

[1547] R 1 and R 2 Each is independently hydrogen, Me, or Et;

[1548] Each T is independently a triazole functional group;

[1549] a is an integer between 0 and 2;

[1550] Each R e Independently selected from nitro, cyano, halogen, -OMe, -NHMe, -NHAc, -NHSO2Me and -OCF3; and

[1551] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1552] In some embodiments, the combination of formula (X) has a structure according to formula (XIX-B):

[1553]

[1554] in:

[1555] X 1 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[1556] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1557] X 2 and X 3 Each is independently -X 4 -NH-CO-X 5 -, where X 4 Selected from **-C3-C 12 Alkylene-L 1-*; and spacer groups B1 to B5 as described herein:

[1558] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; and ** indicates an attachment site to an amino group;

[1559] X 5 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[1560] Where * indicates an attachment point connected to T, ** indicates an attachment point connected to a carbonyl group, and the absence of a spacer group (* or **) indicates that each of the two attachment points can be connected to either T or a carbonyl group.

[1561] Each T is independently a triazole functional group; and

[1562] CpG is an oligodeoxynucleotide that acts as a TLR9 agonist.

[1563] In some embodiments of the combination of formula (XIX-B), X 1 The spacer groups C1 and C3 described herein are selected: where * indicates an attachment site to T, ** indicates an attachment site to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be attached to either T or a carbonyl group; X 2 and X 3 Each is independently -X 4 -NH-CO-X 5 -, where X 4 It is **-C3-C 12 Alkylene-L 1-* ; among which, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates an attachment site at the 5'-O of the terminal nucleotide of CpG; and ** indicates an attachment site to an amino group; or X 4 It is the spacer group B3 as described in this article: wherein, L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to the 3'-O of the CpG-terminal nucleotide; and ** indicates an attachment site to an amino group; X 5The spacer group is selected from C13 as described herein: where * indicates an attachment site to T, and ** indicates an attachment site to a carbonyl group; each T is independently a triazole functional group. In some embodiments, CpG is a thiophosphate-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101).

[1564] In some embodiments, the combination of formula (X) has a structure according to formula (XXVIII):

[1565]

[1566] in:

[1567] X 1 and X 2 Each is independently selected from the spacer groups C1, C3, and C13 described herein;

[1568] Where * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that each of the two attachment sites can be connected to either T or a carbonyl group; and

[1569] T is a triazole functional group.

[1570] In some embodiments of the combination of formula (XXVIII), X 1 and X 2 Each is independently selected from the spacer groups C3 and C13 described herein.

[1571] In some implementations, the combination is represented by the following:

[1572]

[1573] and / or

[1574]

[1575] In some embodiments, this application provides STING agonists released from conjugates having formulas (XXIV), (XXVI), (XXVI-A), and (XXVI-B), wherein the released STING agonist has a structure according to formula (XXVIV):

[1576]

[1577] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, regioisomers, mixtures of two or more regioisomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof;

[1578] in:

[1579] Ar 1 It is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1580] X 1 and X 2 Each is an independent spacer group portion;

[1581] R 1 and R 2 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or

[1582] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[1583] Y 3 and Y 4 Each can be either O or S independently;

[1584] b is an integer of 1 or 2; where, when b = 2, both groups are directly bonded to A;

[1585] Each T is independently a triazole functional group; and

[1586] A is a STING agonist.

[1587] In some embodiments of the STING agonist of formula (XXVIV), the STING agonist is selected from: ADU-S100, MK-1454, BMS-986301, GSK3745417, E7766, SB11285, Or its stereoisomers.

[1588] In some embodiments, the released STING agonist has a structure according to formula (XXVIV-A):

[1589]

[1590] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, regioisomers, mixtures of two or more regioisomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof;

[1591] in:

[1592] Ar 1 It is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group;

[1593] X 1 and X 2 Each is an independent spacer group portion;

[1594] R 1 and R 2 Each is independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, or substituted aryl; or

[1595] R 1 and R 2 Together with the atoms they are attached to, they can link together to form 3-8 membered rings, which may optionally contain one or two heteroatoms;

[1596] Y 3 and Y 4 Each can be either O or S independently;

[1597] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1598] Each T is independently a triazole functional group;

[1599] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1600] The linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist.

[1601] In some embodiments, the released STING agonist has a structure according to formula (XXVIV-B):

[1602]

[1603] in:

[1604] X 1 Selected from the spacer groups D1 to D12 described herein:

[1605] Wherein, * indicates attachment to the selected T, ** indicates attachment to the phenyl group, and the absence of * or ** spacer groups indicates the ability to attach to the T or phenyl group.

[1606] X 2 Selected from the spacer groups C13 to C17 described herein;

[1607] Oxygen can be optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site to T, and ** indicates an attachment site to carbonyl.

[1608] R 1 and R 2 Each is independently hydrogen, Me, or Et;

[1609] Each T is independently a triazole functional group;

[1610] a1 is an integer from 0 to 2;

[1611] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1612] R e1 Selected from nitro, cyano, halogen, -OMe, and -OCF3;

[1613] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1614] The linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist.

[1615] In some embodiments, the released STING agonist has a structure according to formula (XXVIV-C):

[1616]

[1617] in:

[1618] X 1 The spacer groups D5 and D6 described herein are selected: where * indicates an attachment site to the selected T, and ** indicates an attachment site to the phenyl group;

[1619] X 2 Selected from spacer group C19 as described herein: where * indicates an attachment site to T, and ** indicates an attachment site to a carbonyl group;

[1620] b is an integer of 1 or 2; where b = 2, both groups are directly bonded to the CDN;

[1621] Each T is independently a triazole functional group;

[1622] CDN is a cyclic dinucleotide that acts as a STING agonist; and

[1623] The linker is covalently bonded to the thiol group of the cyclic dinucleotide STING agonist.

[1624] In some embodiments of the STING agonists released by formulas (XXVIV), (XXVIV-A), (XXVIV-B), and (XXVIV-C), b is 1. In some embodiments of the STING agonists released by formulas (XXVIV), (XXVIV-A), (XXVIV-B), and (XXVIV-C), b is 2.

[1625] In some embodiments of the STING agonist releasing formulas (XXVIV), (XXVIV-A), (XXVIV-B), and (XXVIV-C), b is 1 and the cyclic dinucleotide is:

[1626] Or its stereoisomers; wherein, * indicates that the S of the thiol group (-SH, where the position of * is not shown) of the cyclic dinucleotide is linked to the linker.

[1627] In some embodiments, this application provides TLR9 agonists released from conjugates of formulas (XII), (XII-A), (XII-B), (XVII), (XVII-A), and (XVII-B), wherein the released TLR9 agonist has a structure according to formula (XX):

[1628]

[1629] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, regioisomers, mixtures of two or more regioisomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof;

[1630] in:

[1631] X 1 and X 2 Each is an independent spacer group portion;

[1632] Y 1 and Y 2 Each can be either O or S independently;

[1633] T is a triazole functional group; and

[1634] CpG is a TLR9 agonist oligodeoxynucleotide; in which one or more atoms in CpG are independently replaced by covalent bonds with X. 2 connect.

[1635] In some embodiments, this application provides complexes having formulas (XIV), (XIV-A), (XIV-B), (XIX), (XIX-A), and (XIX-B), wherein the released TLR9 agonist has a structure according to formula (XXI):

[1636]

[1637] Or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, regioisomers, mixtures of two or more regioisomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof;

[1638] in:

[1639] X 1 X 2 and X 3 Each is an independent spacer group portion;

[1640] Y 1 and Y 2 Each can be either O or S independently;

[1641] Each T is independently a triazole functional group; and

[1642] CpG is a TLR9 agonist oligodeoxynucleotide; in which one or more atoms in CpG are independently replaced by covalent bonds with X. 2 and X 3 connect.

[1643] In certain embodiments of the TLR9 agonists of formulas (XX) and (XXI), X 1 Selected from the spacer groups C1 to C17 described in this article:

[1644] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S or SO2; * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl or thiocarbonyl group, and the absence of a * or ** spacer group indicates that the attachment site can be connected to T or a carbonyl or thiocarbonyl group.

[1645] X 2 and X 3Each is independently -X 4 -NH-CO-X 5 -, where X 4 Selected from **-C3-C 12 Alkylene-L 1-* ; and spacer groups B1 to B5 as described herein:

[1646] Among them, L 1 Independently, it is a bond, -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to a 3'-O or 5'-O nucleotide at the CpG terminus; and ** indicates an attachment site to an amino group;

[1647] X 5 The spacer groups selected from those described herein are C1, C3, C8, C10, C13, C18, and C19:

[1648] Each oxygen atom is independently and optionally replaced by NH, NMe, NAc, S, or SO2; * indicates an attachment site to T, ** indicates an attachment site to a carbonyl group, and the absence of a * or ** spacer group indicates that the attachment site can be attached to either T or a carbonyl group; and

[1649] Y 1 and Y 2 It is O.

[1650] In certain embodiments of the TLR9 agonists of formulas (XX) and (XXI), X 1 The spacer groups C1, C3, C8, C10 to C19 described herein are selected: where * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that the attachment site can be connected to either T or a carbonyl group.

[1651] X 2 and X 3 Each is independently -X 4 -NH-CO-X 5 -, where X 4 It is **-C3-C 12 Alkylene-L 1 -*; where L 1 Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; * indicates an attachment site at the 5'-O of the terminal nucleotide of CpG; and ** indicates an attachment site to an amino group; or X 4 It is the spacer group B3 as described in this article: wherein, L 1Independently, it is -OP(O)(OH)- or -OP(S)(OH)-; and * indicates an attachment site to the 3'-O of the CpG-terminal nucleotide; ** indicates an attachment site to an amino group;

[1652] X 5 The spacer groups C1, C3, and C13 described herein are selected: where * indicates an attachment site connected to T, ** indicates an attachment site connected to a carbonyl group, and the absence of a * or ** spacer group indicates that the attachment site can be connected to either T or a carbonyl group.

[1653] Y 1 and Y 2 It is O.

[1654] In some embodiments of the TLR9 agonists of formulas (XX) and (XXI), wherein X 1 The spacer groups are selected from C3, C10 to C19 as described herein, and X 5 The spacer groups C3 and C13 described herein are selected.

[1655] In some embodiments, CpG is a TLR9 agonist CpG ODN (oligodeoxynucleotide), which is a short synthetic single-stranded DNA molecule containing an unmethylated CpG motif in the following sequence: phosphate thioester linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101), with a spacer group linked at the 3'-O or 5'-O of the terminal nucleotide.

[1656] In some embodiments of the TLR9 agonist of formula (XX), the TLR9 agonist has the following structure:

[1657] or

[1658] Wherein, CpG is an oligodeoxynucleotide linked to a phosphate thioester, and the oligodeoxynucleotide has

[1659] The sequence 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' is linked to a spacer group at the 3'-O position of the terminal nucleotide; or

[1660] TLR9 agonists have the following structure:

[1661] or

[1662] Wherein, the CpG is an oligodeoxynucleotide linked to a thiophosphate, having the sequence 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3', with a spacer group linked to the 5'-O position of the terminal nucleotide.

[1663] In certain embodiments of compounds of formulas (I), (V), (VA), (VB), (VI), (VII), (VII-A), (VII-B), (VIII), (X-1), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII), (XVII-A), (XVII-B), (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), and (XXVII-B), wherein CpG comprises the following formula:

[1664] 5'X1X2CGX3X43'

[1665] Where X1, X2, X3, and X4 are any nucleotides, and

[1666] CpG is attached to a spacer group at the 5'-O and / or 3'-O position of the terminal nucleotide.

[1667] In some implementations, CpG is:

[1668] 5'-GGGGGGGGGGACGATCGTCGGGGGGGGGG-3'(CMP-001); ligated at the 5'-O and / or 3'-O of the terminal nucleotide.

[1669] In certain embodiments of compounds of formulas (I), (V), (VA), (VB), (VI), (VII), (VII-A), (VII-B), (VIII), (X-1), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII), (XVII-A), (XVII-B), (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), and (XXVII-B), wherein CpG comprises the following formula:

[1670] 5'N1X1CGX2N2 3'

[1671] In this sequence, at least one nucleotide isolates a continuous CpG; X1 is adenine, guanine, or thymine; X2 is cytosine or thymine; N is any nucleotide, and N1+N2 is approximately 0 to 26 bases long, provided that N1 and N2 do not contain a CCGG tetramer or more than one CCG or CGG trimer; the nucleic acid sequence is approximately 8 to 30 bases long; and

[1672] CpG is attached to a spacer group at the 5'-O and / or 3'-O position of the terminal nucleotide.

[1673] In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*T*C*G*T*T*T*T*T*T*T*T*T*T*T*T*T*T-3' (PF-3512676); with a spacer group attached at the 5'-O and / or 3'-O of the terminal nucleotide.

[1674] In certain embodiments of compounds of formulas (I), (V), (VA), (VB), (VI), (VII), (VII-A), (VII-B), (VIII), (X-1), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII), (XVII-A), (XVII-B), (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), and (XXVII-B), wherein CpG comprises the following formula:

[1675] a)5'-N x (TCG(N q )) y N w (X1X2CGX2'X1'(CG) p ) z

[1676] Where N is a nucleotide, x = 0, y = 1, w = 0, p = 0 or 1, q = 0, 1 or 2, and z = 1-20, X1 and X1' are self-complementary nucleotides, X2 and X2' are self-complementary nucleotides, and (TCG(N) q )) y The 5'T of the sequence is located at the 5' end of the polynucleotide; and

[1677] b) A palindromic sequence of at least 8 bases, wherein the palindromic sequence contains (X1X2CGX2'X1'(CG)). p ) z The first part of the sequence (X1X2CGX2'X1'), wherein the length of the above polynucleotide sequence is at least 15 bases; and

[1678] CpG is attached to a spacer group at the 5'-O and / or 3'-O position of the terminal nucleotide.

[1679] In some embodiments, CpG is a phosphate thioester-linked 5'-T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*C*G*T*T*C*G*A*A*T–3' (SD-101); with a spacer group attached at the 5'-O and / or 3'-O of the terminal nucleotide.

[1680] In the formula (I), (V), (VA), (VB), (VI), (VII), (VII-A), (VII-B), (VIII), (X-1), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII- A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII), (XVII-A), (XVII-B), (XVIII), (XVIII-A), (XVIII- In certain embodiments of compounds B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), and (XXVII-B), CpG comprises at least two oligonucleotides, internucleotide bonds, or non-nucleotide-functionalized nucleobases or sugars linked together at their 3' ends, wherein at least one of these oligonucleotides is an immunostimulatory oligonucleotide having an accessible 5' end and comprising an immunostimulatory dinucleotide selected from the group consisting of: CG, C # G, CG # and C # G # Where C is cytidine or 2'-deoxycytidine, C # It is 2'-deoxythymidine, cytarabine, 2'-deoxy-2'-substituted cytarabine, 2'-O-substituted cytarabine, 2'-deoxy-5-hydroxycytidine, 2'-deoxy-N4-alkyl-cytidine, 2'-deoxy-4-thiouridine, or other non-natural pyrimidine nucleosides. G is guanosine or 2'-deoxyguanosine. # It is 2'-deoxy-7-denitroguanosine, 2'-deoxy-6-thioguanosine, vidarabine, 2'-deoxy-2'-substituted vidarabine, 2'-O-substituted vidarabine, or other non-natural purine nucleosides, where p is a nucleoside internucleotide selected from the group consisting of phosphate diesters, thiophosphates, and dithiophosphates; and

[1681] CpG is attached to a spacer group at one or both 5'-O positions of the terminal nucleotide and / or internucleotide bond.

[1682] In some embodiments, CpG is a phosphate-thioester-linked 5'-T*C*G1*A*A*C*G1*T*T*C*G1*-X-*G1*C*T*T*G1*C*A*A*G1*C*T*-5', where X is a glycerol linker and G1 is 2'-deoxy-7-dezoguanosine (IMO-2125); it is linked to a spacer group at one or both 5'-O sites and / or at the glycerol site of the terminal nucleotide.

[1683] In some embodiments of these combinations, the formulas (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XH), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII-A), (XV) are given. TLR9 agonist derivatives or STING agonist derivatives of (II-B), (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), (XXVII-B), (XXVIII), (XXVIV), (XXVIV-A), (XXVIV-B), and (XXVIV-C), wherein the triazole functional group has the following structure:

[1684]

[1685] In some embodiments of these combinations, the formulas (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XH), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII-A), (XV) are given. TLR9 agonist derivatives or STING agonist derivatives of (II-B), (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), (XXVII-B), (XXVIII), (XXVIV), (XXVIV-A), (XXVIV-B), and (XXVIV-C), wherein the triazole functional group has the following structure:

[1686] as well as

[1687] In some embodiments, the triazole functional group is

[1688]

[1689] In some embodiments, the T of the combination of formula (X) or the combination of formula (X-1) is connected to -Z via *. 2 -A 2 And T is connected to -Z via **. 1 -or-Z 3 - In some implementations, T is connected to -Z via **. 2 -A 2 And T is connected to -Z via * 1 -or-Z 3 -

[1690] In certain embodiments, Formula (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XH), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII) , (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII-A), (XVII-B) These conjugates, TLR9 agonist derivatives, or STING agonist derivatives of (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), (XXVII-B), (XXVIII), (XXVIV), (XXVIV-A), (XXVIV-B), and (XXVIII-C), TLR9 agonist derivatives, or STING agonist derivatives, are linked to X via **. 2 And connected to X via * 1 In some implementations, T is connected to X via *. 2 And connected to X via ** 1 In some implementations, T is connected to X via **. 4 And connected to X via * 1 In some implementations, T is connected to X via *. 4 And connected to X via ** 1 In some implementations, T is connected to X via **. 3 And connected to X via * 1 In some implementations, T is connected to X via *. 3 And connected to X via ** 1 .

[1691] In certain embodiments, Formula (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XH), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), ( XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII-A), (XVII-B), (XVIII), (XV These conjugates, TLR9 agonist derivatives, or STING agonist derivatives may contain more than one variable (e.g., T, Z in formula (X)). 2 and A 2 ) or variables defined in groups (e.g., Z in formula (X) 1 Z 2 and Z 3 The variables can be the same or different. Whenever a variable appears, its selection is made independently of other variables existing in the same formula, even if the same variable exists in duplicate or more.

[1692] In some embodiments, this application provides a method for preparing a drug-drug conjugate according to scheme (II):

[1693]

[1694] in:

[1695] b1 is an integer that is either 0 or 1;

[1696] b2 is an integer that is either 0 or 1;

[1697] The condition is that b1 + b2 is 1 or 2;

[1698] Each T is independently a triazole functional group;

[1699] Z 1 Z 2 and Z 3 Each is an independent spacer group portion;

[1700] A 1and A 2 Each is independently a therapeutic agent or the active portion of a therapeutic agent; or a compound that can be broken down into a therapeutic agent.

[1701] FG 1 It is possible to achieve this through click chemistry and FG 2 The functional groups of the reaction, FG 2 Selected from azides, alkynyl groups, and cycloalkynyl groups; and

[1702] FG 2 It is possible to achieve this through click chemistry and FG 1 The functional groups of the reaction, FG 1 Selected from azides, alkynyl groups, and cycloalkynyl groups; in some embodiments, Z 1 Z 2 and Z 3 Each is an independent releasable connector portion. In some embodiments, the releasable connector portion is derived from the releasable connectors of formulas (II), (II-A), (II-B), and (II-C). In some embodiments, Z 1 Z 2 and Z 3 Each is an independent non-releasable connector portion. In some embodiments, the cycloalkynyl group is dibenzocyclooctyne (DBCO) or bicyclic [6.1.0]nonyne (BCN).

[1703] In some embodiments of the method for preparing a drug-drug conjugate, the therapeutic agent is a STING agonist, a TLR9 agonist, or a TLR7 / 8 agonist. In some embodiments, the STING agonist is any STING agonist disclosed herein. Exemplary STING agonists are disclosed in WO 2019 / 043634, ADU-S100, MK-1454, BMS-986301, GSK3745417, E7766, SB11285,

[1704] Or its stereoisomers.

[1705] In some embodiments of the method for preparing a drug-drug conjugate, the TLR9 agonist is the TLR9 agonist of formula (I).

[1706] In some embodiments of the method for preparing drug-drug conjugates, the TLR7 / 8 agonist is R848.

[1707] In some embodiments, this application provides pharmaceutical compositions comprising compounds or combinations disclosed herein and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is administered for the treatment of cancer, infection, or autoimmune disease. In some embodiments, the pharmaceutical composition may be administered in combination with other suitable therapeutic agents.

[1708] In some embodiments, the compounds of this application comprise phosphorus atoms bonded to boron atoms to form Lewis acid / Lewis base adducts. The phosphorus-boron bond can be interchangeably described as a coordinate covalent bond (or a coordinate bond) or a covalent bond with a formal charge.

[1709] as well as

[1710] Although one form of Lewis acid / Lewis base adduct is described herein, all such forms are covered within the scope of this application.

[1711] When the compounds provided herein contain an acidic or basic moiety, they may also be provided as pharmaceutically acceptable salts. See Berge et al., J. Pharm. Sci. 1977, 66, 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahland Wermuth Eds; John Wiley & Sons, 2011. In some embodiments, the pharmaceutically acceptable salt of the compounds provided herein is a solvate. In some embodiments, the pharmaceutically acceptable salt of the compounds provided herein is a hydrate.

[1712] Acids suitable for preparing pharmaceutically acceptable salts of the compounds provided herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cycloamidoic acid, cyclohexanesulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactopyric acid, gentian acid, glucoheponic acid, D-gluconic acid, D-glucuronic acid, L- Glutamic acid, α-oxoglutarate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic 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, pyruvic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharinic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanate, p-toluenesulfonic acid, undecenoic acid, and valeric acid.

[1713] Bases suitable for preparing pharmaceutically acceptable salts of the compounds provided herein include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases (such as primary amines, secondary amines, tertiary amines and quaternary amines, aliphatic amines and aromatic amines) including, but not limited to, L-arginine, phenethylamine, benzathine penicillin G, choline, decanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethylamine, etc. Alcohols, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methylglucosamine, hebamin, 1H-imidazolium, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinine ring, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucosamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

[1714] The compounds provided herein can also be provided as prodrugs, which are functional derivatives of the compounds and readily converted into the parent compound in vivo. Prodrugs are often useful because, in some cases, they can be administered more readily than the parent compound. For example, they can achieve bioavailability through oral administration, whereas the parent compound cannot. Prodrugs can also have enhanced solubility in pharmaceutical compositions compared to the parent compound. Prodrugs can be converted into the parent drug through a variety of mechanisms, including enzymatic processes and metabolic hydrolysis.

[1715] Pharmaceutical compositions and formulations

[1716] In one embodiment, this application relates to a pharmaceutical composition comprising formulas (I), (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI), (XVI-1), (XVI-A), (XVI-B), (XVII), (XVII-A), (XVI-B ...A), (XVI-B), (XVI-B), (XVI-B), (XVI-B), (XVI-B), (XVI-A), (XVI-B), (XVI-B), (XVI-B (XVII-B), (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), (XXVII-B), (XXVIII), (XXVIV), (XXVIV-A), (XXVIV-B), or (XXVIV-C) or any of their subgenuses, or their pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates, and one or more pharmaceutically acceptable excipients.

[1717] For various purposes, pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation. In another embodiment, the pharmaceutical composition comprises formulas (I), (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI), (XVI-1), (XVI-A), (XVI-B), (XVII), (XVII-A), (XVII-B), (XVII-B), (XVI-A), (XVII-B), (XVI ... One or more compounds of (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), (XXVII-B), (XXVIII), (XXVIV), (XXVIV-A), (XXVIV-B), or (XXVIV-C) or any subgenus thereof, or a pharmaceutically acceptable salt, its stereoisomer, solvate, or hydrate, further comprising a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutically acceptable carrier comprises pharmaceutically acceptable excipients, binders, and / or diluents. In one embodiment, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc (mica), silica, viscous paraffin, hydroxymethyl cellulose, and polyvinylpyrrolidone.

[1718] In one embodiment, the excipient can be used to deliver a safe, stable, and functional drug, serving not only as part of the overall delivery carrier but also as a means for the recipient to achieve efficient absorption of the active ingredient. The excipient can be simply and directly filled, like an inert filler, or the excipient used herein can be part of a pH-stabilizing system or coating to ensure safe delivery of the ingredient to the stomach. Formulators can also take advantage of the fact that the compounds of this application have improved cellular potency, pharmacokinetic properties, and improved oral bioavailability.

[1719] In some embodiments, the pharmaceutical compositions of this application may additionally include other auxiliary components conventionally found in pharmaceutical compositions, beyond the level of use established in the prior art. Thus, for example, these pharmaceutical compositions may contain additional, compatible, pharmaceutically active materials (such as, for example, antipruritics, astringents, local anesthetics, or anti-inflammatory agents), or may contain additional materials useful in various dosage forms that physically formulate the compositions of this application, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickeners, and stabilizers. However, such materials should not excessively interfere with the bioactivity of the components of the compositions of this application when added. These formulations can be sterilized and, if desired, can be mixed with adjuvants (e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavoring agents, and / or aromatic substances, etc.) that do not produce harmful interactions with one or more oligonucleotides of the formulation.

[1720] Suitable formulations for oral administration include solid dosage forms such as tablets, capsules containing microparticles, liquids or powders, lozenges (including liquid-filled ones), chewables, multiply and nanoparticles, gels, solid solutions, liposomes, membranes (including mucosal adhesives), beads, sprays, and liquid formulations.

[1721] Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations can be used as fillers in soft or hard capsules and typically include a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and one or more emulsifiers and / or suspending agents.

[1722] Liquid formulations can also be prepared by reconstructing solids.

[1723] The compounds of this application may also be used in rapidly dissolving and rapidly disintegrating dosage forms (such as those described in Liang and Chen (2001), Expert Opinion in Therapeutic Patents, 11(6), 981986, the disclosure of which is incorporated herein by reference in its entirety).

[1724] For tablet dosage forms, depending on the dosage, the drug can comprise 1 wt% to 80 wt% of the dosage form, more typically 5 wt% to 60 wt%. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Overall, the disintegrant will comprise 1 wt% to 25 wt% of the dosage form, preferably 5 wt% to 20 wt%.

[1725] Binders are commonly used to impart cohesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate.

[1726] The tablets may also optionally include surfactants (such as sodium lauryl sulfate and polysorbate 80) and flow aids (such as silica and talc). When present, the surfactants may comprise from 0.2% to 5% by weight of the tablets, and the flow aids may comprise from 0.2% to 1% by weight of the tablets.

[1727] Tablets typically also contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant generally constitutes 0.25% to 10% by weight of the tablet, preferably 0.5% to 3% by weight.

[1728] Other possible ingredients include antioxidants, colorants, flavorings, preservatives, and flavor masking agents.

[1729] Tablet blends can be directly compressed or rolled to form tablets. The tablet blend, or portions thereof, may alternatively be wet, dry, melt-granulated, melt-coated, or extruded prior to tableting. The final formulation may include one or more layers and may be coated or uncoated; it may even be encapsulated.

[1730] The formulation of tablets was discussed by H. Lieberman and L. Lachman in "Pharmaceutical Dosage Forms: Tablets, Vol. 1" in Marcel Dekker, NY, 1980 (ISBN 0-8247-6918-X).

[1731] The aforementioned formulations used for the various types of administration discussed herein can be immediate-release formulations and / or modified-release formulations. Modified-release formulations include delayed-release, sustained-release, pulsatile-release, controlled-release, targeted-release, and programmed-release. Suitable modified-release formulations for the purposes of this application are described in US Pat. No. 6,106,864. Details of other suitable release technologies, such as high-energy dispersions and permeable and coated particles, are found in Verma et al., Pharmaceutical Technology Online, 25(2), 1-14 (2001). Controlled-release using chewing gum is described in WO 00 / 35298.

[1732] Preparations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injectable solutions, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the preparation isotonic with the recipient's blood; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. Preparations may be available in single-dose or multi-dose sealed containers, such as ampoules and small flasks, and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, just before use. Injectable solutions and suspensions can be prepared from sterile powders, granules, and tablets of the types described above.

[1733] The solubility of the compounds of this application used for preparing parenteral solutions can be increased by using appropriate formulation techniques (such as incorporating solubility enhancers).

[1734] Formulations intended for parenteral administration can be immediate-release and / or modified-release formulations. Therefore, the compounds of this application can be formulated as solids, semi-solids, or thixotropic liquids for administration as implantable long-acting formulations providing modulated release of the active compound. Examples of such formulations include drug-coated scaffolds and poly(glycolic acid-dl-lactide) or PGLA microspheres.

[1735] The compounds of this application can be combined with soluble macromolecular entities (such as cyclodextrins and suitable derivatives thereof, or polyethylene glycol-containing polymers) to improve their solubility, dissolution rate, taste masking, bioavailability, and / or stability for any of the aforementioned administration modalities. For example, drug-cyclodextrin complexes have been found to be generally suitable for most dosage forms and routes of administration. Both included and non-included complexes can be used. As an alternative to direct complexation with drugs, cyclodextrins can be used as co-additives, i.e., as carriers, diluents, or solubilizers. α-Cyclodextrins, β-cyclodextrins, and γ-cyclodextrins are most commonly used for these purposes, and examples of these can be found in international patent applications WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[1736] Salts of the compounds of this application are preferably pharmaceutically acceptable due to their potential uses in medicine. In one embodiment, the salts of the compounds of this application in a pharmaceutical preparation or pharmaceutical composition are pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts include, but are not limited to, those described in P. Heinrich Stahl and Camille G. Wermuth in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd Edition (Wiley-VCH: 2011), Remington's Pharmaceutical Sciences, 18th Edition (Mack Publishing, Easton PA: 1990), and Remington: The Science and Practice of Pharmacy, 19th Edition (Mack Publishing, Easton PA: 1995). Salts covered in the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this application.

[1737] Salts of the compounds of this application containing basic amines or other basic functional groups can be prepared by any suitable method known in the art, including treatment of the free base with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, formic acid, alginic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranoside amino acids (such as glucuronic acid or galacturonic acid), α-hydroxy acids (such as citric acid or tartaric acid), amino acids (such as aspartic acid or glutamic acid), aromatic acids (such as benzoic acid or cinnamic acid), sulfonic acids (such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.)). Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propynyl esters, oxalates, malonyl esters, succinates, caprylates, sebacic acid esters, fumarates, maleates, butyn-1,4-diacidates, hexyn-1,6-diacidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenyl acetates, phenyl propionates, phenyl butyrates, citrates, lactates, glycolates, resin esters, lactates, camphor sulfonates, tartrate esters, mandelates, and sulfonates (such as xylene sulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, and naphthalene-2-sulfonates).

[1738] Salts of the compounds in this application can be prepared by reacting them with a suitable base. Pharmaceutically acceptable salts include, but are not limited to: alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum and ammonium salts, zinc, and salts made from physiologically acceptable organic bases (such as diethylamine, isopropylamine, ethanolamine, benzathine penicillin, phenethylamine, tromethamine (2-amino-2-(hydroxymethyl)propane-1,3-diol), morpholine, epoisen, piperidine, piperazine, methylpyridine, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, tri-(2-hydroxyethyl)amine, chloroprocaine, choline, decanol, imidazole, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), procaine, dibenzylpiperidine, dehydrorosinamine, glucosamine, trimethylpyridine, quinine, quinolones, tert-butylamine, and basic amino acids (such as lysine and arginine). Other pharmaceutically acceptable salts are known to those skilled in the art.

[1739] Therapeutic uses

[1740] In some embodiments, this application relates to methods of treating diseases and conditions in which regulation of STING (a stimulator of the interferon gene) and / or TLR is beneficial. In one embodiment, this application relates to a method of treating a disease or condition in which regulation of STING and / or TLR is beneficial in a subject, the method comprising administering a therapeutically effective amount of formulas (I), (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI-1), (XVI), (XVI-A) Compounds of (XVI-B), (XVII), (XVII-A), (XVII-B), (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), (XXVII-B), (XXVIII), (XXVIV), (XXVIV-A), (XXVIV-B), or (XXVIV-C), or any subgenus thereof, or pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates thereof.In one embodiment, this application relates to formulas (I), (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII), (XVII-A), (XVII-B), (XVIII), (XV) Compounds of (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), (XXVII-B), (XXVIII), (XXVIV), (XXVIV-A), (XXVIV-B), or (XXVIV-C) or any subgenus thereof, or pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates thereof, are used in the treatment of diseases or conditions in which the regulation of STING and / or TLR is beneficial in the subject.

[1741] In one embodiment, this application relates to a method for regulating STING and / or TLR, the method comprising administering a therapeutically effective amount of formula (I), (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVI-B), ( Compounds of (XVII), (XVII-A), (XVII-B), (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), (XXVII-B), (XXVIII), (XXVIV), (XXVIV-A), (XXVIV-B), or (XXVIV-C), or any subgenus thereof, or pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates thereof. In one embodiment, this application relates to formulas (I), (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII), (XVII-A), (XVII-B) Compounds of (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), (XXVII-B), (XXVIII), (XXVIV), (XXVIV-A), (XXVIV-B) or (XXVIV-C) or any of their subgenus or pharmaceutically acceptable salts, stereoisomers, solvates or hydrates, used to regulate STING and / or TLR.

[1742] In some embodiments, this application relates to a method for inducing, modifying, or stimulating an appropriate immune response in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound of this application or a pharmaceutically acceptable salt thereof. In one embodiment, this application relates to formulas (I), (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII), (XVII-A), (XVII-B), (XV... Compounds of (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), (XXVII-B), (XXVIII), (XXVIV), (XXVIV-A), (XXVIV-B), or (XXVIV-C), or any of their subgenus or pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates, are used to induce, modify, or stimulate an appropriate immune response in mammals. The immune response may include, but is not limited to, specific immune responses, nonspecific immune responses, specific and nonspecific responses, innate responses, primary immune responses, adaptive immunity, secondary immune responses, memory immune responses, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression.

[1743] In some embodiments, these compounds of the present application induce STING- and / or TLR-dependent type I interferon production in subjects (e.g., humans).

[1744] In some implementations, the regulation of STING and / or TLR is beneficial for the disease or condition that is cancer.

[1745] In some embodiments, the compounds of this application can be used to treat cancer. In one embodiment, this application relates to a method of treating cancer, the method comprising administering a therapeutically effective amount of formulas (I), (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII) (XVII-A), (XVII-B), (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), (XXVII-B), (XXVIII), (XXVIV), (XXVIV-A), (XXVIV-B), or (XXVIV-C) compounds or any subgenus thereof or pharmaceutically acceptable salts, stereoisomers, solvates or hydrates thereof. In one embodiment, this application relates to formulas (I), (X), (X-1), (XA), (XB), (XC), (XD), (XE), (XF), (XG), (XI), (XI-A), (XI-B), (XII), (XII-A), (XII-B), (XIII), (XIII-A), (XIII-B), (XIV), (XIV-A), (XIV-B), (XV), (XV-A), (XV-B), (XVI-1), (XVI), (XVI-A), (XVI-B), (XVII), (XVII-A), (XVI Compounds of (I-B), (XVIII), (XVIII-A), (XVIII-B), (XIX), (XIX-A), (XIX-B), (XX), (XXI), (XXIV), (XXV), (XXVI), (XXVI-A), (XXVI-B), (XXVII), (XXVII-A), (XXVII-B), (XXVIII), (XXVIV), (XXVIV-A), (XXVIV-B), or (XXVIV-C), or any subgenus thereof, or pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates thereof, for the treatment of cancer.Non-limiting examples of cancer include colorectal cancer, squamous cell carcinoma of the digestive tract, lung cancer, brain cancer, liver cancer, stomach cancer, bladder cancer, thyroid cancer, adrenal cancer, gastrointestinal cancer, oropharyngeal cancer, esophageal cancer, head and neck cancer, ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, breast cancer, melanoma, prostate cancer, pancreatic cancer, kidney cancer, sarcoma, leukemia, lymphoma, and multiple myeloma.

[1746] In one aspect, this application provides various methods for treating cancer in mammalian subjects in need, including administering a therapeutically effective amount of a pharmaceutical composition comprising a combination or compound containing a STING and / or TLR agonist as disclosed herein. In some embodiments, this application provides methods for treating cancer in mammalian subjects in need, including administering a therapeutically effective amount of a pharmaceutical composition to the subject via intratumoral delivery, the pharmaceutical composition comprising a combination or compound disclosed herein. In another aspect of the method, enteral delivery comprises injecting the pharmaceutical composition into at least one tumor lesion. In other aspects, treating cancer includes inducing the accumulation of tumor antigen-specific T cells in the injected tumor, for example, in a number greater than that of the pharmaceutical composition administered at an extratumor site. In other aspects, treating cancer includes eliciting a systemic tumor antigen-specific T cell response, including, for example, a systemic tumor antigen-specific T cell response of a greater magnitude than that of the immunogenic composition administered at an extratumor site. In other aspects, treating cancer includes eliciting a systemic tumor antigen-specific T cell response. In other aspects, treating cancer includes reducing the number of CD4+FoxPS+ regulatory T cells in the injected tumor. In other aspects, the subject has one or more uninjected tumors (primary or metastatic lesions) in addition to the injected tumor, and treating the cancer includes one or more of the following: (a) reducing the number of uninjected tumors; (b) reducing the volume of uninjected tumors; and (c) delaying the growth of uninjected tumors. In some aspects, treating the cancer includes one or more of the following: (d) increasing the subject's survival time; (e) reducing the volume of the injected tumor; and (f) delaying the growth of the injected tumor. In some embodiments, when the cancer is a solid tumor, “treating” the cancer includes shrinking the size of the solid tumor and any metastatic lesions, or otherwise reducing the number of survivable cancer cells. In other embodiments, when the cancer is a solid tumor, “treating” the cancer includes delaying the growth of the solid tumor and any metastatic lesions. In some aspects, treating the cancer includes increasing progression-free survival or increasing time to progression. In other embodiments, the method further includes administering an effective amount of a second or additional therapeutic agent to the subject. In some embodiments, “treating” the cancer means producing beneficial clinical outcomes, such as causing remission or otherwise prolonging survival compared to expected survival without treatment. In some embodiments, “treating cancer” includes assessing a patient’s response to the immunogenic composition according to the Solid Tumor Response Assessment Criteria (RECIST version 1.1) as described (see, for example, Eisenhauer et al., 2009 Eur J Cancer 45:228-247). Response criteria for determining an objective antitumor response for each RECIST include: complete response, partial response, progressive disease, and stable disease. In some embodiments, the tumor is a sarcoma, carcinoma, or actinic keratosis.In some embodiments, the tumor is lymphoma. In some embodiments, the cancer is selected from breast cancer, prostate cancer, lung cancer, colorectal cancer, uterine cancer, bladder cancer, melanoma, head and neck cancer, non-Hodgkin's lymphoma, kidney cancer, ovarian cancer, pancreatic cancer, and thyroid cancer. In some embodiments, the cancer is a primary cancer at a site selected from the group consisting of: oral cavity, digestive system, respiratory system, skin, breast, reproductive system, urinary system, ocular system, nervous system, endocrine system, and lymphoma.

[1747] In some embodiments, the method further includes administering an effective amount of a second therapeutic agent to the subject. In some of these embodiments, the second therapeutic agent comprises a chemotherapeutic agent selected from the group consisting of: actinomycin, afatinib, alectinib, asparaginase, azacitidine, azathioprine, bicalutamide, bismitinib, bleomycin, bortezomib, camptothecin, carboquidin, capecitabine, carmustine, cetirizine, cisplatin, chlorambucil, cobitinib, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, docetaxel, dofluorouridine, doxorubicin, enlopramide, erlotinib, epirubicin, etc. Pomexin, etoposide, fludarabine, flutamide, fluorouracil, gefinib, g...

Claims

1. A combination wherein, The composite has the structure of formula (XXVII-B): (XXVII-B) in: b is 1; CpG is a sequence with a 5'-T sequence. C G A A C G T T C G A A C G T T C G A A C G T T C G A A The T-3' phosphate thioester-linked oligodeoxynucleotide is linked at the 5'-O position of the terminal nucleotide; CDN is a cyclic dinucleotide that acts as a STING agonist and is covalently bound to the complex via the thiol group of the cyclic dinucleotide STING agonist. T is a triazole functional group, and the triazole functional group is... or ; X 1 yes ; This indicates an attachment point connected to T. This indicates the attachment point connected to the phenyl group; X 2 It is -X 3 -NH-CO-X 4 -, where X 3 yes -C3-C 12 Alkylene-L 1 - L 1 It is -OP(S)(OH)-, This indicates the 5'-O attachment site of the terminal nucleotide linked to CpG, and This indicates the attachment point connected to the amino group; and X 4 yes ,in, This indicates the attachment point connected to T, and This indicates the attachment point connected to the carbonyl group. The cyclic dinucleotide is: ； in, This indicates that the cyclic dinucleotide is covalently bonded to the complex via an S atom.

2. The combination according to claim 1, wherein, The composite has the following structure: ； 。 3. A pharmaceutical composition comprising the combination of claim 1 or 2, and one or more pharmaceutically acceptable excipients.

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