Sting agonist, and preparation and use therefor

Abstract

STING agonist, and preparation and use therefor The STING agonist has a structure represented by formula (I), has outstanding STING agonistic activity, and has a good application prospect.

Description

A STING agonist and its preparation and application

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Chinese Application No. 2023117175178, filed on December 13, 2023. Said application No. 2023117175178 is hereby incorporated by reference in its entirety. Technical Field

[0003] The present invention relates to the field of medicine, and in particular, to a STING agonist. The present invention also relates to the preparation and use of the STING agonist. Background Art

[0004] The stimulator of interferon genes (STING) is a crucial adaptor protein ubiquitously expressed in mammals and localized to the endoplasmic reticulum membrane. It plays a crucial role in immune responses mediated by exogenous or endogenous DNA. DNA from viruses, bacteria, or the cytoplasm itself is recognized by the cytoplasmic DNA sensor cyclic GMP-AMP synthase (cGAS). cGAS catalyzes the ligation of two nucleotides to form cyclic dinucleotides (CDNs, such as 2′,3′-cGAMP). CDNs act as second messengers and bind to STING, activating it. CDN binding to the STING dimer vesicle promotes STING's migration from the endoplasmic reticulum (ER) to the perinuclear Golgi apparatus (GA). Simultaneously, TANK-binding kinase 1 (TBK1) is recruited to the highly conserved CTT region (C-terminal tail domain) of STING, where it phosphorylates and activates TBK1. Activated TBK1 phosphorylates the interferon regulatory factors IRF3 and IRF7, promoting their dimerization and nuclear translocation, ultimately activating the transcription of type I interferon (IFN) and inflammatory cytokine genes. By inducing the production of type I interferons and proinflammatory cytokines, STING eliminates invading pathogens. STING not only plays a crucial role in microbial-induced innate immune responses but also participates in various pathophysiological processes, including tumor immunity, autoimmune inflammation, and autophagy. Tumor antigen-specific CD8+ T cells are a crucial component of the anti-tumor immune response. However, while many cancer patients display endogenous anti-tumor T cell responses, this alone is insufficient to completely eliminate the tumor. Checkpoint blockade therapies, such as PD-1 / PD-L1 antibodies, are currently very effective in overcoming tumor-induced T cell suppression. However, this efficacy is poor when patients lack spontaneous T cell responses. Exogenous STING agonists have the potential to trigger innate immune activation, promoting the priming and recruitment of tumor-specific CD8+ T cells. This, in turn, can control the adaptive immune response that controls tumor growth when used as monotherapy or in combination with checkpoint blockade therapy. Therefore, they represent a promising cancer immunotherapy. Currently, the development of STING agonist anti-tumor drugs is very active. The first generation of STING agonists suitable for human use were cyclic dinucleotides (CDNs) and their derivatives. CDNs, as STING binding ligands, have a direct effect on STING activation. However, due to the rapid clearance of endogenous CDNs from the body and their poor membrane permeability, their druggability is unsatisfactory. The design and synthesis of non-cyclic dinucleotide derivatives has become a research hotspot for STING agonists.However, the efficacy of STING pathway agonists depends on their structural characteristics and the desired route of administration, influenced by factors such as drug stability, immune cell toxicity, drug targeting, and differential immune cell uptake. Currently, clinical trials of drugs targeting STING-related pathways are in the early stages, and further design and optimization of these agonists will greatly enhance their potential for successful clinical application. Summary of the Invention

[0005] The object of the present invention is to provide a STING agonist.

[0006] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof:

[0007] in,

[0008] R is selected from any one of the groups represented by formula (a) or formula (b);

[0009] X1 is selected from: O or S;

[0010] X2 is selected from: N or CR3;

[0011] R1 and R3 are the same or different and are independently selected from the group consisting of H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -OR a 、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R b 、-NR a R b , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or R1 and R3 may be connected to form a substituted or unsubstituted ring;

[0012] R2 is selected from: -C(O)OR x 、-C(O)NR x R y ;

[0013] R4 is selected from: H, D, substituted or unsubstituted C1-C15 alkyl;

[0014] R a 、R bThe same or different, each independently selected from: H, D, substituted or unsubstituted C1-C30 alkyl;

[0015] Ring A is a substituted or unsubstituted monocyclic heteroaryl group containing two or more nitrogen atoms as heteroatoms;

[0016] Ring B is a substituted or unsubstituted heteroaryl group attached via a ring carbon atom;

[0017] A group selected from -O-, -S-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -NR-, -NRC(O)-, -NRC(O)NR-, -NRS(O)2- can be inserted between any two CCs in the above-mentioned alkyl groups, and R is independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl.

[0018] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier and / or excipient.

[0019] In another aspect, the present invention provides a combination pharmaceutical comprising a compound of the present invention and at least one other biologically active agent.

[0020] In another aspect, the present invention provides a therapeutic composition comprising at least two different compounds of the present invention.

[0021] In another aspect, the present invention provides use of the compound of the present invention in the preparation of a STING agonist.

[0022] In another aspect, the present invention provides use of the compound of the present invention in the preparation of a medicament for preventing or treating tumors, infectious diseases, immune diseases and inflammatory diseases.

[0023] In another aspect, the present invention provides a method of treating a disease or condition in a subject, comprising the step of administering to a subject in need thereof a compound of the present invention.

[0024] In another aspect, the present invention provides a process for preparing a compound of the present invention.

[0025] Beneficial effects of the present invention:

[0026] The present invention provides a STING agonist, and also provides its preparation and use. The STING agonist of the present invention has outstanding STING agonist activity and has good application prospects. DETAILED DESCRIPTION

[0027] definition

[0028] Unless otherwise defined, the terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs.The terms used in the specification are for describing particular embodiments only and are not intended to limit the invention.

[0029] Herein, "*" indicates a linking site.

[0030] As used herein, the term "alkyl" refers to a linear or branched fully saturated hydrocarbon group, preferably a C1-30, more preferably a C1-15, and further preferably a C1-12, C1-6, or C1-4 alkyl group. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl (e.g., n-pentyl), hexyl (e.g., n-hexyl), heptyl (e.g., n-heptyl), octyl (e.g., n-octyl), nonyl (e.g., n-nonyl), decyl (e.g., n-decyl), and the like. The alkyl group may be optionally substituted.

[0031] As used herein, the term "alkylene" refers to a group formed by removing a hydrogen atom from a preceding alkyl group, and may be a C1-15, C1-12, C1-6, or C1-4 alkylene group. Examples of alkylene groups include methylene, ethylene (e.g., 1,2-ethylene), propylene (e.g., 1,3-propylene), butylene (e.g., 1,4-butylene), pentylene (e.g., 1,5-pentylene), hexylene (e.g., 1,6-hexylene), and the like. Alkylene groups may be optionally substituted.

[0032] Herein, the term "cycloalkyl" refers to a C3-15 monocyclic or polycyclic alkyl group, preferably a C3-8 monocyclic or polycyclic alkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The cycloalkyl group may be optionally substituted.

[0033] As used herein, the term "alkenyl" refers to a linear or branched hydrocarbon group containing at least one carbon-carbon double bond, preferably a C2-15, more preferably a C2-12, C2-6 or C2-4 alkenyl group. Preferably, the alkenyl group is an α-alkenyl group. Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, (E)-2-butenyl, (Z)-2-butenyl, (E)-2-methyl-2-butenyl, (Z)-2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, (Z)-2-pentenyl, (E)-1-pentenyl, (E)-2-pentenyl, (Z)-2-hexenyl, (E)-1-hexenyl, (Z)-2-hexenyl, (Z)-3-hexenyl, (E)-3-hexenyl, (E)-1,3-hexadienyl, 4-methyl-3-pentenyl, etc. Alkenyl groups can be optionally substituted.

[0034] As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond, preferably a C2-15, more preferably a C2-12, C2-6 or C2-4 alkynyl. Preferably, the alkynyl is an α-alkynyl. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and the like. Alkynyl groups may be optionally substituted.

[0035] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group, which may be a monocyclic or condensed ring, preferably a C6-C30, more preferably a C6-C25, C6-C15, or C6-C10 aryl group. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. Aryl groups may be optionally substituted.

[0036] As used herein, the term "heteroaryl" refers to a 5-18 membered monocyclic or condensed aromatic group containing at least one (e.g., 1, 2, 3, 4, or 5) heteroatom (e.g., N, O, S, or P), preferably a 5-10 membered, more preferably a 5-7 membered, or 5-6 membered aromatic group. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, or 5-pyrimidinyl), pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindole, benzimidazolyl, benzophenone ... oxazolyl, benzopyrazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, carbazolyl (including carbazolyl-9-yl), azacarbazolyl (including azacarbazolyl-9-yl), quinolyl, isoquinolyl, indolizinyl, azaindolizinyl, dibenzofuranyl, dibenzothiophenyl, naphthyridinyl; in addition, it also includes the case where one or more ring carbon atoms in the above groups are further replaced by nitrogen. The heteroaryl group may be optionally substituted.

[0037] As used herein, the term "halogen" refers to F, Cl, Br, and I.

[0038] As used herein, the term "substituted or unsubstituted" or "optionally substituted" means that the molecule / group may be unsubstituted or substituted with 1, 2, 3, 4, 5 or more substituents selected from the group consisting of deuterium, halogen, hydroxy, thiol, carboxyl, cyano, nitro, amino, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, alkylamino, dialkylamino, substituted or unsubstituted amide, substituted or unsubstituted ester, and the like. Preferably, the substituents may be: deuterium, halogen (preferably 1, 2 or 3 halogens), hydroxyl, thiol, carboxyl, cyano, nitro, C1-C10 alkyl (preferably C1-C6 alkyl), halogenated C1-C6 alkyl (preferably CH2F, CHF2, CF3), C3-C7 cycloalkyl, C1-C6 alkoxy (preferably methoxy, ethoxy), halogenated alkoxy (preferably CF3O), C6-C10 aryloxy, C1-C6 Alkyl-S-, C6-C10 aryl-S-, C6-C10 aryl (especially phenyl and substituted phenyl, such as tolyl, trimethylphenyl, pentadeuterated phenyl), 5-7 membered heteroaryl, 5-7 membered heterocyclic group, C1-C6 acyl group, C1-C6 alkylamino group, di(C1-C6 alkyl)amino group, amide group optionally substituted by one or two C1-C6 alkyl groups, C1-C6 ester group, tri(C1-C6 alkyl)silyl group, triphenylsilyl group, etc. Preferably, the substituents can be: halogen, hydroxyl, carboxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, CH2F, CHF2, CF3, methoxy, ethoxy, CF3O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, -COOMe, -COOEt, -COMe, -COEt, amino, methylamino, dimethylamino, ethylamino, diethylamino, -CONH2, -CONHMe, -CONHEt, -CON(Me)2, -CON(Et)2, trimethylsilyl, etc.

[0039] As used herein, the term treatment and other similar synonyms include alleviating, alleviating or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, improving a disease or condition, alleviating symptoms caused by a disease or condition, or terminating the symptoms of a disease or condition, and furthermore, the term encompasses the purpose of prevention. The term also encompasses obtaining a therapeutic effect and / or a prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. In addition, curing or ameliorating one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, for example, an improvement in the patient's condition is observed even though the patient may still be affected by the underlying disease. With respect to a prophylactic effect, the composition can be administered to a patient at risk for a particular disease, or even if a diagnosis of the disease has not yet been made, the composition can be administered to a patient who presents with one or more physiological symptoms of the disease.

[0040] As used herein, the term "pharmaceutically acceptable carriers and / or excipients" refers to carriers and / or excipients that are pharmacologically and / or physiologically compatible with the subject and the active ingredient, and are well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995).

[0041] Unless otherwise indicated, the term "compound" refers to any specific compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and, where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), and pharmaceutically acceptable salts and derivatives thereof (including prodrug forms). When used in this context, the term compound generally refers not only to a single compound, but also to other compounds, such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. The term also refers in this context to prodrug forms of compounds that have been modified to facilitate administration and delivery of the compound to the active site.

[0042] As used herein, the term "pharmaceutically acceptable salt" refers to an addition salt of an active compound with a pharmaceutically acceptable inorganic or organic base or acid, which is relatively non-toxic to the patient and has no harmful activity, and its side effects do not reduce the beneficial effects of the active compound.

[0043] As used herein, the term "prodrug" refers to a functional derivative of a compound that is readily converted in vivo to the desired compound. Thus, in the present therapeutic methods, the term "administering" encompasses treating the various conditions described with a specifically disclosed compound or with a compound that may not be specifically disclosed but is converted in vivo to a specific compound upon administration to a patient. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs," edited by H. Bundgaard, Elsevier, 1985.

[0044] The compounds of the present invention may form solvates with common organic solvents, or form hydrates with water, and such solvates or hydrates are also included in the scope of the present invention.

[0045] The compounds of the present invention include all tautomers and mixtures thereof in any ratio.

[0046] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof:

[0047] in,

[0048] R is selected from any one of the groups represented by formula (a) or formula (b);

[0049] X1 is selected from: O or S;

[0050] X2 is selected from: N or CR3;

[0051] R1 and R3 are the same or different and are independently selected from the group consisting of H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -OR a 、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R b 、-NR a R b , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or R1 and R3 may be connected to form a substituted or unsubstituted ring;

[0052] R2 is selected from: -C(O)OR x 、-C(O)NR x Ry ;

[0053] R4 is selected from: H, D, substituted or unsubstituted C1-C15 alkyl;

[0054] R a 、R b 、R x 、R y The same or different, each independently selected from: H, D, substituted or unsubstituted C1-C30 alkyl;

[0055] Ring A is a substituted or unsubstituted monocyclic heteroaryl group containing two or more nitrogen atoms as heteroatoms;

[0056] Ring B is a substituted or unsubstituted heteroaryl group attached via a ring carbon atom;

[0057] A group selected from -O-, -S-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -NR-, -NRC(O)-, -NRC(O)NR-, -NRS(O)2- can be inserted between any two CCs in the above-mentioned alkyl groups, and R is independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl.

[0058] In one embodiment, X1 is selected from O.

[0059] In one embodiment, X1 is selected from S.

[0060] In one embodiment, X2 is selected from N.

[0061] In one embodiment, X2 is selected from CR3.

[0062] In one embodiment, R1 and R3 are linked to form a substituted or unsubstituted benzene ring, naphthalene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, cyclopentane ring, or cyclohexane ring.

[0063] In one embodiment, Select any one of the following structures:

[0064] In one embodiment, Select any one of the following structures:

[0065] Among them, R 3a the same or different, each independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -OR a、-C(O)OR a 、-C(O)NR a R b 、-NR a R b , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R a 、R b The same or different, each independently selected from: H, D, substituted or unsubstituted C1-C30 alkyl;

[0066] R 3b The same or different, each independently selected from: H, D, halogen, substituted or unsubstituted C1-C15 alkyl;

[0067] k1 is selected from: 1, 2, 3 or 4;

[0068] k2 is selected from: 1, 2, 3, 4, 5, 6, 7 or 8;

[0069] k3 is selected from: 1, 2, 3, 4, 5 or 6;

[0070] A group selected from -O-, -S-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -NR-, -NRC(O)-, -NRC(O)NR-, -NRS(O)2- can be inserted between any two CCs in the above-mentioned alkyl groups, and R is independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl.

[0071] Preferably, R1, R3, R 3a the same or different, each independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, carboxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-trimethylsilylethynyl, CH2F, CHF2, CF3, methoxy, ethoxy, CF3O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0072] R 3b The same or different, each independently selected from: H, D, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.

[0073] More preferably, R1 is selected from: H, D, fluorine, fluorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl, 1-butenyl, ethynyl, 1-propynyl, 1-butynyl, 2-trimethylsilylethynyl, CH2F, CHF2, CF3.

[0074] More preferably, R3 is selected from: H, D.

[0075] More preferably, R 3a Selected from: H, D.

[0076] More preferably, R 3b Selected from: H, D.

[0077] Preferably, R2 is selected from: -C(O)OR x 、-C(O)NR x R y , where R x 、R y The same or different, each independently selected from: H, D, C1-C15 alkyl, -C1-C6 alkylene-L a -(C1-C6 alkylene-L b ) x -C1-C6 alkyl; -L a -、-L b -same or different, each independently selected from: -O-, -S-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -NH-, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, x is selected from: 0, 1 or 2.

[0078] In one embodiment, R4 is selected from the group consisting of: H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.

[0079] In one embodiment, Ring A is selected from any one of the following structures:

[0080] R5 are the same or different and are independently selected from: H, D, halogen, amino, carboxyl, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, -OR a ;

[0081] R6 is selected from the group consisting of: H, D, substituted or unsubstituted C1-C15 alkyl, -C(O)R a ;

[0082] R a Selected from: H, D, substituted or unsubstituted C1-C30 alkyl;

[0083] n is selected from: 1 or 2;

[0084] A group selected from -O-, -S-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -NR-, -NRC(O)-, -NRC(O)NR-, -NRS(O)2- can be inserted between any two CCs in the above-mentioned alkyl groups, and R is independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl.

[0085] Preferably, ring A is selected from any one of the following structures:

[0086] Preferably, R5 are the same or different and are independently selected from: H, D, fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH2F, CHF2, CF3, methoxy, ethoxy, methylamino, dimethylamino, ethylamino, diethylamino.

[0087] Preferably, ring A is selected from any one of the following structures:

[0088] Wherein, *1 indicates the connection site with the carbonyl group, and *2 indicates the connection site with ring B.

[0089] More preferably, Ring A is selected from any one of the following structures:

[0090] In one embodiment, Ring B is selected from any one of the following structures:

[0091] R7 are the same or different and are independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -OR a 、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R b 、-NR a R b , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0092] R8 is selected from the group consisting of: H, D, substituted or unsubstituted C1-C15 alkyl, -C(O)Ra 、-C(O)OR a 、-C(O)NR a R b ;

[0093] R a 、R b The same or different, each independently selected from: H, D, substituted or unsubstituted C1-C30 alkyl;

[0094] m1 is selected from: 1 or 2;

[0095] m2 is selected from: 1, 2, 3 or 4;

[0096] m3 is selected from: 1, 2 or 3;

[0097] A group selected from -O-, -S-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -NR-, -NRC(O)-, -NRC(O)NR-, -NRS(O)2- can be inserted between any two CCs in the above-mentioned alkyl groups, and R is independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl.

[0098] Preferably, ring B is selected from any one of the following structures:

[0099] More preferably, Ring B is selected from any one of the following structures:

[0100] Preferably, R7 is selected from: H, D, fluorine, fluorine, bromine, iodine, hydroxyl, amino, carboxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl, 1-butenyl, ethynyl, 1-propynyl, 1-butynyl, CH2F, CHF2, CF3, methoxy, ethoxy, methylamino, dimethylamino, ethylamino, diethylamino.

[0101] Preferably, R8 is selected from the group consisting of: H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -C(O)CH3, C(O)CH2CH3.

[0102] Preferably, the "substituted or unsubstituted" in the present invention refers to being unsubstituted or being mono- or poly-substituted by groups selected from the following: halogen, hydroxyl, cyano, nitro, amino, methyl, ethyl, n-propyl, isopropyl, CH2F, CHF2, CF3, methoxy, ethoxy, CF3O-, methylamino, dimethylamino, ethylamino, diethylamino.

[0103] Preferably, the phrase "a group selected from -O-, -S-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -NR-, -NRC(O)-, -NRC(O)NR-, -NRS(O)2- may be inserted between any two CC groups of the alkyl group, and R is independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl" in the present invention means that the alkyl group may be selected from: C1-C15 alkyl, -C1-C6 alkylene, -L a -(C1-C6 alkylene-L b ) x -C1-C6 alkyl; -L a -、-L b -same or different, each independently selected from -O-, -S-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -NR-, -NRC(O)-, -NRC(O)NR-, -NRS(O)2-, x is selected from: 0, 1 or 2.

[0104] In some embodiments, the formula (I) is any one of formula (II-A) to formula (II-D):

[0105] Wherein, X1, X2, R1, R2, R4, R5, B, and n are as defined above.

[0106] In some embodiments, the formula (I) is any one of formula (III-A) to formula (III-H):

[0107] Wherein, X1, X2, R1, R2, R4, R5, R7, R8, n, m1, and m3 are as defined above.

[0108] In certain embodiments, the compound of formula (I) of the present invention is selected from:

[0109] Table 1

[0110] Some specific chemical structures of the compounds of formula (I) of the present invention are listed above, but the present invention is not limited to these listed chemical structures. All compounds based on formula (I) and having substituents as defined above should be included.

[0111] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof.

[0112] In a preferred embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

[0113] In a preferred embodiment of the present invention, the pharmaceutical composition further comprises at least one other bioactive agent.

[0114] Preferably, the other bioactive agents are used to prevent or treat tumors, infectious diseases, immune diseases and inflammatory diseases.

[0115] Preferably, the other bioactive agent is an anti-tumor agent.

[0116] More preferably, the anti-tumor agent includes: a platinum agent such as cisplatin, carboplatin, oxaliplatin, JM-216 or satraplatin, CI-973; an antimicrotubule agent such as vinca alkaloids such as vincristine, vinblastine, taxanes such as paclitaxel, docetaxel; antimetabolites such as 5-fluorouracil, methotrexate, fludarabine; an alkylating agent such as cyclophosphamide, melphalan, carmustine, nitrosoureas such as bischloroethyl nitrosourea and hydroxyurea; anthracyclines such as doxorubicin, daunorubicin; an antitumor antibiotic such as mitomycin, idarubicin, doxorubicin, daunorubicin; a topoisomerase inhibitor such as etoposide, camptothecin; an anti-angiogenic agent such as bevacizumab; or any other cytotoxic agent such as estramustine phosphate, prednimustine, hormones or hormone agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors and radiation therapy.

[0117] Therefore, the present invention also provides a combination drug comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug thereof, and at least one other bioactive agent, wherein the bioactive agent is as described above.

[0118] The components of the above-mentioned combination drug can be administered simultaneously or sequentially, and can be administered in the form of a single preparation or different preparations.

[0119] Another aspect of the present invention provides a therapeutic composition comprising at least two different compounds of formula (I) of the present invention or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, prodrugs thereof and a pharmaceutically acceptable carrier and / or excipient.

[0120] The pharmaceutical composition, combined drug, and therapeutic composition can be in the form of tablets, capsules, pills, injections, elixirs, granules, liposomes, and nanoformulations.

[0121] Therefore, another aspect of the present invention provides the use of the compound of formula (I) of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof in the preparation of a STING agonist.

[0122] Another aspect of the present invention provides a compound of formula (I) of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug thereof, as well as the use of the pharmaceutical composition, combination drug, and therapeutic composition of the present invention in the preparation of drugs.

[0123] Preferably, the drug or the STING agonist is used to prevent or treat STING protein-dependent diseases.

[0124] Another aspect of the present invention provides a method for treating a disease or condition in a subject, comprising the following steps: administering to a subject in need thereof a compound of formula (I) of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof.

[0125] In certain embodiments, the disease or disorder is a STING protein-dependent disease.

[0126] Preferably, the STING protein-dependent diseases include tumors, infectious diseases, immune diseases and inflammatory diseases.

[0127] In certain embodiments, the present invention provides the use of a compound of formula (I) of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof in the preparation of a medicament for preventing or treating tumors, infectious diseases, immune diseases, and inflammatory diseases.

[0128] In certain embodiments, the present invention provides a method for treating a disease or condition in a subject, comprising the following steps: administering to a subject in need thereof a compound of formula (I) of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof, wherein the disease or condition includes tumors, infectious diseases, immune diseases, and inflammatory diseases.

[0129] In certain embodiments, the infectious disease includes viral infection, bacterial infection, mycoplasma infection, etc.

[0130] The compounds of the present invention can form conjugates with antibodies and can be prepared into liposome preparations and nanoformulations. Therefore, another aspect of the present invention provides the use of the compound of formula (I) of the present invention or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, and prodrugs in the preparation of antibody-drug conjugates, liposome preparations, and nanoformulations.

[0131] The present invention also provides an antibody-drug conjugate formed by the compound of formula (I) of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof and an antibody.

[0132] The present invention also provides liposome preparations and nanoformulations comprising the compound of formula (I) of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof.

[0133] The present invention also provides a method for preparing the compound of formula (I) of the present invention, but the preparation method of the present invention is not limited thereto. The core structure of the compound of formula (I) can be prepared by the reaction scheme shown below. The substituents can be bonded by methods known in the art, and the type and position of the substituents or the number of substituents can be varied according to techniques known in the art.

[0134] The preparation method of the present invention comprises:

[0135] The compound of formula (M1) and the compound of formula (M2) react in the presence of a catalyst to produce the compound of formula (I).

[0136] The catalyst comprises at least one of an organic or inorganic acid, an organic or inorganic base, a coupling agent, and phosphorus oxychloride, preferably phosphorus oxychloride.

[0137] Preferably, in the preparation method, a group protecting group can be introduced as needed and the protecting group can be removed in a suitable step.

[0138] Preferably, in the preparation method, one compound of formula (I) can be converted into another compound of formula (I) under appropriate conditions.

[0139] In one embodiment, when ring B is selected from the following structures wherein R8 is H, the preparation method comprises:

[0140] Wherein, ring B1 is selected from any one of the following structures:

[0141] PG is an amino protecting group;

[0142] Ring B is selected from any one of the following structures:

[0143] The compound of formula (M1) and the compound of formula (M2') react in the presence of a catalyst to produce the compound of formula (I'), and then the protecting group PG is removed to obtain the compound of formula (I).

[0144] Preferably, PG is selected from (trimethylsilyl)ethoxymethyl (SEM).

[0145] The following describes the preferred embodiments of the invention in detail. The examples are provided to better illustrate the content of the invention, and the content of the invention is not limited to the examples. Non-essential improvements and adjustments to the embodiments according to the content of the invention still fall within the scope of the invention.

[0146] The experimental methods in the following examples are all conventional methods unless otherwise specified. If no specific techniques or conditions are specified in the examples, they were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions.

[0147] 1. Synthesis Example

[0148] Example 1: Synthesis of Compound 4

[0149] Step 1

[0150] Take 32 mg (0.1 mmol) of compound a and 17 mg (0.1 mmol) of ethyl 5-aminothiazole-4-carboxylate, add 101 mg (1 mmol) of triethylamine, add 1 ml of anhydrous acetonitrile, and stir in an ice bath for 1 h. Take 46 mg (0.3 mmol) of phosphorus oxychloride and add it to the reaction solution in three times. After the addition, stir for 2 h. Remove the reaction solution by rotary evaporation at room temperature and purify by column chromatography to obtain 35 mg of the intermediate.

[0151] Step 2

[0152] 35 mg of the product from the previous step was added with 2 ml of dichloromethane and 0.5 ml of trifluoroacetic acid, and stirred at room temperature for 3 h. The solvent was directly dried by spin-drying, and the product was purified and separated by preparative liquid phase to obtain 13 mg of compound 4 as an off-white solid.

[0153] LCMS ([M+H] + =345.1), 1 H NMR (400MHz, DMSO-d6) δ13.46 (s, 1H), 12.83 (s, 1H), 8.75 (s, 2H), 8.45-8.20 (m, 3H), 4.45 (q, J = 7.1Hz, 2H), 1.40 (t, J = 7.1Hz, 3H).

[0154] The synthesis method of the following compounds is the same as that of 4, and the characterization results are shown in Table 2 below:

[0155] Table 2

[0156] Example 2: Synthesis of Compound 8

[0157] Step 1

[0158] Take 31 mg (0.1 mmol) of compound b and 19 mg (0.1 mmol) of ethyl 5-amino-2-methyl-1,3-thiazole-4-carboxylate, add 101 mg (1 mmol) of triethylamine, add 1 ml of anhydrous acetonitrile, and stir in an ice bath for 1 hour. Take 46 mg (0.3 mmol) of phosphorus oxychloride and add it to the reaction solution in three times. After the addition, stir for 2 hours. Remove the reaction solution by rotary evaporation at room temperature and purify by column chromatography to obtain 30 mg.

[0159] Step 2

[0160] 30 mg of the product from the previous step was added with 2 ml of dichloromethane and 0.5 ml of trifluoroacetic acid, and stirred at room temperature for 3 h. The solvent was directly dried by spin-drying, and the product was purified and separated by preparative liquid phase to obtain 7 mg of compound 8 as an off-white solid.

[0161] LCMS ([M+H] + =348.1), 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.96 (s, 1H), 9.44 (s, 1H), 8.59 (s, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 4.40 (q, 2H), 2.62 (s, 3H), 1.38 (t, 3H).

[0162] Example 3: Synthesis of compounds 16 and 17

[0163] Step 1

[0164] Take 1 g (1 eq) of 5-aminothiazole-4-carboxylic acid ethyl ester, add 50 ml of acetonitrile, then add 1 g (1 eq) of NBS and stir at room temperature for 3 h. TLC shows that the reaction is complete; spin dry the solvent, add ice water, precipitate the solid, filter, and rinse with water to obtain 2-bromo-5-aminothiazole-4-carboxylic acid ethyl ester as a beige solid (1.1 g).

[0165] Step 2

[0166] Take compound a 32 mg (0.1 mmol), 2-bromo-5-aminothiazole-4-carboxylic acid ethyl ester 25 mg (0.1 mmol), add triethylamine 101 mg (1 mmol), add anhydrous acetonitrile 1 ml, stir in an ice bath for 1 h, take phosphorus oxychloride 46 mg (0.3 mmol), add it to the reaction solution three times, stir after addition for 2 h, remove the reaction solution by rotary evaporation at room temperature, and purify by column chromatography to obtain 38 mg.

[0167] Step 3

[0168] Take 38 mg of the product from the previous step, add 2 ml of tetrahydrofuran, 30 mg of triethylamine, 5 mg of cuprous iodide, and 5 mg of bistriphenylphosphine palladium dichloride, stir at room temperature for 5 h, directly spin dry the solvent, and purify by column chromatography to obtain 25 mg.

[0169] Step 4

[0170] 25 mg of the product from the previous step was added to 2 ml of dichloromethane and 0.5 ml of trifluoroacetic acid, and stirred at room temperature for 2 h. After the reaction was complete, the product was spin-dried and directly purified by preparative liquid chromatography to obtain 10 mg of compound 16. LCMS ([M+H] + =441.1).

[0171] Step 5

[0172] 10 mg of the product from the previous step was added to tetrahydrofuran and 0.5 ml of tetrabutylammonium fluoride (1M solution), stirred at room temperature for 1 h. After the reaction was complete, the mixture was spin-dried and directly purified by preparative liquid chromatography to obtain 4 mg of compound 17. LCMS ([M+H] + =369.4).

[0173] Example 4: Synthesis of Compounds 21 and 18

[0174] Step 1

[0175] Refer to step 2 of Example 3

[0176] Step 2

[0177] Take 40 mg of the product from the previous step, add 2 ml of DMF, 35 mg of sodium acetate, 5 mg of bistriphenylphosphine palladium dichloride, and 40 mg of tributyl propynyl stannane, heat at 100 degrees and stir for 10 hours. After the reaction is complete, add water and extract with ethyl acetate. The organic phase is spin-dried, mixed, and purified by column chromatography to obtain 22 mg of a brown solid.

[0178] Step 3

[0179] Referring to step 4 of Example 3, separation was performed using preparative liquid phase separation to obtain 21.6 mg of a brown solid compound.

[0180] LCMS ([M+H] + =383.3), 1H NMR (400MHz, DMSO-d6) δ (ppm) 12.84 (s, 1H), 8.71 (s, 1H), 8.31 (m, 3H), 4.43 (q, 2H), 2.18 (s, 3H), 1.39 (t, 3H).

[0181] The synthesis method of compound 18 is the same as that of compound 21:

[0182] LCMS ([M+H] + =394.1).

[0183] Biological activity assay:

[0184] Experimental purpose: To detect the activity of sting agonists at the cellular level and screen drugs

[0185] Experimental cells: ISRE-THP1, NFKB-THP1, derived from stably transfected reporter cell lines constructed in our laboratory containing reporter genes such as luciferase and gfp

[0186] Operation process:

[0187] 1. Cell Preparation

[0188] 1. Cell culture: ISRE-THP1 and NFKB-THP1 cells were cultured in suspension in T75 flasks in RPMI-1640 medium containing 10% FBS, 1% P / S, and 5% CO2 in a 37°C incubator.

[0189] 2. Use a hemocytometer to count cells before administration;

[0190] 3. Take out the calculated cell suspension and centrifuge at 1000 rpm for 3 minutes to collect the cell pellet, and resuspend it in a certain volume of RPMI-1640 culture medium containing 10% FBS, 1% P / S;

[0191] 4. Cells were seeded into 96-well black plates (N=3) and 96-well transparent plates at 50 μl / well according to the standard of 1.0E+5 cells / well. The black plates were used to detect luciferase, and the transparent plates were used to monitor cell status and observe GFP fluorescence.

[0192] 5. Add 50 μl of diluted sting agonist of corresponding concentration into the cells, mix them by gently pipetting with a wall pipette, and culture them in a 5% CO2, 37°C incubator for 6 hours before monitoring.

[0193] 2. Preparation of Compound Dilution

[0194] 1. Prepare a 10 mM stock solution using DMSO according to the molecular weight of the sting agonist. If the solution is not completely dissolved, heat it in a 37°C water bath or sonicate it in a water bath to ensure complete dissolution of the compound.

[0195] 2. Use DMSO to dilute 7-8 concentrations in a 3-fold ratio, and then dilute them again with cell culture medium to make a 2× mixture. Add 50 μl / well to the seeded cells.

[0196] 3. The highest final concentration is 25 μM, which is reduced by 3 times, and the DMSO content is unified to 0.25%.

[0197] 4. Use glass bottles for dilution throughout the process.

[0198] 3. Result detection and analysis

[0199] 1. Monitor cell status and GFP fluorescence 6 hours after administration and take photos

[0200] 2. Thaw the firefly luciferase detection reagent luciferin at -80℃ in advance, and remove the 96-well black plate from the 37℃ incubator and place it at room temperature for 10 minutes to equilibrate the temperature.

[0201] 3. Add luciferin to the culture medium at a ratio of 1:1, i.e., add 100 μl / well of luciferin using a dispenser to ensure consistent addition times. After reacting at room temperature for 5 minutes, use a multi-function fluorescence microplate reader with chemiluminescence assay function to measure the RLU (relative light unit);

[0202] 4. Data processing: Calculate EC using Prism graphpad 50 And draw the dose-effect curve.

[0203] 4. Experimental Results

[0204] The results are shown in the following table, where A represents EC 50 <1μM; B represents EC 50 1-10 μM; C indicates activity and EC 50 >10μMTable 3:

[0205] The preferred embodiments of the present invention are described above, but they are not intended to limit the present invention. Those skilled in the art may make improvements and changes to the embodiments disclosed herein without departing from the scope and spirit of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof: in, R is selected from any one of the groups represented by formula (a) or formula (b); X1 is selected from: O or S; X2 is selected from: N or CR3; R1 and R3 are the same or different and are independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -OR a 、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R b 、-NR a R b , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or R1 and R3 may be connected to form a substituted or unsubstituted ring; R2 is selected from: -C(O)OR x 、-C(O)NR x R y ; R4 is selected from: H, D, substituted or unsubstituted C1-C15 alkyl; R a , R b , R x , R y The same or different, each independently selected from: H, D, substituted or unsubstituted C1-C30 alkyl; Ring A is a substituted or unsubstituted monocyclic heteroaryl group containing two or more nitrogen atoms as heteroatoms; Ring B is a substituted or unsubstituted heteroaryl group attached via a ring carbon atom; A group selected from -O-, -S-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -NR-, -NRC(O)-, -NRC(O)NR-, -NRS(O)2- can be inserted between any two CCs in the above-mentioned alkyl groups, and R is independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl.

2. The compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof according to claim 1, characterized in that: R1 and R3 are connected to form a substituted or unsubstituted benzene ring, naphthalene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, cyclopentane ring, cyclohexane ring; Preferably, Select from any of the following structures: Select from any of the following structures: Among them, R 3a are the same or different and are independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -OR a 、-C(O)OR a 、-C(O)NR a R b 、-NR a R b , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R a , R b The same or different, each independently selected from: H, D, substituted or unsubstituted C1-C30 alkyl; R 3b The same or different, each independently selected from: H, D, halogen, substituted or unsubstituted C1-C15 alkyl; k1 is selected from: 1, 2, 3 or 4; k2 is selected from: 1, 2, 3, 4, 5, 6, 7 or 8; k3 is selected from: 1, 2, 3, 4, 5 or 6; A group selected from -O-, -S-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -NR-, -NRC(O)-, -NRC(O)NR-, -NRS(O)2- can be inserted between any two CCs in the above-mentioned alkyl groups, and R is independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof, characterized in that: R1, R3, R 3a the same or different, each independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, carboxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-trimethylsilylethynyl, CH2F, CHF2, CF3, methoxy, ethoxy, CF3O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R 3b The same or different, each independently selected from: H, D, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.

4. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug, characterized in that: Ring A is selected from any one of the following structures: R5 are the same or different and are independently selected from: H, D, halogen, amino, carboxyl, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, -OR a ; R6 is selected from: H, D, substituted or unsubstituted C1-C15 alkyl, -C(O)R a ; R a Selected from: H, D, substituted or unsubstituted C1-C30 alkyl; n is selected from: 1 or 2; A group selected from -O-, -S-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -NR-, -NRC(O)-, -NRC(O)NR-, -NRS(O)2- may be inserted between any two CCs in the above alkyl groups, and R is independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl; Preferably, ring A is selected from any one of the following structures: R5 are the same or different and are independently selected from: H, D, fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH2F, CHF2, CF3, methoxy, ethoxy, methylamino, dimethylamino, ethylamino, diethylamino; Alternatively, ring A is selected from any one of the following structures: Here, *1 indicates the connection site with the carbonyl group, and *2 indicates the connection site with ring B.

5. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug, characterized in that: Ring B is selected from any one of the following structures: R7 are the same or different and are independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -OR a 、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R b 、-NR a R b , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R8 is selected from: H, D, substituted or unsubstituted C1-C15 alkyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a R b ; R a , R b The same or different, each independently selected from: H, D, substituted or unsubstituted C1-C30 alkyl; m1 is selected from: 1 or 2; m2 is selected from: 1, 2, 3 or 4; m3 is selected from: 1, 2 or 3; A group selected from -O-, -S-, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, -NR-, -NRC(O)-, -NRC(O)NR-, -NRS(O)2- may be inserted between any two CCs in the above alkyl groups, and R is independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl; Preferably, ring B is selected from any one of the following structures: R7 is selected from the group consisting of: H, D, fluorine, fluorine, bromine, iodine, hydroxyl, amino, carboxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl, 1-butenyl, ethynyl, 1-propynyl, 1-butynyl, CH2F, CHF2, CF3, methoxy, ethoxy, methylamino, dimethylamino, ethylamino, diethylamino; R8 is selected from the group consisting of: H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -C(O)CH3, C(O)CH2CH3.

6. The compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof according to claim 1, characterized in that: The formula (I) is any one of formula (II-A) to formula (II-D): Wherein, X1, X2, R1, R2, R4, R5, B, and n are as defined above; Alternatively, the formula (I) is any one of formula (III-A) to formula (III-H): Wherein, X1, X2, R1, R2, R4, R5, R7, R8, n, m1, and m3 are defined as above.

7. The compound of formula (I) according to claim 1 or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug, characterized in that: The compound of formula (I) is selected from:

8. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or prodrug thereof; preferably, the pharmaceutical composition is a liposome preparation or a nanoformulation.

9. Use of the compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug thereof, or the pharmaceutical composition according to claim 8 in the preparation of a drug or a STING agonist.

10. The use according to claim 9, characterized in that: The drug or the STING agonist is used to prevent or treat STING protein-dependent diseases; preferably, the STING protein-dependent diseases include tumors, infectious diseases, immune diseases and inflammatory diseases.

11. Use of the compound of formula (I) according to any one of claims 1 to 7 or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug in the preparation of antibody-drug conjugates, liposome preparations, nanoformulations, and an antibody-drug conjugate formed by the compound of formula (I) according to any one of claims 1 to 7 or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug and an antibody.

12. A method for preparing a compound of formula (I) according to any one of claims 1 to 7, comprising: The compound of formula (M1) and the compound of formula (M2) react in the presence of a catalyst to produce a compound of formula (I); Preferably, in the preparation method, a group protecting group can be introduced as needed and the protecting group can be removed in a suitable step; Preferably, when ring B is selected from any one of the following structures: The preparation method comprises: Wherein, ring B1 is selected from any one of the following structures: PG is an amine protecting group; The compound of formula (M1) and the compound of formula (M2′) react in the presence of a catalyst to generate a compound of formula (I′), and then the protecting group PG is removed to obtain a compound of formula (I); Preferably, PG is selected from (trimethylsilyl)ethoxymethyl (SEM).

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