WO2023103850A1 - Sting小分子激动剂、其制备方法及应用 - Google Patents

Sting小分子激动剂、其制备方法及应用 Download PDF

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WO2023103850A1
WO2023103850A1 PCT/CN2022/135257 CN2022135257W WO2023103850A1 WO 2023103850 A1 WO2023103850 A1 WO 2023103850A1 CN 2022135257 W CN2022135257 W CN 2022135257W WO 2023103850 A1 WO2023103850 A1 WO 2023103850A1
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compound
formula
alkyl
ring
cancer
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French (fr)
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郑明月
侯辉
蒋华良
张素林
杨瑞瑞
单彬
李睿
张柯柯
施健妹
李叙潼
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中国科学院上海药物研究所
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Definitions

  • the invention relates to the technical field of medicine, in particular to a class of STING small molecule agonists and a preparation method and application thereof.
  • Pattern recognition receptors detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and initiate downstream responses to pro-inflammatory cytokines and type I IFNs, thus constituting the first line of defense of the host immune system.
  • PAMPs pathogen-associated molecular patterns
  • DAMPs damage-associated molecular patterns
  • PRRs of host cells As conserved PAMPs, and stimulate immune cells through various signaling pathways Activation and production of immune factors that mediate the innate immune response against infection.
  • Intracellular nucleic acids can also serve as PAMPs, which can be recognized by host cell PRRs.
  • Stimulator of interferon genes is an important adapter protein in the DNA signaling pathway, which plays an important role in signal transmission in the recognition of cytoplasmic DNA and immune defense.
  • STING can directly sense bacterial and viral cyclic dinucleotide CDNs, including c-di-GMP, c-di-AMP, and c-di-GAMP, thereby activating host immunity answer.
  • the STING signaling system can supervise the release of double-stranded DNA (double-stranded DNA, dsDNA) into the cytoplasm by cGAS from dead cells or tumor cells.
  • cGAS utilizes 2',5'-phosphodiester bonds and 3',5-' phosphodiester bonds to synthesize the second messenger cGAMP, thereby activating the STING pathway.
  • cytosolic mitochondrial DNA mitochondrial DNA (mitochondrial DNA, mtDNA) leakage caused by mitochondrial DNA instability can also cause activation of STING in adjacent phagocytes.
  • the combination of CDNs into the STING dimer pocket can promote STING dimerization and transfer from the endoplasmic reticulum to the perinuclear vesicles through the Golgi apparatus (golgi apparatus, GA), and the recognition signal is released to the C-terminus of STING to promote STING polymerization.
  • TBK1 is recruited to the highly conserved C-terminus of STING, resulting in TBK1 autophosphorylation and STING tail phosphorylation.
  • Phosphorylated STING tails go on to recruit stem IRF3, which is subsequently phosphorylated by TBK1.
  • Phosphorylated IRF3 dimers eventually enter the nucleus and activate the transcription of IFNs and pro-inflammatory cytokine genes.
  • STING is essential in the process of host resistance to retroviruses such as HIV, SIV and MLV.
  • the antiviral mechanism of action of STING has been attributed to the secretion of IFNs, pro-inflammatory cytokines and chemokines, and the immune response to adaptive pathogen-specific stimuli.
  • CD8+ T cell priming requires the production of IFNs by DCs, whereas IFN ⁇ signaling requires the involvement of innate immune sensors.
  • IFN ⁇ signaling requires the involvement of innate immune sensors.
  • the cGAS-STING signaling pathway involves the expression of IFN ⁇ and is associated with tumor-derived DNA uptake. Activation of the STING signaling pathway in tumor cells can induce the secretion of chemokines CCL5 and CXCL10, thereby promoting the recruitment and activation of NK cells and T cells in tumor cells.
  • the cGAS-STING pathway participates in the process of cellular senescence through the induction of anti-tumor mechanisms of IFNs and senescence-associated secreted phenotypic factors.
  • intratumoral injection of CDNs or CDNs analogs can reduce tumor volume and increase the survival rate of model mice. Therefore, activation of the STING pathway shows great potential for the prevention and treatment of infectious diseases or in the field of anti-tumor immunity.
  • STING agonists are mainly CDN analogs, such as ADU-S100 and MK-1454, but these compounds have complex structures and are difficult to synthesize chemically. In addition, due to its fast clearance rate and poor membrane permeability, its therapeutic application is limited to intratumoral injection, which greatly limits its clinical application.
  • STING small molecule agonists such as DMXAA and CMA, are both mouse-specific STING agonists. Due to species differences, both of them lack effective binding to human STING.
  • diABZI was reported as the first non-nucleoside Acids are potent agonists for STING.
  • SR-717 and MSA-2 were successively reported, both of which can induce STING into a closed conformation and produce STING-dependent anti-tumor effects.
  • the object of the present invention is to provide a novel small molecule STING agonist and its preparation method and application.
  • a compound a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or Prodrug, wherein, the compound is selected from formula I and formula II:
  • W is selected from O or NH
  • R 1 is selected from -C(O)OR 7 , -C(O)NHR 8 , cyano, 3-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S, C6-C10 Aryl, 3-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, S,
  • R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from: H, D, halogen, hydroxyl, amino, carboxyl, C1-C6 alkyl, C3-C8 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl; wherein the substituted substituent is selected from C1- C6 alkyl, C3-C8 cycloalkyl;
  • R 2 and R 3 together with the carbon atoms connected to them form a saturated or unsaturated 5-6 membered ring, especially a benzene ring;
  • R 3 and R 4 or R 6 together with the carbon atoms connected to them form a saturated or unsaturated 5-6 membered ring, especially a benzene ring;
  • R 7 and R 8 are each independently selected from: H, D, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 ring Alkyl, C6-C10 aryl, 3-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S, 3-membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S -10-membered heteroaryl, unsubstituted or benzyl substituted by C1-C6 alkoxy, carboxyl;
  • n 0, 1;
  • X 1 , X 2 are independently selected from CR 9 , N;
  • R9 is selected from H, D, halogen, hydroxyl, amino, carboxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, C1-C6 alkoxy , C3-C8 cycloalkoxy, C1-C6 haloalkyl;
  • W 1 , W 2 and W 3 are each independently selected from CR b or NR c ;
  • ring A is selected from the following group:
  • Y is selected from O, S or NH.
  • the compound of formula I is selected from formula I-1 or formula I-2,
  • the compound of formula II is selected from formula II-1 or formula II-2,
  • X, R 1 , R 2 , R 3 , and n are as defined above;
  • Ring A1 is selected from
  • Ring A2 is selected from
  • Y is selected from O, S or NH.
  • the compound of formula I-1 is formula I-1A,
  • R 1 is -C(O)OR 7 ;
  • R 3 and R 6 are each independently selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, C1-C6 alkoxy, C1-C6 haloalkyl; or R 3 and R 6 together with the carbon atom connected to it constitutes a saturated or unsaturated 5-6 membered ring, especially a benzene ring;
  • R 7 is selected from H, C1-C6 alkyl
  • n 0 or 1
  • Ring A1 is defined as above;
  • the A1 ring is selected from the following structures:
  • the compound of formula I-2 is formula I-2A,
  • R 1 is -C(O)OR 7 ;
  • R 3 and R 6 are each independently selected from halogen, C1-C6 alkyl, C2-C6 alkynyl, cyano, C1-C6 alkoxy, C1-C6 haloalkyl; or R 3 and R 6 together with the The carbon atoms together form a saturated or unsaturated 5-6 membered ring, especially a benzene ring;
  • R 7 is selected from H, C1-C6 alkyl
  • n 0 or 1
  • Ring A2 is defined as above;
  • the A2 ring is selected from the following structures:
  • the compound of formula II-1 is formula II-1A, formula II-1B or formula II-1C,
  • R 1 is-C(O)OR 7 ;
  • R 2 , R 3 , R 4 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkynyl, cyano, C1-C6 alkoxy, C1-C6 haloalkyl; or R 2 and R 3 together with the carbon atoms connected to it form a saturated or unsaturated 5-6 membered ring, especially benzene ring or cyclohexane;
  • R 7 is selected from H, C1-C6 alkyl
  • a 1 ring is defined as above.
  • alkyl refers to a straight or branched chain saturated hydrocarbon group containing 1-18 carbon atoms, especially 1-6 carbon atoms.
  • Typical "alkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, isopentyl, heptyl, 4,4-dimethylpentyl Base, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc.
  • C1-C6 alkyl refers to straight or branched chain alkyl, including 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, iso butyl.
  • Substituted alkyl means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • alkenyl refers to a straight or branched chain hydrocarbon group containing 2 to 18 carbon atoms and at least one carbon-carbon double bond.
  • C2-C6 alkenyl refers to a straight-chain or branched hydrocarbon group containing 2-6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, 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)-1-hexenyl, (E)-2-hexenyl, (Z)-3-hexenyl, (E)-3-hexenyl, (E)-3-
  • Substituted alkenyl means that one or more positions in the alkenyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: hydrogen, deuterium, halogen (e.g., monohalogen or polyhalogen substituents), nitrile, nitro, oxygen (e.g.
  • alkynyl refers to a straight or branched chain hydrocarbon group containing 2 to 18 carbon atoms and at least one carbon-carbon triple bond. Typical groups include ethynyl.
  • C2-C6 alkynyl refers to a straight-chain or branched hydrocarbon group containing 2-6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl.
  • Substituted alkynyl means that one or more positions in the alkynyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: hydrogen, deuterium, halogen (e.g., monohalogen or polyhalogen substituents), nitrile, nitro, oxygen (e.g.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group, including 1-4 rings, each containing 3-8 carbon atoms, such as 3-18 carbon atoms, especially 3 - 14 carbon atoms, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornane. "Substituted cycloalkyl” means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocycle (excluding heteroaryl rings), bridged cycloalkyl, bridged cycloalkenyl, Bridged ring heterocycle (excluding heteroaryl ring), fused ring alkyl group, fused ring alkenyl group, condensed ring heterocyclic group or condensed ring aromatic ring group, the above-mentioned cycloalkyl group, cycloalkenyl group, heterocyclic group and heterocyclic aromatic ring group
  • the groups can be optionally substituted.
  • aryl refers to an aromatic cyclic hydrocarbon group having 1-5 rings, eg containing 6-18 carbon atoms, especially 6-14 carbon atoms. Especially monocyclic and bicyclic radicals such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic rings, etc.), the aromatic rings of the aryl groups can be linked by a single bond (such as biphenyl), or fused (such as naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused cycloalkyl, fused cycloalkenyl, fused heterocyclic or fused aromatic ring, the above cycloalkyl, cycloalkenyl, heterocyclic and heteroaryl
  • the groups can be optionally substituted.
  • heteroaryl refers to an aromatic ring group containing 1-4 heteroatoms (preferably 1 or 2), 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole Base, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazazinyl, triazolyl, purine, carbazole, indolyl, indazolyl, benzothienyl , benzofuryl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazo
  • Heteroaryl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Thio, oxo, carboxyl and carboxylate groups.
  • heterocyclyl refers to a non-aromatic cyclic group containing 1-4 heteroatoms (preferably 1 or 2), 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur, such as dihydrogen Pyridyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, bis -tetrahydrofuryl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, azacyclooctene Base, pyranyl, chromenyl, xantheny
  • halogen refers to fluorine, chlorine, bromine, iodine.
  • Haloalkyl refers to straight or branched chain haloalkyl, such as “C1-C6 haloalkyl”, which refers to a straight or branched chain having 1 to 6 carbon atoms containing one or more identical or different halogen atoms.
  • Chain haloalkyl including without limitation -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Br, -CHBr 2 , -CBr 3 , CF 3 CH2 , CCl3CH2 , CBr3CH2 .
  • alkoxy refers to a straight chain or branched chain alkoxy group, such as "C1-C6 alkoxy group”, which refers to a straight chain or branched chain alkoxy group with 1 to 6 carbon atoms, without limitation Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. Preference is given to C1-C4 alkoxy.
  • alkylamino refers to a straight chain or branched chain alkyl substituted by an amino group, such as "C1-C6 alkylamino", which refers to a straight chain or branched chain alkyl group substituted by an amino group having 1 to 6 carbon atoms, not Limitatively include H 2 N-CH 2 -, H 2 N-CH 2 CH 2 -, H 2 N-CH 2 CH 2 CH2-, H 2 N-CH(CH 3 )CH 2 -, and the like.
  • hydroxymethyl refers to -CH2OH .
  • saturated or unsaturated 5-6 membered ring includes aromatic rings (such as benzene rings), heteroaromatic rings (such as ), heterocycles (such as ), saturated hydrocarbon rings (such as cyclohexane).
  • pharmaceutically acceptable salt refers to non-toxic, physiologically acceptable salts, including organic and inorganic salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate or sulfuric acid Hydrogen salts, nitrates, phosphates or acid phosphates, perchlorates, formates, acetates, trifluoroacetates, propionates, pyruvates, glycolates, oxalates , malonate, succinate, glutarate, maleate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, Benzoate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, ascorbate, camphorate or camphorsulfonate, etc.
  • organic and inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate
  • Salts can also be formed at R7 , such as lithium, sodium, potassium salts, etc.
  • solvates such as alcoholates, hydrates, etc., but are not limited thereto. These solvates are also included in the scope defined by the claims of the present invention.
  • the compounds involved in this application and their pharmaceutically acceptable salts may have isomers, such as optical isomers (including diastereomers and enantiomers), atropisomers, geometric isomers (cis-trans isomers), conformational isomers, tautomers, mixtures thereof, etc., but not limited thereto. These isomers are also included in the scope defined by the claims of the present invention.
  • the compound of formula I is selected from the following compounds:
  • the present invention finds that a class of compounds and their drug combinations have STING agonistic activity, and the positive compound SR-717 In comparison, the preferred compounds of the present invention exhibit better STING binding ability, and can significantly up-regulate the expression levels of IFN- ⁇ , CXCL10 and IL-6mRNA in human THP-1 cells and mouse RAW264.7 cells, This provides new ideas for the development of drugs for the treatment of malignant tumors and infectious diseases.
  • a method for preparing a compound of formula I which is one of the following methods:
  • ester compound M1 and the borate compound M2 undergo suzuki coupling reaction to obtain the intermediate M3, and then hydrolyze to obtain the carboxylic acid compound M4, and further undergo a condensation reaction with M5 or condense and then hydrolyze to obtain the compound of formula I;
  • ester compound M1' and the amine compound M2 ' or M2 " undergo a nucleophilic substitution reaction to obtain the intermediate M3 ', which is hydrolyzed to obtain M4 ', which is further condensed with M5 or condensed and then hydrolyzed to obtain the compound of formula I ;
  • Carboxylic acid compound M1a reacts with oxalyl chloride to obtain acid chloride M2a, and then reacts with amine compound M5 to obtain M3a, M3a reacts with borate compound M2 through suzuki coupling reaction, or reacts with amine compound M2' or M2" through nucleophilic substitution
  • the reaction obtains the compound of formula I, or obtains the compound of formula I through one-step hydrolysis reaction;
  • Compound M2-1 reacts with trimethylethynyl silicon M2-2 to obtain compound M2-3, compound M2-4 after deprotection reacts with compound M2-5 to obtain compound M2-6, and then compound M2- 6 is hydrolyzed to obtain compound M2-7, compound M2-7 is condensed with compound M5 to obtain a compound of formula I, or a compound of formula I is obtained through a further hydrolysis reaction;
  • R 1 , R 2 , R 3 , X, X 1 , X 2 , X 3 , W, W 1 , W 2 , W 3 , R a , n, and ring A are as defined above.
  • the suzuki coupling reaction between the ester compound M1 or M3a and the borate compound is carried out under palladium catalyzed conditions.
  • the above suzuki coupling reaction is usually carried out at 80-120°C, preferably at 100-120°C, and the reaction is usually completed within about 5-12 hours, preferably within 8-12 hours.
  • the nucleophilic substitution reaction between the ester compound M1' or M3a and the amine compound is under basic conditions (preferably the base is K 2 CO 3 , NaH, N,N-diisopropyl ethylamine and triethylamine).
  • the above nucleophilic substitution reaction is usually carried out at 0°C or at room temperature, preferably at room temperature, and the reaction is usually completed within about 1-5 hours, preferably within 2-3 hours.
  • the above-mentioned hydrolysis reaction is carried out under alkaline conditions.
  • the above hydrolysis reaction is usually carried out at 0°C or at room temperature, preferably at room temperature, and the reaction is usually completed within about 1-5 hours, preferably within 1-3 hours.
  • the condensation reaction of M4 or M4' with M5 is in a condensing agent (preferred condensing agent combination is HATU, HBTU, HOBT/EDCI, TCFH/NMI).
  • a condensing agent combination is HATU, HBTU, HOBT/EDCI, TCFH/NMI.
  • the subsequent hydrolysis reaction is carried out under basic conditions (preferably base LiOH, aqueous NaOH).
  • the above condensation reaction is usually carried out at room temperature-120°C, preferably at room temperature-80°C, and the reaction is usually completed within about 6-12 hours, preferably within 8 hours.
  • the reaction of M1a with oxalyl chloride is carried out at 0°C-room temperature, and the reaction is usually completed within 1-12 hours, preferably within 5 hours.
  • acid chlorides M2a and M5 are usually carried out under basic conditions (preferably bases are N,N-diisopropylethylamine and triethylamine).
  • the reaction is usually carried out at 0°C-room temperature, preferably at room temperature.
  • the reaction is usually complete in 1-5 hours.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from formula I, its isomer, prodrug, solvate, hydrate, pharmaceutically acceptable One or more of accepted salts, active metabolites.
  • the compounds according to the present invention can be used alone or in combination with other drugs to prevent or treat tumors, viral infections, immune diseases and inflammatory diseases.
  • the compounds of the general formula I of the present invention can be administered alone, or combined with other pharmaceutically Acceptable therapeutic drug combinations are administered.
  • the pharmaceutically acceptable therapeutic drugs include, but are not limited to, for example, traditional cytotoxic chemotherapeutic small molecule drugs, such as methotrexate, 5-fluorouracil, doxorubicin, paclitaxel, imatinib, etc.; Point modulators, such as Opdivo and Keytruda, etc.
  • the components of the above-mentioned pharmaceutical combination can be administered simultaneously or sequentially, and can also be administered in the form of a single preparation or different preparations. Said combination includes the combination of the compound of general formula I and one or more other acceptable therapeutic drugs.
  • the pharmaceutical composition is tablet, capsule, pill, injection, pill, powder or granule.
  • the administration method of the compound of the present invention or its pharmaceutical composition is not particularly limited, representative administration methods, but not limited to oral administration, intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, local administration and the like.
  • a compound represented by formula I its pharmaceutically acceptable salt, or its enantiomer, diastereoisomer, tautomer, solvent Compounds, polymorphs or prodrugs or the pharmaceutical composition described above in the preparation of STING agonists purposes.
  • a compound represented by formula I its pharmaceutically acceptable salt, or its enantiomer, diastereoisomer, tautomer, solvent Compounds, polymorphs or prodrugs or the pharmaceutical composition described above are used to prepare medicines for treating STING protein-dependent diseases, especially medicines for tumors, viral infections, immune diseases and inflammatory diseases, which are a class of Drugs with a new mechanism of action.
  • the tumors are selected from the tumors independently selected from: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer , brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
  • the immune and inflammatory diseases are selected from the group consisting of rejection of transplanted organs, gout, rhinitis, alopecia, Alzheimer's disease, appendicitis, atherosclerosis, asthma, arthritis, atopic dermatitis, Bechet's disease, bullous skin disease, cholecystitis, chronic idiopathic thrombocytopenic purpura, chronic obstructive pulmonary disease, liver cirrhosis, degenerative joint disease, dermatitis, dermatomyositis, eczema, enteritis, encephalitis, gastritis, Nephritis, Hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatory bowel disease, irritable bowel syndrome, Kawasaki disease, meningitis, multiple sclerosis, myocarditis, myasthenia gravis, mycosis fungoides, myositis, Nephritis, osteomyelitis, pan
  • the activity of the compound described in the present invention is significantly stronger than that of the positive compound SR-717 at the molecular and cellular levels.
  • Fig. 1 is the expression level of the mRNA of the IFN-beta of experimental example inspection of the present invention
  • Fig. 2 is the expression level of the mRNA of CXCL10 that the experimental example of the present invention checks;
  • Fig. 3 is the expression level of IL-6 mRNA tested in the experimental example of the present invention.
  • the commercially available raw materials and reagents used in the examples and experimental examples are conventional raw materials and reagents in the art, and the experimental methods are conventional experimental methods that can be searched using Scifinder or Reaxy.
  • step 1
  • step 1
  • step 1 Z2 (1 g, 5.65 mmol) obtained in step 1 was dissolved in 20 mL of dry dichloromethane, and methyl 2-amino-4,5-difluorobenzoate (2 g, 11.30 mmol) and DPIEA were added at 0 °C (1.97mL, 11.30mmol) in 20mL of dichloromethane, reacted for 5h, and then filtered to give Z3 without further purification.
  • Dissolve Z4 (50 mg, 0.14 mmol) from step 3 in 2 mL THF.
  • Lithium hydroxide monohydrate (8.78 mg, 0.21 mmol) was weighed and dissolved in 1 mL of water, added to the THF solution, reacted at room temperature for 1 h, concentrated the solvent under reduced pressure, and finally adjusted the pH to about 2 with 1N HCl, filtered the precipitated white solid, That is compound 26.
  • Dissolve compound 1 (10mg, 0.03mmol) in DMSO (0.8mL), add 0.1M LiOH aqueous solution (0.33mL, 0.04mmol) to the system, and react the mixed system at room temperature for 3h, then add 1N HCl to adjust the pH to about 2 , a white solid appeared, and compound 6 was obtained by filtration and drying.
  • Cell lines THP1-BLUE ISG and Raw-Lucia ISG were purchased from Invivogen. According to the culture manual, the cell culture conditions were 2 mmol L -1 L-glutamine, 25 mmol L -1 HEPES, 10% heat-inactivated Gibco FBS (56°C, 30 min), penicillin and streptomycin (100 ⁇ g mL -1 , 100 ⁇ g ⁇ mL -1 ) of RPMI 1640 medium.
  • SR-717 was purchased from Shanghai Haoyuan Biomedical Technology Co., Ltd.
  • QUANTI-BLUE was purchased from Invivogen, and qPCR primers were synthesized by Sangon Bioengineering Co., Ltd.
  • the gene encoding the human STING H232 CTD (carboxy-terminal domain, residues 139-378) was inserted into a modified Pet28a vector, and a his-sumo tag was added.
  • Table 3 shows the activity results of the compounds at the molecular level of mouse STING WT and mouse Raw264.7 cells.
  • RNA rapid extraction kit (Nanjing Novizan Biotechnology Co., Ltd.), and the general method is as follows: lyse the cells with 500 ⁇ L lysate and transfer to a spin column, collect the filtrate and add 0.5 volume of absolute ethanol to mix, transfer To the RNA collection column, centrifuge at 12,000 rpm for 30 s, add 700 ⁇ L of washing solution 1, centrifuge at 12,000 rpm for 30 s, add 700 ⁇ L of washing solution 2, centrifuge at 12,000 rpm for 30 s, add 500 ⁇ L of washing solution 2, and centrifuge at 12,000 rpm for 2 min.
  • RNA solution Move the spin column to a 1.5 mL RNase-free EP tube, add 20-100 ⁇ L DEPC H 2 O to the center of the spin column, and centrifuge at 12,000 rpm for 1 min to obtain an RNA solution.
  • Human ACTB forward primer catgtacgttgctatccaggc (SEQ ID NO.1),
  • Human ACTB reverse primer ctccttaatgtcacgcacgat (SEQ ID NO.2);
  • Human IFNB forward primer cagcatctgctggttgaaga (SEQ ID NO.3)
  • Human IFNB reverse primer cattacctgaaggccaagga (SEQ ID NO.4);
  • Human CXCL10 reverse primer tgcatcgattttgctcccct (SEQ ID NO.6);
  • Human IL6 forward primer ttcggtccagttgccttctc (SEQ ID NO.7)
  • Human IL6 reverse primer tacatgtctcctttctcagggc (SEQ ID NO.8).
  • RT-qPCR uses CFX96TM real-time PCR detection system (BioRad, Shanghai, China).
  • the thermal cycling process included initial denaturation at 95°C for 30s, followed by 5s at 95°C and 30s at 60°C as a cycle, and the number of cycles was set to 40.
  • the expression level of the target gene was analyzed according to the melting curve.
  • Use Folds 2- ⁇ Ct to represent the multiple ratio relationship between the experimental group and the control group.
  • the Folds value is the relative gene expression level, corresponding to the ordinate values in Figures 1 to 3, where the control group (blank control) is the same concentration DMSO administration group.
  • Ct is the threshold cycle number, which refers to the number of cycles experienced when the fluorescent signal in each reaction tube reaches the set threshold during the PCR cycle;
  • Ct purpose indicates that the primer is the threshold cycle number of each group except ACTB;
  • Ct internal parameter Indicates that the primer is the threshold cycle number of each group of ACTB;
  • the experimental group represents the difference between the threshold cycle number corresponding to the specific primer (except ACTB) of the administration group and the corresponding threshold cycle number of ACTB;
  • Ct purpose -Ct internal reference) Ct ( internal reference ) control group represents the difference between the threshold cycle number corresponding to the specific primer (except ACTB) of the blank control group and the threshold cycle number corresponding to ACTB;
  • ⁇ Ct represents the difference between the experimental group and the blank control group threshold cycle number.
  • compounds according to the present invention can promote IFN- ⁇ (relative to interferon- ⁇ ), CXCL10 (relative to chemokine ligand 10), IL-6 (relative to Interleukin-6) mRNA expression level.

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Abstract

本发明提供了STING小分子激动剂、其制备方法及应用。具体地，本发明提供了式I所示的化合物，其具有STING激动活性，在THP-1细胞和RAW264.7细胞中，均可明显上调IFN-β，CXCL10及IL-6 mRNA的表达水平，从而达到治疗恶性肿瘤和感染性疾病的目的。

Description

STING小分子激动剂、其制备方法及应用
优先权信息
本发明请求于2021年12月7日向中国国家知识产权局提交的、申请号为2021114831123、发明名称为“STING小分子激动剂、其制备方法及应用”的中国专利申请的优先权，并且其全部内容通过引用结合在本发明中。
技术领域
本发明涉及医药技术领域，尤其是涉及一类STING小分子激动剂及其制备方法和应用。
背景技术
模式识别受体(pattern recognition receptors，PRRs)可检测病原体相关分子模式(pathogen-associated molecular patterns,PAMPs)和损伤相关分子模式(damage-associated molecular patterns,DAMPs)，并启动下游对促炎性细胞因子和I型IFNs的应答，从而构成宿主免疫系统的第一道防线。当病原体入侵机体后，病毒包膜蛋白、病毒DNA或RNA，细菌表面的复合物(如脂多糖、毛蛋白)等均作为保守PAMPs被宿主细胞的PRRs识别，并通过多种信号途径刺激免疫细胞活化和免疫因子的产生，介导抗感染固有免疫应答。胞内核酸同样可作为PAMP，可被宿主细胞的PRRs识别。
干扰素基因刺激因子(stimulator of interferon genes,STING)是DNA信号通路中重要的接头蛋白，在识别胞质DNA和免疫防御方面起着重要的信号传递作用。在环GMP-AMP合成酶cGAS的催化下，STING可直接感知细菌和病毒的环二核苷酸CDNs，包括c-di-GMP、c-di-AMP和c-di-GAMP，从而激活宿主免疫应答。除了对病原体的免疫应答外，STING信号系统可通过cGAS监督死亡细胞或肿瘤细胞释放到胞质双链DNA(double-stranded DNA，dsDNA)。STING检测到细胞质DNA后，cGAS利用2',5'-磷酸二酯键和3',5-'磷酸二酯键合成第二信使cGAMP，从而激活STING通路。此外，由线粒体DNA的不稳定造成的细胞溶质线粒体DNA(mitochondrial DNA，mtDNA)泄漏也会引起相邻吞噬细胞STING的激活。CDNs结合到STING二聚体口袋内可促进STING二聚并从内质网通过高尔基体(golgiapparatus，GA)转移到核周囊泡，识别信号释放到STING的C末端，促进STING聚合。与此同时，TBK1被招募到STING高度保守的C端，导致TBK1自身磷酸化和STING尾端磷酸化。磷酸化的STING尾端继续招募干IRF3，随后被TBK1磷酸化。磷酸化的IRF3二聚体最终进入细胞核内，激活IFNs和促炎性细胞因子基因的转录。
在成纤维细胞、巨噬细胞和DC细胞等多种细胞中，多种病毒或释放dsDNA的菌种诱导IFNs表达的过程完全依赖于STING。研究证明，在宿主抵抗HIV、SIV和MLV等逆转录病毒过程中，STING是必不可少的。STING的抗病毒作用机制归因于IFNs、促炎性细胞因子和趋化因子的分泌，以及对适应性病原体特异性刺激的免疫反应。
肿瘤抗原通过抗原呈递细胞到CD8+T细胞的交叉呈递在抗肿瘤活性方面发挥着关键 的作用。启动CD8+T细胞需要由DC细胞产生IFNs，而IFNβ信号引发需要先天免疫传感器的参与。研究表明，cGAS-STING信号通路涉及IFNβ的表达，并且与肿瘤来源的DNA摄取有关。肿瘤细胞中STING信号通路的激活可诱导趋化因子CCL5和CXCL10的分泌，从而促进肿瘤细胞中NK细胞和T细胞的招募和激活。cGAS-STING通路通过诱导IFNs和衰老相关的分泌表型因子的抗肿瘤机制参与细胞衰老进程。此外，在结肠癌、脑癌、皮肤癌、胰腺癌、乳腺癌及B细胞恶性肿瘤小鼠模型中，瘤内注射CDNs或CDNs类似物会减小肿瘤体积，同时增加模型小鼠存活率。因此，激活STING通路对于预防和治疗感染性疾病或在抗肿瘤免疫领域显示出巨大潜力。
目前已被报道的STING激动剂主要为CDN类似物，比如ADU-S100、MK-1454，但该类化合物结构复杂，化学合成的难度较大。另外，由于其清除速率快、膜通透性差，其治疗应用仅限于肿瘤内注射，极大地限制了临床应用。近年来，发展的STING小分子激动剂，比如DMXAA和CMA均为鼠特异性STING激动剂，由于存在物种差异，两者与人源STING均缺乏有效结合，2018年，diABZI被报道为首类非核苷酸类STING有效的激动剂。2020年，SR-717和MSA-2被相继报道，两者均能诱导STING产生闭合构象，且产生STING依赖性的抗肿瘤效应。
目前报道的STING激动剂均处于临床早期研发管线，且非核苷酸类化合物结构类型缺乏多样性。因此，需要进一步开发结构简单、易于合成的新型小分子STING激动剂。
有鉴于此，特提出本发明。
发明内容
本发明的目的在于提供一种新型小分子STING激动剂及其制备方法和应用。
根据本发明的一个方面，提供了一种化合物、其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，所述化合物选自式I和式II：
Figure PCTCN2022135257-appb-000001
其中：
W选自O或NH；
X选自O、S、-N＝C(R 4)-或-C(R 5)＝C(R 6)-；
R 1选自-C(O)OR 7、-C(O)NHR 8、氰基、含1-3个选自N、O、S的杂原子的3-8元杂环 基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-10元杂芳基、
Figure PCTCN2022135257-appb-000002
R 2、R 3、R 4、R 5和R 6各自独立地选自：H、D、卤素、羟基、氨基、羧基、C1-C6烷基、C3-C8环烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基、C6-C10芳基；其中所述取代的取代基选自C1-C6烷基、C3-C8环烷基；
或者，R 2与R 3连同与其相连的碳原子共同构成一个饱和或不饱和5-6元环，特别是苯环；
或者R 3与R 4或R 6连同与其相连的碳原子共同构成一个饱和或不饱和5-6元环，特别是苯环；
R 7和R 8各自独立地选自：H、D、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-8元杂环基、含1-3个选自N、O、S的杂原子的3-10元杂芳基、未取代或被C1-C6烷氧基、羧基取代的苄基；
n为0，1；
X 1、X 2独立地选自CR 9、N；
X 3选自S、N＝N、O、NH；
R 9选自H、D、卤素、羟基、氨基、羧基、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C2-C6炔基、氰基、C1-C6烷氧基、C3-C8环烷氧基、C1-C6卤代烷基；
A环选自取代或未取代C3-12环烷基、取代或未取代含1-5个选自N、O、S的杂原子的杂环基、取代或未取代C6-C14芳基、取代或未取代的包含1-5个N、O、S的杂原子的杂芳基、哒嗪酮基；其中，所述取代的取代基选自下组的一个或多个：H、D、卤素、羟基、氨基、羧基、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6烷氨基、羟甲基、CH 3-(C＝O)-。
在一些实施方案中，n＝0，A环选自如下结构：
Figure PCTCN2022135257-appb-000003
其中：
W 1、W 2和W 3各自独立地选自CR b或NR c；
R a、R b各自独立地选自H、D、卤素、羟基、氨基、羧基、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C2-C6炔基、氰基、C1-C6烷氧基、C3-C8环烷氧基、C1-C6卤代烷基、-CH 2OH、CH 3-(C＝O)-；
R c不存在或选自H、D、卤素、羟基、氨基、羧基、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基、-CH 2OH、CH 3-(C＝O)-。
优选地，在式I中，A环选自下组：
Figure PCTCN2022135257-appb-000004
其中，R 1a、R 1b、R 1c、R 2a、R 2b、R 2c、R 3a、R 3b、R 3c、R 3d、R 4a、R 4b、R 4c、R 5a、R 5b、R 5c、R 6a、R 6b、R 6c、R 6d各自独立地选自H、D、卤素、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基、-NH 2、-OH、-CH 2OH、CH 3-(C＝O)-；
Y选自O、S或NH。
在一些实施方案中，式I化合物选自式I-1或式I-2，
Figure PCTCN2022135257-appb-000005
式II化合物选自式II-1或式II-2，
Figure PCTCN2022135257-appb-000006
其中，X、R 1、R 2、R 3、n的定义如上所述；
A1环选自
Figure PCTCN2022135257-appb-000007
Figure PCTCN2022135257-appb-000008
A2环选自
Figure PCTCN2022135257-appb-000009
Figure PCTCN2022135257-appb-000010
R 1a、R 1b、R 1c、R 2a、R 2b、R 2c、R 3a、R 3b、R 3c、R 3d、R 4a、R 4b、R 4c、R 5a、R 5b、R 5c、R 6a、R 6b、R 6c、R 6d各自独立地选自H、卤素、C1-C6烷基、C2-C6烯基、氰基、C1-C6烷氧基、C1-C6卤代烷基、-NH 2、-OH、-CH 2OH、CH 3-(C＝O)-；
Y选自O、S或NH。
在一些实施方案中，式I-1化合物为式I-1A，
Figure PCTCN2022135257-appb-000011
其中：
R 1为-C(O)OR 7；
R 3和R 6各自独立地选自卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基；或R 3和R 6连同与其相连的碳原子共同构成一个饱和或不饱和5-6元环，特别是苯环；
R 7选自H、C1-C6烷基；
n为0或1；
A1环的定义如上所述；
优选地，A1环选自如下结构：
Figure PCTCN2022135257-appb-000012
Figure PCTCN2022135257-appb-000013
在一些实施方案中，式I-2化合物为式I-2A，
Figure PCTCN2022135257-appb-000014
其中：
R 1为-C(O)OR 7；
R 3和R 6各自独立地选自卤素、C1-C6烷基、C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基；或R 3和R 6连同与其相连的碳原子共同构成一个饱和或不饱和5-6元环，特别是苯环；
R 7选自H、C1-C6烷基；
n为0或1；
A2环的定义如上所述；
优选地，A2环选自如下结构：
Figure PCTCN2022135257-appb-000015
在一些实施方案中，式II-1化合物为式II-1A、式II-1B或式II-1C，
Figure PCTCN2022135257-appb-000016
其中：R 1为-C(O)OR 7；
R 2、R 3、R 4各自独立地选自氢、卤素、C1-C6烷基、C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基；或R 2和R 3连同与其相连的碳原子共同构成一个饱和或不饱和5-6元环，特别是苯环或环己烷；
R 7选自H、C1-C6烷基；
n，A 1环的定义如上所述。
本发明中的术语定义如下：
术语“烷基”是指直链或支链饱和烃基，包含1-18个碳原子，尤其指1-6个碳原子。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、戊基、异戊基、庚基、4,4–二甲基戊基，辛基，2,2,4-三甲基戊基，壬基，癸基、十一烷基，十二烷基等等。术语“C1-C6烷基”指的是直链或支链烷基，包括1-6个碳原子，如甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基。“取代烷基”是指烷基中的一个或多个位置被取代，尤其 是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(＝O)Re、S(＝O) 2Re、P(＝O) 2Re、S(＝O) 2ORe、P(＝O) 2ORe、NRbRc、NRbS(＝O) 2Re、NRbP(＝O) 2Re、S(＝O) 2NRbRc、P(＝O) 2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)Ore、NRdC(＝O)NRbRc、NRdS(＝O) 2NRbRc、NRdP(＝O) 2NRbRc、NRbC(＝O)Ra、或NRbP(＝O) 2Re，其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说Rb和Rc与N原子一起可以形成杂环；Re可以独立表示氢、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以被任选取代。
术语“烯基”是指直链或支链烃基，含有2-18个碳原子和至少一个碳碳双键。术语“C2-C6烯基”是指直链或支链的含有2-6个碳原子且至少有一个碳碳双键的烃基，如乙烯基、丙烯基、2-丙烯基、(E)-2-丁烯基、(Z)-2-丁烯基、(E)-2-甲基-2-丁烯基、(Z)-2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基、(Z)-2-戊烯基、(E)-1-戊烯基、(E)-2-戊烯基、(Z)-2-己烯基、(E)-1-己烯基、(Z)-1-己烯基、(E)-2-己烯基、(Z)-3-己烯基、(E)-3-己烯基、(E)-1,3-己二烯基、4-甲基-3-戊烯基。“取代烯基”是指烯基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(＝O)Re、S(＝O) 2Re、P(＝O) 2Re、S(＝O) 2ORe、P(＝O) 2ORe、NRbRc、NRbS(＝O) 2Re、NRbP(＝O) 2Re、S(＝O) 2NRbRc、P(＝O) 2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe、NRdC(＝O)NRbRc、NRdS(＝O) 2NRbRc、NRdP(＝O) 2NRbRc、NRbC(＝O)Ra、或NRbP(＝O) 2Re，其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说Rb和Rc与N原子一起可以形成杂环；Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。
术语“炔基”是指直链或支链烃基，含有2-18个碳原子和至少一个碳碳三键。典型的基团包括乙炔基。术语“C2-C6炔基”是指直链或支链的含有2-6个碳原子和至少有一个碳碳三键的烃基，如乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、1-己炔基、2-己炔基、3-己炔基。“取代炔基”是指炔基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(＝O)Re、S(＝O) 2Re、P(＝O) 2Re、S(＝O) 2ORe、P(＝O) 2ORe、NRbRc、NRbS(＝O) 2Re、 NRbP(＝O) 2Re、S(＝O) 2NRbRc、P(＝O) 2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)Ore、NRdC(＝O)NRbRc、NRdS(＝O) 2NRbRc、NRdP(＝O) 2NRbRc、NRbC(＝O)Ra、或NRbP(＝O) 2Re，其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说Rb和Rc与N原子一起可以形成杂环；Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。典型的取代基可以任选取代。
术语“环烷基”是指完全饱和的环状烃类化合物基团，包括1-4个环，每个环中含有3-8个碳原子，例如包含3-18个碳原子，尤其指3-14个碳原子，非限制性地包括环丙基、环丁基、环戊基、环己基或降莰烷。“取代环烷基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(＝O)Re、S(＝O) 2Re、P(＝O) 2Re、S(＝O) 2ORe、P(＝O) 2ORe、NRbRc、NRbS(＝O) 2Re、NRbP(＝O) 2Re、S(＝O) 2NRbRc、P(＝O) 2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe、NRdC(＝O)NRbRc、NRdS(＝O) 2NRbRc、NRdP(＝O) 2NRbRc、NRbC(＝O)Ra或NRbP(＝O) 2Re，其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说Rb和Rc与N原子一起可以形成杂环；Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括螺环、桥环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“芳基”是指芳香环状烃基，具有1-5个环，例如包含6-18个碳原子，尤其指6-14个碳原子。尤其指单环和双环基团，如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)、芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代，尤其是1-3个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(＝O)Re、S(＝O) 2Re、P(＝O) 2Re、S(＝O) 2ORe、P(＝O) 2ORe、NRbRc、NRbS(＝O) 2Re、NRbP(＝O) 2Re、S(＝O) 2NRbRc、P(＝O) 2NRbRc、C(＝O)ORd、C(＝O)Ra、C(＝O)NRbRc、OC(＝O)Ra、OC(＝O)NRbRc、NRbC(＝O)ORe、NRdC(＝O)NRbRc、NRdS(＝O) 2NRbRc、NRdP(＝O) 2NRbRc、NRbC(＝O)Ra、或NRbP(＝O) 2Re，其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环， 或者说Rb和Rc与N原子一起可以形成杂环；Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基，尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂芳基”指包含1-4个杂原子(优选1或2个)、5-14个环原子的芳香环状基团，其中杂原子选自氧、氮和硫。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、噁二唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基、嘌呤、咔唑、吲哚基、吲唑基、苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并三唑基、苯并噻唑基、苯并噻二唑基、苯并噁唑基、异构化的喹啉基、酞嗪基、喹喔啉基、喹唑啉基、噌啉基或萘啶基及四氮唑基等。“杂芳基”可以是取代的或者非取代的，当被取代时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“杂环基”指包含1-4个杂原子(优选1或2个)、5-14个环原子的非芳香环状基团，其中杂原子选自氧、氮和硫，例如二氢吡啶基、四氢吡啶基(哌啶基)、四氢噻吩基、硫氧化的四氢噻吩基、4-哌啶酮基、吡咯烷基、2-吡咯烷酮基、吡咯啉基、四氢呋喃基、双-四氢呋喃基、四氢吡喃基、双-四氢吡喃基、四氢喹啉基、四氢异喹啉基、十氢喹啉基、八氢异喹啉基、氮杂环辛四烯基、吡喃基、色烯基、呫吨基、2H-吡咯基、嘌呤基、萘啶基、蝶啶基、菲啶基、异色满基、色满基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、哌嗪基、吲哚啉基、异吲哚啉基、奎宁环基、吗啉基、噁唑烷基、苯并噁唑啉基。
术语“卤素”或“卤”是指氟、氯、溴、碘。
“卤代烷基”是指直链或支链卤代烷基，如“C1-C6卤代烷基”，其是指具有1至6个碳原子的包含一个或多个相同或不同的卤素原子的直链或支链卤代烷基，非限制性地包括-CH 2Cl、-CHCl 2、-CCl 3、-CH 2F、-CHF 2、-CF 3、-CH 2Br、-CHBr 2、-CBr 3、CF 3CH 2、CCl 3CH 2、CBr 3CH 2。
术语“烷氧基”是指直链或支链烷氧基，如“C1-C6烷氧基”，其是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。
术语“烷氨基”是指氨基取代的直链或支链烷基，如“C1-C6烷氨基”，其是指具有1至6个碳原子的氨基取代的直链或支链烷基，非限制性地包括H 2N-CH 2-、H 2N-CH 2CH 2-、H 2N-CH 2CH 2CH2-、H 2N-CH(CH 3)CH 2-等。
术语“羧基”是指-COOH。
术语“羟甲基”是指-CH 2OH。
术语“饱和或不饱和5-6元环”包括芳环(例如苯环)、杂芳环(例如
Figure PCTCN2022135257-appb-000017
)、杂环 (例如
Figure PCTCN2022135257-appb-000018
)、饱和烃环(例如环己烷)。
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。
在此使用的术语“药学上可接受的盐”是指无毒，生理可接受的盐，包括有机盐和无机盐，如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐或硫酸氢盐、硝酸盐、磷酸盐或酸式磷酸盐、高氯酸盐、甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、丁二酸盐、戊二酸盐、马来酸盐、富马酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、苦味酸盐、谷氨酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、水杨酸盐、抗坏血酸盐、樟脑酸盐或樟脑磺酸盐等。
也可在R 7处成盐，如锂、钠、钾盐等。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本发明的权利要求所限定的范围中。
本申请所涉及的化合物及其药学可接受的盐可形成溶剂合物，如醇合物、水合物等，但不限于此。这些溶剂合物也包含在本发明的权利要求所限定的范围中。
本申请所涉及的化合物及其药学可接受的盐可具有异构体，例如光学异构体(包括非对映异构体和对映异构体)、阻转异构体、几何异构体(顺反异构体)、构象异构体、互变异构体以及它们的混合物等，但不限于此。这些异构体也包含在本发明的权利要求所限定的范围中。
本申请所涉及的化合物及其药学可接受的盐、溶剂合物可具有多晶型物。这些多晶型物也包含在本发明的权利要求所限定的范围中。
在一些实施方式中，式I化合物选自下列化合物：
Figure PCTCN2022135257-appb-000019
Figure PCTCN2022135257-appb-000020
Figure PCTCN2022135257-appb-000021
Figure PCTCN2022135257-appb-000022
Figure PCTCN2022135257-appb-000023
Figure PCTCN2022135257-appb-000024
Figure PCTCN2022135257-appb-000025
Figure PCTCN2022135257-appb-000026
Figure PCTCN2022135257-appb-000027
Figure PCTCN2022135257-appb-000028
本发明基于SR-717与STING复合物的晶体结构及现有的STING激动剂，结合分子对接及分子动力学模拟，发现了一类化合物及其药物组合具有STING激动活性，与阳性化合物SR-717相比，本发明的优选化合物表现出更好的STING结合能力，在人源THP-1细胞和鼠源RAW264.7细胞中，均可明显上调IFN-β，CXCL10及IL-6mRNA的表达水平，从而为恶性肿瘤和感染性疾病治疗药物的研发提供新思路。
根据本发明的第二个方面，提供一种式I化合物的制备方法，其为下列方法之一：
方法1：
Figure PCTCN2022135257-appb-000029
酯类化合物M1与硼酸酯类化合物M2经suzuki偶联反应得到中间体M3，接着水解得到羧酸类化合物M4，进一步与M5发生缩合反应或者缩合后再水解得到式I的化合物；
方法2：
Figure PCTCN2022135257-appb-000030
酯类化合物M1’与胺类化合物M 2’或M 2”经亲核取代反应得到中间体M 3’，水解得到M 4’，进一步与M5发生缩合反应或者缩合后再水解得到式I的化合物；
方法3：
Figure PCTCN2022135257-appb-000031
羧酸类化合物M1a与草酰氯反应得到酰氯M2a，随后与胺类化合物M5反应得到M3a，M3a与硼酸酯类化合物M2经suzuki偶联反应，或与胺类化合物M2’或M2”经亲核取代反应得到式I化合物，或再经过一步水解反应得到式I化合物；
方法4：
Figure PCTCN2022135257-appb-000032
化合物M2-1与三甲基乙炔基硅M2-2反应得到化合物M2-3，脱保护基后的化合物M2-4与化合物M2-5发生环加成反应得到化合物M2-6，接着化合物M2-6水解得到化合物M2-7，化合物M2-7与化合物M5缩合后得到式I化合物，或再经一步水解反应得到式I化合物；
或者将上述方法1-4任一个中的M5替换为
Figure PCTCN2022135257-appb-000033
(M5a)得到式II化合物；
其中，R 1、R 2、R 3、X、X 1、X 2、X 3、W、W 1、W 2、W 3、R a、n、A环的定义如上所述。
在一些优选的实施方案中，酯类化合物M1或M3a与硼酸酯类化合物之间的suzuki偶联反应是在钯催化条件下进行的。
上述suzuki偶联反应通常在80-120℃下进行，优选100-120℃下进行，反应通常在约5-12小时，优选在8-12小时内完成。
在一些优选的实施方案中，酯类化合物M1’或M3a与胺类化合物之间的亲核取代反应是在碱性条件(优选碱为K 2CO 3、NaH、N,N-二异丙基乙胺和三乙胺)下进行的。
上述亲核取代反应通常在0℃或室温下进行，优选室温下进行，反应通常在约1-5小时，优选在2-3小时内完成。
在一些优选的实施方案中，上述的水解反应是在碱性条件下进行的。
上述水解反应通常在0℃或室温下进行，优选室温下进行，反应通常在约1-5小时，优选在1-3小时内完成。
在一些优选的实施方案中，M4或M4’与M5的缩合反应是在缩合剂(优选缩合剂组合为HATU、HBTU、HOBT/EDCI、TCFH/NMI)。任选地，接着水解反应是碱性条件(优选碱LiOH、NaOH水溶液)下进行的。
上述缩合反应通常在室温-120℃下进行，优选在室温-80℃下进行，反应通常在约6-12小时，优选在8个小时内完成。
在一些优选的实施方案中，M1a与草酰氯的反应是在0℃-室温条件下进行的，反应通 常在1-12小时之间完成，优选在5小时内完成。
在一些优选的实施方案中，酰氯M2a与M5通常在碱性条件(优选碱为N,N-二异丙基乙胺和三乙胺)下进行。反应通常在0℃-室温条件下进行，优选室温条件。反应通常在1-5小时完成。
根据本发明的第三个方面，提供了一种药物组合物，包含治疗有效量的选自式I所示的化合物，其异构体、前药、溶剂合物、水合物、其药学上可接受的盐、活性代谢物中的一种或多种。
根据本发明的化合物可以单独使用或与其它药物联用以预防或治疗肿瘤、病毒感染、免疫性疾病和炎症性疾病。
本发明的通式I化合物，特别是通式I-1或I-2所示的哒嗪类化合物和噻二唑类化合物及其药学上可接受的盐可以单独给药，或者与其他药学上可接受的治疗药物联合给药。所述的药学上可接受的治疗药物包括但不限于，例如，传统细胞毒化疗小分子药物，如甲氨蝶呤、5-氟尿嘧啶、阿霉素、紫杉醇、伊马替尼等；免疫检查位点调制剂，如Opdivo和Keytruda等。上述药物组合的各成分可以同时给药或顺序给药，亦单一制剂或不同制剂形式给药。所述的组合包括通式I化合物与一种或多种其他可接受的治疗药物的组合。
所述的药物组合物为片剂、胶囊剂、丸剂、注射剂、丸剂、散剂或颗粒剂。
本发明的化合物或其药物组合物给药方式没有特别限制，代表性的给药方式，但不限于口服、静脉注射、腹腔注射、肌肉内注射、皮下注射、局部给药等。
根据本发明的第四个方面，提供了一种式I所示的化合物、其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药或上述所述的药物组合物在制备STING激动剂中的用途。
根据本发明的第五个方面，提供了一种式I所示的化合物、其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药或上述所述的药物组合物用于制备治疗STING蛋白依赖型疾病的药物，特别是肿瘤、病毒感染、免疫性疾病和炎症性疾病的治疗药物，是一类全新作用机制的治疗药物。
所述肿瘤选自所述的肿瘤各自独立地选自：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌、胰腺癌等。
所述免疫性疾病和炎症性疾病选自移植器官的排斥反应、痛风、鼻炎、脱发、阿尔茨海默氏病、阑尾炎、动脉粥样硬化、哮喘、关节炎、过敏性皮炎、贝切特氏病、大疱性皮肤病、胆囊炎、慢性特发性血小板减少性紫癜、慢性阻塞性肺病、肝硬化、退行性关节病、皮肤炎、皮肌炎、湿瘆、肠炎、脑炎、胃炎、肾炎、桥本氏甲状腺炎、肝炎、垂体炎、炎性肠病、肠易激综合征、川崎病、脑脊膜炎、多发性硬化、心肌炎、重症肌无力、蕈样真菌病、肌炎、肾炎、骨髓炎、胰腺炎、帕金森病、心包炎、恶性贫血、肺炎、原发性胆汁性硬化性胆管炎、结节性多动脉炎、银肩病、纤维化、红斑狼疮、组织移植排斥、甲状腺 炎、I型糖尿病、尿道炎、葡萄膜炎、血管炎、白癜风和瓦尔登斯特伦氏巨球蛋白血症等。
本发明所述的化合物在分子和细胞水平的活性均比阳性化合物SR-717有显著增强。
附图说明
图1为本发明实验例检验的IFN-β的mRNA的表达水平；
图2为本发明实验例检验的CXCL10的mRNA的表达水平；
图3为本发明实验例检验的IL-6的mRNA的表达水平。
具体实施方式
下列实施例和实验例进一步阐明本发明，但并不限制本发明的范围。
除特殊说明外，在实施例和实验例中所采用的商业可得的原料和试剂等均为本领域常规的原料和试剂，实验方法是可使用Scifinder或Reaxy搜索到的常规的实验方法。
实施例1
化合物27和化合物62的制备：
Figure PCTCN2022135257-appb-000034
步骤1：
称取咪唑(347mg,5.1mmol)溶于THF(20mL)中，将体系温度降至0℃后，加入NaH，搅拌30min后加入5-溴-1,3,4-噻二唑-2-羧酸乙酯M1(1.0g,4.2mmol),保持0℃反应1h。TLC监测反应完毕后，加甲醇淬灭反应，减压去除溶剂，向残留物中加水，用乙酸乙酯萃取，浓缩后快速柱层析得化合物M2。
步骤2：
将化合物M2(570mg,2.5mmol)溶于CH 3OH(12mL)中，降至0℃后加入2.5M LiOH水溶液(1.2mL,3.1mmol)，缓慢升至室温反应大约1h。TLC监测反应完毕后，向体系中缓慢滴加2M HCl水溶液，调节pH＝5-6，将析出的固体滤出，置于60℃下真空干燥过夜得到化合物M3。
步骤3：
将化合物M3(128mg,0.65mmol)和2-氨基-4,5-二氟苯甲酸甲酯(159mg,0.85mmol)加入反应瓶中，加CH 3CN将底物溶解，降温至0℃后依次加入TCFH和NMI，缓慢升至室温反应大约3h。TLC监测反应完毕后，加水淬灭反应，用乙酸乙酯萃取，干燥浓缩后快速柱层析得到化合物27。
步骤4：
将化合物27(913mg,2.5mmol)溶于CH 3OH(12mL)中，降至0℃后加入2.5M LiOH水溶液(1.2mL,3.1mmol)，缓慢升至室温反应大约1h。TLC监测反应完毕后，向体系中缓慢滴加2M HCl水溶液，调节pH＝5-6，将析出的固体滤出，置于60℃下真空干燥过夜得到化合物62。
实施例2
化合物26的制备：
Figure PCTCN2022135257-appb-000035
步骤1：
称取6-氯哒嗪-3-羧酸Z1(3g,18.92mmol)置于50mL的无水二氯甲烷中，在0℃条件下加入草酰氯(1.92mL，22.71mmol)，随后再加入0.5mL的DMF，反应逐渐升至室温，待不溶物完全溶解，停止反应，浓缩得到Z2。
步骤2：
将步骤1中得到的Z2(1g,5.65mmol)溶解在20mL干燥的二氯甲烷中，于0℃下加入2-氨基-4,5-二氟苯甲酸甲酯(2g，11.30mmol)和DPIEA(1.97mL，11.30mmol)的二氯甲烷溶液20mL，反应5h，随后过滤即得到Z3，不需要进一步纯化。
步骤3：
取步骤2得到的Z3(200mg，0.61mmoL)和吡咯(81.90mg，1.22mmol)溶解在5mL干燥的DMF中，随后加入叔丁醇钠(117.32mg,1.22mmol),体系在60-80℃的条件下过夜反应。反应经柱层析最后得到Z4。
步骤4：
将步骤3中的Z4(50mg，0.14mmol)溶解在2mL THF中。称取一水氢氧化锂(8.78mg，0.21mmol)溶于1mL水中，加入到THF溶液中，室温反应1h，减压浓缩溶剂，最后用1N HCl调节pH为2左右，过滤析出的白色固体，即为化合物26。 1H NMR(500MHz,DMSO-d 6)δ14.54(s,1H),8.82(dd,J＝13.7,7.6Hz,1H),8.39(d,J＝9.2Hz,1H),8.32(d,J＝9.2Hz,1H),8.01(dd,J＝11.6,9.4Hz,1H),7.91(t,J＝2.3Hz,2H),6.46(t,J＝2.3Hz,2H).
实施例3
化合物1和化合物6的制备：
Figure PCTCN2022135257-appb-000036
参考实施例2步骤1和2合成Z3。
化合物1的合成：
称取Z3(100mg，0.31mmol)和1,2,4-三氮唑(21.35mg,0.31mmol)溶解在干燥的DMF(2mL)中，在120℃反应2h。加水稀释，得到白色固体，经PTLC制备得到化合物1。 1H NMR(600MHz,DMSO-d 6)δ13.09(s,1H),9.81(s,1H),8.82(dd,J＝13.4,7.5Hz,1H),8.59(d,J＝9.0Hz,1H),8.50(s,1H),8.40(d,J＝9.0Hz,1H),8.07(dd,J＝11.1,8.9Hz,1H),3.95(s,3H).
化合物6的合成：
将化合物1(10mg，0.03mmol)溶解在DMSO(0.8mL)中，向体系加入0.1M的LiOH水溶液(0.33mL，0.04mmol)，混合体系在室温反应3h，随后加入1N HCl调节pH为2左右，出现白色固体，过滤干燥即得化合物6。 1H NMR(600MHz,DMSO-d 6)δ13.33(s,1H),9.80(s,1H),8.87(dd,J＝13.5,7.5Hz,1H),8.60(d,J＝9.0Hz,1H),8.50(s,1H),8.41(d,J＝9.0Hz,1H),8.07(dd,J＝11.1,9.0Hz,1H).
实施例4
化合物10和化合物15的制备：
Figure PCTCN2022135257-appb-000037
参考实施例2步骤1和2合成Z3。
化合物10的制备：
称取5-氟咪唑(20mg，0.23mmol)溶解在1mL干燥DMF中，冷却至0℃，随后加入NaH(10.22mg，0.26mmol)升至室温搅拌30min，最后将Z3(91.4mg，0.28mmol)溶解于1mL DMF滴加到上述体系中，过夜反应，加水稀释体系，过滤得到的固体，经柱层析得到化合物10。 1H NMR(400MHz,Chloroform-d)δ13.38(s,1H),8.92(dd,J＝13.0,7.5Hz,1H),8.54(d,J＝9.1Hz,1H),8.25(s,1H),7.96(dd,J＝10.8,8.7Hz,1H),7.74(d,J＝9.1Hz,1H),7.39(dd,J＝8.2,1.8Hz,1H),4.03(s,3H).
化合物15的制备：
称取化合物10(20mg，0.05mmol)溶解在混合溶剂7mL(V THF：V MeOH：V H2O＝3:3:1)中，随后加入2.5M的LiOH水溶液(26μL，0.06mmol)在室温条件下反应3h，随后用1N HCl调节pH 2-3，过滤析出的白色固体，干燥即得化合物15。 1H NMR(600MHz,DMSO-d 6)δ14.19(s,1H),13.25(s,1H),8.83(dd,J＝13.5,7.4Hz,1H),8.60(s,1H),8.56(d,J＝9.1Hz,1H),8.44(d,J＝9.2Hz,1H),8.04(dd,J＝12.8,7.3Hz,1H),7.97(d,J＝8.0Hz,1H).
实施例5
化合物21和化合物22的制备：
Figure PCTCN2022135257-appb-000038
参考实施例2步骤1和2合成Z3。
化合物21的制备：
称取4-硼酸酯哒嗪(150mg，0.73mmol)、Z3(287mg，0.87mmol)和醋酸钾(143mg，1.46mmol)溶于1,4-二氧六环和水的混合溶剂(V:V＝1:1,20mL)中，超声脱气30min，最后将四三苯基膦钯(42mg，0.04mmol)加入，置换氩气3次，在110℃条件下反应12h。反应结束后，将溶剂浓缩，经柱层析得到化合物21。 1H NMR(600MHz,DMSO-d 6)δ13.18(s,1H),10.08(d,J＝2.3Hz,1H),9.53(d,J＝5.3Hz,1H),8.87(dd,J＝13.3,7.5Hz,1H),8.79(d,J＝8.8Hz,1H),8.57(d,J＝8.8Hz,1H),8.52(dd,J＝5.7,2.3Hz,1H),8.12(t,J＝10.0Hz,1H),3.97(s,3H).ESI:372.3(M+H).
化合物22的制备：
称取化合物21(20mg，0.05mmol)溶解在混合溶剂(V THF：V MeOH：V H2O＝1:1:1)3mL中，随后加入2.5M的LiOH水溶液(26μL，0.06mmol)在室温条件下反应2h，随后用1N HCl调节pH 2-3，过滤析出的白色固体，干燥即得化合物22。 1H NMR(600MHz,DMSO-d 6)δ13.40(s,1H),10.06(s,1H),9.52(d,J＝5.3Hz,1H),8.88(dd,J＝13.4,7.4Hz,1H),8.77(d,J＝8.8Hz,1H),8.57(s,1H),8.50(d,J＝5.0Hz,1H),8.07(t,J＝10.0Hz,1H).
实施例6
化合物34和54的制备：
Figure PCTCN2022135257-appb-000039
步骤1：中间体Z5的制备
称取中间体Z4(2g,11.59mmol)溶解于20mL THF中，随后依次加入三甲基硅乙炔(8mL,58.00mmol)、Pd(PPh 3) 2Cl 2(814mg,1.16mmol)、CuI(441mg,2.32mmol)和三乙胺(1.6mL,11.59mmol)，在超声条件下脱气30min，置于室温反应3h，反应浓缩，纯化得到2.18g淡黄色固体。
将上述得到淡黄色固体(2.18g,9.30mmol)溶解在30mL无水乙醇中，向其中加入K 2CO 3(2.57g,18.61mmol)在室温下反应2h。反应结束后向体系中加入H 2O(100mL)，用DCM(30mL*3)萃取，最后浓缩有机层得到中间体Z5。 1H NMR(600MHz,Chloroform-d)δ8.18(d,J＝8.6Hz,1H),7.74(d,J＝8.6Hz,1H),4.09(s,3H),3.58(s,1H).
步骤2：中间体Z6的制备
称取Z5(1.03g,6.35mmol)置于100mL的封管中，加入1,4-二氧六环(40mL)进行溶解，随后向其中加入1,2,4,5-四嗪(573.43mg,6.99mmol)，在140℃条件下反应6h。最后纯化得到中间体Z6。 1H NMR(600MHz,DMSO-d 6)δ10.03(d,J＝1.2Hz,1H),9.51(d,J＝5.4Hz,1H),8.70(d,J＝8.8Hz,1H),8.47(dd,J＝5.4,2.4Hz,1H),8.44(d,J＝8.8Hz,1H),4.01(s,3H).
步骤3：中间体Z7的制备
称取上述得到的中间体Z6(300mg,1.39mmol),加入V THF：V MeOH：V H2O＝2:2:1(10mL)溶剂进行溶解，在室温条件下加入LiOH的2.5M水溶液(1.11mL,2.78mmol)，室温反应1h，减压蒸除大量溶剂，最后用1N HCl调节pH到2左右，析出大量白色固体，过滤，干燥滤饼即为中间体Z7。 1H NMR(600MHz,DMSO-d 6)δ14.09(s,1H),10.03(s,1H),9.51(d,J＝5.3Hz,1H),8.67(d,J＝8.8Hz,1H),8.46(dd,J＝5.4,2.4Hz,1H),8.40(d,J＝8.8Hz,1H).
步骤4：化合物34的制备
称取中间体Z7(80mg,395.70μmol)，邻氨基苯甲酸甲酯(71.78mg,474.86μmol),TCFH(133.23mg,474.86μmol)和NMI(113.71mg,1.38mmol)，加入无水乙腈(20mL)在75℃下反应10h。最后纯化得到淡黄色固体化合物34。 1H NMR(600MHz,DMSO-d 6)δ13.15(s,1H),10.23–9.88(m,1H),9.53(dd,J＝5.4,1.3Hz,1H),8.86(dd,J＝8.5,1.2Hz,1H),8.79(d,J＝8.8Hz,1H),8.57(d,J＝8.8Hz,1H),8.52(dd,J＝5.4,2.4Hz,1H),8.11(dd,J＝8.0,1.6Hz,1H),7.76(ddd,J＝8.7,7.3,1.7Hz,1H),7.31(ddd,J＝8.1,7.3,1.2Hz,1H),3.96(s,3H).
步骤5：化合物54的制备
称取化合物34(50mg,149.11μmol)，溶解在V THF：V MeOH：V H2O＝2:2:1(5mL)中，在冰浴条件下加入2.5M的LiOH水溶液(120μL,298.22μmol)，室温条件下反应2h。蒸除大量溶剂，用1N HCl调节pH到2左右，析出白色固体，过滤，得到滤饼真空干燥得到化合物54。 1H NMR(600MHz,DMSO-d 6)δ13.76(s,1H),13.38(s,1H),10.09–10.06(m,1H),9.53(dd,J＝5.4,1.2Hz,1H),8.88(d,J＝8.4Hz,1H),8.78(d,J＝8.8Hz,1H),8.56(d,J＝ 8.8Hz,1H),8.51(dd,J＝5.4,2.4Hz,1H),8.11(dd,J＝7.9,1.7Hz,1H),7.75–7.70(m,1H),7.29(t,J＝7.6Hz,1H).
按照上述类似方法制备其他化合物，结果如下：
Figure PCTCN2022135257-appb-000040
Figure PCTCN2022135257-appb-000041
Figure PCTCN2022135257-appb-000042
Figure PCTCN2022135257-appb-000043
Figure PCTCN2022135257-appb-000044
Figure PCTCN2022135257-appb-000045
Figure PCTCN2022135257-appb-000046
Figure PCTCN2022135257-appb-000047
Figure PCTCN2022135257-appb-000048
Figure PCTCN2022135257-appb-000049
Figure PCTCN2022135257-appb-000050
Figure PCTCN2022135257-appb-000051
Figure PCTCN2022135257-appb-000052
Figure PCTCN2022135257-appb-000053
Figure PCTCN2022135257-appb-000054
Figure PCTCN2022135257-appb-000055
Figure PCTCN2022135257-appb-000056
Figure PCTCN2022135257-appb-000057
Figure PCTCN2022135257-appb-000058
Figure PCTCN2022135257-appb-000059
Figure PCTCN2022135257-appb-000060
Figure PCTCN2022135257-appb-000061
实验例
材料与方法：
细胞株
细胞株THP1-BLUE ISG和Raw-Lucia ISG购自Invivogen公司。参照培养说明书，细胞培养条件为2mmol·L -1L-谷氨酰胺、25mmol·L -1HEPES、10％热灭活Gibco FBS(56℃,30min)、青链霉素(100μg·mL -1、100μg·mL -1)的RPMI 1640培养基。
试剂
SR-717购自上海皓元生物医药科技有限公司。QUANTI-BLUE购自Invivogen公司，qPCR引物由生工生物工程股份有限公司合成。
蛋白表达与纯化
将编码人类STING H232CTD的基因(羧基末端结构域，139-378残基)插入修饰的Pet28a载体中，并添加his-sumo标签。该重组蛋白在大肠杆菌BL21(DE3)菌株中表达。细胞在37℃下培养，用0.3mM异丙基-β-D-硫代半乳糖苷(IPTG)在18℃下诱导过夜。3000rpm离心30min收集细胞，在裂解缓冲液(20mM HEPES,pH＝7.4,200mM氯化钠,10mM咪唑,1mMTCEP)中超声裂解。离心后，将上清液载入HistrapFF柱，用50mM咪唑洗涤，用300mM咪唑洗脱。标签用ULP-1酶裂解，使用Histrap FF柱移除标签。用Superdex 75 increase分子筛进一步纯化STING蛋白。将纯化后的蛋白在缓冲液(20mM HEPES，pH＝7.4,200mM氯化钠)中浓缩并存储在-80℃。
其他人源不同亚型STING及鼠源STING蛋白的表达与纯化参考以上方法。
蛋白热迁移
采用CFX Manager TM Software实时PCR系统检测了STING蛋白的热稳定性。化合物和相同浓度的DMSO(作为空白对照)与2μM STING蛋白和5XSYPRO orange(invitrogene)在缓冲液(20mM HEPES，pH＝7.4，200mM氯化钠)中孵育。在47min内监测和收集从25℃到95℃的荧光信号值。使用蛋白热迁移分析软件测定STING蛋白的T m值，与对照组的差值△T m(℃)结果如表1所示，△T m(℃)不为0，代表化合物与蛋白有结合，差距越大，结合越强。
THP-1BLUE和Raw-Lucia ISG检测
将100μL状态良好的细胞以5×10 5个/ml铺至圆底96孔细胞培养板，每孔分别加入10μL不同浓度SR-717和化合物，设立三个平行孔，37℃，5％CO 2细胞培养箱孵育24h，取180μLQUANTI-BLUE检测试剂加入96孔细胞培养板，随后每孔加入20μL上清液加入，轻轻拍打孔板混匀溶液，37℃孵育30min并在650nM处检测化学发光值(TECAN酶标仪)。以实验组相对于对照组的基因表达倍数和对应浓度用GraphPad Prism 8作图，拟合出EC 50值，即是指能引起50％最大效应的浓度。
化合物的人源STING R232H分子水平和THP1细胞活性结果如表1所示。
表1
Figure PCTCN2022135257-appb-000062
Figure PCTCN2022135257-appb-000063
Figure PCTCN2022135257-appb-000064
Figure PCTCN2022135257-appb-000065
Figure PCTCN2022135257-appb-000066
化合物在人源STING不同亚型分子水平活性结果如表2所示。
表2
Figure PCTCN2022135257-appb-000067
化合物在鼠源STING WT分子水平及鼠源Raw264.7细胞活性结果如表3所示。
表3
Figure PCTCN2022135257-appb-000068
qPCR
使用RNA快速提取试剂盒(南京诺唯赞生物科技股份有限公司)提取细胞总RNA，大致方法如下：用500μL裂解液裂解细胞后移至离心柱，收集滤液加入0.5体积无水乙醇混匀，转移至RNA收集柱，12000rpm离心30s，加入700μL漂洗液1，12000rpm离心30s，加入700μL漂洗液2，12000rpm离心30s，加入500μL漂洗液2，12000rpm离心2min。将离心柱移至1.5mL RNase-free EP管上，并加20～100μL DEPC H 2O至离心柱中央，12000rpm离心1min得到RNA溶液。使用TECAN多功能酶标仪的核酸定量模块检测 RNA的浓度，而后用逆转录试剂盒逆转录得到cDNA溶液。
为了检验IFN-β、CXCL10、IL6的mRNA水平，本研究使用了SYBRgreen qPCR Mix和96孔实时荧光定量PCR仪，并设计合成了一系列引物，序列如下:
人ACTB正向引物:catgtacgttgctatccaggc(SEQ ID NO.1)，
人ACTB反向引物:ctccttaatgtcacgcacgat(SEQ ID NO.2)；
人IFNB正向引物:cagcatctgctggttgaaga(SEQ ID NO.3)，
人IFNB反向引物:cattacctgaaggccaagga(SEQ ID NO.4)；
人CXCL10正向引物:ccacgtgttgagatcattgct(SEQ ID NO.5),
人CXCL10反向引物:tgcatcgattttgctcccct(SEQ ID NO.6)；
人IL6正向引物:ttcggtccagttgccttctc(SEQ ID NO.7),
人IL6反向引物:tacatgtctcctttctcagggc(SEQ ID NO.8)。
RT-qPCR采用CFX96TM实时PCR检测系统(BioRad，上海，中国)。热循环的过程包括95℃下初始变性30s，然后以95℃下5s和60℃下30s为一个循环，设定循环数为40运行。
根据熔融曲线分析目的基因的表达水平。以Folds＝2-ΔΔCt表示实验组与对照组目的基因表达的倍比关系，Folds值即为相对基因表达水平，对应图1～3的纵坐标数值，其中对照组(空白对照)为用相同浓度DMSO给药组。
ΔΔCt的计算公式如下：
ΔΔCt＝(Ct 目的-Ct 内参)实验组-(Ct 目的-Ct 内参)对照组
其中，Ct即阈值循环数，指在PCR循环过程中，每个反应管内的荧光信号达到设定阈值时所经历的循环次数；Ct 目的表示引物为除ACTB外的各组阈值循环数；Ct 内参表示引物为ACTB的各组阈值循环数；(Ct 目的-Ct 内参)实验组表示给药组的特定引物(除ACTB外)对应阈值循环数与ACTB对应阈值循环数的差值；(Ct 目的-Ct 内参)对照组表示空白对照组的特定引物(除ACTB外)对应阈值循环数与ACTB对应阈值循环数的差值；ΔΔCt表示实验组相对于空白对照组阈值循环数的差值。
结果如图1-图3所示。
从图1-图3可以看出，在人类THP细胞中，根据本发明的化合物可促进IFN-β(相对干扰素-β)、CXCL10(相对趋化因子配体10)、IL-6(相对白介素-6)的mRNA的表达水平。
以上各实施例仅用以说明本发明的技术方案，而非对其限制。尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解，在不脱离本发明的精神和实质的范围内，可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；这些修改或者替换仍然在本发明权利要求所限定的范围内。

Claims (10)

  1. 一种化合物、其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，所述化合物选自式I和式II：
    Figure PCTCN2022135257-appb-100001
    其中：
    W选自O或NH；
    X选自O、S、-N＝C(R 4)-或-C(R 5)＝C(R 6)-；
    R 1选自-C(O)OR 7、-C(O)NHR 8、氰基、含1-3个选自N、O、S的杂原子的3-8元杂环基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-10元杂芳基、
    Figure PCTCN2022135257-appb-100002
    R 2、R 3、R 4、R 5和R 6各自独立地选自：H、D、卤素、羟基、氨基、羧基、C1-C6烷基、C3-C8环烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基、C6-C10芳基；其中所述取代的取代基选自C1-C6烷基、C3-C8环烷基；
    或者，R 2与R 3连同与其相连的碳原子共同构成一个饱和或不饱和5-6元环，特别是苯环；
    或者，R 3与R 4或R 6连同与其相连的碳原子共同构成一个饱和或不饱和5-6元环，特别是苯环；
    R 7和R 8各自独立地选自：H、D、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、含1-3个选自N、O、S的杂原子的3-8元杂环基、含1-3个选自N、O、S的杂原子的3-10元杂芳基、未取代或被C1-C6烷氧基、羧基取代的苄基；
    n为0，1；
    X 1和X 2各自独立地选自CR 9、N；
    X 3选自S、N＝N、O、NH；
    R 9选自H、D、卤素、羟基、氨基、羧基、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C2-C6炔基、氰基、C1-C6烷氧基、C3-C8环烷氧基、C1-C6卤代烷基；
    A环选自取代或未取代C3-12环烷基、取代或未取代含1-5个选自N、O、S的杂原子的杂环基、取代或未取代C6-C14芳基、取代或未取代的包含1-5个N、O、S的杂原子的杂芳基、哒嗪酮基；其中，所述取代的取代基选自下组的一个或多个：H、D、卤素、羟基、氨基、羧基、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6烷氨基、羟甲基、CH 3-(C＝O)-。
  2. 根据权利要求1所述的化合物、其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，
    n＝0，A环选自如下结构：
    Figure PCTCN2022135257-appb-100003
    其中：
    W 1、W 2和W 3各自独立地选自CR b或NR c；
    R a和R b各自独立地选自H、D、卤素、羟基、氨基、羧基、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C2-C6炔基、氰基、C1-C6烷氧基、C3-C8环烷氧基、C1-C6卤代烷基、-CH 2OH、CH 3-(C＝O)-；
    R c不存在或选自H、D、卤素、羟基、氨基、羧基、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基、-CH 2OH、CH 3-(C＝O)-；
    优选地，式I中，A环选自如下结构：
    Figure PCTCN2022135257-appb-100004
    Figure PCTCN2022135257-appb-100005
    其中，R 1a、R 1b、R 1c、R 2a、R 2b、R 2c、R 3a、R 3b、R 3c、R 3d、R 4a、R 4b、R 4c、R 5a、R 5b、R 5c、R 6a、R 6b、R 6c、R 6d各自独立地选自H、D、卤素、C1-C6烷基、C3-C8环烷基、C2-C6烯基、C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基、-NH 2、-OH、-CH 2OH、CH 3-(C＝O)-；
    Y选自O、S或NH。
  3. 根据权利要求1或2所述的化合物、其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，
    式I化合物选自式I-1或式I-2，
    Figure PCTCN2022135257-appb-100006
    式II化合物选自式II-1或式II-2，
    Figure PCTCN2022135257-appb-100007
    其中，X、R 1、R 2、R 3、n的定义如相应权利要求；
    A1环选自
    Figure PCTCN2022135257-appb-100008
    Figure PCTCN2022135257-appb-100009
    A2环选自
    Figure PCTCN2022135257-appb-100010
    Figure PCTCN2022135257-appb-100011
    其中，R 1a、R 1b、R 1c、R 2a、R 2b、R 2c、R 3a、R 3b、R 3c、R 3d、R 4a、R 4b、R 4c、R 5a、R 5b、R 5c、R 6a、R 6b、R 6c、R 6d各自独立地选自H、卤素、C1-C6烷基、C2-C6烯基、氰基、C1-C6烷氧基、C1-C6卤代烷基、-NH 2、-OH、-CH 2OH、CH 3-(C＝O)-；
    Y选自O、S或NH。
  4. 根据权利要求3所述的化合物、其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，
    式I-1化合物为式I-1A，
    Figure PCTCN2022135257-appb-100012
    其中：
    R 1为-C(O)OR 7；
    R 3和R 6各自独立地选自氢、卤素、C1-C6烷基、C2-C6烯基、C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基；或R 3和R 6连同与其相连的碳原子共同构成一个饱和或不饱和5-6元环，特别是苯环；
    R 7选自H、C1-C6烷基；
    n，A1环的定义如相应权利要求；
    式I-2化合物为式I-2A，
    Figure PCTCN2022135257-appb-100013
    其中：
    R 1为-C(O)OR 7；
    R 3和R 6各自独立地选自氢、卤素、C1-C6烷基、C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基；或R 3和R 6连同与其相连的碳原子共同构成一个饱和或不饱和5-6元环，特别是苯环；
    R 7选自H、C1-C6烷基；
    n，A2环的定义如相应权利要求；
    式II-1化合物为式II-1A、式II-1B或式II-1C，
    Figure PCTCN2022135257-appb-100014
    其中：R 1为-C(O)OR 7；
    R 2、R 3、R 4各自独立地选自氢、卤素、C1-C6烷基、C2-C6炔基、氰基、C1-C6烷氧基、C1-C6卤代烷基；或R 2和R 3连同与其相连的碳原子共同构成一个饱和或不饱和5-6元环，特别是苯环或环己烷；
    R 7选自H、C1-C6烷基；
    n，A 1环的定义如相应权利要求。
  5. 根据权利要求4所述的化合物、其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，
    A1环选自如下结构：
    Figure PCTCN2022135257-appb-100015
    Figure PCTCN2022135257-appb-100016
    Figure PCTCN2022135257-appb-100017
    和/或
    A2环选自如下结构：
    Figure PCTCN2022135257-appb-100018
  6. 根据权利要求1所述的化合物、其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，式I或II化合物选自下列化合物：
    Figure PCTCN2022135257-appb-100019
    Figure PCTCN2022135257-appb-100020
    Figure PCTCN2022135257-appb-100021
    Figure PCTCN2022135257-appb-100022
    Figure PCTCN2022135257-appb-100023
    Figure PCTCN2022135257-appb-100024
    Figure PCTCN2022135257-appb-100025
    Figure PCTCN2022135257-appb-100026
    Figure PCTCN2022135257-appb-100027
    Figure PCTCN2022135257-appb-100028
  7. 一种权利要求1-6任一项所述的化合物的制备方法，其为下列方法之一：
    方法1：
    Figure PCTCN2022135257-appb-100029
    酯类化合物M1与硼酸酯类化合物M2经suzuki偶联反应得到中间体M3，接着水解得到羧酸类化合物M4，进一步与M5发生缩合反应或者缩合后再水解得到式I化合物；
    方法2：
    Figure PCTCN2022135257-appb-100030
    酯类化合物M1与胺类化合物M 2’或M 2”经亲核取代反应得到中间体M 3’，水解得到M 4’，进一步与M5发生缩合反应或者缩合后再水解得到式I化合物；
    方法3：
    Figure PCTCN2022135257-appb-100031
    羧酸类化合物M1a与草酰氯反应得到酰氯M2a，随后与胺类化合物M5反应得到M3a，M3a与硼酸酯类化合物M2经suzuki偶联反应，或与胺类化合物M2’或与M2”经亲核取代反应得到式I化合物，或再经过一步水解反应得到式I化合物；
    方法4：
    Figure PCTCN2022135257-appb-100032
    化合物M2-1与三甲基乙炔基硅M2-2反应得到化合物M2-3，脱保护基后的化合物M2-4与化合物M2-5发生环加成反应得到化合物M2-6，接着化合物M2-6水解得到化合物M2-7，化合物M2-7与化合物M5缩合后得到式I化合物，或再经一步水解反应得到式I化合物；
    或者将上述方法1-4任一个中的M5替换为
    Figure PCTCN2022135257-appb-100033
    得到式II化合物；
    其中，R 1、R 2、R 3、X、X 1、X 2、X 3、W、W 1、W 2、W 3、R a、n、A环的定义如相应权利要求。
  8. 一种药物组合物，其包括权利要求1-6任一项所述的化合物、其药学上可接受的 盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药以及药学上可接受的辅料。
  9. 一种权利要求1-6任一项所述的化合物、其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药或权利要求8所述的药物组合物在制备STING激动剂中的用途。
  10. 一种权利要求1-6任一项所述的化合物、其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药或权利要求8所述的药物组合物在制备治疗STING蛋白依赖型疾病的药物中的用途，特别是肿瘤、病毒感染、免疫性疾病和炎症性疾病的治疗药物中的用途；
    特别地，所述肿瘤选自：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌、胰腺癌；
    所述免疫性疾病和炎症性疾病选自：移植器官的排斥反应、痛风、鼻炎、脱发、阿尔茨海默氏病、阑尾炎、动脉粥样硬化、哮喘、关节炎、过敏性皮炎、贝切特氏病、大疱性皮肤病、胆囊炎、慢性特发性血小板减少性紫癜、慢性阻塞性肺病、肝硬化、退行性关节病、皮肤炎、皮肌炎、湿瘆、肠炎、脑炎、胃炎、肾炎、桥本氏甲状腺炎、肝炎、垂体炎、炎性肠病、肠易激综合征、川崎病、脑脊膜炎、多发性硬化、心肌炎、重症肌无力、蕈样真菌病、肌炎、肾炎、骨髓炎、胰腺炎、帕金森病、心包炎、恶性贫血、肺炎、原发性胆汁性硬化性胆管炎、结节性多动脉炎、银屑病、纤维化、红斑狼疮、组织移植排斥、甲状腺炎、I型糖尿病、尿道炎、葡萄膜炎、血管炎、白癜风、瓦尔登斯特伦氏巨球蛋白血症。
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