Tricyclic ynamide compound and application thereof

Abstract

Provided are a compound having a tricyclic ynamide structure, a preparation method therefor, and a use thereof. The structure of the compound is as represented by general formula I, and definitions of each substituent are as described in the description and claims. The compound can be used in the treatment and / or prevention of inflammatory diseases and autoimmune diseases.

Description

Tricyclopyridine amide compounds and their applications Technical Field

[0001] This invention relates to compounds having a tricyclic acetylenic amide structure, their preparation methods and uses, particularly the use of this series of compounds or pharmaceutical compositions containing this series of compounds and therapeutic agents for treating inflammatory diseases, autoimmune diseases, tumors or cancers, infectious diseases, fibrotic diseases and other conditions and diseases. Background Technology

[0002] The human body's response to tissue damage is an inflammatory response, which is usually self-limiting. Innate immunity is the first line of defense in the host's immune system. Pattern recognition receptors (PRRs) in host cells can recognize conserved components of invading pathogens: pathogen-associated molecular patterns (PAMPs) and host-associated molecular patterns (DAMPs). These include DNA from viruses and bacteria, and the host's own DNA (nuclear or mitochondrial) which can act as PAMPs / DAMPs. Host cells sense the invasion of pathogens through PRRs. Infection signals are transmitted downstream via adaptor proteins, kinases, and transcription factors, inducing the expression of type I interferon and pro-inflammatory cytokines, ultimately clearing the invading pathogens.

[0003] STING (stimulator of interferon genes), also known as TMEM173, MPYS, MITA, or ERIS, is a protein encoded by the TMEM173 gene in humans. STING has been shown to play a role in innate immunity. When cells are infected with intracellular pathogens, STING can mediate the production of type I interferon. STING-mediated type I interferon protects infected cells and nearby cells from local infection in both autocrine and paracrine modes.

[0004] The STING signaling pathway is crucial for cytoplasmic DNA recognition. Cytoplasmic DNA can bind to cyclic GMP-AMP synthase (cGAS) to produce 2',3'-cGMP-AMP (cGAMP) as a second messenger. STING is the cGAMP second messenger receptor. Furthermore, STING also acts as a receptor for bacterial cyclic dinucleotides (CDNs) and small molecule agonists. Upon activation, STING recruits TANK-binding kinase 1 (TBK1), which then phosphorylates interferon regulatory factor 3 (IRF3), inducing the production of type I interferons and cytokines. Through a series of cascade reactions, this activates the adaptive immune system. Following signal transduction, STING is rapidly degraded; this step is considered crucial for terminating the inflammatory response.

[0005] The cGAS-STING signaling pathway is precisely regulated, involving post-translational modifications of proteins and small molecule regulators. While activation of the cGAS-STING pathway is a crucial response to tissue damage and infection, overactivation of this pathway can induce harmful inflammatory responses, potentially triggering autoimmune or inflammatory diseases such as Sjögren's syndrome. STING syndrome (SS), Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), and STING-associated infantile vascular disease (SAVI) are among the conditions for treatment. Therefore, targeted inhibition of STING could be a potential treatment for these autoimmune and inflammatory diseases.

[0006] Currently, there is still a need in the field for more structurally novel STING inhibitors as candidate drugs for the detection, prevention, and treatment of diseases mediated by STING overactivation. Summary of the Invention

[0007] The purpose of this invention is to provide a STING inhibitor.

[0008] In a first aspect, the present invention provides a compound of general formula (I) or a stereoisomer, enantiomer, diastereomer, transisomer, optical isomer, racemate, tautomer, or a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, or an isotopically labeled compound thereof.

[0009] In this context, dashed lines represent single or double bonds; W is selected from O, S, N(H), N(D), N(C1-C6 alkyl), N(C3-C6 cycloalkyl), N(6-10 aryl), and N(5-12 heteroaryl).

[0010] X 1 X 2 X 3 Selected independently from C(R) a ), N; X 4 X 5 Selected independently from C and C(R) a ), N;

[0011] Ring A is selected from 1-5 Qs. 1 Replacement C3-C 10 Cycloalkyl, 3-10 membered heterocyclic, C6-C 10 aryl or 5-12 heteroaryl; preferably, ring A is selected from any one or two Q groups. 1 Substituted groups: phenyl, 6-membered heteroaryl or 5-membered heteroaryl;

[0012] m is selected from the following set of integers: 1, 2, 3, 4; each Y is independently selected from C(R). e (R) f ), C(R a ), N(R c ), N, C(=O), C(=S), C(=NR d ), O, S, S(=O), S(=O)2; when m is greater than 1, the connecting bond between the two Ys is a single bond or a double bond;

[0013] R e R f Each time it appears, it is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, halogenated C2-C6 alkenyl, C2-C6 ynyl, halogenated C2-C6 ynyl, cyano, hydroxyl, nitro, oxo, thio, -(C1-C6 alkyl)-L 4 -R 10 -(C2-C6 alkenyl)-L 4 -R 10 -(C2-C6 ynyl)-L 4 -R 10 -(halogenated C1-C6 alkyl)-L 4 -R 10 -(C2-C6 alkenyl)-L 4 -R 10 -(C2-C6 ynyl)-L 4 -R 10 -L4 -R 10 -L 4 -(by 0-5 Rs) 10 Substituted C3-C14 cycloalkyl), -L 4 -(by 0-5 Rs) 10 Substituted 3-14 membered heterocyclic groups), -L 4 -(by 0-5 Rs) 10 Substituted C6-C14 aryl), -L 4 -(by 0-5 Rs) 10 Substituted 5-14 heteroaryl groups), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted C3-C14 cycloalkyl), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted 3-14 membered heterocyclic groups), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted C6-C14 aryl), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted 5-14 heteroaryl groups);

[0014] Or R e and R f Together with the C atoms connecting them, they form optional groups of 1-5 Q atoms. 3 Substituted from the group consisting of: C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups; preferably, R e and R f And together with the C atoms connecting them, they form an optional structure consisting of one, two, or three Q atoms. 3 Substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group;

[0015] R 1 Selected from hydrogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 ynyl, halo-C2-C6 ynyl, Q 2 , by 1-5 R 10 Replacement Q 2 ;

[0016] R 2 For Q 2 , by 1-5 R 10 Replacement Q 2 ;

[0017] Or, R 1 and R2 Together with the N atoms connecting them, they form optional groups of 1-5 Q atoms. 3 The substituted 4-11 membered heterocyclic group; preferably, R1 and R2, together with the N atom connecting them, form a group optionally surrounded by one, two, or three Q atoms. 3 Substituted groups: 5-membered heterocyclic group, 6-membered heterocyclic group, 7-membered heterocyclic group;

[0018] R a Q 1 Q 3 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, halogenated C2-C6 alkenyl, C2-C6 ynyl, halogenated C2-C6 ynyl, cyano, hydroxyl, nitro, oxo, thio, -(C1-C6 alkyl)-L 4 -R 10 -(C2-C6 alkenyl)-L 4 -R 10 -(C2-C6 ynyl)-L 4 -R 10 -(halogenated C1-C6 alkyl)-L 4 -R 10 -(C2-C6 alkenyl)-L 4 -R 10 -(C2-C6 ynyl)-L 4 -R 10 -L 4 -R 10 -L 4 -(by 0-5 Rs) 10 Substituted C3-C14 cycloalkyl), -L 4 -(by 0-5 Rs) 10 Substituted 3-14 membered heterocyclic groups), -L 4 -(by 0-5 Rs) 10 Substituted C6-C14 aryl), -L 4 -(by 0-5 Rs) 10 Substituted 5-14 heteroaryl groups), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted C3-C14 cycloalkyl), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted 3-14 membered heterocyclic groups), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted C6-C14 aryl), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10Substituted 5-14 heteroaryl groups);

[0019] Q 2 Each time it appears, it is independently selected from -(C1-C6 alkyl)-L 5 -R 10 -(C2-C6 alkenyl)-L 5 -R 10 -(C2-C6 ynyl)-L 5 -R 10 -(halogenated C1-C6 alkyl)-L 5 -R 10 -(halogenated C2-C6 alkenyl)-L 5 -R 10 -(halogenated C2-C6 ynyl)-L 5 -R 10 -L 5 -(by 0-5 Rs) 10 Substituted C3-C14 cycloalkyl), -L 5 -(by 0-5 Rs) 10 Substituted 3-14 membered heterocyclic groups), -L 5 -(by 0-5 Rs) 10 Substituted C6-C14 aryl), -L 5 -(by 0-5 Rs) 10 Substituted 5-14 heteroaryl groups), -L 5 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted C3-C14 cycloalkyl), -L 5 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted 3-14 membered heterocyclic groups), -L 5 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted C6-C14 aryl), -L 5 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted 5-14 heteroaryl groups);

[0020] L 4 Each occurrence is independent of: bond, C1-C6 alkyl, -O-, -S-, N(R) 9 )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)N(R 9 )-、-N(R 9 )C(=O)-、-N(R 9 )C(=O)N(R 9 -, -S(=O)2-, -N(R 9 )S(=O)2-、-N(R9 )S(=O)-、-S(=O)2N(R 9 )-、-S(=O)N(R 9 )-;

[0021] L 5 Each occurrence is independent as: key, -O-, -S-, -N(R) 9 )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)N(R 9 )-、-N(R 9 )C(=O)-、-N(R 9 )C(=O)N(R 9 -, -S(=O)2-, -N(R 9 )S(=O)2-、-N(R 9 )S(=O)-、-S(=O)2N(R 9 )-、-S(=O)N(R 9 )-;

[0022] R c R d R 9 R 10Each time it appears, it is independently selected from the group consisting of: H, D, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, hydroxyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, amino, amino-substituted C1-C6 alkyl, amino substituted with 1-2 C1-C6 alkyl groups, nitro, nitro-substituted C1-C6 alkyl, cyano, cyano-substituted C1-C6 alkyl, 5-8 membered heteroaryl, C2-C6 alkenyl. C2-C6 alkynyl, -C(=O)OH, -C(=O)O-(C1-C6 alkyl), -OC(=O)H, -OC(=O)-(C1-C6 alkyl), -OS(=O)OH, -OS(=O)O-(C1-C6 alkyl), -OS(=O)2OH, -OS(=O)2O-(C1-C6 alkyl), -S(=O)2OH, -S(=O)2O-(C1-C6 alkyl), -S(=O) 2-(C1-C6 alkyl), -N(H)S(=O)2-(C1-C6 alkyl), -N(C1-C6 alkyl)S(=O)2-(C1-C6 alkyl), -C(=O)NH2, -C(=O)N(H)(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -N(H)C(=O)H, -N(H)C(=O)-(C1-C6 alkyl), -N(C1-C6 alkyl)2C =O)-(C1-C6 alkyl), -C(=O)H, -C(=O)-(C1-C6 alkyl), -OP(=O)(OH)2, -OP(=O)(C1-C6 alkyl)(C1-C6 alkyl), -N(H)P(=O)(OH)2, -N(H)P(=O)(C1-C6 alkyl)2, -N(C1-C6 alkyl)P(=O)(C1-C6 alkyl)(C1-C6 alkyl), oxo, thio.

[0023] In another preferred embodiment, the compound is selected from formulas (II-1) and (II-2).

[0024] Among them, W is selected from O and S; ring A is selected from any 1-5 Qs. 1 Substituted phenyl or 5-6-membered heteroaryl;

[0025] Ring B is selected from 1-5 R's. a2 Substituted groups: phenyl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 5-membered cycloalkenyl, 6-membered cycloalkenyl, 7-membered cycloalkenyl, 8-membered cycloalkenyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl; R a2 Each time it appears, it is independently selected from R. a Or R c ;

[0026] The ring Z is selected from the following group: 5-membered heterocyclic group, 6-membered heterocyclic group, and 7-membered heterocyclic group;

[0027] n is selected from the following set of integers: 0, 1, 2, 3, 4;

[0028] R 2 X 1 X 2 X 3 X 4 X 5 Q 1 Y, R a R c Q 3 The definition is the same as before.

[0029] In another preferred embodiment, the compound is selected from formulas (III-1) and (III-2):

[0030] Among them, W is selected from O and S; X 6 X 7 X 8 X 9 Selected independently from C(R) a ), N;

[0031] m is selected from the following set of integers: 1, 2, 3;

[0032] The ring Z is selected from the following group: 5-membered heterocyclic group, 6-membered heterocyclic group, 7-membered heterocyclic group, 7-membered cycloalkenyl group, 8-membered cycloalkenyl group, 5-membered heteroaryl group, 6-membered heteroaryl group, 7-membered heteroaryl group;

[0033] n is selected from the following set of integers: 0, 1, 2, 3, 4; R 2 X 1 X 2 X 3 R a Y, Q 3 The definition is the same as before.

[0034] In another preferred embodiment, W is selected from O and S;

[0035] R 1 Selected from hydrogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl; R 2 Selected from Q 2 , by 1-5 R 10 Replacement Q 2 ;

[0036] Or, R 1 and R 2 Together with the N atoms connecting them, they form the following group of groups that can be optionally substituted with one, two, or three Q3 atoms: 5-membered heterocyclic groups, 6-membered heterocyclic groups, and 7-membered heterocyclic groups;

[0037] X1 X 2 X 3 Each is independently selected from CH and N;

[0038] Ring A is selected from either one or two Qs. 1 Substituted groups: phenyl, 6-membered heteroaryl or 5-membered heteroaryl;

[0039] Ring B is selected from 1-5 R's. a2 Substituted groups: 5-membered heteroaryl, 6-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 5-membered cycloalkenyl, 6-membered cycloalkenyl, 7-membered cycloalkenyl, 8-membered cycloalkenyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, R a2 Each time it appears, it is independently selected from R. a Or R c The R a R c The definition is the same as before.

[0040] In another preferred example, X 1 X 2 X 3 Each can be independently CH or N; X 4 X 5 The answer is C;

[0041] Ring A is selected from either one or two Qs. 1 Substituted groups: phenyl, 6-membered heteroaryl or 5-membered heteroaryl;

[0042] m is selected from the following set of integers: 1, 2, 3, 4;

[0043] Each Y group is independently selected from C(R) e (R) f ), C(R a ), N(R c ), N, O, S, S(=O), S(=O)2; when m is greater than 1, the connecting bond between the two Ys is a single bond or a double bond;

[0044] R a Selected from: hydrogen, deuterium, oxo, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0045] R c Selected from: hydrogen, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl;

[0046] R e R f Each can be independently selected from: H, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; or R. e and Rf Together with the C atoms connecting them, they form an array optionally bounded by one or two Q atoms. 3 Substituted groups: C3-C6 cycloalkyl, 3-6 membered heterocyclic groups;

[0047] W represents O or S;

[0048] R 1 Selected from hydrogen, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, and C3-C6 cycloalkyl;

[0049] R 2 -(C1-C6 alkyl)-L 5 -R 10 Or be 1-5 R 10 Substituted -(C1-C6 alkyl)-L 5 -R 10 ;

[0050] Among them, L 5 Selected from key, -O-, -S-, -N(R) 9 )-, -C(=O)-, -S(=O)2-, -N(R 9 )S(=O)2-、-N(R 9 )S(=O)-、-S(=O)2N(R 9 )-、-S(=O)N(R 9 )-;

[0051] Or, R 1 and R 2 Together with the N atoms connecting them, they form the following group of groups that can be optionally substituted with one, two, or three Q3 atoms: 5-membered heterocyclic groups, 6-membered heterocyclic groups, and 7-membered heterocyclic groups;

[0052] R 9 R 10 Q 1 Q 3 As defined above.

[0053] In another preferred example, X 1 X 3 For CH; X 2 For CH or N; X 4 X 5 The answer is C.

[0054] In another preferred embodiment, ring A is a benzene ring, a thiazole ring, a pyridine ring, a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, or a pyrimidine ring, optionally substituted by one or two groups selected from the group consisting of: deuterium, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, or hydroxyl.

[0055] In another preferred example, -(Y)m -Selected from: -CH2=CH2-, -O-, -S-, -C(O)-, -C(CH3)2-, -C(F)2-, -CH2-O-, -CH2-, -CH2-O-CH2- , -N(CH3)-, -O-CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2-O-, -O-CH2CH2-, -N=N-, -NH-,

[0056] In another preferred example, W is O.

[0057] In another preferred embodiment, R 1 Selected from hydrogen, deuterium, C1-C4 alkyl, halogenated C1-C4 alkyl, and C3-C6 cycloalkyl;

[0058] R 2 -(C1-C4 alkyl)-L 5 -R 10 , by 1-5 R 10 Substituted -(C1-C6 alkyl)-L 5 -R 10 ;R 10 It can be H, amino, C1-C4 alkyl, 5-6 heteroaryl, hydroxyl, or hydroxyl-substituted C1-C4 alkyl;

[0059] Among them, L 5 Selected from key, -O-, -S-, -N(R) 9 )-, -C(=O)-, -S(=O)2-, -N(R 9 )S(=O)2-、-N(R 9 )S(=O)-、-S(=O)2N(R 9 )-、-S(=O)N(R 9 )-;R 9 It is H or C1-C4 alkyl;

[0060] Or, R 1 and R 2 Together with the N atoms connecting them, they form a group optionally bounded by one, two, or three Q atoms. 3 The following groups of substitutions: 5-membered heterocyclic groups, 6-membered heterocyclic groups, 7-membered heterocyclic groups; wherein the heterocycle, except for N, optionally has 1, 2, or 3 heteroatoms selected from the following group: N, O, S; wherein, Q 3 Selected from: C1-C4 alkyl, hydroxyl, =O, halogenated C1-C4 alkyl, C3-C6 cycloalkyl.

[0061] In another preferred embodiment, Q1 is selected from the group consisting of halogens, C1-C4 alkoxy groups, and C1-C4 haloalkoxy groups.

[0062] In another preferred embodiment, Q3 is selected from the group consisting of C1-C4 alkyl, hydroxyl, and oxo.

[0063] In another preferred embodiment, R 10 Selected from the following group: H, amino, C1-C4 alkyl, 5-6 heteroaryl, hydroxyl, hydroxy-substituted C1-C4 alkyl.

[0064] In another preferred embodiment, the compound is compound 1 to compound 50.

[0065] A second aspect of the present invention provides a pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and

[0066] One or more of the compounds described in the first aspect, or their stereoisomers, enantiomers, diastereomers, scavenged isomers, optical isomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, their prodrugs, their hydrates or solvates, or their isotopically labeled compounds.

[0067] A third aspect of the present invention provides a STING inhibitor comprising one or more compounds described in the first aspect or their stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts thereof, their prodrugs, their hydrates or solvates, or pharmaceutical compositions according to the second aspect.

[0068] A fourth aspect of the invention provides for the preparation of a medicament using the compound of the first aspect or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, isotopically labeled compounds thereof, the pharmaceutical composition of the second aspect or the STING inhibitor of the third aspect, said medicament for:

[0069] 1) Detection and / or prevention and / or treatment of diseases mediated by the STING signaling pathway;

[0070] 2) Detection and / or prevention and / or treatment of autoimmune diseases and inflammatory diseases;

[0071] 3) Detection and / or prevention and / or treatment of tumors or cancer-related diseases;

[0072] 4) Detection and / or prevention and / or treatment of infectious diseases and fibrotic diseases.

[0073] In another preferred embodiment, the diseases associated with STING protein levels are selected from the group consisting of: AGS, STING-associated vascular disease in infants (SAVI), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), acute myocardial infarction, macular degeneration, colitis, nephritis, cardiac inflammation, inflammation in other sites, kidney and / or heart and / or other organ damage, kidney and / or heart and / or other organ poisoning, heart failure, myocardial infarction, myocardial hypertrophy, obesity, age-related diseases / conditions, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, acute pancreatitis, bacterial infection, fungal infection, viral infection, coronavirus infection, lung cancer, liver cancer, brain cancer, gastrointestinal cancer, breast cancer, leukemia, uterine cancer, testicular cancer, and / or cancers / tumors in various sites.

[0074] In another preferred embodiment, the tumor or cancer is selected from: colon cancer, diffuse large B-cell lymphoma, follicular lymphoma, other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer; brain tumors, including neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma; cervical cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors and soft tissue sarcomas.

[0075] A fifth aspect of the invention provides the use of the compound described in the first aspect or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers or their pharmaceutically acceptable salts, prodrugs, hydrates or solvates, isotopically labeled compounds thereof, the pharmaceutical composition described in the second aspect or the STING inhibitor described in the third aspect, for the preparation of reagents or medicaments for detecting and / or preventing and / or treating diseases, including but not limited to the following:

[0076] Singleton-Merten syndrome (SMS), Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), familial frostbite lupus erythematosus (FCL), retinal vascular disease and leukodystrophy (RVCL), STING-associated infantile vascular disease (SAVI), scleroderma, psoriasis, Sjögren's syndrome (Sjögren's syndrome), Syndrome (SS), rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, Crohn's disease, ulcerative colitis, autoimmune colitis, small bowel malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, pulmonary fibrosis, aging, cardiovascular disease and neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), Parkinson's syndrome (PD), and non-alcoholic steatohepatitis (NASH).

[0077] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0078] The inventors of this application, through extensive and in-depth research, have developed a tricyclic acetylide compound that exhibits significant inhibitory effects on the STING signaling pathway. As a STING inhibitor, it can be used to treat inflammatory diseases, autoimmune diseases, tumors or cancers, infectious diseases, fibrotic diseases, and other conditions and illnesses. Based on this, the present invention was completed.

[0079] the term

[0080] Unless otherwise expressly stated, the terms used in this invention and herein have the following meanings:

[0081] The terms "C1-C6" refer to rings with 1, 2, 3, 4, 5, or 6 carbon atoms, "C1-C8" refers to rings with 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and so on. "5-8 membered rings" refer to rings with 5, 6, 7, or 8 ring atoms, and so on.

[0082] A "substituent" refers to an atom or group that can replace a hydrogen atom in a substituted compound. Examples are as follows (but are not limited to): deuterated, alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, isocyanate, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, oxo, thio, -C(=O)R n -C(=O)OR n -C(=O)NR n R o -NR n R o -NR n C(=O)R o -NRn C(=O)OR o NR n C(=O)NR o R p -NR n S(=O)R o NR n S(=O)NR o R p -NR n S(=O)2R o NR n S(=O)2NR o R p -OR n -SR n -OC(=O)R n -OC(=O)NR n R o -OC(=O)OR n -S(=O)NR n R o -S(=O)2NR n R o -BR n R o B(OR) n (OR) o ), -SiR n R o R p -OP(=O)R n R o -P(=O)R n R o -OP(=O)2R n -P(=O)2R n -NP(=O)R n R o -NP(=O)R n R o -NP(=O)2R n -NP(=O)2R n etc., where R n R o R p Each time it appears, it is independently selected from the group consisting of: H, D, C1-C12 alkyl, halogenated C1-C12 alkyl, C1-C12 heteroalkyl, halogenated C1-C12 heteroalkyl, C3-C12 cycloalkyl, halogenated C3-C12 cycloalkyl, C3-C12 aryl, halogenated C3-C12 aryl, C3-C12 aryl, halogenated C3-C12 aryl, C3-C12 heteroaryl, halogenated C3-C12 heteroaryl; optionally, Rn R o Together with the atoms they are attached to, they can form ring structures. Those skilled in the art will understand that the combinations of substituents and substituted substances contemplated in this invention are those stable or chemically feasible combinations.

[0083] "Substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents at each position may be the same or different. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. Such substituents include (but are not limited to): alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, oxo, thio, -C(=O)R n -C(=O)OR n -C(=O)NR n R o -NR n R o -NR n C(=O)R o -NR n C(=O)OR o NR n C(=O)NR o R p -NR n S(=O)R o NR n S(=O)NR o R p -NR n S(=O)2R o NR n S(=O)2NR o R p -OR n -SR n -OC(=O)R n -OC(=O)NR n R o -OC(=O)OR n -S(=O)NR n R o -S(=O)2NR n R o-BR n R o B(OR) n (OR) o ), -SiR n R o R p -OP(=O)R n R o -P(=O)R n R o -OP(=O)2R n -P(=O)2R n -NP(=O)R n R o -NP(=O)R n R o -NP(=O)2R n -NP(=O)2R n etc., where R n R o R p The definition is the same as above.

[0084] "alkyl" refers to a saturated aliphatic hydrocarbon group, which may be straight-chain or branched. The alkyl group may be independently substituted by one or more substituents described in this invention. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, and 3-methylpentyl. The alkyl group may be optionally substituted or unsubstituted.

[0085] "Alkenyl" refers to a straight-chain or branched hydrocarbon group, wherein at least one C group is sp. 2 The double bond, wherein the alkenyl group may be independently and optionally replaced by one or more substituents described in this invention, wherein specific examples include, but are not limited to, vinyl, allyl, allyl, and alkyl groups. And so on. The alkenyl group can be optionally substituted or unsubstituted.

[0086] "Alynyl" refers to a straight-chain or branched hydrocarbon group, wherein at least one C-C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted by one or more substituents described in this invention, specific examples including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be optionally substituted or unsubstituted.

[0087] "Ring structure" refers to monocyclic or polycyclic structures. Typically, it is a closed structure formed by the connection of two or more segments on a single atom in a ring structure. Examples include, but are not limited to, cycloalkanes, heterocyclic alkanes, cyclic lactams, aromatics, heteroaromatics, fused rings, bridged rings, and spirocyclic structures, such as cyclopropane, cyclobutane, oxacyclobutane, cyclopentane, cyclohexane, adamantane, cyclohexene, cyclooctyne, pyrazole, benzene, pyridine, 3,4-dihydro-1,4-benzoxazolopyridine-5(2H)-one, naphthalene, anthracene, phenanthrene, quinoline, pyrrolopyridine, pyrazolopyridine, indole, dihydroindole, steroidal rings, and porphyrin rings. The ring structure can be optionally substituted or unsubstituted. When it appears as a substituent, it means that one or more hydrogen atoms on the monocyclic or polycyclic ring are removed, thus allowing it to act as a substituent for the substituted substance.

[0088] "Halogen" refers to F, Cl, Br, or I. "Halogenated" means substituted by one or more halogens.

[0089] "Aryl" refers to a substituent in a carbocyclic aromatic system containing one or more rings, wherein the rings do not contain heteroatoms. Optionally, the aryl group may be fused with a heteroaryl, heterocyclic, or other cyclic structure. Examples are as follows (but are not limited to): phenyl, naphthyl, tetrahydronaphthyl, ... The aryl group may be optionally substituted or unsubstituted. When the aryl group is described as "C6-C14 aryl", it means that the aromatic ring connected to the parent structure has 6-14 carbon atoms, but the aryl group may optionally be fused with other ring structures, which refer to ring structures with 3-18 ring atoms, and these other ring structures may be optionally substituted or unsubstituted.

[0090] "Heteroaryl" refers to an aromatic ring substituent containing one or more rings, which may contain one or more atoms selected from N, O, or S atoms. Optionally, the aryl group may be fused with an aryl, heterocyclic, cycloalkyl, or other ring structure. Examples are as follows (but not limited to): furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl group may be optionally substituted or unsubstituted. When the heteroaryl group is described as a "5-14 membered heteroaryl group", it means that the heteroaryl group and the parent structure together form a heteroaryl ring with 5-14 ring atoms. However, the heteroaryl group may optionally be fused with other ring structures, which refer to ring structures with 3-18 ring atoms. These other ring structures may be optionally substituted or unsubstituted.

[0091] "Cycloalkyl" refers to a substituent in a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. Partially unsaturated monocyclic or polycyclic hydrocarbons with a double bond are also called cycloalkenyl groups, and partially unsaturated monocyclic or polycyclic hydrocarbons with a triple bond are also called cycloynyl groups. The first ring structure directly attached to the substituted compound is non-aromatic. Examples of monocyclic cycloalkyl groups (but not limited to the following): cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, cyclooctyynyl, etc.; Examples of polycyclic cycloalkyl groups (but not limited to the following): spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Optionally, the cycloalkyl group may be fused with an aryl, heterocyclic, cycloalkyl, or other cyclic structure to form a spirocyclic ring. Examples of fusion with other cyclic structures to form a spirocyclic ring (but not limited to the following): The cycloalkyl group may be optionally substituted or unsubstituted. When the cycloalkyl group is described as "C3-C14 cycloalkyl", it means that the cycloalkyl ring connected to the parent structure has 3-14 carbon atoms. However, the cycloalkyl group may optionally be fused with other ring structures or form a spiro ring. The other ring structures refer to ring structures with 3-18 ring atoms, and the other ring structures may be optionally substituted or unsubstituted.

[0092] "Heterocyclic group" refers to a monocyclic or polycyclic substituent whose at least one ring atom is a heteroatom (e.g., O, N, S atom, etc.) and is saturated or partially unsaturated. Examples are as follows (but not limited to): tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrroliyl, tetrahydrothiophenyl, piperidinyl, piperazine, aziridine, aziridine-butyl, aziridine-heptyl, morpholinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, etc. The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is the heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted. When the heteroalkyl group is described as a "3-10 membered heterocyclic group", it means that the heterocyclic group connected to the parent structure has 3-10 ring atoms. However, the heterocyclic group may be fused with other ring structures or form a spirocyclic ring. The other ring structures refer to ring structures with 3-18 ring atoms. The other ring structures may be optionally substituted or unsubstituted.

[0093] "Tautomerism" refers to structural isomers with different energies that can overcome a low energy barrier and thus interconvert. For example, proton tautomerism (i.e., proton transmutation) includes interconversion via proton migration, such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole, etc. and Valence tautomers include those that undergo tautomerism through some recombination of bonding electrons.

[0094] "Stereoisomers" refer to molecules that have atoms with the same connectivity but different spatial arrangements. For example, two compounds containing a chiral center and having the same two-dimensional connectivity, such as R-glyceraldehyde and S-glyceraldehyde, or R-serine and S-serine.

[0095] "Enantiomers" refer to stereoisomers that are mirror images of each other and cannot be superimposed. For example, R-serine and S-serine.

[0096] "Diarrhetinic isomers" refer to stereoisomers of molecules that have two or more chiral centers and are not mirror images of each other. Tartaric acid is an example.

[0097] "Restricted isomers" refers to a group of conformational isomers of a molecule that are produced because rotation around a single bond is restricted. For example, the various stereoisomers of 6,6'-dinitro-2,2'-biphenyldicarboxylic acid.

[0098] "Optical isomers" refer to compounds in which two or more molecules have the same two-dimensional connection, but exhibit different optical rotations due to differences in configuration. For example, levamlodipine and dextroamlodipine.

[0099] "Racemate" refers to compounds with the same two-dimensional linkage but which are optical isomers, and when mixed together, they ultimately exhibit no optical activity. Example: racemic amlodipine.

[0100] The pharmaceutically acceptable salts described in this invention can be salts formed by anion and a positively charged group on a compound of formula (I). Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate, or maleate. Similarly, salts can be formed by cations and negatively charged groups on a compound of formula (I). Suitable cations include sodium, potassium, magnesium, calcium, and ammonium ions, such as tetramethylammonium ions.

[0101] In another preferred embodiment, "pharmaceutically acceptable salt" refers to a salt formed by a compound of formula (I) with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pyric acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, and hydroxyethanesulfonic acid; or a sodium, potassium, calcium, aluminum, or ammonium salt formed by a compound of formula (I) with an inorganic base; or a methylamine, ethylamine, or ethanolamine salt formed by a compound of general formula I with an organic base.

[0102] Preparation methods of compounds

[0103] The following schemes and examples describe one method for preparing compounds of formula (I). Starting materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of steps in performing the reaction scheme may be altered to promote the reaction or avoid unwanted byproducts.

[0104] Among them, R G1 The leaving group is preferably a halogen, trifluoromethanesulfonyl (Tf), or p-toluenesulfonyl (Ts);

[0105] R G2 The protecting group is preferably -Si(CH3)3 or (C1-C8 alkyl)3Si-;

[0106] s1) In an inert solvent, compound r-1 reacts with r-2 to give compound r-3;

[0107] s2) In an inert solvent, compound r-3 was deprotected under appropriate conditions to give compound r-4;

[0108] s3) In an inert solvent, compound r-4 reacts with a suitable reagent (e.g., dry ice) to give r-5;

[0109] s4) In an inert solvent, compounds r-5 and r-6 undergo amide condensation to obtain the target compound (Ⅰ).

[0110] Most of the compounds can be easily prepared using the above-described method, while the remaining compounds can be synthesized according to the specific methods described herein.

[0111] Pharmaceutical Composition

[0112] The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more therapeutically effective amounts of the compound of the present invention or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers or their pharmaceutically acceptable salts, prodrugs, hydrates or solvates, or isotopically labeled compounds.

[0113] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 50-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0114] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0115] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0116] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0117] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0118] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0119] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0120] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0121] In addition to the active compound, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0122] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0123] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0124] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-inflammatory drugs).

[0125] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0126] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 5–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0127] application

[0128] The therapeutically active compounds of this invention comprise, for example, compounds of formula (I). The compounds described in the examples, and pharmaceutically acceptable salts of the compounds thereof, are administered to patients for the therapeutic purpose of preventing and / or treating diseases mediated by the STING signaling pathway. The term "administration" means providing a compound to an individual in need of treatment. When the compounds of this invention are used in combination with one or more other drugs, "administration" means providing a patient with the compound of this patent, its pharmaceutically acceptable salts, and in combination with other drugs.

[0129] The compounds disclosed in this invention can be STING inhibitors. These compounds can be used for autoimmune diseases, inflammatory diseases, tumor or cancer-related diseases, infectious diseases, and fibrotic diseases, including but not limited to: Singleton-Merten syndrome (SMS), Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), familial frostbite lupus erythematosus (FCL), retinal vascular disease and leukodystrophy (RVCL), STING-associated infantile vascular disease (SAVI), scleroderma, psoriasis, Sjögren's syndrome (Sjögren's syndrome), Syndrome (SS), rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, Crohn's disease, ulcerative colitis, autoimmune colitis, small bowel malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, pulmonary fibrosis, aging, cardiovascular disease and neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), Parkinson's syndrome (PD), and non-alcoholic steatohepatitis (NASH).

[0130] As used in this article, the term "treatment" refers to all processes that may involve slowing, interrupting, preventing, controlling, or stopping the progression of the disease or disorder described herein. These terms do not necessarily imply the complete elimination of all symptoms of the disease or disorder.

[0131] The term “administration” should be understood to include providing a subject with the compound described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above.

[0132] In one embodiment, the amount of the compound may be an "effective amount" or a "therapeutic effective amount" that will elicit a biological or medical (i.e., treatment-related) response in the tissue, system, animal, or human being sought by the researcher, veterinarian, physician, or other clinician. In another embodiment, the amount of the compound may be an "effective amount" or a "therapeutic effective amount" such that an administration of the test compound will, respectively, elicit a response in the tissue, system, animal, or person sought by the researcher, veterinarian, physician, or other clinician. This effective amount is not necessarily based on considerations of toxicity and safety related to the administered compound.

[0133] The effective amount of a compound will vary depending on the specific compound selected (e.g., taking into account the compound's activity, efficacy, and / or half-life); the route of administration; the treatment context and the severity of the condition being treated; the age, size, weight, and physical condition of the subject being treated; the subject's medical history; the duration of treatment; the nature of any adjunctive therapy; the expected therapeutic effect; and similar factors that can be determined by a person skilled in the art.

[0134] The compounds disclosed herein may be administered via any appropriate route, including oral and non-oral administration. Non-oral administration is typically by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion.

[0135] The compounds disclosed in this patent can be administered once or according to a dosing regimen in which multiple doses are administered at different time intervals within a given period of time. For example, they can be administered once, twice, three times, or four times daily. The dosage is continued until the desired therapeutic effect is achieved or maintained indefinitely. A reasonable dosing regimen for the compounds disclosed herein depends on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, properties that can be determined by those skilled in the art. Furthermore, for the compounds disclosed herein, a reasonable dosing regimen, including the duration of administration, depends on the disease or condition being treated, the severity of the disease or condition, the age and physical condition of the treated subject, the medical history of the treated subject, the attributes of synergistic therapy, the desired therapeutic effect, and similar factors within the knowledge and expertise of those skilled in the art. Those skilled in the art will adjust the established dosing regimen based on the individual subject's response to the dosing regimen or according to the individual subject's needs. Typical daily doses may vary depending on the specific route of administration chosen.

[0136] One embodiment of the present invention provides a method for detecting and / or preventing and / or treating a disease, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt of the aforementioned compound.

[0137] Main advantages of this invention:

[0138] 1. The compounds of the present invention have novel structures and exhibit STING signaling pathway inhibitory activity, and can be used for inflammatory diseases and autoimmune diseases.

[0139] 2. The compounds of the present invention have good pharmacokinetic properties, in vitro efficacy, and in vivo efficacy.

[0140] The detailed experimental procedures in the following examples will further illustrate the invention. These example compounds are drawn in neutral form in the examples below. In some cases, the compounds are isolated as salts depending on the method used for final purification and / or intrinsic molecular properties. These examples are for illustrative purposes only and are not intended to limit the scope of this patent in any way. Unless otherwise defined or stated, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art.

[0141] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer.

[0142] The raw materials and equipment used in the specific embodiments of this invention are all known products and were obtained through commercial purchase. The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR determination was performed using a Bruker NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (Chloroform-d), and deuterated acetone (Acetone-d6) as the solvent, and tetramethylsilane (TMS) as the internal standard. Column chromatography generally used 300-400 mesh silica gel as the support. The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from major reagent companies. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0143] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The implementation methods and materials described herein are for illustrative purposes only.

[0144] abbreviation

[0145] SMS: Singleton-Merten syndrome; AGS: Aicardi-Goutières syndrome

[0146] SLE: Systemic lupus erythematosus; FCL: Familial frostbite lupus erythematosus

[0147] RVCL: retinal vascular disease and leukodystrophy; PRRs: pattern recognition receptors;

[0148] SAVI: Sting-related infantile vascular lesions

[0149] SS: Sjögren's syndrome (Sjögren's syndrome) syndrome)

[0150] ALS: Amyotrophic Lateral Sclerosis; PD: Parkinson's Syndrome; NASH: Nonalcoholic Steatohepatitis;

[0151] PAMPs: pathogen-associated molecular patterns; DAMPs: damage-associated molecular patterns.

[0152] STING: Stimulator of interferon genes

[0153] cGAS: cyclic GMP-AMP synthase

[0154] cGAMP: 2',3'-cGMP-AMP; CDN: Cyclic dinucleotide

[0155] TBK1: TANK-binding kinase 1

[0156] IRF3: Interferon regulatory factor 3 (phosphointerferon)

[0157] NMR: Nuclear magnetic resonance; MS: Mass spectrometry; DMSO-d6: Deuterated dimethyl sulfoxide;

[0158] Chloroform-d: deuterated chloroform; Acetone-d6: deuterated acetone; CD3OD: deuterated methanol

[0159] TMS: Tetramethylsilane; Tf: Trifluoromethanesulfonyl; Ts: p-Toluenesulfonyl; Et3N: Triethylamine

[0160] DCM: Dichloromethane; nBuLi: n-Butyllithium; HOBT: 1-Hydroxybenzotriazole

[0161] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DIPEA: diisopropylethylamine

[0162] ESI-MS: Electrospray ionization-mass spectrometry; Boc: tert-butyloxycarbonyl

[0163] NFSI: N-fluorobis(benzenesulfonamide); LiHMDS: lithium bis(trimethylsilylamine); IR: inhibition rate

[0164] Example 1: 1-(4-methylpiperazin-1-yl)-3-(2-phenanthracene)prop-2-yn-1-one (Compound 1)

[0165] Compound I-0 (4.0 g, 15.6 mmol) was dissolved in 40 mL of triethylamine. Under an argon atmosphere, palladium dichloride dichloride (562 mg, 0.8 mmol), cuprous iodide (152 mg, 0.8 mmol), and trimethylsilyl yne (3.1 g, 31.1 mmol) were added. The mixture was reacted at 85 °C for 12 hours. The mixture was filtered through diatomaceous earth, and the filtrate was collected. The solvent was removed by vacuum distillation, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 99:1) to give a yellow solid, which was compound I-1 (3.5 g, 81%). 1H NMR (400MHz, CD3OD) δ8.79-8.68(m,2H),8.03(s,1H),7.93(d,J=7.7Hz,1H),7.81(d,J=8.9Hz,1H),7.76-7.62(m,4H),0.30(d,J=1.1Hz,9H).

[0166] Compound I-1 (2.0 g, 7.3 mmol) was dissolved in 30 mL of a mixture of dichloromethane and methanol (dichloromethane:methanol = 1:1), and potassium carbonate (517 mg, 3.75 mmol) was added. The mixture was reacted at room temperature for 15 minutes, and the reaction solution was poured into 100 mL of water. The mixture was extracted three times with 50 mL of dichloromethane, and the combined dichloromethane solution was washed once with 100 mL of saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 99:1) to give a yellow solid, which is compound I-2 (1.3 g, 88%). 1 H NMR (400MHz, Acetone-d6) δ8.80(d,J=8.4Hz,2H),8.13(s,1H),7.99(d,J=7.7Hz,1H),7.90-7.80(m,2H),7.76-7.62(m,3H),3.79(s,1H).

[0167] Compounds 1-2 (1.3 g, 6.4 mmol) were dissolved in anhydrous tetrahydrofuran (25 mL), purged with argon, and the reaction mixture was transferred to -78 °C. A 2.4 M solution of n-butyllithium in cyclohexane (2.8 mL, 7.0 mmol) was slowly added dropwise. After 30 minutes, dry ice was added, and the reaction was transferred to room temperature for 3 hours. The reaction was then quenched with 10 mL of saturated ammonium chloride, followed by the addition of 50 mL of 1 M sodium hydroxide solution. The mixture was extracted three times with 30 mL of ethyl acetate. The aqueous layer was adjusted to pH 2 with 1 M hydrochloric acid, filtered, and the filter cake was retained to give a pale yellow solid, compound I-3 (5.6 g, 87%). ESI-MS: m / z 247.1 [M+H] +

[0168] Compound I-3 (20 mg, 0.08 mmol) was dissolved in 3 mL of N,N-dimethylformamide, and N-methylpiperazine (20 mg, 0.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol), 1-hydroxybenzotriazole (16 mg, 0.12 mmol), and N,N-diisopropylethylamine (47 mg, 0.36 mmol) were added. The mixture was reacted at room temperature for 12 hours. The reaction solution was poured into 30 mL of water and extracted three times with 15 mL of ethyl acetate. The ethyl acetate layer was washed once with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 90:10) to give a white solid, which was compound 1 (8.7 mg, 33%). 1 H NMR (400MHz, CD3OD) δ8.80(dd,J=16.4,8.4Hz,2H),8.23(s,1H),7.97(d,J=7.7Hz,1H),7.90-7.77(m,3H),7.71(dt,J=1 8.4,7.2Hz,2H),3.99(t,J=5.2Hz,2H),3.75(t,J=5.2Hz,2H),2.62(t,J=5.1Hz,2H),2.52(t,J=5.3Hz,2H),2.39(s,3H).

[0169] Example 2: 1-((3S,4S)-3,4-dihydroxypyrrolidone-1-yl)-3-(phenanthrene-2-yl)prop-2-en-1-one (Compound 2)

[0170] Following the method of Example 1, N-methylpiperazine was replaced with (3S,4S)-pyrrolidine-3,4-diol to obtain compound 2. 1 HNMR (400MHz, CD3OD) δ8.79(dd,J=16.6,8.4Hz,2H),8.21(d,J=1.7Hz,1H),7.95(dd,J=7.7,1.6Hz,1H),7.87-7.77(m,3H),7.73(s,2 H), 4.21 (t, J = 5.0Hz, 2H), 4.03 (dd, J = 11.9, 3.9Hz, 1H), 3.88 (d, J = 11.8Hz, 1H), 3.71 (dd, J = 13.3, 4.2Hz, 1H), 3.55 (d, J = 13.2Hz, 1H).

[0171] Example 3: 3-(benzophenanthrene-2-yl)-N-(2-sulfonamide ethyl)malonimide (compound 3)

[0172] Following the method of Example 1, N-methylpiperazine was replaced with 2-aminoethanesulfonamide hydrochloride to obtain compound 3. 1 H NMR (400MHz, CD3OD) δ8.83-8.73(m,2H),8.18(d,J=1.7Hz,1H),7.94(dd,J=7.7,1.6Hz,1H),7.84(d ,J=8.9Hz,1H),7.80-7.75(m,2H),7.74-7.63(m,2H),3.77(t,J=6.9Hz,2H),3.36(t,J=6.9Hz,2H).

[0173] Example 4: 3-(phenanthrene-2-yl)-1-thiomorpholino-2-propyn-1-one (compound 4)

[0174] Following the method of Example 1, N-methylpiperazine was replaced with thiomorpholine to obtain compound 4. 1 H NMR (400MHz, CD3OD) δ8.79(dd,J=16.8,8.3Hz,2H),8.22(d,J=1.8Hz,1H),7.95(dd,J=7.7,1.6Hz,1H),7.82(dt,J =19.3,8.9Hz,3H),7.75-7.64(m,2H),4.25-4.18(m,2H),4.00-3.92(m,2H),2.84-2.77(m,2H),2.72-2.65(m,2H).

[0175] Example 5: 3-(phenanthrene-2-yl)-1-(piperidin-1-yl)prop-2-yn-1-one (compound 5)

[0176] Following the method of Example 1, N-methylpiperazine was replaced with piperidine to obtain compound 5. 1 H NMR (400MHz, DMSO-d6) δ8.92-8.83(m,2H),8.33(d,J=1.6Hz,1H),8.05-8.00(m,1H),7.91(q,J=8.7Hz,2H),7.84(dt,J= 8.7,1.6Hz,1H),7.77-7.68(m,2H),3.81(t,J=5.3Hz,2H),3.54(t,J=5.3Hz,2H),1.67-1.59(m,4H),1.52-1.47(m,2H).

[0177] Example 6: N-(2-methoxyethyl)-3-(phenanthrene-2-yl)propynamide (Compound 6)

[0178] Following the method of Example 1, N-methylpiperazine was replaced with 2-methoxyethylamine to obtain compound 6. 1 H NMR (400MHz, DMSO-d6) δ8.95-8.8.90(m,2H),8.88-8.83(m,1H),8.28(d,J=1.8Hz,1H),8.03(dd,J=8.0,1.8Hz,1H),7 .97-7.87(m,2H),7.80(dd,J=8.0,1.8Hz,1H),7.77-7.69(m,2H),3.42-3.40(m,2H),3.42-3.30(m,2H),3.27(s,3H).

[0179] Example 7: 3-(phenanthrene-2-yl)-N-(3-sulfonylpropyl)propionamide (Compound 7)

[0180] Following the method of Example 1, N-methylpiperazine was replaced with 3-aminopropane-1-sulfonamide to obtain compound 7. 1 HNMR (400MHz, DMSO-d6) δ9.07(t,J=5.8Hz,1H),8.89(dd,J=20.8,8.3Hz,2H),8.29(d,J=1.8Hz,1H),8.04(dd,J=7.4,1.9Hz,1H),7.92(q,J=9 .0Hz,2H),7.82(dd,J=8.5,1.8Hz,1H),7.74(qt,J=7.6,3.9Hz,2H),6.87(s,2H),3.29(q,J=6.6Hz,2H),3.08-2.97(m,2H),1.98-1.84(m,2H).

[0181] Example 8: N-(2-(methylsulfonamido)ethyl)-3-(phenanthrene-2-yl)propionamide (Compound 8)

[0182] Following the method of Example 1, N-methylpiperazine was replaced with N-(2-aminoethyl)methanesulfonamide hydrochloride to obtain compound 8. 1 H NMR (400MHz, DMSO-d6) δ8.98-8.82(m,3H),8.28(d,J=1.8Hz,1H),8.02(dd,J=7.3,1.8Hz,1H),7.95-7.87 (m,2H),7.82-7.68(m,3H),7.19-7.16(m,1H),3.30(q,J=6.4Hz,2H),3.08(q,J=6.4Hz,2H),2.94(s,3H).

[0183] Example 9: N-(3-amino-3-oxopropyl)-3-(phenanthrene-2-yl)propionamide (Compound 9)

[0184] Following the method of Example 1, N-methylpiperazine was replaced with β-propanamide hydrochloride to obtain compound 9. 1 HNMR (400MHz, DMSO-d6) δ8.92-8.83(m,3H),8.27(d,J=1.8Hz,1H),8.04-8.00(m,1H),7.93(d,J=8.7Hz,1H),7.88(d,J=8.7Hz ,1H),7.80(dd,J=8.7,1.8Hz,1H),7.76-7.69(m,2H),7.38(s,1H),6.87(s,1H),3.36(t,J=7.1Hz,2H),2.32(t,J=7.1Hz,2H).

[0185] Example 10: N-(2-(4H-1,2,4-triazol-3-yl)ethyl)-3-(phenanthrene-2-yl)propionamide (Compound 10)

[0186] Following the method of Example 1, N-methylpiperazine was replaced with 3-aminoethyl-1H-[1,2,4]triazole dihydrochloride to obtain compound 10. 1 H NMR (400MHz, DMSO-d6) δ13.75(s,1H),8.98(s,1H),8.93-8.82(m,2H),8.45(s,1H),8.33(d,J=1.6Hz,1H),8.27(d,J=1.8Hz,1H),8.02 (d,J=1.8Hz,1H),7.91(q,J=8.7Hz,2H),7.79(dd,J=8.7,1.8Hz,1H),7.72(pd,J=6.9,1.6Hz,2H),3.52(q,J=6.9Hz,2H),2.92(s,2H).

[0187] Example 11: N-(2-(methanesulfonyl)ethyl)-3-(phenanthrene-2-yl)propionamide (compound 11)

[0188] Following the method of Example 1, N-methylpiperazine was replaced with 2-(methylsulfonyl)ethylamine hydrochloride to obtain compound 11. 1HNMR (400MHz, DMSO-d6) δ9.19-8.83(m,1H),8.94-8.82(m,2H),8.28(d,J=1.8Hz,1H),8.02(d,J=1.8Hz,1H),7.9 1(q,J=8.8Hz,2H),7.80(dd,J=8.8,1.8Hz,1H),7.76-6.68(m,2H),3.64-3.57(m,2H),3.38(s,2H),3.06(s,3H).

[0189] Example 12: N-(2-(N-methylsulfonamide)ethyl)-3-(phenanthrene-2-yl)propionamide (Compound 12)

[0190] Following the method of Example 1, N-methylpiperazine was replaced with 2-amino-N-methylethanesulfonamide hydrochloride to obtain compound 12. 1 H NMR (400MHz, DMSO-d6) δ9.05-8.83(m,1H),8.93-8.83(m,2H),8.28(d,J=1.8Hz,1H),8.05-8.00(m,1H),7.91(q,J=8.7Hz,2H),7.80( dd,J=8.7,1.8Hz,1H),7.76-7.69(m,2H),7.05(q,J=5.0Hz,1H),3.52(q,J=6.9Hz,2H),3.25(t,J=6.9Hz,2H),2.62(d,J=5.0Hz,3H).

[0191] Example 13: 1-morpholino-3-(phenanthrene-2-yl)prop-2-yn-1-one (compound 13)

[0192] Following the method of Example 1, N-methylpiperazine was replaced with morpholine to obtain compound 13. 1 H NMR (400MHz, DMSO-d6) δ8.96-8.83(m,2H),8.36(d,J=1.7Hz,1H),8.03(dd,J=7.3,1.7Hz, 1H),7.96-7.83(m,3H),7.73(pd,J=7.3,1.7Hz,2H),3.87-3.68(m,4H),3.65-3.55(m,4H).

[0193] Example 14: 3-(phenanthrene-2-yl)-1-(piperazin-1-yl)prop-2-yn-1-one (compound 14)

[0194] Following the method of Example 1, N-methylpiperazine was replaced with 1-Boc-piperazine to obtain a white solid, compound I-4. ESI-MS: m / z 415.2 [M+H] +

[0195] Compound I-4 (11 mg, 0.03 mmol) was dissolved in 5 mL of dichloromethane, and 0.1 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 12 hours. The reaction was quenched with 10 mL of 1 M sodium hydroxide solution. The mixture was extracted three times with 10 mL of dichloromethane. The combined dichloromethane extract was washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 90:10) to give a white solid, namely compound 14 (8.4 mg, 99%). 1 H NMR (400MHz, CD3OD) δ8.80-8.71(m,2H),8.18(d,J=1.8Hz,1H),7.93(d,J=1.8Hz,1H),7.84-7.73(m,3H),7. 72-7.62(m,2H),3.95(t,J=4.1Hz,2H),3.70(t,J=4.1Hz,2H),2.99(t,J=4.4Hz,2H),2.89(t,J=4.4Hz,2H).

[0196] Example 15: N-(2-(methylamino)ethyl)-3-(phenanthrene-2-yl)propyneamide (Compound 15)

[0197] Following the method of Example 1, N-methylpiperazine was replaced with N-Boc-N-methylethylenediamine to obtain a white solid, compound I-5. ESI-MS: m / z 403.2 [M+H] +

[0198] Compound I-5 (16 mg, 0.04 mmol) was dissolved in 5 mL of dichloromethane, and trifluoroformic acid (0.1 mL) was added. The mixture was reacted at room temperature for 12 hours. The reaction was quenched with 10 mL of 1 M sodium hydroxide solution. The mixture was extracted three times with 10 mL of dichloromethane. The combined dichloromethane extract was washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 90:10) to give a white solid, namely compound 15 (11.9 mg, 99%). 1H NMR (400MHz, CD3OD) δ8.80-8.73(m,2H),8.17(d,J=1.8Hz,1H),7.94(dd,J=8.3,1.8Hz,1H),7.84(d,J=8. 3Hz,1H),7.80-7.74(m,2H),7.72-7.63(m,2H),3.47(t,J=6.4Hz,2H),2.79(t,J=6.4Hz,2H),2.44(s,3H).

[0199] Example 16: N-(2-(N-isopropylsulfonamido)ethyl)-3-(phenanthrene-2-yl)propynamide (Compound 16)

[0200] Following the method of Example 1, N-methylpiperazine was replaced with 2-amino-N-(prop-2-yl)ethane-1-sulfonamide hydrochloride to obtain compound 16. 1 H NMR (400MHz, DMSO-d6) δ9.01-8.97(m,1H),8.93-8.83(m,2H),,8.28(d,J=1.8Hz,1H),8.05-8.00(m,1H),7.92(q,J=8.8Hz,2H),7.80(dd,J=8.8,1. 8Hz,1H),7.77-7.68(m,2H),7.15(d,J=7.5Hz,1H),3.52(q,J=5.9Hz,2H), 3.45(dq,J=7.5,6.5Hz,1H), 3.20(t,J=5.9Hz,2H), 1.15(d,J=6.5Hz,6H).

[0201] Example 17: 3-(3-(phenanthrene-2-yl)propynamido)propionic acid (compound 17)

[0202] Following the method of Example 1, N-methylpiperazine was replaced with methyl 3-aminopropionate hydrochloride to obtain compound I-6. ESI-MS: m / z 332.1 [M+H] +

[0203] Compound I-6 (23 mg, 0.07 mmol) was dissolved in 6 mL of a 5:1 mixture of tetrahydrofuran and water. Lithium hydroxide (23 mg) was added, and the mixture was reacted at room temperature for 12 hours. Then, 20 mL of 1 M sodium hydroxide solution was added, and the mixture was extracted three times with 10 mL of ethyl acetate. The pH of the aqueous layer was adjusted to 2 with 1 M hydrochloric acid. The mixture was filtered, and the filter cake was retained to obtain a white solid, namely compound 17 (21.8 mg, 99%). 1H NMR (400MHz, CD3OD) δ8.76-8.70(m,2H),8.14(d,J=1.7Hz,1H),7.92(dd,J=8.3,1.7Hz,1H),7.81(d ,J=8.3Hz,1H),7.77-7.72(m,2H),7.71-7.62(m,2H),3.56(t,J=6.8Hz,2H),2.61(t,J=6.8Hz,2H).

[0204] Example 18: 1-(1,1-Thiomorpholino)-3-(Phenanthro-2-yl)prop-2-yn-1-one (Compound 18)

[0205] Following the method of Example 1, N-methylpiperazine was replaced with thiomorpholine-1,1-dioxide to obtain compound 18. 1 HNMR(600MHz,DMSO-d6)δ8.94-8.86(m,2H),8.38(s,1H),8.03(d,J=8.9Hz,1H),7.95(d,J=8.9Hz,1H),7.92-7.86(m ,2H),7.79-7.69(m,2H),4.27(t,J=5.6Hz,2H),3.99(t,J=5.6Hz,2H),3.38(t,J=5.6Hz,2H),3.24(t,J=5.6Hz,2H).

[0206] Example 19: 3-(dibenzo[b,d]furan-3-yl)-1-(piperazin-1-yl)prop-2-yn-1-one (Compound 19)

[0207] Compound II-0 (4.9 g, 15.6 mmol) was dissolved in a mixed solution consisting of 40 mL of N,N-dimethylformamide, 6 mL of triethylamine, and 6 mL of N,N-diisopropylethylamine. Under an argon atmosphere, palladium dichloride dichloride (562 mg, 0.8 mmol), cuprous iodide (152 mg, 0.8 mmol), and trimethylsilyl yne (3.1 g, 31.1 mmol) were added. The mixture was reacted at 120 °C for 12 hours. The mixture was filtered through diatomaceous earth, and the filtrate was collected. The solvent was removed by vacuum distillation, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to give a yellow solid, which is compound I-1 (2.5 g, 60%). 1H NMR (400MHz, DMSO-d6) δ8.18(d,J=7.2Hz,1H),8.16(d,J=8.0Hz,1H),7.82(s,1H),7.73(d,J =8.3Hz,1H),7.60-7.54(m,1H),7.50(dd,J=8.0,1.3Hz,1H),7.47-7.41(m,1H),0.27(s,9H).

[0208] The protecting group was removed according to the method in Example 1, yielding a yellow solid, namely compound II-2. 1 H NMR(400MHz,DMSO-d6)δ8.20-8.15(m,2H),7.86(s,1H),7.73(d,J=8.2Hz,1H ),7.60-7.54(m,1H),7.52(d,J=8.0Hz,1H),7.47-7.41(m,1H),4.33(s,1H).

[0209] Following the method in Example 1, a pale yellow solid, namely compound II-3, was obtained. ESI-MS: m / z 237.1 [M+H] +

[0210] Referring to the method in Example 1, I-3 was replaced with II-3, and N-methylpiperazine was replaced with 1-Boc-piperazine, resulting in a white solid, namely compound II-4. 1 H NMR (400MHz, Acetone-d6) δ8.21-8.14(m,2H),7.93(d,J=1.3Hz,1H),7.71-7.56(m,3H),7.49-7.41(m,1H ),3.91(t,J=4.2Hz,2H),3.63(t,J=4.2Hz,2H),3.56(t,J=5.3Hz,2H),3.46(t,J=5.3Hz,2H),1.47(s,9H).

[0211] Referring to the method of Example 14, replacing I-4 with II-4 yields a white solid, namely compound 19. 1 H NMR (400MHz, CD3OD) δ8.08(dd,J=8.1,5.9Hz,2H),7.84(d,J=1.3Hz,1H),7.64-7.58(m,2H),7.55(ddd,J=8.1,5.9,1.3 Hz,1H),7.44-7.38(m,1H),3.93(t,J=4.2Hz,2H),3.68(t,J=4.2Hz,2H),2.96(t,J=5.3Hz,2H),2.87(t,J=5.3Hz,2H).

[0212] Example 20: 3-(6H-benzo[c]chromen-3-yl)-1-(piperazin-1-yl)prop-2-yn-1-one (Compound 20)

[0213] Following the method of Example 18, II-0 was replaced with II-5 to obtain compound 20. 1 H NMR (400MHz, CD3OD) δ7.85(d,J=8.1Hz,1H),7.81-7.77(m,1H),7.41(td,J=7.5,1.4Hz,1H),7.35(td,J=7.5,1.4Hz,1H),7.28(dd,J=8.1,1.6Hz,1H), 7.23(d,J=7.5Hz,1H),7.17(d,J=1.6Hz,1H),5.13(s,2H),3.94(t,J=4.2H z, 2H), 3.72 (t, J = 4.2Hz, 2H), 3.04 (t, J = 5.3Hz, 2H), 2.95 (t, J = 5.3Hz, 2H).

[0214] Example 21: 3-(5,7-dihydrodibenzo[c,e]oxohepyn-3-yl)-1-(piperazin-1-yl)prop-2-yn-1-one (Compound 21)

[0215] Following the method of Example 18, II-0 was replaced with II-6 to obtain compound 21. 1 H NMR (400MHz, CD3OD) δ7.74(dd,J=7.9,1.7Hz,1H),7.70(d,J=1.7Hz,1H),7.65(d,J=7.9Hz,1H),7.60(d,J=7.9Hz,1H),7.57-7.52 (m,1H),7.48-7.45(m,2H),4.32(s,2H),4.30(s,2H),3.94-3.89(m,2H),3.72-3.67(m,2H),3.00-2.95(m,2H),2.91-2.86(m,2H).

[0216] Example 29: 3-(6H-benzo[c]pyrrolidine-3-yl)-1-(4-methylpiperazin-1-yl)prop-2-yn-1-one (Compound 29)

[0217] Following the method of Example 1, I-0 was replaced with II-7 to obtain compound 29. 1H NMR (400MHz, MeOD) δ7.86(d,J=8.1Hz,1H),7.82-7.76(m,1H),7.47-7.38(m,1H),7.36(dd,J=7.4,1.3Hz,1H),7.28(dd,J=8.0,1.7Hz,1H),7.23(dd,J =7.4,1.3Hz,1H),7.17(d,J=1.7Hz,1H),5.14(s,2H),3.94-3.87(m,2H),3. 77-3.66(m,2H),2.57(t,J=5.2Hz,2H),2.49(t,J=5.2Hz,2H),2.36(s,3H).

[0218] Example 30: N-(2-hydroxyethyl)-N-methyl-3-(phenanthrene-2-yl)propanolamide (Compound 30)

[0219] Following the method of Example 1, N-methylpiperazine was replaced with N-(2-methoxyethyl)methylamine to obtain a white solid, compound I-7. ESI-MS: m / z 318.1 [M+H] +

[0220] Compound I-7 (19 mg, 0.06 mmol) was dissolved in 5 mL of dichloromethane, and boron tribromide (0.2 mL, 1.0 min Hexane) was added. The mixture was reacted at room temperature for 4 hours, and the reaction was quenched with 13 mL of methanol. The solvent was removed by vacuum distillation, and the residue was purified by column chromatography (dichloromethane:methanol = 90:10) to give a white solid, namely compound 30 (15.3 mg, 84%). 1 H NMR (400MHz, MeOD) δ8.83-8.74(m,2H),8.20(s,1H),7.98-7.92(m,1H),7.86-7.76(m,3H),7.73-7. 64(m,2H),3.90-3.83(m,2H),3.77(t,J=5.6Hz,1H),3.63t,J=5.6Hz,1H),3.46(s,1H),3.10(s,2H).

[0221] Example 31: (R)-N-(1-amino-3-hydroxy-1-oxopropane-2-yl)-3-(phenanthrene-2-yl)propionamide (Compound 31)

[0222] Following the method of Example 1, N-methylpiperazine was replaced with 2-amino-3-hydroxypropionamide to obtain compound 31. 1HNMR (400MHz, DMSO) δ8.92(d,J=8.1Hz,1H),8.86(d,J=8.1Hz,1H),8.78(d,J=8.1Hz,1H),8.36-8.26(m,1H),8.08-7.99(m,1H), 7.98-7.80(m,3H),7.78-7.68(m,2H),7.45(s,1H),7.16(s,1H),5.95-4.92(m,1H),4.33(q,J=6.4Hz,1H),3.64(q,J=6.4Hz,2H).

[0223] Example 32: 1-((3S,4R)-3,4-dihydroxypyrrolidone-1-yl)-3-(phenanthrene-2-yl)prop-2-yn-1-one (Compound 32)

[0224] Following the method of Example 1, N-methylpiperazine was replaced with cis-3,4-dihydroxypyrrolidine hydrochloride to obtain compound 32. 1 H NMR (400MHz, MeOD) δ8.79(dd,J=16.6,8.4Hz,2H),8.20(d,J=1.7Hz,1H),7.95(dd,J=8.2,1.4Hz,1H),7.85(d,J=8.9Hz,1H),7.81-7.76(m,2H),7.74-7. 64(m,2H),4.31(q,J=4.8Hz,2H),4.02(dd,J=11.5,5.2Hz,1H),3.80(dd,J=1 1.3, 4.8Hz, 1H), 3.70 (dd, J=13.2, 5.7Hz, 1H), 3.48 (dd, J=13.0, 4.6Hz, 1H).

[0225] Example 33: 3-(9H-fluorene-2-yl)-1-(piperazin-1-yl)prop-2-yn-1-one (Compound 33)

[0226] Following the method of Example 18, II-0 was replaced with II-8 to obtain compound 33. 1H NMR (400MHz, MeOD) δ7.88(d,J=4.0Hz,1H),7.86(d,J=4.0Hz,1H),7.78(s,1H),7.60(t,J=8.0Hz,2H),7.40((t,J=8.0Hz,1H),7.37- 7.33(m,J=4.0,8.0Hz,1H),3.93(s,2H),3.92(t,J=4.0Hz,2H),3.69(t,J=4.0Hz,2H),2.99(t,J=4.0Hz,2H),2.90(t,J=4.0Hz,2H).

[0227] Example 34: 3-(9-methyl-9H-carbazole-2-yl)-1-(piperazin-1-yl)prop-2-yn-1-one (Compound 34)

[0228] Following the method of Example 18, II-0 was replaced with II-9 to obtain compound 34. 1 H NMR(400MHz,MeOD)δ8.14-8.12(m,1H),8.12-8.10(m,1H),7.79(s,1H),7.54-7.52(m,1H),7.53-7.51(m,1H),7.43-7.39(m,1 H),7.27-7.22(m,1H),3.95(t,J=4.2Hz,2H),3.89(s,3H),3.69(t,J=4.2Hz,2H),2.99(t,J=4.2Hz,2H),2.90(t,J=4.2Hz,2H).

[0229] Example 35: 2-(3-oxo-3-(piperazin-1-yl)prop-1-yn-1-yl)-9H-fluorene-9-one (Compound 35)

[0230] Following the method of Example 18, II-0 was replaced with II-10 to obtain compound 35. 1 H NMR(400MHz,MeOD)δ7.84-7.75(m,4H),7.69(dt,J=7.4,1.0Hz,1H),7.64(td,J=7.5,1.2Hz,1H),7.44(td,J =7.5,1.0Hz,1H),3.90(t,J=4.3Hz,2H),3.70(t,J=4.3Hz,2H),2.99(t,J=4.3Hz,2H),2.90(t,J=4.3Hz,2H).

[0231] Example 36: 3-(9,9-dimethyl-9H-fluoren-2-yl)-1-(piperazin-1-yl)prop-2-yn-1-one (Compound 36)

[0232] Following the method of Example 18, II-0 was replaced with II-11 to obtain compound 36. 1 H NMR(400MHz,MeOD)δ7.84-7.78(m,2H),7.73(s,1H),7.60-7.57(m,1H),7.52-7.49(m,1H),7.39-7.34(m,2 H), 3.95 (t, J = 4.0Hz, 2H), 3.72 (t, J = 4.0Hz, 2H), 3.03 (t, J = 4.0Hz, 2H), 2.94 (t, J = 4.0Hz, 2H), 1.49 (s, 6H).

[0233] Example 37: 3-(dibenzo[b,d]thiophene-3-yl)-1-(piperazin-1-yl)prop-2-yn-1-one (compound 37)

[0234] Following the method of Example 18, II-0 was replaced with II-12 to obtain compound 37. 1 H NMR(400MHz,MeOD)δ8.31-8.28(m,2H),8.18(s,1H),7.97-7.91(m,1H),7.70-7.67(m,1H),7.58-7.5 0(m,2H),3.93(t,J=5.2Hz,2H),3.70(t,J=5.2Hz,2H),2.98(t,J=5.2Hz,2H),2.89(t,J=5.2Hz,2H).

[0235] Example 38: 3-(9H-carbazol-2-yl)-1-(piperazin-1-yl)prop-2-yn-1-one (Compound 39)

[0236] Following the method of Example 18, II-0 was replaced with II-14 to obtain compound 39. 1 H NMR(400MHz,MeOD)δ8.15-8.09(m,2H),7.73(s,1H),7.52-7.43(m,2H),7.41-7.39(m,1H),7.24-7.2 0(m,1H),3.99(t,J=5.3Hz,2H),3.74(t,J=5.3Hz,2H),3.05(t,J=5.3Hz,2H),2.95(t,J=5.3Hz,2H).

[0237] Example 39:

[0238] Following the method of Example 18, II-0 was replaced with III-1 to obtain compound 41. 1 H NMR(400MHz,MeOD)δ7.89(s,1H),7.83-7.78(m,3H),7.69-7.67(m,1H),7.60(t,J=1.05Hz,1H),7.48(t,J =1.05Hz,1H),4.01(t,J=8.0Hz,2H),3.79(t,J=8.0Hz,2H),3.14(t,J=8.0Hz,2H),3.05(t,J=8.0Hz,2H).

[0239] The preparation method of intermediate III-1 is as follows:

[0240] Compound III-0 (122 mg, 0.5 mmol) and N-fluorobis(benzenesulfonamide) (472 mg, 1.5 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), and the atmosphere was replaced with argon. The reaction mixture was transferred to -78 °C, and a 1.0 M solution of bis(trimethylsilylamino)lithium in cyclohexane (2.0 mL, 2.0 mmol) was slowly added dropwise. After 3 hours, the reaction mixture was transferred to room temperature, and the reaction was quenched with 10 mL of saturated ammonium chloride solution. The mixture was extracted three times with 30 mL of ethyl acetate. The combined ethyl acetate extract was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 99:1) to give a pale yellow solid, compound III-1 (101 mg, 72%). ESI-MS: m / z 282.1 [M+H] + .

[0241] Example 40:

[0242] Following the method of Example 18, II-0 was replaced with IV-4 to obtain compound 42. 1 H NMR (400MHz, DMSO) δ8.24(d,J=8.0Hz,1H),8.03(s,1H),7.81(d,J=2.7Hz,1H),7.69-7.63(m,2H),7.18(d,J=2. 7Hz, 1H), 3.88 (s, 3H), 3.86 (t, J = 4.0Hz, 2H), 3.59 (t, J = 4.0Hz, 2H), 2.95 (t, J = 4.0Hz, 2H), 2.85t, J = 4.0Hz, 2H).

[0243] The preparation method of intermediate IV-4 is as follows:

[0244] A 1.6 mL aqueous solution of sodium nitrite (0.45 g, 6.5 mmol) was added dropwise to a 6.5 mL aqueous solution of 9% hydrochloric acid containing IV-0 (1.00 g, 6.1 mmol). The mixture was stirred at 0 °C for 1.5 h to form a diazonium salt. The diazonium salt solution was slowly added to a 54 mL aqueous solution of 1,4-benzoquinone (0.80 g, 7.4 mmol) and sodium acetate (1.2 g, 14.6 mmol). The reaction was allowed to proceed at room temperature for 1 h. The precipitate was separated by filtration and washed with water (3 × 10 mL) to give a yellow solid, compound IV-1 (909 mg, 63%). ESI-MS: m / z 296.9 [M+H] + .

[0245] IV-1 (900 mg, 3.0 mmol) was dissolved in 20 mL of diethyl ether, and saturated sodium dithionite solution (10 mL) was added dropwise. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction solution was then poured into 20 mL of water and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 60:40) to give a brown oily substance, compound IV-2 (680 mg, 75%). ESI-MS: m / z 298.9 [M+H] + .

[0246] IV-2 (100 mg, 0.33 mmol) was dissolved in 10 mL of acetonitrile, and potassium hydroxide (66 mg, 1.2 mmol) and sodium acetate (83 mg, 1.0 mmol) were added. Argon gas was displaced, and the mixture was reacted at 150 °C for 1 hour. The reaction solution was poured into 10 mL of water and extracted with dichloromethane (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to give a yellow solid, compound IV-3 (47 mg, 53%). ESI-MS: m / z 263.0 [M+H] + .

[0247] IV-3 (40 mg, 0.15 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and potassium carbonate (62 mg, 0.45 mmol) was added. The mixture was stirred at room temperature for 0.5 hours, followed by the addition of iodomethane (32 mg, 0.22 mmol). The reaction mixture was reacted at room temperature for 4 hours. The reaction solution was poured into 10 mL of water and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated sodium chloride solution (5 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 90:10) to give a white solid, compound IV-4 (35 mg, 82%). ESI-MS: m / z 277.0 [M+H] + .

[0248] Example 43: Inhibitory activity of the compound on the STING signaling pathway in THP1-Dual cells

[0249] Compound incubation: The appropriate concentration of the compound and a final concentration of 10 μM of the STING agonist MSA-2 (CAS No.: 129425-81-6) were added to each well of a 96-well cell culture plate, along with 5 × 10⁶ THP1-Dual cells. 5 Incubate with 190 μL of medium per ml, with a final volume of 200 μL for each test well. Add 200 μL of culture medium to the blank control group.

[0250] Detection of colorimetric reaction: After 24 hours, transfer 20 μL of culture medium from each well to a new bottom-transparent 96-well plate, and add the luciferase assay reagent QUANTI-Luc. TM 50 μL, and immediately measure the fluorescence value.

[0251] Results analysis: The inhibition rate of each well was calculated using the formula: "Inhibition rate (IR, %) = (Fluorescence value of blank group - Fluorescence value of experimental group) / Fluorescence value of blank group × 100". 50 The values ​​were calculated using GraphPad Prism software.

[0252] Table 1: Inhibitory activity of compounds on the STING signaling pathway in THP1-Dual cells

[0253] Where "+" indicates IC50 is less than (≤) 10 μM; "-" indicates IC50 is less than (≤) 10 μM. 50 Greater than (>) 10 μM

[0254] The above experimental results show that the compound of the present invention has a significant inhibitory effect on the STING signaling pathway in THP1-Dual cells.

[0255] Example 44: Inhibitory activity of the compound on the STING signaling pathway in RAW-lucia cells

[0256] Compound incubation: The appropriate concentration of the compound and a final concentration of 50 μM of the STING agonist DMXAA were added to each well of a 96-well cell culture plate, followed by the addition of RAW-lucia cells (2.5 × 10⁻⁶). 5 Incubate with 190 μL of medium per ml, with a final volume of 200 μL for each test well. Add 200 μL of culture medium to the blank control group.

[0257] Detection of colorimetric reaction: After 24 hours, transfer 20 μL of culture medium from each well to a new bottom-transparent 96-well plate, and add the luciferase assay reagent QUANTI-Luc.TM 50 μL, and immediately measure the fluorescence value.

[0258] Results analysis: The inhibition rate of each well was calculated using the formula: "Inhibition rate (IR, %) = (Fluorescence value of blank group - Fluorescence value of experimental group) / Fluorescence value of blank group × 100". 50 The values ​​were calculated using GraphPad Prism software.

[0259] Table 2: Inhibitory activity of compounds on the STING signaling pathway in RAW-lucia cells

[0260] Where "+" represents IC 50 Less than (≤) 10μM; "-" indicates IC 50 Greater than (>) 10 μM

[0261] The above experimental results show that the compound of the present invention has a significant inhibitory effect on the STING signaling pathway in RAW-lucia cells.

[0262] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

A compound of general formula (I) or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers or pharmaceutically acceptable salts thereof, its prodrugs, its hydrates or solvates, or its isotopically labeled compounds. in, Dashed lines indicate single or double bonds; W is selected from O, S, N(H), N(D), N(C1-C6 alkyl), N(C3-C6 cycloalkyl), N(6-10 aryl), N(5-12 heteroaryl); X 1 X 2 X 3 Selected independently from C(R) a ), N; X 4 X 5 Selected independently from C and C(R) a ), N; Ring A is selected from 1-5 Qs. 1 Replacement C3-C 10 Cycloalkyl, 3-10 membered heterocyclic, C6-C 10 aryl or 5-12 heteroaryl; preferably, ring A is selected from any one or two Q groups. 1 Substituted groups: phenyl, 6-membered heteroaryl or 5-membered heteroaryl; m is selected from the following set of integers: 1, 2, 3, 4; Each Y is independently selected from C(R) e (R) f ), C(R a ), N(R c ), N, C(=O), C(=S), C(=NR d ), O, S, S(=O), S(=O)2; when m is greater than 1, the connecting bond between the two Ys is a single bond or a double bond; R e R f Each time it appears, it is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, halogenated C2-C6 alkenyl, C2-C6 ynyl, halogenated C2-C6 ynyl, cyano, hydroxyl, nitro, oxo, thio, -(C1-C6 alkyl)-L 4 -R 10 -(C2-C6 alkenyl)-L 4 -R 10 -(C2-C6 ynyl)-L 4 -R 10 -(halogenated C1-C6 alkyl)-L 4 -R 10 -(C2-C6 alkenyl)-L 4 -R 10 -(C2-C6 ynyl)-L 4 -R 10 -L 4 -R 10 -L 4 -(by 0-5 Rs) 10 Substituted C3-C14 cycloalkyl), -L 4 -(by 0-5 Rs) 10 Substituted 3-14 membered heterocyclic groups), -L 4 -(by 0-5 Rs) 10 Substituted C6-C14 aryl), -L 4 -(by 0-5 Rs) 10 Substituted 5-14 heteroaryl groups), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted C3-C14 cycloalkyl), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted 3-14 membered heterocyclic groups), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted C6-C14 aryl), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted 5-14 heteroaryl groups); Or R e and R f Together with the C atoms connecting them, they form optional groups of 1-5 Q atoms. 3 Substituted from the group consisting of: C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups; preferably, R e and R f And together with the C atoms connecting them, they form an optional structure consisting of one, two, or three Q atoms. 3 Substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group; R 1 Selected from hydrogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 ynyl, halo-C2-C6 ynyl, Q 2 , by 1-5 R 10 Replacement Q 2 ; R 2 Selected from: Q 2 , by 1-5 R 10 Replacement Q 2 ; Or, R 1 and R 2 Together with the N atoms connecting them, they form optional groups of 1-5 Q atoms. 3 The substituted 4-11 membered heterocyclic group; preferably, R1 and R2, together with the N atom connecting them, form a group optionally surrounded by one, two, or three Q atoms. 3 Substituted groups: 5-membered heterocyclic group, 6-membered heterocyclic group, 7-membered heterocyclic group; R a Q 1 Q 3 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, halogenated C2-C6 alkenyl, C2-C6 ynyl, halogenated C2-C6 ynyl, cyano, hydroxyl, nitro, oxo, thio, -(C1-C6 alkyl)-L 4 -R 10 -(C2-C6 alkenyl)-L 4 -R 10 -(C2-C6 ynyl)-L 4 -R 10 -(halogenated C1-C6 alkyl)-L 4 -R 10 -(C2-C6 alkenyl)-L 4 -R 10 -(C2-C6 ynyl)-L 4 -R 10 -L 4 -R 10 -L 4 -(by 0-5 Rs) 10 Substituted C3-C14 cycloalkyl), -L 4 -(by 0-5 Rs) 10 Substituted 3-14 membered heterocyclic groups), -L 4 -(by 0-5 Rs) 10 Substituted C6-C14 aryl), -L 4 -(by 0-5 Rs) 10 Substituted 5-14 heteroaryl groups), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted C3-C14 cycloalkyl), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted 3-14 membered heterocyclic groups), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted C6-C14 aryl), -L 4 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted 5-14 heteroaryl groups); Q 2 Each time it appears, it is independently selected from -(C1-C6 alkyl)-L 5 -R 10 -(C2-C6 alkenyl)-L 5 -R 10 -(C2-C6 ynyl)-L 5 -R 10 -(halogenated C1-C6 alkyl)-L 5 -R 10 -(halogenated C2-C6 alkenyl)-L 5 -R 10 -(halogenated C2-C6 ynyl)-L 5 -R 10 -L 5 -(by 0-5 Rs) 10 Substituted C3-C14 cycloalkyl), -L 5 -(by 0-5 Rs) 10 Substituted 3-14 membered heterocyclic groups), -L 5 -(by 0-5 Rs) 10 Substituted C6-C14 aryl), -L 5 -(by 0-5 Rs) 10 Substituted 5-14 heteroaryl groups), -L 5 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted C3-C14 cycloalkyl), -L 5 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted 3-14 membered heterocyclic groups), -L 5 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted C6-C14 aryl), -L 5 -(C1-C6 alkyl)-(with 0-5 R's) 10 Substituted 5-14 heteroaryl groups); L 4 Each occurrence is independent of: bond, C1-C6 alkyl, -O-, -S-, N(R) 9 )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)N(R 9 )-、-N(R 9 )C(=O)-、-N(R 9 )C(=O)N(R 9 -, -S(=O)2-, -N(R 9 )S(=O)2-、-N(R 9 )S(=O)-、-S(=O)2N(R 9 )-、-S(=O)N(R 9 )-; L 5 Each occurrence is independent as: key, -O-, -S-, -N(R) 9 )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)N(R 9 )-、-N(R 9 )C(=O)-、-N(R 9 )C(=O)N(R 9 -, -S(=O)2-, -N(R 9 )S(=O)2-、-N(R 9 )S(=O)-、-S(=O)2N(R 9 )-、-S(=O)N(R 9 )-; R c R d R 9 R 10 Each time it appears, it is independently selected from the group consisting of: H, D, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, hydroxyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, amino, amino-substituted C1-C6 alkyl, amino substituted with 1-2 C1-C6 alkyl groups, nitro, nitro-substituted C1-C6 alkyl, cyano, cyano-substituted C1-C6 alkyl, 5-8 membered heteroaryl, C2-C6 alkenyl. C2-C6 alkynyl, -C(=O)OH, -C(=O)O-(C1-C6 alkyl), -OC(=O)H, -OC(=O)-(C1-C6 alkyl), -OS(=O)OH, -OS(=O)O-(C1-C6 alkyl), -OS(=O)2OH, -OS(=O)2O-(C1-C6 alkyl), -S(=O)2OH, -S(=O)2O-(C1-C6 alkyl), -S(=O) 2-(C1-C6 alkyl), -N(H)S(=O)2-(C1-C6 alkyl), -N(C1-C6 alkyl)S(=O)2-(C1-C6 alkyl), -C(=O)NH2, -C(=O)N(H)(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, -N(H)C(=O)H, -N(H)C(=O)-(C1-C6 alkyl), -N(C1-C6 alkyl)2C =O)-(C1-C6 alkyl), -C(=O)H, -C(=O)-(C1-C6 alkyl), -OP(=O)(OH)2, -OP(=O)(C1-C6 alkyl)(C1-C6 alkyl), -N(H)P(=O)(OH)2, -N(H)P(=O)(C1-C6 alkyl)2, -N(C1-C6 alkyl)P(=O)(C1-C6 alkyl)(C1-C6 alkyl), oxo, thio. The compound according to claim 1, or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, polymorphs, tautomers, or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, or isotopically labeled compounds thereof, is characterized in that, The compound is selected from formulas (II-1) and (II-2). Among them, W is selected from O and S; ring A is selected from any 1-5 Qs. 1 Substituted phenyl or 5-6-membered heteroaryl; Ring B is selected from 1-5 R's. a2 Substituted groups: phenyl, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 5-membered cycloalkenyl, 6-membered cycloalkenyl, 7-membered cycloalkenyl, 8-membered cycloalkenyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl; R a2 Each time it appears, it is independently selected from R. a Or R c ; The ring Z is selected from the following group: 5-membered heterocyclic group, 6-membered heterocyclic group, and 7-membered heterocyclic group; n is selected from the following set of integers: 0, 1, 2, 3, 4; R 2 X 1 X 2 X 3 X 4 X 5 Q 1 Y, R a R c Q 3 The definition is the same as in claim 1. The compound according to claim 1, or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, polymorphs, tautomers, or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, or isotopically labeled compounds thereof, is characterized in that, The compound is selected from formulas (III-1) and (III-2): Among them, W is selected from O and S; X 6 X 7 X 8 X 9 Selected independently from C(R) a ), N; m is selected from the following set of integers: 1, 2, 3; The ring Z is selected from the following group: 5-membered heterocyclic group, 6-membered heterocyclic group, 7-membered heterocyclic group, 7-membered cycloalkenyl group, 8-membered cycloalkenyl group, 5-membered heteroaryl group, 6-membered heteroaryl group, 7-membered heteroaryl group; n is selected from the following set of integers: 0, 1, 2, 3, 4; R 2 X 1 X 2 X 3 R a Y, Q 3 The definition is the same as in claim 1. According to claim 1, the compound of formula (I) or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, polymorphs, tautomers or their pharmaceutically acceptable salts, prodrugs, hydrates or solvates, or isotopically labeled compounds are characterized in that: W is selected from O and S; R 1 Selected from hydrogen, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl; R 2 Selected from Q 2 , by 1-5 R 10 Replacement Q 2 ; Or, R 1 and R 2 Together with the N atoms connecting them, they form the following group of groups that can be optionally substituted with one, two, or three Q3 atoms: 5-membered heterocyclic groups, 6-membered heterocyclic groups, and 7-membered heterocyclic groups; X 1 X 2 X 3 Each is independently selected from CH and N; Ring A is selected from either one or two Qs. 1 Substituted groups: phenyl, 6-membered heteroaryl or 5-membered heteroaryl; Ring B is selected from 1-5 R's. a2 Substituted groups: 5-membered heteroaryl, 6-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 5-membered cycloalkenyl, 6-membered cycloalkenyl, 7-membered cycloalkenyl, 8-membered cycloalkenyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, R a2 Each time it appears, it is independently selected from R. a Or R c The R a R c The definition is the same as in claim 1. According to claim 1, the compound of formula (I) or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, polymorphs, tautomers or their pharmaceutically acceptable salts, prodrugs, hydrates or solvates, or isotopically labeled compounds are characterized in that: X 1 X 2 X 3 Each can be independently CH or N; X 4 X 5 The answer is C; Ring A is selected from either one or two Qs. 1 Substituted groups: phenyl, 6-membered heteroaryl or 5-membered heteroaryl; m is selected from the following set of integers: 1, 2, 3, 4; Each Y group is independently selected from C(R) e (R) f ), C(R a ), N(R c ), N, O, S, S(=O), S(=O)2; when m is greater than 1, the connecting bond between the two Ys is a single bond or a double bond; R a Selected from: hydrogen, deuterium, oxo, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; R c Selected from: hydrogen, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; R e R f Each can be independently selected from: H, deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl; or R. e and R f Together with the C atoms connecting them, they form an array optionally bounded by one or two Q atoms. 3 Substituted groups: C3-C6 cycloalkyl, 3-6 membered heterocyclic groups; W represents O or S; R 1 Selected from hydrogen, deuterium, C1-C6 alkyl, halogenated C1-C6 alkyl, and C3-C6 cycloalkyl; R 2 Selected from -(C1-C6 alkyl)-L 5 -R 10 , by 1-5 R 10 Substituted -(C1-C6 alkyl)-L 5 -R 10 ; Among them, L 5 Selected from key, -O-, -S-, -N(R) 9 )-, -C(=O)-, -S(=O)2-, -N(R 9 )S(=O)2-、-N(R 9 )S(=O)-、-S(=O)2N(R 9 )-、-S(=O)N(R 9 )-; Or, R 1 and R 2 Together with the N atoms connecting them, they form the following group of groups that can be optionally substituted with one, two, or three Q3 atoms: 5-membered heterocyclic groups, 6-membered heterocyclic groups, and 7-membered heterocyclic groups; R 9 R 10 Q1 and Q3 are as defined in claim 1. The compound according to claim 1, or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, polymorphs, tautomers, or pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, or isotopically labeled compounds thereof, is characterized in that, The compound is: A pharmaceutical composition, characterized in that, Includes: pharmaceutically acceptable carriers; and One or more of the compounds described in any one of claims 1-6, or their stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, their prodrugs, their hydrates or solvates, or their isotopically labeled compounds. A STING inhibitor, characterized in that, It comprises one or more compounds according to any one of claims 1-6, or their stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates, or pharmaceutical compositions according to claim 7. Use of a compound according to any one of claims 1-6, or a stereoisomer, enantiomer, diastereomer, transisomer, optical isomer, racemate, tautomer, or a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, an isotopically labeled compound thereof, a pharmaceutical composition according to claim 7, or a STING inhibitor according to claim 8, characterized in that, Used in the preparation of a drug, said drug being used for: 1) Detection and / or prevention and / or treatment of diseases mediated by the STING signaling pathway; 2) Detection and / or prevention and / or treatment of autoimmune diseases and inflammatory diseases; 3) Detection and / or prevention and / or treatment of tumors or cancer-related diseases; 4) Detection and / or prevention and / or treatment of infectious diseases and fibrotic diseases. Use of a compound according to any one of claims 1-6, or a stereoisomer, enantiomer, diastereomer, transisomer, optical isomer, racemate, tautomer, or a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or solvate thereof, an isotopically labeled compound thereof, a pharmaceutical composition according to claim 7, or a STING inhibitor according to claim 8, characterized in that, Reagents or drugs used to prepare for the detection and / or prevention and / or treatment of diseases, including but not limited to the following: Singleton-Merten syndrome (SMS), Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), familial frostbite lupus erythematosus (FCL), retinal vascular disease and leukodystrophy (RVCL), STING-associated infantile vascular disease (SAVI), scleroderma, psoriasis, Sjögren's syndrome (Sjögren's syndrome), Syndrome (SS), rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, Crohn's disease, ulcerative colitis, autoimmune colitis, small bowel malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, pulmonary fibrosis, aging, cardiovascular disease and neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), Parkinson's syndrome (PD), non-alcoholic steatohepatitis (NASH).

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