Compounds and compositions for treating conditions associated with STING activity

Abstract

The disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts, and / or hydrates, and / or co-crystals, and / or pharmaceutical combinations of such compounds) that inhibit (e.g., antagonize) interferon gene stimulating factor (STING). The chemical entities may be used, for example, to treat a condition, disease or disorder (e.g., cancer) in a subject (e.g., a human) where increased (e.g., excessive) STING activation (e.g., STING signaling) promotes the condition and / or symptom and / or progression of the condition, disease or disorder. The disclosure also features compositions containing the same as well as methods of use and preparation thereof. Formula (I)

Description

Cross-references to related applications

[0001] This application is an international patent application and claims the benefit of U.S. Provisional Application No. 63 / 540,868, filed September 27, 2023, the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0002] This disclosure is characterized by chemical entities (e.g., compounds or pharmaceutically acceptable salts, and / or hydrates, and / or cocrystals, and / or pharmaceutical combinations) that inhibit (e.g., antagonize) interferon gene-stimulating factor (STING). These chemical entities can be used, for example, to treat a subject (e.g., a human) for conditions, diseases, or disorders (e.g., cancer) in which increased (e.g., excessive) STING activation (e.g., STING signaling) promotes the symptoms and / or progression of the condition, disease, or disorder. This disclosure also features compositions containing these entities, as well as their use and methods of preparation. Background Technology

[0003] STING, also known as transmembrane protein 173 (TMEM173) and MPYS / MITA / 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 such as viruses, mycobacteria, and intracellular parasites, STING induces 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 pathway is crucial in mediating the recognition of cytosolic DNA. In this context, STING, a transmembrane protein located in the endoplasmic reticulum (ER), acts as a second messenger receptor for 2',3' cyclic GMP-AMP (cGAMP, which is produced by cGAS after dsDNA binding). Furthermore, STING also acts as a major pattern recognition receptor for bacterial cyclic dinucleotides (CDNs) and small molecule agonists. Recognition of endogenous or prokaryotic CDNs occurs via the C-terminal domain of STING, which faces the cytosol and creates a V-shaped binding pocket formed by STING homodimers. Ligand-induced activation of STING triggers its relocation to the Golgi apparatus, a process essential for promoting the interaction of STING with TBK1. This protein complex then signals via the transcription factor IRF-3 to induce type I interferon (IFN) and other co-regulated antiviral factors. Additionally, STING demonstrates its ability to trigger NF-κB and MAP kinase activation. After initiating signal transduction, STING is rapidly degraded, a step considered important for terminating the inflammatory response.

[0005] Overactivation of STING is associated with a subset of monogenic autoinflammatory disorders, known as type I interferon diseases. Examples of these include a clinical syndrome called STING-associated angiopathy (SAVI) with infancy onset, caused by gain-of-function mutations in TMEM173 (the gene name for STING). Furthermore, STING is linked to the pathogenesis of Aicardi-Goutières syndrome (AGS) and the genetic form of lupus. In contrast to SAVI, dysregulation of nucleic acid metabolism forms the basis of persistent innate immune activation in AGS. Beyond these genetic disorders, emerging evidence suggests a more pervasive pathogenic role for STING in a range of inflammatory disorders such as systemic lupus erythematosus, rheumatoid arthritis, and cancer. Therefore, small-molecule-based pharmacological interventions targeting the STING signaling pathway hold great potential for treating a broad spectrum of diseases. Summary of the Invention

[0006] This disclosure is characterized by chemical entities (e.g., compounds or pharmaceutically acceptable salts, and / or hydrates, and / or cocrystals, and / or pharmaceutical combinations) that inhibit (e.g., antagonize) interferon gene-stimulating factor (STING). These chemical entities can be used, for example, to treat a subject (e.g., a human) for conditions, diseases, or disorders (e.g., cancer) in which increased (e.g., excessive) STING activation (e.g., STING signaling) promotes the symptoms and / or progression of the condition, disease, or disorder. This disclosure also features compositions containing these entities, as well as their use and methods of preparation.

[0007] STING "antagonists" include compounds that directly bind to or modify STING at the protein level, thereby reducing STING activity, for example, by inhibiting, blocking, or preventing agonist-mediated responses, altering distribution, or otherwise. STING antagonists include chemical entities that interfere with or inhibit STING signaling.

[0008] In one respect, it is characterized by compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0009]

[0010] (I)

[0011] Among them, rings A, B, L, and R 1 R 2 R a1 R a2 R b1 and R b2 It can be defined as anywhere in this document.

[0012] Furthermore, unless otherwise specified, when a symbol in one formula in this specification is also used in other formulas, the same symbol has the same meaning.

[0013] Furthermore, the present invention relates to a pharmaceutical composition for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases, comprising a compound of formula (I) or a salt thereof.

[0014] Herein, the pharmaceutical composition includes an agent for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases, comprising a compound of formula (I) or a salt thereof. Furthermore, the present invention relates to a compound of formula (I) or a salt thereof, which is a STING inhibitor; a compound of formula (I) or a salt thereof for use as a STING inhibitor; a STING inhibitor comprising a compound of formula (I) or a salt thereof; use of a compound of formula (I) or a salt thereof for manufacturing a pharmaceutical composition for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases; use of a compound of formula (I) or a salt thereof for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases; use of a compound of formula (I) or a salt thereof in the treatment of autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases; and a method for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a subject. Here, "subject" is a person or non-human animal in need of treatment, and in one embodiment, a person in need of treatment.

[0015] Compounds of formula (I) or their salts have STING inhibitory activity and can be used as agents for the treatment of autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases.

[0016] Other embodiments include those described in the detailed embodiments and / or the claims.

[0017] Other definitions

[0018] To facilitate understanding of the disclosures set forth herein, several additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures described herein in organic chemistry, medicinal chemistry, and pharmacology are those well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Every patent, application, published application, and other publication mentioned throughout this specification, as well as any appendices, is incorporated herein by reference in its entirety.

[0019] As used herein, the term “STING” means, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous STING molecules, isotypes, precursors, mutants, variants, derivatives, splice variants, alleles, different species and their active fragments.

[0020] As used herein, the term “acceptable” in relation to formulations, compositions or ingredients means that there is no lasting adverse effect on the general health of the subject being treated.

[0021] "API" refers to active pharmaceutical ingredient.

[0022] As used herein, the term "effective amount" or "therapeutic effective amount" refers to a sufficient amount of a chemical entity applied to alleviate, to a certain extent, one or more symptoms of the disease or condition being treated. Results include reduction and / or relief of signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising compounds as disclosed herein required to achieve a clinically significant reduction in the symptoms of a disease. The appropriate "effective" amount in any individual case is determined using any suitable technique such as dose-escalation studies.

[0023] The term "excipient" or "pharmaceuticalally acceptable excipient" means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in a sense that it is compatible with the other components of a pharmaceutical formulation and is suitable for contact with human or animal tissues or organs without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, in proportion to a reasonable benefit / risk ratio. See, for example, Remington: The Science and Practice of Pharmacy, 21st edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th edition; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd edition; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd edition; Gibson, ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0024] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is applied and does not eliminate the biological activity and properties of the compound. In some cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In other cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acidic groups with a base to form salts such as ammonium salts, alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as calcium or magnesium salts), organic bases (such as dicyclohexylamine, N-methyl-D-glucosamine, tris(hydroxymethyl)methylamine), and salts with amino acids such as arginine, lysine, etc. There are no particular limitations on the pharmaceutical use of pharmaceutically acceptable salts, provided that they can be used in a drug. Examples of salts formed by the compounds described herein with bases include: salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, specifically examples of addition salts with the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0025] The term "pharmaceutical composition" refers to a mixture of the compound described herein with other chemical components (collectively referred to herein as "excipients") such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners. Pharmaceutical compositions facilitate the administration of the compound to a living organism. Various techniques for administering compounds exist in the art, including but not limited to: rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0026] The term "subject" refers to an animal, including but not limited to primates (e.g., humans), monkeys, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein, for example, with respect to mammalian subjects (such as humans).

[0027] In the context of treating a disease or disorder, the term “treat, treating, and treatment” is intended to include relieving or eliminating a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition; or slowing the progression, spread, or worsening of a disease, disorder, or condition or one or more symptoms thereof. “Treatment of cancer” refers to one or more of the following effects: (1) inhibiting tumor growth to some extent, including (i) slowing and (ii) complete growth arrest; (2) reducing the number of tumor cells; (3) maintaining tumor size; (4) reducing tumor size; (5) inhibiting, including (i) reducing, (ii) slowing or (iii) completely preventing tumor cell infiltration into surrounding organs; (6) inhibiting, including (i) reducing, (ii) slowing or (iii) completely preventing metastasis; (7) enhancing the antitumor immune response, which may result in (i) maintaining tumor size, (ii) reducing tumor size, (iii) slowing tumor growth, (iv) reducing, slowing or preventing invasion and / or (8) alleviating to some extent the severity or number of one or more symptoms associated with the disorder. The term “halo” refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0028] The term "alkyl" refers to a saturated acyclic hydrocarbon group, which may be straight-chain or branched and contains the indicated number of carbon atoms. For example, C 1-10 The indicated group may have from 1 to 10 carbon atoms (including the terminal value). The alkyl group may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. As used in this context, the term "saturated" means that only a single bond exists between the constituent carbon atom and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0029] The term "haloalkyl" or halogenoalkyl refers to an alkyl group in which one or more hydrogen atoms are independently halogenated.

[0030] The term "alkoxy" refers to -O-alkyl (e.g., -OCH3).

[0031] The term "alkylene" refers to a divalent alkyl group (e.g., -CH2-).

[0032] The term "alkenyl" refers to a straight-chain or branched acyclic hydrocarbon chain that can have one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2-6The indicated group may have 2 to 6 carbon atoms (including the terminal value). The alkenyl group may be unsubstituted or substituted with one or more substituents.

[0033] The term "alkynyl" refers to a straight-chain or branched acyclic hydrocarbon chain that can have one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2-6 The indicated group may have 2 to 6 carbon atoms (including the terminal number). The alkynyl group may be unsubstituted or substituted with one or more substituents.

[0034] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group consisting of 6 to 20 carbon atoms, wherein at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring can be substituted with substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, dihydro-1H-indenyl, etc.

[0035] As used herein, the term "cycloalkyl" refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons, or 3 to 10 ring carbons, or 3 to 6 ring carbons, wherein the cycloalkyl group may optionally be substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may include multiple fused rings and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl groups include: bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, etc. Cycloalkyl groups also include spirocyclic (e.g., spirobicyclic, where the two rings are connected by only one atom). Non-limiting examples of spirocycloalkyl groups include spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, spiro[3.6]decyl, spiro[5.5]undecyl, etc. As used in this context, the term "saturated" means that only single bonds exist between the constituent carbon atoms.

[0036] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons, or 3 to 10 ring carbons, or 3 to 6 ring carbons, wherein the cycloalkenyl group may optionally be substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As a partially unsaturated cyclic hydrocarbon group, the cycloalkenyl group can have any degree of unsaturation, provided that one or more double bonds are present in the ring, none of the rings in the cyclic system is aromatic, and the cycloalkenyl group is generally incompletely saturated. The cycloalkenyl group may comprise multiple fused and / or bridged and / or spirocyclic rings.

[0037] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; and having 6, 10, or 14 π electrons common in the ring array; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (but not necessarily a ring containing heteroatoms, such as tetrahydroisoquinolinyl, for example, tetrahydroquinolinyl). Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thiophene, pyridinyl, furanyl, oxazolyl, oxadiazolyl, pyrroleyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothiophene, benzooxadiazolyl, benzofuranyl, benzoimidazolyl, benzotriazolyl, cenylyl, indazole, indolyl, isoquinolinyl, isothiazolyl, naphridinyl, purine, thiophene-pyridinyl, and pyrido[2,3-d]pyrimidine. The heteroaryl group is selected from thienyl, pyridyl, quinazolinyl, quinolinyl, thienyl[2,3-c]pyridyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[4,3-b]pyridyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]m-dioxacyclopentenyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxothiocyclohexadienyl, isoindololinyl, etc. In some embodiments, the heteroaryl group is selected from thienyl, pyridyl, furanyl, pyrazolyl, imidazoleyl, isoindololinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0038] The term "heterocyclic group" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated ring system having 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic systems), having 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), or 1-9 heteroatoms (if tricyclic or polycyclic), wherein the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 N, O, or S heteroatoms respectively, if monocyclic, bicyclic, or tricyclic), wherein 0, 1, 2, or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclic groups include piperazine, pyrrolyl, dioxyl, morpholinyl, tetrahydrofuranyl, etc. Heterocyclic groups can include multiple fused rings and bridged rings. Non-limiting examples of fused / bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2-azabicyclo[1.1.1]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, octahydrocyclopentadien[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, 2-azabicyclo[2.2.2]octyl, 3 -Azabicyclo[3.2.1]octyl, 2-oxabicyclo[1.1.0]butyl, 2-oxabicyclo[2.1.0]pentyl, 2-oxabicyclo[1.1.1]pentyl, 3-oxabicyclo[3.1.0]hexyl, 5-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 7-oxabicyclo[2.2.1]heptyl, 6-oxabicyclo[3.1.1]heptyl, 7-oxabicyclo[4.2.0]octyl, 2-oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2.1]octyl, etc. Heterocyclic groups also include spirocyclic (e.g., spirobicyclo, where the two rings are connected by only one atom).Non-limiting examples of spirocyclic heterocyclic groups include 2-azaspiro[2.2]pentyl, 4-azaspiro[2.5]octyl, 1-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2-azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, 1,7-diazaspiro[4.5]decyl, 7-azaspiro[4.5]decyl, 2,5-diazaspiro[3.6]decyl, 3-azaspiro[5.5]undecyl, 2-oxo Spirospiro[2.2]pentyl, 4-oxellaspiro[2.5]octyl, 1-oxellaspiro[3.5]nonyl, 2-oxellaspiro[3.5]nonyl, 7-oxellaspiro[3.5]nonyl, 2-oxellaspiro[4.4]nonyl, 6-oxellaspiro[2.6]nonane, 1,7-dioxellaspiro[4.5]decyl, 2,5-dioxellaspiro[3.6]decyl, 1-oxellaspiro[5.5]undecyl, 3-oxellaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl, etc. As used in this context, the term "saturated" means that only single bonds exist between the constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0039] As used herein, the term "heterocyclic alkenyl" refers to a partially unsaturated cyclic ring system having 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic systems), having 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), or 1-9 heteroatoms (if tricyclic or polycyclic), wherein the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 N, O, or S heteroatoms, respectively, if monocyclic, bicyclic, or tricyclic), wherein 0, 1, 2, or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclic alkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrroleyl, dihydrofuranyl, and dihydrothiophenyl. As partially unsaturated cyclic groups, heterocyclic alkenes can have any degree of unsaturation, provided that one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and the heterocyclic alkenes are generally incompletely saturated. Heterocyclic alkenes may include multiple fused and / or bridged and / or spirocyclic rings.

[0040] As used herein, when a ring is described as “aromatic,” it means that the ring has a continuous delocalized π-electron system. Typically, the number of out-of-plane π-electrons corresponds to Hückel’s rule (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridinone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, etc.

[0041] As used herein, when a ring is described as “partially unsaturated,” it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation attributable to the ring itself; for example, one or more double or triple bonds between the ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, etc.

[0042] For the avoidance of ambiguity, and unless otherwise stated, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclic, heterocyclic alkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) containing a sufficient number of ring atoms to form bicyclic or higher-order ring systems (e.g., tricyclic, polycyclic systems), it should be understood that such rings and cyclic groups include those having fused rings, including those where the fusion point is located at (i) adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents a zero-atom bridge (e.g., ...). (ii) Monocyclic atoms (spiro-fused ring systems) (e.g., , ,or ); or (iii) a continuous array of ring atoms (a bridged ring system with all bridge lengths > 0) (e.g., , ,or Those on ).

[0043] Furthermore, the atoms constituting the compounds of embodiments of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms with the same number of atoms but different mass numbers. By way of example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0044] Furthermore, the compounds disclosed herein, either generally or specifically, are intended to include all tautomer forms. Therefore, by way of example, compounds containing the following moiety are included: Including tautomer forms containing the following parts: Similarly, pyridyl or pyrimidinyl moieties described as optionally substituted with hydroxyl groups include pyridinone or pyrimidinone tautomer forms.

[0045] As used herein, when used in conjunction with a structural moiety (e.g., alkyl), the phrase "optionally substituted" is intended to include both unsubstituted structural moieties (i.e., where no substituted hydrogen atom is replaced by one or more non-hydrogen substituents) and substituted structural moieties substituted by non-hydrogen substituents within an indicated range. For example, "optionally substituted by 1-4 R..." a "Substituted C1-C4 alkyl" is intended to include unsubstituted C1-C4 alkyl groups and those substituted with 1-4 R groups.a Both substituted C1-C4 alkyl groups.

[0046] Details of one or more embodiments of the present invention are set forth in the accompanying drawings and the description below. Further features and advantages of the invention will become apparent from the specification, the drawings, and the claims. Detailed Implementation

[0047] In this disclosure, unless otherwise stated, the following terms will have the following meanings. The following definitions are intended to clarify, but are not limiting. If a particular term is not specifically defined as used herein, it will be used within the meaning accepted by those skilled in the art.

[0048] The compound of formula (I) is provided here:

[0049]

[0050] Formula I

[0051] Or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

[0052] Ring A can be selected from the following groups:

[0053] •C 3-10 cycloalkyl or C 3-10 Cycloalkenyl;

[0054] • Heterocyclic groups or heterocyclic alkenyl groups with 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently chosen from N, N(H), N(R). d ), O and S(O) 0-2 The group consists of R d Choose from the following groups: C 1-4 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4 Alkoxy groups, wherein each occurrence of R' and R'' is independently selected from the group consisting of H and C. 1-4 alkyl;

[0055] • A heteroaryl group with 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently chosen from N, N(H), and N(R). d ), O and S(O) 0-2 The group consists of R d Choose from the following groups: C1-4 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4 Alkoxy groups, wherein each occurrence of R' and R'' is independently selected from the group consisting of H and C. 1-4 Alkyl groups; and

[0056] •C 6-10 Aryl;

[0057] Ring B can be selected from the following groups:

[0058] •C 3-10 cycloalkyl or C 3-10 Cycloalkenyl;

[0059] • Heterocyclic groups or heterocyclic alkenyl groups with 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently chosen from N, N(H), N(R). d ), O and S(O) 0-2 The group consists of R d Choose from the following groups: C 1-4 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4 Alkoxy groups, wherein each occurrence of R' and R'' is independently selected from the group consisting of H and C. 1-4 alkyl;

[0060] • A heteroaryl group with 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently chosen from N, N(H), and N(R). d ), O and S(O) 0-2 The group consists of R d Choose from the following groups: C 1-4 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4Alkoxy groups, wherein each occurrence of R' and R'' is independently selected from the group consisting of H and C. 1-4 Alkyl groups; and

[0061] •C 6-10 Aryl;

[0062] or

[0063] Rings A, B, and L together form a tricyclic fused aromatic or heterocyclic ring system;

[0064] R a1 and R a2 H independently, C optionally substituted 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Alkylene-C 2-6 alkenyl, -OC 1-6 Alkylene-C 2-6 Alkyne, halogen, halogenated -C 1-6 Alkyl, -O-halogen-C 1-6 Alkyl, (OH)-halogenated-C 1-6 Alkyl group, -OH group; -NHC(O)(C 1-4 Alkyl), C3-C6 cycloalkyl, phenyl, oxoyl, CN, CONR 1 R 2 SO2NR 1 R 2 S(O)(NH)NR 1 R 2 NR-CO-NR 1 R 2 NRSO2NR 1 R 2 Where R is H or C 1-4 Alkyl; or

[0065] R a1 and R a2 Together with the ring atoms to which they are attached, they form C3-C6 cycloalkyl groups or 4- to 7-membered saturated heterocyclic groups;

[0066] R b1 and R b2 H and C independently 1-6 Alkyl, -OC 1-6 Alkyl, Halogenated -C 1-6 Alkyl, -O-halogen-C 1-6 Alkyl, (OH)-halogenated-C 1-6 Alkyl, halogen, -C 1-6 alkylene -OH, -C 1-6 Alkylene-NR c R d-C(=O)-NR c R d -NR c R d -CN or -OH; C3-C6 cycloalkyl, phenyl, oxoyl, SO2NR 1 R 2 S(O)(NH)NR 1 R 2 NR-CO-NR 1 R 2 NRSO2 NR 1 R 2 Where R is H or C 1-4 Alkyl; or

[0067] R b1 and R b2 Together with the ring atoms to which they are attached, they form C3-C6 cycloalkyl groups or 4- to 7-membered saturated heterocyclic groups;

[0068] R c and R d H and C independently 1-6 Alkyl, C 3-8 Cycloalkyl, -C(=O)-C 1-6 Alkyl group, or -S(=O)2-C 1-6 Alkyl, or,

[0069] R c and R d They can be optionally connected to each other to communicate with R. c and R d The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be surrounded by one or two R atoms. e replace;

[0070] R e It is C 1-6 Alkyl, -OC 1-6 Alkyl or halogen;

[0071] R 1 H, or C which can be substituted. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 4- to 7-membered saturated heterocyclic groups, optionally substituted phenyl groups, or optionally substituted heteroaryl groups;

[0072] R 2 Is it by one or two Rs 3 Replacement C 1-6 Alkyl, with one or two R 4 Replacement C 3-8 cycloalkyl, with one or two R 5The substituted 4- to 7-membered saturated heterocyclic group, or the group replaced by one or two R groups. 6 Substituted phenyl; or

[0073] R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be fused with a phenyl or a 5- to 6-membered heteroaryl group, and the heterocyclic group and / or the fused phenyl group may optionally be surrounded by one to three R groups. 7 replace;

[0074] Each R 3 Independently -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C) 1-6 Alkyl group 2, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkylene -OH, -NH-S(=O)2-C 1-6 Alkylenes -C(=O)-OH, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, C3-C6 cycloalkyl, or -S(=O)(=NH)-C 1-6 alkyl;

[0075] Each R 4 Independently -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C) 1-6 Alkyl group 2, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, or C3-C6 cycloalkyl, -S(=O)(=NH)-C 1-6 alkyl;

[0076] Each R 5 It can be -OH, oxo group, or imino group independently;

[0077] Each R 6 Independently, it is a halogenated group, -C(=O)-OH, -S(=O)2-NH2, or -S(=O)2-C 1-6 Alkyl group, -S(=O)(=NH)-C 1-6 Alkyl, C3-C6 cycloalkyl, or -NH-S(=O)2-C 1-6 alkyl;

[0078] Each R 7 Independently, it is a halogenated group, C 1-6 Alkyl, -C 1-6 Alkylene-OH, Halogenated-C 1-6 Alkyl, -C 1-6 alkylene-C(=O)-OH, C 3-8 cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)(=NH)-C 1-6 Alkyl, -C(=O)-OH, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C) 1-6 Alkyl group, oxo group, imino group, -C 1-6 Alkylene-C3-C6 cycloalkyl, C3-C6 cycloalkyl, phenyl, or optionally C 1-6 Alkyl groups or 4- to 7-membered saturated heterocyclic groups substituted with one or two oxo groups; and,

[0079] L represents -O-, -S-, -NH-, -N(C) 1-6 Alkyl group, -S(=O)2-, -C(=O)-, -NH-C(=O)-, -C(=O)NH-, C 1-6 Alkylene, -NHSO2-, -SO2NH-, -NHS(O)NR)-, -NRS(O)NH)-, -OC 1-6 alkylene, or C 1-6 Alkylene-O-;

[0080] "Halogen" means F, Cl, Br, or I. In one embodiment, "halogen" is F or Cl; in another embodiment, it is F; in yet another embodiment, it is Cl; Br is in other embodiments; or I is in yet another embodiment.

[0081] Halogenated C 1-6"alkyl" is a straight-chain or branched carbon atom substituted with one or more halogens. 1-6 Alkyl group. In the examples, "halogenated C" 1-6 "alkyl" is trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, fluoromethyl, fluoroethyl, chloromethyl, bromomethyl, or iodomethyl; in another embodiment it is trifluoromethyl or difluoromethyl; in yet another embodiment it is trifluoromethyl; or in yet another embodiment it is difluoromethyl.

[0082] "Oxo" is a group represented by (=O), and "imino" is a group represented by (=NH).

[0083] "A 6-membered heteroaryl group containing one or two nitrogen atoms" means pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In one embodiment, "a 6-membered heteroaryl group containing one or two nitrogen atoms" is pyridyl; in another embodiment it is pyrazinyl; in yet another embodiment it is pyrimidinyl; or in yet another embodiment it is pyridazinyl.

[0084] A “six-membered saturated or partially unsaturated heterocyclic group” is a six-membered hydrocarbon ring that is saturated or has a double bond in the ring, and has one or more heteroatoms replacing carbon atoms, especially oxygen, nitrogen, or sulfur atoms, as constituent atoms of the ring and can form bridging bicyclic or spirocyclic rings. Examples of “six-membered saturated or partially unsaturated heterocyclic groups” include, but are not limited to, tetrahydropyran, piperidine, tetrahydrothiaran, morpholine, piperazine, thiomorpholine, dioxane, dihydropyran, tetrahydropyridine, or dihydrothiaran. In an embodiment, the “six-membered saturated or partially unsaturated heterocyclic group” is tetrahydropyran, dihydropyran, piperidine, tetrahydropyridine, or morpholine; or in another embodiment, it is tetrahydropyran or dihydropyran.

[0085] "4- to 7-membered saturated heterocyclic groups" are 4- to 7-membered saturated hydrocarbon rings that have one or more heteroatoms replacing carbon atoms, particularly oxygen, nitrogen, or sulfur atoms, as the constituent atoms of the ring, and can form bridging bicyclic or spirocyclic rings. Examples of "4- to 7-membered saturated heterocyclic groups" include, but are not limited to, oxoheterocyclic butyl, azaheterocyclic butyl, thioheterocyclic butyl, tetrahydrofuranyl, pyrrolyl, tetrahydrothiophene, tetrahydropyranyl, piperidinyl, tetrahydrothiophene, oxoheptanyl, azaheptanyl, thioheptanyl, dioxopentyl, imidazoalkyl, pyrazolyl, dithiopentanyl, oxazolyl, isoxazolyl, thiazoalkyl, isothiazolyl, dioxazolyl, and dioxane. 2,6-diazaspiro[3.3]heptyl, dithiaalkyl, morpholino, thiomorpholino, oxothiacyclohexyl, dioxacycloheptanyl, diazacycloheptanyl, dithiacycloheptanyl, oxaazacycloheptanyl, thiaazacycloheptanyl, oxathiacycloheptanyl, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azabicyclo[2.2.1]heptyl or 6-azaspiro[2.5]octyl. In the embodiments, “4- to 7-membered saturated heterocyclic groups” are oxoheterobutyl, azaheterobutyl, tetrahydrofuranyl, pyrrolyl, tetrahydrothiophene, tetrahydropyranyl, piperidinyl, tetrahydrothiophene, morpholinyl, piperazine, thiomorpholinyl, or 2,6-diazaspiro[3.3]heptyl; in another embodiment, they are azaheterobutyl, tetrahydrofuranyl, pyrrolyl, tetrahydrothiophene, tetrahydropyranyl, piperidinyl, morpholinyl, piperazine, or thiomorpholinyl. 2,6-diazaspiro[3.3]heptyl; in another embodiment, it is azirrocyclobutyl, pyrrolithyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl or 2,6-diazaspiro[3.3]heptyl; in another embodiment, it is tetrahydropyranyl; in another embodiment, it is tetrahydrofuranyl or pyrrolithyl; in another embodiment, it is tetrahydrothiophenyl; in the embodiments, it is azirrocyclobutyl, pyrrolithyl, piperidinyl or thiomorpholinyl.

[0086] “R c and R d They can be optionally connected to each other to communicate with R. c and R d The "4- to 7-membered saturated heterocyclic group" in "the attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group" is a 4- to 7-membered saturated hydrocarbon ring having at least one nitrogen atom instead of the carbon atom in the "4- to 7-membered saturated heterocyclic group" described above, for example, a nitrogen-containing heterocyclic butyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazine, or thiomorpholinyl. In the examples, "R" c and R d They can be optionally connected to each other to communicate with R. c and R d The “4- to 7-membered saturated heterocyclic group” in the phrase “the attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group” refers to piperidinyl or morpholinyl.

[0087] “R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be fused with a phenyl group. The “4- to 7-membered saturated heterocyclic group” is a 4- to 7-membered saturated hydrocarbon ring having at least one nitrogen atom instead of the carbon atom in the “4- to 7-membered saturated heterocyclic group” described above, for example, azaspiro[3.3]heptyl. “The heterocyclic group may optionally be fused with a phenyl group” means that the heterocyclic group is not fused with the phenyl ring or the heterocyclic group is fused with the phenyl ring to form a bicyclic ring, for example, indolinyl, isoindolinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl. In the examples, “R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be fused with a phenyl group. Examples of such heterocyclic groups are azirrocyclobutane, pyrrolithyl, piperidinyl, or thiomorpholinyl; in another embodiment, azirrocyclobutane, pyrrolithyl, or piperidinyl; in yet another embodiment, pyrrolithyl; in another embodiment, thiomorpholinyl; or in yet another embodiment, indolinel.

[0088] The "5-membered heterocyclic group" in "phenyl that may optionally be fused with a 5-membered heterocyclic group" is a 5-membered unsaturated hydrocarbon ring having one or more heteroatoms replacing a carbon atom, particularly an oxygen atom, a nitrogen atom, or a sulfur atom, as the constituent atoms of the ring. Examples of "5-membered heterocyclic groups" include, but are not limited to, dihydrofuranyl, furanyl, dihydropyrroleyl, pyrroleyl, dihydrothiophenyl, thiophenyl, dihydrooxazolyl, oxazolyl, dihydroimidazoyl, imidazoyl, dihydrothiazoyl, thiazoyl, dioxacyclopentenyl, or 2-oxodihydropyrroleyl. "Phenyl that may optionally be fused with a 5-membered heterocyclic group" is a phenyl or a phenyl that is fused with a "5-membered heterocyclic group" to form a bicyclic ring by sharing its double bond. Examples of "phenyl groups that can optionally fused with a 5-membered heterocyclic group" include, but are not limited to, phenyl, indolyl, benzofuranyl, benzothiophenyl, indazoleyl, benzimidazolyl, benzoisoxazolyl, benzoxazolyl, benzoisothiazolyl, benzothiazolyl, 1,3-benzodioxacyclopentenyl, or 1-oxoisoindolynyl. In the examples, "phenyl groups that can optionally fused with a 5-membered heterocyclic group" is phenyl.

[0089] "A phenyl group that may optionally be fused with a phenyl group or a 6-membered heteroaryl group containing one or two nitrogen atoms" is a phenyl group or a phenyl group fused with another phenyl group or a 6-membered heteroaryl group having one or two nitrogen atoms. Examples of "a phenyl group that may optionally be fused with a phenyl group or a 6-membered heteroaryl group containing one or two nitrogen atoms" include, but are not limited to, naphthyl, quinolinyl, quinazolyl, or quinoxalinyl. In an embodiment, "a phenyl group that may optionally be fused with a phenyl group or a 6-membered heteroaryl group containing one or two nitrogen atoms" is a phenyl or quinolinyl; in another embodiment, it is a phenyl group; or in yet another embodiment, it is a quinolinyl group.

[0090] In this specification, the expression "optionally substituted" includes "it is unsubstituted" or "it is substituted by one or more substituents" (e.g., substituents as defined below). Substitution can occur anywhere a hydrogen atom is normally present on the group. In one embodiment, "optionally substituted" means "optionally substituted by 1 to 5 substituents," and in another embodiment, it means "optionally substituted by 1 to 3 substituents." In the case of multiple substitutions, the substituents can be the same as or different from each other.

[0091] "Optionally substituted phenyl", "Optionally substituted heteroaryl", "Optionally substituted C" 1-6 Alkyl group, optional substituted C 3-8 Examples of substituents “cycloalkyl” and “optionally substituted 4- to 7-membered saturated heterocyclic groups” include, but are not limited to, those in R 3 R 4 R 5 R 6 or R 7 The substituents described in [the document].

[0092] "Optionally by one or two R" e "Replacement" means that something is not replaced or is replaced by one or two Rs. e Replacement. In embodiments, "optionally replaced by one or two R..." e "Replace" is by two Rs e Replaced; in another embodiment, it is replaced by an R e Replaced; or in another embodiment, not replaced. In the case of two Rs e In the case of replacement, these two Rs e They can be the same as or different from each other.

[0093] "By one or two R" y Replace (where R) y R represents 3 R 4 R 5 or R 6 (This means being controlled by one or two Rs) y Replacement. In the embodiment, "by one or two Rs"y "Replace" is by two Rs y Replaced; in another embodiment, it is replaced by an R y Replaced. In the case of two Rs y In the case of replacement, these two Rs y They can be the same as or different from each other.

[0094] "Optionally selected by one to three Rs" 7 "Replace" means not replaced or replaced by one to three Rs. 7 Replacement. In embodiments, "optionally replaced by one to three R..." 7 "Replace" is optionally replaced by one or two Rs. 7 Replaced; in another embodiment, it is replaced by three R 7 Replaced; in another embodiment, it is replaced by two R 7 Replace; in another embodiment, it is replaced by an R 7 Replaced; or in yet another embodiment, not replaced. When replaced by two or three R 7 In the case of replacement, these two or three R 7 They can be the same as or different from each other.

[0095] One or more embodiments may be combined with different embodiments, even if the combination is not specifically described. That is, all embodiments can be combined in any way.

[0096] In this article, "autoimmune diseases" refers to a group of diseases including systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, Crohn's disease, ulcerative colitis, type 1 diabetes mellitus, vasculitis, antiphospholipid syndrome, systemic sclerosis, polymyositis, dermatomyositis, mixed connective tissue disease, IgG4-related disease, microscopic polyangiitis, granulomatous disease with polyangiitis, eosinophilic granulomatous disease with polyangiitis, rapidly progressive glomerulonephritis, Behcet's disease, adult-onset Still's disease, ankylosing spondylitis, autoimmune hepatitis, primary biliary cholangitis, pemphigus, bullous pemphigoid, Hashimoto's disease, Basel's disease, primary immune thrombocytopenic purpura, autoimmune pulmonary alveolar proteinosis, autoimmune hemolytic anemia, Goodpasture's syndrome, myasthenia gravis, celiac disease, and psoriasis. However, "autoimmune diseases" are not limited to these diseases. In the embodiments, "autoimmune disease" is systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, Crohn's disease, ulcerative colitis, type 1 diabetes mellitus, vasculitis, systemic sclerosis, dermatomyositis, myasthenia gravis, or psoriasis; in other embodiments, it is systemic lupus erythematosus and Sjögren's syndrome; in yet another embodiment, it is systemic lupus erythematosus; or in yet another embodiment, it is Sjögren's syndrome. "Systemic lupus erythematosus" as used herein includes several subtypes of lupus, including but not limited to lupus nephritis, neuropsychiatric lupus erythematosus, and cutaneous lupus erythematosus. In the embodiments, "systemic lupus erythematosus" is lupus nephritis; in another embodiment, it is neuropsychiatric lupus; or in yet another embodiment, it is cutaneous lupus erythematosus. In another embodiment, "systemic lupus erythematosus" refers to systemic lupus erythematosus without symptoms of lupus nephritis; in another embodiment, it refers to systemic lupus erythematosus without symptoms of neuropsychiatric lupus; and in yet another embodiment, it refers to systemic lupus erythematosus without symptoms of either lupus nephritis or neuropsychiatric lupus. Furthermore, "systemic lupus erythematosus" as used herein includes systemic lupus erythematosus complicated by Sjögren's syndrome.

[0097] In this document, "neurodegenerative diseases" refers to a group of diseases including multiple sclerosis, amyotrophic lateral sclerosis (ALS), frontotemporal degeneration, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Lewy body dementia, Huntington's disease, age-dependent macular degeneration, stroke, and traumatic brain injury, but "neurodegenerative diseases" are not limited to these diseases. In one embodiment, "neurodegenerative disease" is multiple sclerosis; in another embodiment, it is amyotrophic lateral sclerosis; in other embodiments, it is Parkinson's disease, multiple system atrophy, or Lewy body dementia; in yet another embodiment, it is frontotemporal degeneration; in yet another embodiment, it is Huntington's disease; in other embodiments, it is stroke; or in other embodiments, it is traumatic brain injury.

[0098] In this article, "Type I interferon disease" refers to a disease group including Ecardi-Gutill syndrome (AGS), STING-associated vascular disease with infancy (SAVI), COPA syndrome, spinal achondroplasia, ataxia-telangiectasia, and familial frostbite-like lupus, but "Type I interferon disease" is not limited to these diseases. In the embodiments, "Type I interferon disease" is Ecardi-Gutill syndrome (AGS) or STING-associated vascular disease with infancy (SAVI); in another embodiment, it is Ecardi-Gutill syndrome (AGS); or in yet another embodiment, it is STING-associated vascular disease with infancy (SAVI).

[0099] In this document, "other STING-mediated diseases" refers to a group of diseases including non-alcoholic steatohepatitis (NASH), alcoholic liver disease, acute pancreatitis, acute kidney injury, sepsis, myocardial infarction, and chronic heart failure, but is not limited to these diseases. In one embodiment, "other STING-mediated diseases" is non-alcoholic steatohepatitis (NASH) or alcoholic liver disease; in another embodiment, it is acute pancreatitis; in yet another embodiment, it is acute kidney injury; in yet another embodiment, it is sepsis; or in another embodiment, it is myocardial infarction or chronic heart failure.

[0100] Formula I compound

[0101] In one respect, this disclosure is characterized by compounds of formula (I):

[0102]

[0103] Formula I

[0104] Or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

[0105] Ring A can be selected from the following groups:

[0106] •C 3-10 cycloalkyl or C 3-10 Cycloalkenyl;

[0107] • Heterocyclic groups or heterocyclic alkenyl groups with 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently chosen from N, N(H), N(R). d ), O and S(O) 0-2 The group consists of R d Choose from the following groups: C 1-4 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2NR'R'';-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4 Alkoxy groups, wherein each occurrence of R' and R'' is independently selected from the group consisting of H and C. 1-4 alkyl;

[0108] • A heteroaryl group with 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently chosen from N, N(H), and N(R). d ), O and S(O) 0-2 The group consists of R d Choose from the following groups: C 1-4 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4 Alkoxy groups, wherein each occurrence of R' and R'' is independently selected from the group consisting of H and C. 1-4 Alkyl groups; and

[0109] •C 6-10 Aryl;

[0110] Ring B can be selected from the following groups:

[0111] •C 3-10 cycloalkyl or C 3-10 Cycloalkenyl;

[0112] • Heterocyclic groups or heterocyclic alkenyl groups with 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently chosen from N, N(H), N(R). d ), O and S(O) 0-2 The group consists of R d Choose from the following groups: C 1-4 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4 Alkoxy groups, wherein each occurrence of R' and R'' is independently selected from the group consisting of H and C. 1-4 alkyl;

[0113] • A heteroaryl group with 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently chosen from N, N(H), and N(R). d ), O and S(O) 0-2 The group consists of R d Choose from the following groups: C 1-4 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4 Alkoxy groups, wherein each occurrence of R' and R'' is independently selected from the group consisting of H and C. 1-4 Alkyl groups; and

[0114] •C 6-10 Aryl;

[0115] or

[0116] Rings A, B, and L together form a tricyclic fused aromatic or heterocyclic ring system;

[0117] R a1 and R a2 H independently, C optionally substituted 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Alkylene-C 2-6 alkenyl, -OC 1-6 Alkylene-C 2-6 Alkyne, halogen, halogenated -C 1-6 Alkyl, -O-halogen-C 1-6 Alkyl, (OH)-halogenated-C 1-6 Alkyl group, -OH group; -NHC(O)(C 1-4 Alkyl), C3-C6 cycloalkyl, phenyl, oxoyl, CN, CONR 1 R 2 SO2NR 1 R 2 S(O)(NH)NR 1 R 2 NR-CO-NR 1 R 2 ,NRSO2NR 1 R 2 Where R is H or C 1-4 Alkyl; or

[0118] R a1 and R a2Together with the ring atoms to which they are attached, they form C3-C6 cycloalkyl groups or 4- to 7-membered saturated heterocyclic groups;

[0119] R b1 and R b2 H and C independently 1-6 Alkyl, -OC 1-6 Alkyl, Halogenated -C 1-6 Alkyl, -O-halogen-C 1-6 Alkyl, (OH)-halogenated-C 1-6 Alkyl, halogen, -C 1-6 alkylene -OH, -C 1-6 Alkylene-NR c R d -C(=O)-NR c R d -NR c R d -CN or -OH; C3-C6 cycloalkyl, phenyl, oxoyl, SO2NR 1 R 2 S(O)(NH)NR 1 R 2 NR-CO-NR 1 R 2 NRSO2 NR 1 R 2 Where R is H or C 1-4 Alkyl; or

[0120] R b1 and R b2 Together with the ring atoms to which they are attached, they form C3-C6 cycloalkyl groups or 4- to 7-membered saturated heterocyclic groups;

[0121] R c and R d H and C independently 1-6 Alkyl, C 3-8 Cycloalkyl, -C(=O)-C 1-6 Alkyl group, or -S(=O)2-C 1-6 Alkyl, or,

[0122] R c and R d They can be optionally connected to each other to communicate with R. c and R d The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be surrounded by one or two R atoms. e replace;

[0123] R e It is C 1-6 Alkyl, -OC 1-6Alkyl or halogen;

[0124] R 1 H, or C which can be substituted. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 4- to 7-membered saturated heterocyclic groups, optionally substituted phenyl groups, or optionally substituted heteroaryl groups;

[0125] R 2 Is it by one or two Rs 3 Replacement C 1-6 Alkyl group, with one or two R 4 Replacement C 3-8 cycloalkyl, with one or two R 5 The substituted 4- to 7-membered saturated heterocyclic group, or the group replaced by one or two R groups. 6 Substituted phenyl; or

[0126] R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be fused with a phenyl or a 5- to 6-membered heteroaryl group, and the heterocyclic group and / or the fused phenyl group may optionally be surrounded by one to three R groups. 7 replace;

[0127] Each R 3 Independently -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C) 1-6 Alkyl group 2, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkylene -OH, -NH-S(=O)2-C 1-6 Alkylenes -C(=O)-OH, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, C3-C6 cycloalkyl, or -S(=O)(=NH)-C 1-6 alkyl;

[0128] Each R 4 Independently -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C)1-6 Alkyl group 2, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, or C3-C6 cycloalkyl, -S(=O)(=NH)-C 1-6 alkyl;

[0129] Each R 5 It can be -OH, oxo group, or imino group independently;

[0130] Each R 6 Independently, it is a halogenated group, -C(=O)-OH, -S(=O)2-NH2, or -S(=O)2-C 1-6 Alkyl group, -S(=O)(=NH)-C 1-6 Alkyl, C3-C6 cycloalkyl, or -NH-S(=O)2-C 1-6 alkyl;

[0131] Each R 7 Independently, it is a halogenated group, C 1-6 Alkyl, -C 1-6 Alkylene-OH, Halogenated-C 1-6 Alkyl, -C 1-6 alkylene-C(=O)-OH, C 3-8 cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)(=NH)-C 1-6 Alkyl, -C(=O)-OH, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C) 1-6 Alkyl group, oxo group, imino group, -C 1-6 Alkylene-C3-C6 cycloalkyl, C3-C6 cycloalkyl, phenyl, or optionally C 1-6 Alkyl groups or 4- to 7-membered saturated heterocyclic groups substituted with one or two oxo groups; and,

[0132] L represents -O-, -S-, -NH-, -N(C) 1-6Alkyl group, -S(=O)2-, -C(=O)-, -NH-C(=O)-, -C(=O)NH-, C 1-6 Alkylene, -NHSO2-, -SO2NH-, -NHS(O)NR)-, -NRS(O)NH)-, -OC 1-6 alkylene, or C 1-6 Alkylene-O-;

[0133] (1-1) A compound or a salt thereof, wherein ring A is a phenyl group that may optionally be fused with a 5-membered heterocyclic group, a 6-membered heteroaryl group containing one or two nitrogen atoms, a pyrazolyl group, or a 6-membered saturated or partially unsaturated heterocyclic group.

[0134] (1-2) A compound or a salt thereof, wherein ring A is a phenyl group, a 6-membered heteroaryl group containing one or two nitrogen atoms, a pyrazolyl group, or a 6-membered saturated or partially unsaturated heterocyclic group.

[0135] (1-3) A compound or a salt thereof, wherein ring A is a phenyl, pyrazolyl or a 6-membered saturated or partially unsaturated heterocyclic group.

[0136] (1-4) A compound or a salt thereof, wherein ring A is a phenyl group.

[0137] (2-1) A compound or a salt thereof, wherein ring B is a phenyl group that may optionally be fused with a phenyl group or a 6-membered heteroaryl group containing one or two nitrogen atoms, a 6-membered heteroaryl group containing one or two nitrogen atoms, a pyrazolyl group or an imidazolyl group.

[0138] (2-2) A compound or a salt thereof, wherein ring B is a phenyl, a 6-membered heteroaryl or pyrazolyl containing one or two nitrogen atoms.

[0139] (2-3) A compound or a salt thereof, wherein ring B is a phenyl or a 6-membered heteroaryl group containing one or two nitrogen atoms.

[0140] (2-4) A compound or a salt thereof, wherein ring B is of formula (V), and X is CH or N. [Chemical Formula 14]

[0141] (V)

[0142] (2-5) A compound or a salt thereof, wherein ring B is of formula (V) and X is CH.

[0143] (2-6) A compound or a salt thereof, wherein ring B is of formula (V) and X is N.

[0144] (2-7) A compound or a salt thereof, wherein ring B is of formula (Va). [Formula 15]

[0145] (Va)

[0146] (2-8) A compound or a salt thereof, wherein ring B is of formula (Vb). [Formula 16]

[0147] (Vb)

[0148] (3-1) A compound or a salt thereof, wherein R a1 and R a2 H and C independently 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Alkylene-C 2-6 alkenyl, -OC 1-6 Alkylene-C 2-6 Alkyne, halogen, halogenated -C 1-6 Alkyl, -O-halogen-C 1-6 Alkyl or -OH.

[0149] (3-2) A compound or a salt thereof, wherein R a1 and R a2 H and C independently 1-6 Alkyl, halogen, halogenated -C 1-6 Alkyl or -O-halogenated -C 1-6 alkyl.

[0150] (3-3) A compound or a salt thereof, wherein R a1 and R a2 Independently, it is H, halogen, or halogenated-C. 1-6 Alkyl or -O-halogenated -C 1-6 alkyl.

[0151] (3-4) A compound or a salt thereof, wherein R a1 and R a2 Independently, it is H, halogenated-C 1-6 Alkyl or -O-halogenated -C 1-6 alkyl.

[0152] (3-5) A compound or a salt thereof, wherein R a1 and R a2 Independently, it is H or -O-halogenated-C 1-6 alkyl.

[0153] (3-6) A compound or a salt thereof, wherein R a1 It is H and R a2 It is -O-halogenated-C 1-6 alkyl.

[0154] (3-7) A compound or a salt thereof, wherein R a1 and R a2 It's H.

[0155] (4-1) A compound or a salt thereof, wherein R b1 and R b2 H and C independently 1-6 Alkyl, -OC 1-6 Alkyl, Halogenated -C 1-6 Alkyl, -O-halogen-C 1-6 Alkyl, halogen, -C 1-6 alkylene -OH, -C 1-6 Alkylene-NR c R d -C(=O)-NR c R d -NR c R d -CN or -OH.

[0156] (4-2) A compound or a salt thereof, wherein R b1 and R b2 Independently, it is H, halogenated-C 1-6 Alkyl or -C 1-6 Alkylene-NR c R d .

[0157] (4-3) A compound or a salt thereof, wherein R b1 and R b2 Independently H or halogenated-C 1-6 alkyl.

[0158] (4-4) A compound or a salt thereof, wherein R b1 It is H and R b2 It is halogenated-C 1-6 alkyl.

[0159] (5) A compound or a salt thereof, wherein R a1 R a2 R b1 Or R b2 At least one of them is not H.

[0160] (6-1) A compound or a salt thereof, wherein R c and R d H and C independently 1-6 Alkyl, C 3-8 Cycloalkyl, -C(=O)-C 1-6 Alkyl group, or -S(=O)2-C 1-6 Alkyl, or, R c and R d They can be optionally connected to each other to communicate with R. c and R dThe attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be surrounded by one or two R atoms. e replace.

[0161] (6-2) A compound or a salt thereof, wherein R c and R d Independently, it is H or C 1-6 Alkyl, or, R c and R d They can be optionally connected to each other to communicate with R. c and R d The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be surrounded by one or two R atoms. e replace.

[0162] (6-3) A compound or a salt thereof, wherein R c and R d Independently, it is H or C 1-6 alkyl.

[0163] (6-4) A compound or a salt thereof, wherein R c and R d Connect to each other to R c and R d The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be surrounded by one or two R atoms. e replace.

[0164] (7-1) A compound or a salt thereof, wherein R e It is C 1-6 Alkyl, -OC 1-6 Alkyl or halogen.

[0165] (7-2) A compound or a salt thereof, wherein R e Yes - OC 1-6 alkyl.

[0166] (8-1) A compound or a salt thereof, wherein R 1 H, or C which can be substituted. 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted 4- to 7-membered saturated heterocyclic groups, optionally substituted phenyl or optionally substituted heteroaryl groups, R 2 Is it by one or two Rs 3 Replacement C 1-6 Alkyl, with one or two R 4 Replacement C 3-8 cycloalkyl, with one or two R 5 The substituted 4- to 7-membered saturated heterocyclic group, or the group replaced by one or two R groups. 6 Substituted phenyl, or, R1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be fused with a phenyl group, and the heterocyclic group and / or the fused phenyl group may optionally be coated with one to three R atoms. 7 replace.

[0167] (8-2) A compound or a salt thereof, wherein R 1 It is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclic groups, optionally substituted phenyl or optionally substituted heteroaryl groups, R 2 Is it by one or two Rs 3 Replacement C 1-6 Alkyl, with one or two R 4 Replacement C 3-8 cycloalkyl, with one or two R 5 The substituted 4- to 7-membered saturated heterocyclic group, or the group replaced by one or two R groups. 6 Substituted phenyl, or, R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be fused with a phenyl group, and the heterocyclic group and / or the fused phenyl group may optionally be surrounded by one or two R atoms. 7 replace.

[0168] (8-3) A compound or a salt thereof, wherein R 1 It is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclic groups, phenyl, or optionally substituted heteroaryl groups, R 2 Is it by one or two Rs 3 Replacement C 1-6 Alkyl, with one or two R 4 Replacement C 3-8 Cycloalkyl groups or those with one or two R groups 5 Substituted 4- to 7-membered saturated heterocyclic groups, or, R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be surrounded by one or two R atoms. 7 replace.

[0169] (8-4) A compound or a salt thereof, wherein R 1 and R 2Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be surrounded by one or two R atoms. 7 replace.

[0170] (8-5) A compound or a salt thereof, wherein R 1 It is H, R 2 Is it by one or two Rs 3 Replacement C 1-6 Alkyl, or, R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form an azahexacyclic butyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl group, wherein the azahexacyclic butyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl group may optionally be surrounded by one or two R groups. 7 replace.

[0171] (8-6) A compound or a salt thereof, wherein R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form an azahexacyclic butyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl group, wherein the azahexacyclic butyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl group may optionally be surrounded by one or two R groups. 7 replace.

[0172] (8-7) A compound or a salt thereof, wherein R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a pyrrolidinyl group, wherein the pyrrolidinyl group may optionally be surrounded by one or two R atoms. 7 replace.

[0173] (8-8) A compound or a salt thereof, wherein R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a pyrrolidinyl group, wherein the pyrrolidinyl group is formed by two R atoms. 7 replace.

[0174] (8-9) A compound or a salt thereof, wherein R 1 It is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclic groups, optionally substituted phenyl or optionally substituted heteroaryl groups,

[0175] R2 Is it by one or two Rs 3 Replacement C 1-6 Alkyl, with one or two R 4 Replacement C 3-8 cycloalkyl, with one or two R 5 The substituted 4- to 7-membered saturated heterocyclic group, or the group replaced by one or two R groups. 6 Substituted phenyl, or,

[0176] R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be fused with a phenyl group, and the heterocyclic group may optionally be surrounded by one or two R atoms. 7 replace.

[0177] (9-1) A compound or a salt thereof, wherein each R 3 Independently -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C) 1-6 Alkyl group 2, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkylene -OH, -NH-S(=O)2-C 1-6 Alkylenes -C(=O)-OH, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl or -S(=O)(=NH)-C 1-6 alkyl.

[0178] (9-2) A compound or a salt thereof, wherein each R 3 Independently, it is -OH, -C(=O)- NH2, -NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl or -S(=O)2-NH2.

[0179] (9-3) A compound or a salt thereof, wherein each R 3 It is independently -OH or -C(=O)- NH2.

[0180] (10-1) A compound or a salt thereof, wherein each R 4 Independently -OH, -OC1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C) 1-6 Alkyl group 2, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl or -S(=O)(=NH)-C 1-6 alkyl.

[0181] (10-2) A compound or a salt thereof, wherein each R 4 Independently, it is -OH, -C(=O)- NH2, -NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl or -S(=O)2-NH2. (10-3) Compounds or salts thereof, wherein R 4 It is -OH.

[0182] (11-1) A compound or a salt thereof, wherein each R 5 It can be -OH, oxo, or imino on its own.

[0183] (11-2) A compound or a salt thereof, wherein each R 5 It can be either -OH or an oxo group.

[0184] (11-3) A compound or a salt thereof, wherein R 5 It is -OH.

[0185] (11-4) A compound or a salt thereof, wherein R 5 It is an oxygen group.

[0186] (11-5) A compound or a salt thereof, wherein each R 5 It is either an oxo group or an imino group.

[0187] (12-1) A compound or a salt thereof, wherein each R 6 Independently, they are -C(=O)-OH, -S(=O)2-NH2, and -S(=O)2-C 1-6 Alkyl group, -S(=O)(=NH)-C 1-6 Alkyl or -NH-S(=O)2-C 1-6 alkyl.

[0188] (12-2) A compound or a salt thereof, wherein each R 6It is independently -C(=O)-OH or -S(=O)2-NH2.

[0189] (12-3) A compound or a salt thereof, wherein R 6 It is -C(=O)-OH. (12-4) A compound or its salt, wherein R 6 It is -S(=O)2-NH2.

[0190] (13-1) A compound or a salt thereof, wherein each R 7 C is independent 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 alkylene-C(=O)-OH, C 3-8 cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)(=NH)-C 1-6 Alkyl, -C(=O)-OH, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C) 1-6 Alkyl group, oxo group, imino group, or 4- to 7-membered saturated heterocyclic group that may optionally be substituted with one or two oxo groups.

[0191] (13-2) A compound or a salt thereof, wherein each R 7 C is independent 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 alkylene-C(=O)-OH, C 3-8 Cycloalkyl, -OH, -NH2, -C(=O)-OH, -C(=O)-NH2, oxo, imino, or 4- to 7-membered saturated heterocyclic groups that may optionally be substituted with one or two oxo groups.

[0192] (13-3) A compound or a salt thereof, wherein each R 7 Independently is -C 1-6 Alkylene groups -OH, -OH, -C(=O)-NH2, oxo groups, or imino groups.

[0193] (13-4) A compound or a salt thereof, wherein each R 7 Independently is -C 1-6 Alkylene -OH, -OH or -C(=O)-NH2.

[0194] (13-5) A compound or a salt thereof, wherein R 7 It is -OH.

[0195] (14) A compound or a salt thereof, wherein L is -O-, -S-, -NH-, -N(C 1-6 Alkyl group, -S(=O)2-, -C(=O)-, -NH-C(=O)-, 4- to 7-membered saturated heterocyclic group -O-, or C 1-6 alkyl.

[0196] (14-1) A compound or a salt thereof, wherein L is -O-.

[0197] (14-2) A compound or a salt thereof, wherein L is -S-.

[0198] (14-3) A compound or a salt thereof, wherein L is -NH-.

[0199] (14-4) A compound or a salt thereof, wherein L is -N(C 1-6 alkyl)-.

[0200] (14-5) A compound or a salt thereof, wherein L is -S(=O)2-.

[0201] (14-6) A compound or a salt thereof, wherein L is -C(=O)-.

[0202] (14-7) A compound or a salt thereof, wherein L is -NH-C(=O)-.

[0203] (14-8) A compound or a salt thereof, wherein L is C 1-6 alkyl.

[0204] (15) A compound or a salt thereof, which is a combination of two or more embodiments that do not contradict each other in the group of embodiments described in (1-1) to (13-5). Examples include, but are not limited to, the following combinations.

[0205] (15-1) A compound or a salt thereof, which is a combination of (1-1), (2-1), (3-1), (4-1), (6-1), (7-1), (8-1), (9-1), (10-1), (11-1), (12-1), (13-1) and (14).

[0206] (15-2) A compound or a salt thereof, which is a combination of (1-1), (2-2), (3-2), (4-2), (6-2), (7-1), (8-2), (9-2), (10-2), (11-2), (12-2), (13-2) and (14-1).

[0207] (15-3) A compound or a salt thereof, which is a combination of (1-2), (2-4), (3-2), (4-2), (5), (6-2), (7-1), (8-3), (9-2), (10-3), (11-2), (13-2) and (14-2).

[0208] (15-4) A compound or a salt thereof, which is a combination of (1-2), (2-4), (3-2), (4-4), (8-4), (13-2) and (14).

[0209] (15-5) A compound or a salt thereof, which is a combination of (1-4), (2-4), (3-7), (4-4), (8-5), (9-3), (13-3) and (14).

[0210] (15-6) A compound or its salt, which is a combination of (1-4), (2-4), (3-7), (4-4), (8-6), (13-3) and (14).

[0211] (15-7) A compound or a salt thereof, which is a combination of (1-4), (2-5), (3-7), (4-4), (8-8), (13-5) and (14).

[0212] (15-8) A compound or a salt thereof, which is a combination of (1-1), (2-2), (3-2), (4-2), (6-2), (7-1), (8-9), (9-2), (10-2), (11-2), (12-2), (13-2) and (14).

[0213] Examples of specific compounds included in this invention also include compounds listed in Table A that are in free base form or salts thereof.

[0214] Regarding compounds of formula (I), depending on the type of substituents, tautomers or geometric isomers may exist. In this specification, in some cases, compounds of formula (I) and their salts may be described as only one form of isomer, but the invention includes other isomers, isolated forms of isomers, or mixtures thereof. Furthermore, in some cases, some of the compounds of formula (I) may have asymmetric carbon atoms or axial chirality, and accordingly, enantiomers (optical isomers) may exist. The invention includes isolated forms of individual enantiomers of compounds of formula (I) or mixtures thereof, including racemic mixtures or others. In one embodiment, the enantiomer is "stereochemically pure." "Stereochemically pure" means a stereochemical purity level that would be considered substantially "pure" by those skilled in the art. In another embodiment, the enantiomer is a compound having a stereochemical purity greater than 90% ee (enantiomer excess), greater than 95% ee, greater than 98% ee, greater than 99% ee, or greater than 99.5% ee.

[0215] Furthermore, in some cases, depending on the type of substituent, the salt of a compound of formula (I) is a pharmaceutically acceptable salt of a compound of formula (I), and the compound of formula (I) can form an acid addition salt or a salt with a base. Specifically, examples include acid addition salts with inorganic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid) and with organic acids (such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, xylyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid), as well as salts with metal anions (such as sodium, potassium, magnesium, calcium, and aluminum), and salts with organic bases (such as methylamine, ethylamine, ethanolamine, lysine, and ornithine), salts with various amino acids (such as acetylleucine), or derivatives of amino acids, ammonium salts, etc.

[0216] Furthermore, the present invention also includes various hydrates or solvates of compounds of formula (I) and their salts, as well as crystalline polymorphs. The present invention includes all pharmaceutically acceptable isotope-labeled compounds of the present invention having one or more radioactive or non-radioactive isotopes. Examples of isotopes suitable for isotope labeling of compounds of the present invention include isotopes of hydrogen (such as...). 2 H and 3 H), carbon isotopes (such as H), and carbon isotopes (e.g. 11 C 13 C and 14 C) Isotopes of chlorine (such as...) 36 Cl), isotopes of fluorine (such as Cl), and fluorine isotopes (such as Cl) 18 F), isotopes of iodine (such as...) 123 I and125 I) Isotopes of nitrogen (such as 13 N and 15 N), isotopes of oxygen (such as N), and oxygen isotopes (e.g. 15 O、 17 O and 18 O), isotopes of phosphorus (such as O), and phosphorus isotopes (e.g. 32 P) and isotopes of sulfur (such as P) and sulfur isotopes (e.g. 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies. For this purpose, given their ease of incorporation and detection, the radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C). Replace with a heavier isotope, for example, deuterium (i.e., 2 Replacing hydrogen with H can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, reduced drug-drug interference, and therefore can be used in some cases. Using positron-emitting isotopes (such as...) 11 C 18 F, 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples and preparations, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0217] (Production Method) Compounds of Formula (I) or their salts can be prepared by applying various known synthetic methods, using characteristics based on their basic structure or the type of substituents. In some cases, depending on the type of functional group, it is effective from a technical perspective to protect the functional group with a suitable protecting group (a group that can be readily converted into a functional group) during the steps from starting material to intermediate. Examples of protecting groups include those described in "Greene's Protective Groups in Organic Synthesis" (4th edition, 2006), edited by PGM Wuts and TW Greene, which can be appropriately selected and used depending on the reaction conditions. In these methods, the desired compound can be obtained by introducing a protecting group to carry out the reaction and then (if desired) removing the protecting group. Pharmaceutically acceptable prodrugs are compounds having groups that can be decomposed by solvents or converted into amino, hydroxyl, carboxyl, etc., under physiological conditions. Examples of groups forming prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) or “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), Vol. 7, Drug Design, 163-198. Furthermore, prodrugs of compounds of formula (I) can be prepared by introducing specific groups during the steps from starting materials to intermediates in the same manner as the protecting groups described above, or by further reacting the obtained compound of formula (I). Reactions can be carried out using methods known to those skilled in the art, such as common esterification, amidation, and dehydration. Typical methods for preparing compounds of formula (I) will be described below. Each of these methods can also be referred to the documents appended to this specification. Furthermore, the methods of preparation of the present invention are not limited to the examples shown below.

[0218] Non-limiting exemplary compounds

[0219] In some embodiments, the compounds are selected from the group consisting of the compounds described in Table A or their pharmaceutically acceptable salts.

[0220] Table A

[0221]

[0222] Pharmaceutical composition and administration

[0223] Overview

[0224] In some embodiments, a chemical entity (e.g., a compound that inhibits (e.g., antagonizes) STING, or a pharmaceutically acceptable salt, and / or hydrate, and / or cocrystal, and / or pharmaceutical combination thereof) is administered as a pharmaceutical composition comprising the chemical entity and one or more pharmaceutically acceptable excipients and optionally one or more additional therapeutic agents as described herein.

[0225] In some embodiments, the chemical entity may be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (such as d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (such as Tween, poloxamer, or other similar polymer delivery matrices), serum proteins (such as human serum albumin), buffering substances (such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glycerol ester mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts)), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrins), or other dissolved derivatives, may also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions containing 0.005% to 100% of the chemical entities described herein, with the balance made up by non-toxic excipients, can be prepared. The intended compositions may contain 0.001%–100%, 0.1%–95% in one example, 75%–85% in another example, and 20%–80% in yet another example of the chemical entities provided herein. Practical methods for preparing such dosage forms are known or will be obvious to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, UK, 2012).

[0226] Application route and composition components

[0227] In some embodiments, the chemical entities or pharmaceutical compositions thereof described herein may be administered to subjects in need via any acceptable route of administration. Acceptable routes of administration include, but are not limited to, sublingual, skin, intracervical, intrasinusial, tracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracystic, intracerebral, intracisary, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepithelial, intraepithelial, intraesophageal, intragastric, intragingival, intraileum, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinusial, spinal, intrasynovial, intratestinal, intrasheath, intracanthal, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, epidural, rectal, inhalation, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal administration. In some embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0228] The compositions can be formulated for parenteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectable liquid solutions or suspensions; they can also be prepared in solid forms suitable for the preparation of solutions or suspensions when liquids are added prior to injection; and the formulations can also be emulsified. The preparation of such formulations will be known to those skilled in the art according to this disclosure.

[0229] Suitable drug forms for injectable applications include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the provisional preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must have a degree of flowability sufficient for easy injection. It should also be stable under manufacturing and storage conditions and must be preserved against microbial contamination such as bacteria and fungi.

[0230] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Suitable flowability can be maintained, for example, by using coatings (e.g., lecithin), maintaining the desired particle size in the case of dispersions, and by using surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In many cases, isotonic agents, such as sugars or sodium chloride, are preferred. The absorption of the injectable composition can be prolonged by using agents that delay absorption (e.g., aluminum monostearate and gelatin) in the composition.

[0231] Sterile injectable solutions are prepared by combining the active compound in the required amount with various other components listed above (as needed) in a suitable solvent, followed by filtration sterilization. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile medium containing an alkaline dispersion medium and desired other components from those listed above. For sterile powders used to prepare sterile injectable solutions, preferred methods of preparation include vacuum drying and freeze-drying techniques, which produce powders of the active ingredient plus any additional desired components from its previously sterile filtered solution.

[0232] Intratumoral injection is discussed, for example, in Lammers et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems”, Neoplasia. [Tumor Formation] 2006, 10, 788–795.

[0233] Pharmacologically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, any one or more of the following: glyceryl cocoa butter, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointments), glycerin, glyceryl gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycol and its fatty acid esters of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxidase, etc. SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, methylparaben, sodium paraben, propylparaben, diethylamine, carbomer, carboplatin, methoxybenzoate, polyethylene glycol cetearyl ether, cocoyl octanoyl decanoate, isopropanol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metasulfite, sodium edetate, sodium benzoate, potassium metasulfite, grape seed extract, methanesulfonyl methane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E), and potassium acetate.

[0234] In some embodiments, the suppository can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers (such as cocoa butter, polyethylene glycol, or suppository wax), which are solid at ambient temperature but liquid at body temperature, and thus melt in the rectum and release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

[0235] In other embodiments, the compounds or pharmaceutical compositions thereof described herein are suitable for local delivery to the digestive or gastrointestinal (GI) tract via oral administration (e.g., solid or liquid dosage forms).

[0236] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For capsules, tablets, and pills, dosage forms may also include buffers. Excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol may also be used as fillers in soft-filled and hard-filled gelatin capsules.

[0237] In one embodiment, the composition is in the form of a unit dosage form, such as a pill or tablet, and therefore the composition may contain, along with the chemical entities provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate, etc.; and a binder such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, powders, marumes, solutions, or suspensions (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) are encapsulated in capsules (gelatin- or cellulose-based capsules). Unit dosage forms in which one or more chemical entities or additional active agents provided herein are physically separate are also contemplated; for example, capsules containing particles of each drug (or tablets within capsules); bilayer tablets; double-compartment gel caps, etc. Enteric-coated or delayed-release oral dosage forms are also contemplated.

[0238] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersants, or preservatives specifically designed to prevent the growth or action of microorganisms. Various preservatives are well-known and include, for example, phenol and ascorbic acid.

[0239] In some embodiments, the excipients are sterile and generally do not contain unwanted substances. These compositions can be sterilized using conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules, sterility is not required. USP / NF standards are generally sufficient.

[0240] In some embodiments, the solid oral dosage form may further comprise one or more components that chemically and / or structurally facilitate the delivery of the chemical entity to the stomach or lower GI; for example, the ascending colon and / or transverse colon and / or distal colon and / or small intestine. Exemplary formulation techniques are described, for example, in Filipski, KJ et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

[0241] Examples include upper-GI targeting technologies, such as the Accordion Pill (Intec Pharma), floating capsules, and materials that can adhere to mucosal walls.

[0242] Other examples include lower-GI targeting technologies. Several enteric / pH-responsive coatings and excipients are available for targeting various regions of the gut. These materials are typically polymers designed to dissolve or erode within a specific pH range selected based on the desired GI region for drug release. These materials are also used to protect acid-insensitive drugs from gastric juices or to limit exposure in cases where the active ingredient can stimulate the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methyl methacrylate copolymer), and Marcoat). Other technologies include dosage forms responsive to local flora in the gastrointestinal (GI) tract, pressure-controlled colonic delivery capsules, and Pulsincap.

[0243] Ophthalmic compositions may include, but are not limited to, any one or more of the following: thickeners (viscogen) (e.g., carboxymethyl cellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Prolactin (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloride complex; Allergan, Inc.)).

[0244] Topical compositions may include ointments and creams. Ointments are semi-solid formulations, typically based on petrolatum or other petroleum derivatives. Creams containing selected active agents are typically viscous liquids or semi-solid emulsions, usually oil-in-water or water-in-oil. Cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase (sometimes referred to as the "internal" phase) typically consists of petrolatum and fatty alcohols (such as cetyl alcohol or stearyl alcohol); the aqueous phase is usually (though not necessary) larger in volume than the oil phase and typically contains a wetting agent. Emulsifiers in cream formulations are typically nonionic, anionic, cationic, or amphoteric surfactants. Regarding other carriers or mediators, the ointment base should be inert, stable, non-irritating, and non-sensitizing.

[0245] In any of the foregoing embodiments, the pharmaceutical composition described herein may include one or more of the following: lipids, multilayer vesicles with interlayer crosslinking, nanoparticles or microparticles based on biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA] or based on polyanhydride, and nanoporous particle-supported lipid bilayers.

[0246] dose

[0247] Dosage can be varied depending on the patient's needs, the severity of the condition being treated, and the specific compound used. The appropriate dosage for a particular situation can be determined by a medical professional. The total daily dose can be divided and administered in divided doses throughout the day or administered via a continuous delivery method.

[0248] In some embodiments, the compounds described herein are administered in doses ranging from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0.1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 10 mg / kg).

[0249] plan

[0250] The aforementioned dosage can be administered on a daily basis (e.g., as a single dose or as two or more separate doses) or on a non-daily basis (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0251] In some embodiments, the application of the compounds described herein may last for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In another embodiment, the period of discontinuation of application may last for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one embodiment, the therapeutic compound is administered to an individual for a period of time, followed by independent periods of time. In another embodiment, the therapeutic compound is administered for a first period of time followed by a second period of time, during which administration is stopped, followed by a third period of time initiating administration of the therapeutic compound and then a fourth period of time following the cessation of administration of the third period. In one aspect of this embodiment, the period of administration followed by the period of cessation of administration is repeated for a determined or undetermined period of time. In another embodiment, the administration period lasts for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In another embodiment, the period of cessation of application may last for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0252] Treatment

[0253] In some embodiments, a method is provided for treating a subject suffering from a condition, disease, or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) promotes the condition, disease, or disorder (e.g., immune disorder, cancer) symptoms and / or progression.

[0254] Indications

[0255] In some embodiments, the symptom, disease, or disorder is cancer. Non-limiting examples of cancer include melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoma. More specific examples of such cancers include breast cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, clear cell carcinoma, lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), cervical cancer, ovarian cancer, prostate cancer, prostate tumors, liver cancer, bladder cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer (including gastrointestinal cancer and gastrointestinal stromal tumors), pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, theca cell tumor, androgenetic adenomas, liver cancer, hematologic malignancies (including non-Hodgkin's lymphoma (NHL)), multiple myeloma, and spinal dysplasia. Disorders, myeloproliferative disorders, chronic myeloid leukemia and acute hematologic malignancies, endometrial cancer or uterine cancer, endometriosis, endometrial stromal sarcoma, fibrosarcoma, choriocarcinoma, salivary gland cancer, vulvar cancer, thyroid cancer, esophageal cancer, liver cancer, anal cancer, penile cancer, nasopharyngeal cancer, laryngeal cancer, Kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin cancer, schwannoma, oligodendroglioma, neuroblastoma, neuroectodermal tumor, rhabdomyosarcoma, osteoblastic sarcoma, leiomyosarcoma, Ewing's sarcoma, peripheral primitive neuroectodermal tumor, urinary tract cancer, thyroid cancer, Wilms' tumor, and abnormal angiogenesis, edema (such as edema associated with brain tumors), and Megs syndrome associated with nevus hamartoma. In some cases, the cancer is melanoma.

[0256] In some embodiments, the condition, disease, or disorder is a neurological disorder, including disorders involving the central nervous system (brain, brainstem, and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both the central and peripheral nervous systems). Non-limiting examples of neurological disorders include acquired epileptic aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; agenesis of the corpus callosum; agnosia; Eckaldi syndrome; Alexander disease; Alpert disease; alternating hemiplegia; Alzheimer's disease; vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; hemangioma; hypoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia. Telegiectasia); Attention Deficit Hyperactivity Disorder; Autism; Autonomic Dysfunction; Back Pain; Behcet's Disease; Bell's Paralysis; Benign Idiopathic Blepharospasm; Benign Focal Leukocytosis; Amyotrophic Muscular Atrophy; Benign Intracranial Hypertension; Binswanger Disease; Blepharospasm; Bloch-Sulzberger Syndrome; Brachial Plexus Injury; Brain Abscess; Brain Injury; Brain Tumors (including astrocytomas); Spinal Cord Tumors; Brown-Segard Syndrome; Canavan Disease; Carpal Tunnel Syndrome; Burning Pain; Central Pain Syndrome; Central Pontic Myelinolysis; Head Disorders; Cerebral Aneurysm; Cerebral Arteriosclerosis; Brain Atrophy; Cerebral Gigantism; Cerebral Palsy; Charcot-Marie-Tooth Disease; Chemotherapy-Induced Peripheral Neuropathy and Neuropathic Pain; Chiari Malformation; Chorea; Chronic Inflammatory Demyelinating Polyneuropathy; Chronic Pain; Chronic Regional Pain Syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital bilateral facial paralysis; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorder; Cushing's syndrome; cytomegalovirus infection; oculofoot chorea; Dandy-Walker syndrome; Dawson's disease; Demosia syndrome; Dezelin-Kronopk's paralysis; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis. Familial autonomic dysfunction; writing disorders; reading disorders; dystonia; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephalocele; trigeminal neuralgia; epilepsy; Oberle's palsy; essential tremor; Fabry disease; Fahr's syndrome; syncope; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich's ataxia; frontotemporal dementia and other "protein diseases"; Gaucher disease; Gostelmann syndrome; giant cell arteritis; giant cell inclusion body disease;Globular cell leukodystrophy; Guillain-Barré syndrome; HTLV-1 related myelopathy; Hastings-Schwarzman syndrome; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; polyneuritis-type hereditary motor ataxia; herpes zoster of the ear; herpes zoster; Hirayama syndrome; HIV-related dementia and neuropathy (also a neurological manifestation of AIDS); holohemorrhagic forebrain malformation; Huntington's disease and other polyglutamine repeat diseases; hydrocephalus; hydrocephalus; Cushing's syndrome; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; pigmentary disorders; infantile phytate storage disease; infantile Rif-Symes disease; infantile spasms; inflammatory myopathy; intracranial cysts; intracranial hypertension; Joubert syndrome; Karns-Sell syndrome; Kennedy's disease; Kingsburn syndrome; Klippel Feil syndrome; Krabby's disease; Kugelberg-Weyland disease; Kuru's disease; Rafael's disease; Lambert-Eton myasthenic syndrome; Landau-Kleffner syndrome; Wallenberg syndrome; learning disability; Lewy's disease; Lennox-Gustaut syndrome; Lesch-Niehan syndrome; leukodystrophy; Lewy body dementia; gyriosis; locked-in syndrome; Lou Griggs disease (i.e., motor neuron disease or amyotrophic lateral sclerosis); lumbar spine Intervertebral disc disease; Lyme disease—neurological sequelae; Machado-Joseph disease; macrocephaly; megalencephaly; Ménière syndrome; Meniere's disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-stroke; mitochondrial myopathy; Murbius syndrome; unilateral muscular atrophy; motor neuron disease; Moyamoya disease; mucopolysaccharidosis; multiple infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; β-muscular dystrophy Symptoms; Myasthenia gravis; Myelinolytic diffuse sclerosis; Early infantile myoclonic encephalopathy; Myoclonus; Myopathy; Congenital myotonia; Somnolence; Neurofibromatosis; Neurodegenerative malignant syndrome; Neurological manifestations of AIDS; Neurological sequelae of lupus; Neurogenic myotonia; Neuronal ceroid lipofuscin deposition syndrome; Neuronal migration disorder; Niemann-Pick disease; O'Sullivan-McLeod syndrome; Occipital neuralgia; Incomplete closure sequence of the occult neural tube; Otahara syndrome; Olivary pontocerebellar atrophy Strabismus myoclonus; Optic neuritis; Orthostatic hypotension; Overuse syndrome; Sensory abnormalities; Parkinson's disease; Congenital paramyotonia; Paraneoplastic disease; Paroxysmal seizures; Parkinson's-Robber syndrome; Peyronie's-Merck disease; Periodic paralysis; Peripheral neuropathy; Painful neuropathy and neuropathic pain; Persistent vegetative state; Pervasive developmental disorder; Photosensitive sneezing reflex; Phytanic acid storage disease; Picker's disease; Nerve compression; Pituitary tumor; Polymyositis; Holter slits; Post-poliomyelitis sequelae; Postherpetic neuralgia;Post-infectious encephalomyelitis; postural hypotension; Predwell syndrome; primary lateral sclerosis; prion disease; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerotic gray matter dystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsey-Hunter syndrome (types I and II); Rasmussen's encephalitis; reflex sympathetic dystrophy syndrome; Rif-Sym disease; repetitive motion disorder; repetitive pressure injury; restless legs syndrome; retrotranscriptase-associated myelopathy; Rett syndrome; Reye's syndrome; St. West chorea; Sankhoff's disease; Sheldr's disease; schizophrenia; optic-septal dysplasia; shaken baby syndrome; herpes zoster; Hedgren's syndrome; Sjögren's syndrome; sleep apnea; Sot O'S syndrome; spasm; spina bifida; spinal cord injury; spinal cord tumor; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; Sidnam's chorea; syncope; syringomyelia; tardive dyskinesia; Tey-Sachs disease; temporal arteritis; tethered cord syndrome; Thomsen's disease; thoracic outlet syndrome; trigeminal neuralgia; Todd's paralysis; Tourette syndrome; transient ischemic attack; infectious cavernous encephalopathy; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraplegia; tuberous sclerosis; vascular dementia (multiple infarct dementia); vasculitis, including temporal arteritis; von Heber-Lindau syndrome (Von Heber-Lindau syndrome) Hippel-Lindau disease); Wallenberg syndrome; Wednisch-Hoffmann disease; West syndrome; whiplash syndrome; Williams syndrome; Wildon's disease; amyotrophic lateral sclerosis (ALS) and Zelweg syndrome.

[0257] In some embodiments, the condition, disease, or disorder is a STING-related condition, such as type I interferon disease (e.g., STING-associated angiopathy with onset in infancy (SAVI)), Aicardi-Goutières syndrome (AGS), genetic forms of lupus, and inflammation-related disorders such as systemic lupus erythematosus and rheumatoid arthritis. In some embodiments, the condition, disease, or disorder is an autoimmune disease (e.g., a cytoplasmic DNA-triggered autoinflammatory disease). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) (a chronic inflammatory disease with polygenic susceptibility). In some embodiments, the condition is inflammatory bowel disease. In some embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapy agents, colitis induced by adoptive cell therapy, colitis associated with one or more alloimmune diseases (such as graft-versus-host disease, e.g., acute graft-versus-host disease and chronic graft-versus-host disease), radiation colitis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In some of these embodiments, the condition is an alloimmune disease (such as graft-versus-host disease, e.g., acute graft-versus-host disease and chronic graft-versus-host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophagitis, or intestinal mucositis).

[0258] In some embodiments, STING provides treatment for diseases (including diseases caused by exogenous factors) through the modulation of the immune system. Exemplary infections caused by exogenous factors that can be treated and / or prevented by the methods of the present invention include bacterial infections (e.g., Gram-positive or Gram-negative bacteria), fungal infections, parasitic infections, and viral infections. In one embodiment of the invention, the infection is a bacterial infection (e.g., infection with Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Staphylococcus aureus, Streptococcus spp., or vancomycin-resistant enterococci) or sepsis. In another embodiment, the infection is a fungal infection (e.g., infection with molds, yeasts, or higher fungi). In yet another embodiment, the infection is a parasitic infection (e.g., infection with single-celled or multi-celled parasites, including Giardia lamblia, Cryptosporidium microsporidium, Cyclospora spp., and Toxoplasma gondii). In yet another embodiment, the infection is a viral infection (e.g., infection with a virus associated with AIDS, avian influenza, chickenpox, cold rash, the common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, lower or upper respiratory tract infection (e.g., respiratory syncytial virus), Ebola, Zika, and SARS-CoV-2 (COVID19).

[0259] In some embodiments, the symptom, disease, or disorder is hepatitis B (see, for example, WO 2015 / 061294).

[0260] In some embodiments, the condition, disease, or disorder is selected from cardiovascular diseases (including, for example, myocardial infarction).

[0261] In some embodiments, the condition, disease, or disorder is age-related macular degeneration.

[0262] In some embodiments, the symptom, disease, or disorder is mucositis, also known as stomatitis, which may occur as a result of chemotherapy or radiotherapy alone or in combination, as well as damage caused by exposure to radiation in addition to the background of radiotherapy.

[0263] In some embodiments, the symptom, disease, or disorder is uveitis, which is an inflammation of the uvea (e.g., anterior uveitis, such as iridocyclitis or iritis; intermediate uveitis (also known as pars plana cyclitis); posterior uveitis; or choroidal retinitis, such as panuveitis).

[0264] In some embodiments, the condition, disease, or disorder is selected from the group consisting of cancer, neurological disorders, autoimmune diseases, hepatitis B, uveitis, cardiovascular diseases, age-related macular degeneration, and mucositis.

[0265] In some embodiments, the condition, disease, or disorder is selected from the group consisting of: familial frostbite-like lupus, RVCL (autosomal dominant retinal vascular disease with leukodystrophy), lupus nephritis (LN), Sjögren's syndrome (SS), pulmonary inflammation, acute pulmonary inflammation, idiopathic pulmonary fibrosis, liver and kidney fibrosis, nonalcoholic steatohepatitis (NASH), cirrhosis, endocardial myocardial fibrosis, acute and chronic kidney injury, APOL1-associated podocyte disease, acute pancreatitis, chronic obstructive pulmonary disease (COPD), aging, and degeneration.

[0266] Other examples may include those indications discussed in this article and below in the envisioned combination therapy regimens.

[0267] Combination therapy

[0268] This disclosure anticipates both monotherapy regimens and combination therapy regimens.

[0269] In some embodiments, the methods described herein may further include administering one or more adjunctive therapies (e.g., one or more adjunctive therapeutic agents and / or one or more treatment regimens) in combination with the administration of the compounds described herein.

[0270] In some embodiments, the methods described herein may further include administering one or more additional cancer therapies.

[0271] This one or more additional cancer therapy may include, but is not limited to, surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, hepatitis B vaccine, Oncophage, Provenge), and gene therapy, as well as combinations thereof. Immunotherapy, including but not limited to adoptive cell therapy, stem cell and / or dendritic cell derivatization, blood transfusion, irrigation, and / or other treatments, including but not limited to cryotherapy of tumors.

[0272] In some embodiments, the one or more additional cancer treatments are chemotherapy, which may include the administration of one or more additional chemotherapeutic agents.

[0273] In some embodiments, the additional chemotherapeutic agent is an immunomodulatory component, such as an immune checkpoint inhibitor. In some of these embodiments, the immune checkpoint inhibitor targets immune checkpoint receptors selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1–PD-L1, PD-1–PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T-cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galactoglobulin 9–TIM3, phosphatidylserine–TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II–LAG3, 4-1BB–4-1BB ligand, OX40–OX40 ligand, GITR, GITR ligand– GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25–TL1A, CD40L, CD40–CD40 ligand, HVEM–LIGHT–LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM–BTLA–CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2–TMIGD2, prolactin including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86- CD28, CD86 – CTLA, CD80 – CD28, CD39, CD73 adenosine – CD39 – CD73, CXCR4 – CXCL12, phosphatidylserine, TIM3, phosphatidylserine – TIM3, SIRPA – CD47, VEGF, neurociliacin, CD160, CD30, and CD155; e.g., CTLA-4 or PD1 or PD-L1). See, for example, Postow, MJ Clin. Oncol. [Journal of Clinical Oncology] 2015, 33, 1.

[0274] In some of these embodiments, the immune checkpoint inhibitors are selected from the group consisting of: urorelizumab, PF-05082566, MEDI6469, TRX518, variruzumab, CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-L1), averuzumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, lirelizumab, IPH2201, imetuzumab, INCB024360, galunisertib, urorelizumab, BKT140, bavitimab, CC-90002, bevacizumab, and MNRP1685A and MGA271.

[0275] In some embodiments, the additional chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because of their ability to alkylate numerous nucleophilic functional groups under conditions present in cells, including but not limited to cancer cells. In other embodiments, alkylating agents include, but are not limited to, cisplatin, carboplatin, nitrogen mustard, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin. In embodiments, alkylating agents may act by impairing cellular function through covalent bonding with amino, carboxyl, thiol, and phosphate groups in biologically important molecules, or they may act by modifying the cell's DNA. In other embodiments, the alkylating agent is synthetic, semi-synthetic, or a derivative.

[0276] In some embodiments, the additional chemotherapeutic agent is antimetabolites. Antimetabolites masquerade as purines or pyrimidines (building blocks of DNA) and typically prevent these substances from being incorporated into DNA during the "S" phase (of the cell cycle), thus inhibiting normal development and division. Antimetabolites can also affect RNA synthesis. In embodiments, antimetabolites include, but are not limited to, azathioprine and / or mercaptopurine. In other embodiments, antimetabolites are synthetic, semi-synthetic, or derivatives.

[0277] In some embodiments, additional chemotherapeutic agents are plant alkaloids and / or terpenoids. These alkaloids are derived from plants and typically block cell division by inhibiting microtubule function. In embodiments, plant alkaloids and / or terpenoids are vinca alkaloids, podophyllotoxin, and / or taxanes. Vinca alkaloids typically bind to specific sites on tubulin, inhibiting tubulin assembly into microtubules, typically during the M phase of the cell cycle. In embodiments, vinca alkaloids are derived from, but not limited to, Madagascar periwinkle (Catharanthus roseus) (formerly known as Vincarosea). In embodiments, vinca alkaloids include, but are not limited to, vincristine, vinblastine, vinorelbine, and / or vindesine. In embodiments, taxanes include, but are not limited to, paclitaxel, taxol, and / or docetaxel. In other embodiments, plant alkaloids or terpenoids are synthetic, semi-synthetic, or derivatives. In other embodiments, podophyllotoxin is, but is not limited to, etoposide and / or teniposide. In the embodiments, taxane is, but not limited to, docetaxel and / or oxaliplatin.

[021] In the embodiments, the cancer therapeutic agent is a topoisomerase. Topoisomerases are essential enzymes for maintaining the topological structure of DNA. Inhibition of type I or type II topoisomerases interferes with both DNA transcription and replication by disrupting the proper supercoiling of DNA. In other embodiments, the topoisomerase is, but not limited to, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In the embodiments, a type I topoisomerase inhibitor is, but not limited to, camptothecin. In another embodiment, camptothecin is, but not limited to, ixotecan, irinotecan, letopotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67), and / or ST1481. In the embodiments, a type II topoisomerase inhibitor is, but not limited to, epipodophyllotoxin. In other embodiments, epipodophyllotoxin is, but not limited to, acridine, etoposid, etoposide phosphate, and / or teniposide. In another embodiment, the topoisomerase is synthetic, semi-synthetic, or a derivative, including those found in nature, such as, but not limited to, epipodophyllotoxin, a substance naturally occurring in the roots of Podophyllum peltatum.

[0278] In some embodiments, the additional chemotherapeutic agent is a dicarboxylic acid derivative. In other embodiments, the dicarboxylic acid derivative includes, but is not limited to, resveratrol, paclitaxel, pinocembrin, pterostilbene, α-glucan, scutellarin A, scutellarin E, diptoindonesin C, diptoindonesin F, ε-glucan, Flexuosol A, Gnetin H, Hemsleyanol D, Hopeaphenol, trans-Diptoindonesin B, astringin, spruce glycoside, and diptoindonesin A. In other embodiments, the dicarboxylic acid derivative is synthetic, semi-synthetic, or a derivative.

[0279] In some embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. In embodiments, the cytotoxic antibiotic is, but is not limited to, actinomycin, anthraquinone, anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and / or chlorophenazine. In embodiments, actinomycin is, but is not limited to, actinomycin D, bacitracin, colistin (polymyxin E), and / or polymyxin B. In another embodiment, anthraquinone is, but is not limited to, mitoxantrone and / or pifrazanol. In another embodiment, anthracycline is, but is not limited to, bleomycin, doxorubicin (adriamycin), daunorubicin (daunorubicin), epirubicin, idarubicin, mitomycin, procainomycin, and / or penoxorubicin. In another embodiment, the cytotoxic antibiotic is synthetic, semi-synthetic, or a derivative.

[0280] In some embodiments, additional chemotherapeutic agents are selected from endostatin, angiopoietin, angiostatin, chemokines, angioarrestin, angiostatin (plasminogen fragment), basement membrane collagen-derived anti-angiogenic factors (tumor stomatitis, angiostatin, or inhibitory proteins), anti-angiogenic antithrombin III, signal transduction inhibitors, chondroitin derivatives (CDI), CD59 complement fragment, fibronectin fragment, gro-β, heparinase, heparin hexose fragment, human chorionic gonadotropin (hCG), interferon α / β / γ, interferon-induced protein (IP-10), interleukin-12, kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs), 2-methoxyestradiol, placental ribonuclease inhibitors, plasminogen activator inhibitors, platelet factor-4 (PF4), and prolactin-16. kD fragments, proliferation protein-related protein (PRP), various retinoids, tetrahydrocortisol-S, platelet-reactive protein-1 (TSP-1), transforming growth factor-β (TGF-β), vasculostatin, angiogenesis inhibin (calreticulin fragment), etc.

[0281] In some embodiments, additional chemotherapeutic agents are selected from abiraterone acetate, hexamethylmelamine, vinblastine, orlistatin, besalodin, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, N,N-dimethyl-L-valine-L-valine-N-methyl-L-valine-L-prolyl-1-L-proline-tert-butyramide, cachexia, cemadotin, chlorambucil, cyclophosphamide, 3′,4′-disodehydro-4′-deoxy-8′-norvincine ditartrate, docetaxel, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, candidone, cyclophosphamide Amines, Cytarabine, Dacarbazine (DTIC), Dermatomycin, Doxorubicin, Decitabine, Tail-sea harein, Doxorubicin (Axorubicin), Etoposide, 5-Fluorouracil, Finasteride, Flutamide, Hydroxyurea and Hydroxyurea Taxane, Ifosfamide, Liarozole, Lonidamine, Lomustine (CCNU), MDV3100, Dichloromethyldiethylamine (Nitrogen Mustard), Melphalan, Mivobulin (Hydroxyethylsulfonic acid) Isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxane, nilumethicone, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, retinoic acid, vinblastine, vincristine, vindesine sulfate, and vinflunine.

[0282] In some embodiments, additional chemotherapeutic agents include platinum, cisplatin, carboplatin, oxaliplatin, nitrogen mustard, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinorelbine, vindesin, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, acridine, etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide, and doxorubicin. Other agents include inhibitors of mTOR (the mammalian target of rapamycin), including but not limited to rapamycin, everolimus, tesimolimus, and deforolimus.

[0283] In other embodiments, additional chemotherapeutic agents may be selected from those described in U.S. Patent 7,927,613, which is incorporated herein by reference in its entirety.

[0284] In some embodiments, additional therapeutic agents and / or regimens are those that can be used to treat other STING-related conditions, such as type I interferon diseases (e.g., STING-associated vascular disease with onset in infancy (SAVI)), Aicardi-Goutières syndrome (AGS), genetic forms of lupus, and inflammatory disorders such as systemic lupus erythematosus and rheumatoid arthritis).

[0285] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of rheumatoid arthritis include nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), disease-modifying antirheumatic drugs (DMARDs; e.g., methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), leflunomide (Arava®), hydroxychloroquine (Plaquenil), PF-06650833, iguratimod, tofacitinib (Xeljanz®), ABB V-599, evatinib and sulfasalazine (Azulfidine®) and biologics (e.g., abatacept (Orencia®), adalimumab (Humira®), anaspirin (Kineret®), cetozumab (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), infliximab (Remicade®), rituximab (Rituxan®), tocilizumab (Actemra®), vobalizumab, salivalurumb (Kevzara®), secukinumab, ABP 501, CHS-0214, ABC-3373 and tocilizumab (ACTEMRA®)).

[0286] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of lupus include steroids, topical immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), thalidomide (Thalomid®), nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., hydroxychloroquine (Plaquenil)), corticosteroids (e.g., prednisone) and immunomodulators (e.g., evatinib, iberdomide, voclosporin, cenerimod, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®) and cyclosporine (Neoral, Sandimmune®, Gengraf® and mycophenolate mofetil), baricitinib, ellamod, and felotinib. Filogotinib, GS-9876, rapamycin, and PF-06650833) and biologics (e.g., Benlysta®, anifrolumab, prezalumab, MEDI0700, obinutuzumab, vobarilizumab, lulizumab, atacicept, PF-06823859 and lupizior, rituximab, BT063, BI655064, BIIB059, interleukin®, dapirizumab, erythritol, IFN-α-kinoid, OMS721, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab®).For example, non-restricted treatments for systemic lupus erythematosus include nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., hydroxychloroquine (Plaquenil)), corticosteroids (e.g., prednisone), and immunomodulators (e.g., iberdomide, voclosporin, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), as well as mycophenolate mofetil, baricitinib, filogotinib, and PF-06650833) and biological agents. Formulations (e.g., Benlysta®, anifrolumab, prezalumab, MEDI0700, vobarilizumab, lulizumab, atacicept, PF-06823859, lupizier, rituximab, BT063, BI655064, BIIB059, interleukin®, dapirizumab, erythritol, IFN-α-kinoid, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab (Stelara®)). As another example, non-limiting examples for the treatment of cutaneous lupus include steroids, immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), GS-9876, filogotinib, and thalidomide (Thalomid®). Medications and regimens for the treatment of drug-induced and / or neonatal lupus may also be administered.

[0287] Non-limiting examples of other therapeutic agents and / or regimens for treating STING-associated vascular lesions (SAVI) that occur in infancy include JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[0288] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of Aicardi-Goutières syndrome (AGS) include physical therapy, treatment of respiratory complications, anticonvulsant therapy for seizures, tube feeding, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine (e.g., Emtriva®), tenofovir (e.g., Viread®), emtricitabine / tenofovir (e.g., Truvada®), zidovudine, lamivudine, and abacavir) and JAK inhibitors (e.g., tofacitinib, ruxolitinib, filogrinib, and baricitinib).

[0289] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of IBD include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, amluzumab, apremilast, ATR-107 (PF0530900), autologous CD34-selective peripheral blood stem cell transplantation, azathioprine, bertilimumab, BI655066, BMS-936557, cetozumab (Cimzia®), cobitolimod, corticosteroids (e.g., prednisone, methylprednisolone, prednisone), CP-690 550, CT-P13, Cyclosporine, DIMS0150, E6007, E6011, etrasimod, etradictrine, fecal microbiota transplantation, filogrinib, fingolimod, filtrates (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, gusecucurbita, golimumab, GSK1399686, HMPL-004 (Andrographis paniculata extract), IMU-838, infliximab, interleukin-2 (IL-2), Janus kinase (JAK) inhibitor, laquimod, masatitinib (AB1010), matrix metalloproteinase 9 (MMP) 9) Inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mijirubumab (LY3074828), natezumab, NNC 0142-0000-0002, NNC0114-0006, ozamod, peftitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin, irizorubumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tilatizumab (MK 3222), TJ301, TNF-Kinoid®, tofacitinib, trorolurumab, TRK-170, utpatinib, ustekinumab, UTTR1147A, V565, valerate, VB-201, vedozimab, and vidofludimus.

[0290] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of irritable bowel syndrome include alosetron, bile acid sequestrants (e.g., cholestyramine, colestipol, colesvelin), chloride channel activators (e.g., lubiprostone), peppermint oil-coated capsules, desipramine, bicyclic amine, ebastine, iludolin, farnesol X receptor agonists (e.g., obeticholic acid), fecal microbiota transplantation, fluoxetine, gabapentin, guanylate cyclase-C agonists (e.g., linaclotide, purcanatide), epoderm, imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, ondansetron, opioids, paroxetine, pinavel, polyethylene glycol, pregabalin, probiotics, ramosetron, rifaximin, and tanananor.

[0291] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of scleroderma include nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), immunomodulators (e.g., azathioprine, methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Ge (ngraf®), anti-thymocyte globulin, mycophenolate mofetil, intravenous immunoglobulin, rituximab, sirolimus, and afaxicept), calcium channel blockers (e.g., nifedipine), alpha blockers, serotonin receptor antagonists, angiotensin II receptor inhibitors, statins, topical nitrates, iloprost, phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan, tetracycline antibiotics, endothelin receptor antagonists, prostaglandin derivatives, and tyrosine kinase inhibitors (e.g., imatinib, nilotinib, and dasatinib).

[0292] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of Crohn's disease (CD) include adalimumab, autologous CD34-selective peripheral blood stem cell transplantation, 6-mercaptopurine, azathioprine, pegylated cetrusuzumab (Cimzia®), corticosteroids (e.g., prednisone), etrazilizumab, E6011, fecal microbiota transplantation, filogrinib, gusekumab, infliximab, IL-2, JAK inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, natezilizumab, ozamod, RHB-104, rifaximin, levozizumab, SHP647, sulfasalazine, thalidomide, utpatinib, V565, and vedolizumab.

[0293] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of UC include AbGn-168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, bertilimumab, brecurumab (MEDI2070), cobitolimod, pegylated cerutuzumab (Cimzia®), CP-690, 550, and corticosteroids (e.g., multimax budesonide). Budesonide, methylprednisolone, cyclosporine, E6007, etrasimod, etracilzumab, fecal microbiota transplantation, filogrinib, gusekumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mesalamine, mijizumab (LY3074828), RPC1063, lijizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tetrajizumab (MK 3222), tofacitinib, tofacitinib, ustekinumab, UTTR1147A, and vedolizumab.

[0294] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, for example, U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0295] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of iatrogenic autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, TIP60 inhibitors (see, for example, U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0296] Non-limiting examples of other therapeutic agents and / or regimens for treating colitis induced by one or more chemotherapy agents include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, for example, U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0297] Non-limiting examples of other therapeutic agents and / or regimens for treating colitis induced by adoptive cell therapy include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, TIP60 inhibitors (see, for example, U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0298] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of colitis associated with one or more alloimmune diseases include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), sulfasalazine, and eicopentaenoic acid.

[0299] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of radiation enteritis include teduglutide, amifostine, angiotensin-converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moxipril, perindopril, quinapril, ramipril, and qundolipril), probiotics, selenium supplements, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin), sucralfate, and vitamin E.

[0300] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of collagenous colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia carterii extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0301] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of lymphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), loperamide, mesalamine, methotrexate, and sulfasalazine.

[0302] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of microscopic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia carterii extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), fecal microbiota transplantation, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0303] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of alloimmune diseases include intrauterine platelet transfusion, intravenous immunoglobulin, maternal steroids, abatacept, alenzab, α1-antitrypsin, AMG592, antithymocyte globulin, barcitinib, baliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defibrinolytic acid, and denileukin. diftitox), glasdegib, ibrutinib, IL-2, infliximab, itatinib, LBH589, maraviro, mycophenolate mofetil, natezumab, neihulizumab, pentostatin, pevonedistat, photobiological regulation, photodisplacement, ruxolitinib, sirolimus, sonidigi, tacrolimus, tocilizumab, and vemodigi.

[0304] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of multiple sclerosis (MS) include alemtuzumab (Lemtrada®), ALKS 8700, amiloride, ATX-MS-1467, azathioprine, baclofen (Lioresal®), interferon-β (e.g., IFN-β-1a, IFN-β-1b), clatrabine, corticosteroids (e.g., methylprednisolone), daklizumab, dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), fluoxetine, glatiramer acetate (Copaxone®), hydroxychloroquine, ibuprofen, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (Biotin), mitoxantrone, montelukast, natezumab (Tysabri®), NeuroVax TM Orizumab, ofamumab, pioglitazone and RPC1063.

[0305] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of graft-versus-host disease include abatacept, alemtuzumab, α1-antitrypsin, AMG592, antithymocyte globulin, barcitinib, baliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defibrinolytic acid, and denileukin. diftitox), glasdegib, ibrutinib, IL-2, imatinib, infliximab, itatinib, LBH589, maraviro, mycophenolate mofetil, natezumab, neihulizumab, pentostatin, pevonedistat, photobiological regulation, photodisplacement, ruxolitinib, sirolimus, sonidigi, tacrolimus, tocilizumab, and vemodigi.

[0306] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of acute graft-versus-host disease include alemtuzumab, alpha-1 antitrypsin, antithymocyte globulin, baliximab, bortezomib, brentuximab, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defibrinolytic acid, denileukin diftitox, ibrutinib, infliximab, itatinib, LBH589, mycophenolate mofetil, nitrazepam, neihulizumab, pentostatin, photodisplacement therapy, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.

[0307] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of chronic graft-versus-host disease include abatacept, alemtuzumab, AMG592, anti-thymocyte globulin, baliximab, bortezomib, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, denileukindiftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiological modulation, photodisplacement, ruxolitinib, sirolimus, sonidigi, tacrolimus, tocilizumab, and vemodigi.

[0308] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of celiac disease include AMG 714, AMY01, Aspergillus niger proline endopeptidase, BL-7010, CALY-002, GBR 830, Hu-Mik-β-1, IMGX003, KumaMax, larizolide acetate, Nexvan2®, pancreatic lipase, TIMP-GLIA, vedozizumab, and ZED1227.

[0309] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of psoriasis include topical corticosteroids, topical criborrox / AN2728, topical SNA-120, topical SAN021, topical benzylmod, topical tocafinib, topical IDP-118, topical M518101, topical calcipotriol and betamethasone dipropionate (e.g., MC2-01 cream and Taclonex®), topical P-3073, and topical LEO. 90100 (Enstilar®), topical betamethasone dipropionate (Sernivo®), ultraverate®, vitamin D analogs (e.g., calcipotriol (Dovonex® and calcitriol (Vectical®)), dithranol (e.g., Dritho-scalp® and Dritho-crème®), topical retinoids (e.g., tazarotene (e.g., Tazorac® and Avage®)), calcineurin inhibitors (e.g., tacrolimus (Prograf® and pimecrolimus (Elidel®)), salicylic acid, coal tar, humectants, phototherapy (e.g., sun exposure, UVB phototherapy, narrowband UVB phototherapy, Gökman therapy, psoralen plus UVA). (PUVA) therapy and excimer laser), retinoids (e.g., atratin (Soriatane®)), methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), Apo805K1, baricitinib, FP187, KD025, prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (slopitan), utpatinib (ABT-494), aprmilast, tofacitinib, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biologics (e.g.,Enbrel®, Elrezi® (Etanercept-szzs), Remicade® (Infliximab), Humira® (Adalimumab), Cyltezo® (Adalimumab-adbm), Stelara® (Ustekinumab), Simponi® (Golimumab), Otezla® (Apremilast), Cosentyx® (Secukinumab), Certolixumab pegol (Pegylated Pegol), Secukinumab, Temstrol-asmn (Tetragergizumab), DYYB (Infliximab), Abatacept, Taltz® (Ikezumab), ABP 710, BCD-057, BI695501, Bimecrolimus (UCB4940), CHS-1420, GP2017, Gusekumab (CNS) 1959), HD203, M923, MSB11022, migelizumab (LY3074828), PF-06410293, PF-06438179, ligelizumab (BI655066), SB2, SB4, SB5, siliq (brolimumab), namexizumab (MT203, tetragelizumab (MK-3222) and ixekizumab (Taltz®)), thioguanine and hydroxyurea (e.g., Droxia® and Hydrea®).

[0310] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of cutaneous T-cell lymphoma include phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow-band UVB phototherapy, Gökman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photodynamic therapy, radiotherapy (e.g., spot radiation and whole-body electron beam therapy), stem cell transplantation, corticosteroids, imiquimod, besalodine gel, topical dichloroethyl-nitrourea, nitrogen mustard gel, vorinostat (Zolinza®), romedixin (Istodax®), pralatrexate (Folotyn®), and biologics (e.g., alemtuzumab (Campath®), bentuximab (SGN-35), mogamulizumab (mogamulizumab), and IPH4102).

[0311] Non-limiting examples of other therapeutic agents and / or regimens for the treatment of uveitis include corticosteroids (e.g., intravitreal triamcinolone acetonide injection suspension), antibiotics, antiviral drugs (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide (Cytoxan®, Neosar®, Endoxan®) and cyclosporine (Neoral®, Sandimmune®, Gengraf®), chlorambucil, azathioprine, methotrexate and mycophenolate mofetil), biologics (e.g., infliximab (Remicade®), adalimumab (Humira®), etanercept (Enbrel®), golimumab (Simpon) i®, Cimzia®, Rituxan®, Orencia®, Simulect®, Kinetet®, Ilaris®, Gevokixumab (XOMA052), Actemra®, Camppath®, Raptiva®, LFG316, Santen®, Abatacept, Kevzara®, and Zenapax®, cytotoxic drugs, surgical implants (e.g., fluocinolone acetonide inserts), and vitrectomy.

[0312] Non-limiting examples of other therapeutic agents and / or regimens for treating mucositis include AG013, SGX942 (duseklimide), amifostine (Ethyol®), cryotherapy, cepacol lonzenges, capsaicin tablets, mucosal adhesives (e.g., MuGard®), oral diphenhydramine (e.g., Benadry® elixir), oral bioadhesives (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), and oral lubricants (e.g., oral...). Balance®, caphosol, chamomile mouthwash, edible grape plant exosomes, antibacterial mouthwashes (e.g., chlorhexidine gluconate (e.g., Peridex® or Periodard®), topical analgesics (e.g., lidocaine, benzocaine, dacronine hydrochloride, lidocaine (e.g., viscous lidocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, parivmin (keratinocyte growth factor; Kepivance®). ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble β-1,3 / 1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, granules containing blueberry extract, borage alkaloids and echinacea angustifolia extract (e.g., SAMITAL®) and gastrointestinal mixtures (acid reducing agents such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungal agents (e.g., nystatin) and analgesics (e.g., Hurricane Liquid)).For example, non-limiting examples for the treatment of oral mucositis include AG013, amifostine (Ethyol®), cryotherapy, cepacol lonzenges, mucosal adhesives (e.g., MuGard®), oral diphenhydramine (e.g., Benadry® elixir), oral bioadhesives (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), and oral lubricants (e.g., oral...). Balance®, caphosol, chamomile mouthwash, edible grape plant exosomes, antibacterial mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periodard®), topical analgesics (e.g., lidocaine, benzocaine, dapoxetine hydrochloride, lidocaine (e.g., viscous lidocaine 2%) and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen, naproxen, acetaminophen and opioids), GC4419, parivmin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin Soluble β-1,3 / 1,6-glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, and gastrointestinal mixtures (acid reducing agents, such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungal agents (e.g., nystatin), and analgesics (e.g., Hurricane Liquid)). As another example, non-limiting examples for the treatment of esophagitis include lidocaine (e.g., gel-viscous lidocaine 2%). As another example, treatment for the treatment of intestinal mucositis, treatment for improving intestinal mucositis, and treatment for the signs and symptoms of intestinal mucositis include gastrointestinal mixtures (acid reducing agents, such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungal agents (e.g., nystatin), and analgesics (e.g., Hurricane Liquid)).

[0313] In some embodiments, a second therapeutic agent or regimen is administered to the subject prior to contact with or application of the chemical entity (e.g., approximately 1 hour, 6 hours, 12 hours, 24 hours, 48 ​​hours, 1 week, or 1 month prior).

[0314] In other embodiments, the second therapeutic agent or regimen is administered to the subject approximately simultaneously with contact with or application of the chemical entity. As an example, the second therapeutic agent or regimen and the chemical entity are administered to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are administered to the subject simultaneously in separate dosage forms.

[0315] In other embodiments, the second therapeutic agent or regimen is administered to the subject after contact with or application of the chemical entity (e.g., about 1 hour, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 1 week, or about 1 month thereafter).

[0316] Patient selection

[0317] In some embodiments, the methods described herein further include the step of identifying subjects (e.g., patients) who require such treatment (e.g., by biopsy, endoscopy, or other conventional methods known in the art). In some embodiments, the STING protein can be used as a biomarker for certain types of cancer, such as colon and prostate cancer. In other embodiments, identifying subjects may include determining the absence of T cells and / or the presence of exhausted T cells in a patient's tumor microenvironment, for example, a patient with one or more cold tumors. Such patients may include those resistant to treatment with checkpoint inhibitors. In some embodiments, such patients may be treated with the chemical entities described herein, for example, to recruit T cells to the tumor, and in some cases, further treated with one or more checkpoint inhibitors, for example, once the T cells become exhausted.

[0318] In some embodiments, the chemical entities, methods, and compositions described herein may be applied to certain refractory patient populations (e.g., patients resistant to checkpoint inhibitors; e.g., patients with one or more cold tumors (e.g., tumors lacking T cells or exhausted T cells)).

[0319] Compound preparation

[0320] As will be apparent to those skilled in the art, the methods for synthesizing compounds having the formula herein will be obvious to those skilled in the art. The synthetic chemical transformations and protecting group methods (protection and deprotection) used to synthesize the compounds described herein are known in the art and include, for example, methods described in the following literature: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The starting materials used in the preparation of the compounds of the present invention are known, prepared by known methods, or commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein are interchangeable with alternative equivalents recognized in the art. For example, in many reactions, triethylamine can be interchanged with other bases, such as non-nucleophilic bases (e.g., diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

[0321] Those skilled in the art will recognize that a variety of analytical methods can be used to characterize the compounds described herein, including, for example... 1 ¹H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of characterization methods available to those skilled in the art and is not intended to be limiting.

[0322] To further illustrate the foregoing, the following non-limiting exemplary synthetic methods are included. Variations of these examples within the scope of the claims are within the capabilities of those skilled in the art and are considered to fall within the scope of the invention as described and claimed herein. The reader will recognize that those skilled in the art, possessing the knowledge of this disclosure, can prepare and use the invention without exhaustive examples. Example

[0323] Example 1: Compound 101

[0324]

[0325] In this reaction, aryl bromides and propargyl amides are used in equal amounts, or in excess, one of these compounds. The mixture of these compounds is stirred under cooling or heating to reflux, preferably at room temperature to 190°C, in the presence of a catalyst, a co-catalyst, and a base, in a solvent inactive to the reaction, or in the absence of a solvent, typically for 0.1 hours to 5 days. Examples of catalysts used herein include, but are not limited to, Pd(PPh3)4, PdCh(PPh3)2, PdCh(dppf) / CH2Ch, Pd2(dba)3, Pd(OAc)2, and combinations thereof. Examples of co-catalysts used herein include, but are not limited to, Cul. Examples of bases include, but are not limited to, DBU, Et3N, and DIPEA. Examples of solvents include, but are not limited to, ethers such as THF, 2-methyltetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, CH3CN, NMP, DMF, DMSO, and mixtures thereof. In some cases, it may be advantageous to carry out the reaction in the presence of sodium iodide to facilitate its progress. The reaction can be carried out under microwave radiation.

[0326] The analogues prepared in the following table were prepared using the same method described for Example 1.

[0327] Table A

[0328]

[0329] Example 2: Compound 122

[0330] Step 1

[0331]

[0332] Aliphatic aldehydes can be converted to alkynes using the ohira-Bestmann reagent in the presence of protic solvents (such as methanol) or polar solvents (such as DMF, DMP, etc.), in the presence of inorganic bases (such as K2CO3, Na2CO3, etc.), or in organic bases (such as, but not limited to, DBU, Et3N, and DIPEA). (See, for example, J. Org. Chem. 2014, 79, 19, 9423–9426).

[0333]

[0334] This is the procedure for preparing alkanonic acids by reacting alkyne compounds with carbon dioxide. The reaction is carried out first by using an alkyne and an organolithium reagent in a solvent inactive to the reaction, under cooling or at room temperature, to obtain a lithium acetylenide intermediate. The lithium acetylenide intermediate is then added to excess dry ice under cooling or at room temperature to obtain the alkanonic acid. The entire reaction typically takes from 0.1 hours to 1 day. Examples of organolithium reagents include, but are not limited to, n-butyllithium, tert-butyllithium, and diisopropylaminolithium. Examples of solvents include, but are not limited to, hydrocarbons such as n-hexane or n-pentane, and ethers such as THF or 1,4-dioxane.

[0335]

[0336] This is the procedure for preparing the final compound (I) by reacting an alkanic acid with an amine. In this reaction, the alkanic acid and amine compounds are used in equal amounts, or in excess. The mixture of these compounds is stirred under cooling or heating to reflux, preferably at room temperature to 100°C, in the presence of a condensing agent and a base, in a solvent inactive to the reaction, or in the absence of a solvent, typically for 0.1 hours to 5 days. Examples of condensing agents include, but are not limited to, T3P (registered trademark), HATU, EDC, EDC·HCl, COMU, 2-chloro-1-methylpyridinium iodide, etc. Examples of bases include, but are not limited to, Et3N and DIPEA. Examples of solvents include, but are not limited to, ethers such as THF, 2-methyltetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, halogenated hydrocarbons such as CH2Ch and CHCh, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. In some cases, it may be advantageous to carry out the reaction in the presence of HOBt to facilitate its progress.

[0337] This step can also be performed by using a chlorinating agent as a condensing agent.

[0338] The reaction is carried out first by obtaining an acyl chloride intermediate using an alkanic acid and a chlorinating agent in a solvent inactive to the reaction, or in the absence of a solvent, under cooling or heating to reflux, preferably at 0°C to room temperature. The acyl chloride intermediate is then added to a mixture of a base and an amine in a solvent inactive to the reaction, under cooling or heating to reflux, preferably at 0°C to room temperature. The entire reaction typically takes place from 0.1 hours to 1 day. Examples of chlorinating agents include, but are not limited to, (COCl)₂, phosphoryl chloride (POCb), and thionyl chloride (SOCh). Examples of bases include, but are not limited to, Na₂CO₃, NaHCO₃, K₂CO₃, Et₃N, DIPEA, and pyridine.

[0339] Examples of solvents include, but are not limited to, haloalkanes such as CH₂Cl₂ or CHCl₃, and ethers such as THF or 1,4-dioxane. Water may be added as a co-solvent.

[0340] The analogues prepared in the following table were prepared using the same method described for Example 2.

[0341] .

Claims

1. A compound of formula (I): Formula I Or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: Ring A can be selected from the following groups: •C 3-10 cycloalkyl or C 3-10 Cycloalkenyl; • Heterocyclic groups or heterocyclic alkenyl groups with 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently chosen from N, N(H), N(R). d ), O and S(O) 0-2 The group consists of R d Choose from the following groups: C 1-4 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4 Alkoxy groups, wherein each occurrence of R' and R'' is independently selected from the group consisting of H and C. 1-4 alkyl; • A heteroaryl group with 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently chosen from N, N(H), and N(R). d ), O and S(O) 0-2 The group consists of R d Choose from the following groups: C 1-4 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4 Alkoxy groups, wherein each occurrence of R' and R'' is independently selected from the group consisting of H and C. 1-4 Alkyl groups; and •C 6-10 Aryl; Ring B can be selected from the following groups: •C 3-10 cycloalkyl or C 3-10 Cycloalkenyl; • Heterocyclic groups or heterocyclic alkenyl groups with 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently chosen from N, N(H), N(R). d ), O and S(O) 0-2 The group consists of R d Choose from the following groups: C 1-4 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4 Alkoxy groups, wherein each occurrence of R' and R'' is independently selected from the group consisting of H and C. 1-4 alkyl; • A heteroaryl group with 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently chosen from N, N(H), and N(R). d ), O and S(O) 0-2 The group consists of R d Choose from the following groups: C 1-4 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 Alkyl); -OH; and C 1-4 Alkoxy groups, wherein each occurrence of R' and R'' is independently selected from the group consisting of H and C. 1-4 Alkyl groups; and •C 6-10 Aryl; or Rings A, B, and L together form a tricyclic fused aromatic or heterocyclic ring system; R a1 and R a2 H independently, C optionally substituted 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Alkylene-C 2-6 alkenyl, -OC 1-6 Alkylene-C 2-6 Alkyne, halogen, halogenated -C 1-6 Alkyl, -O-halogen-C 1-6 Alkyl, (OH)-halogenated-C 1-6 Alkyl, -OH, -NHC(O)(C 1-4 Alkyl), C3-C6 cycloalkyl, phenyl, oxoyl, CN, CONR 1 R 2 SO2NR 1 R 2 S(O)(NH)NR 1 R 2 NR-CO-NR 1 R 2 ,NRSO2NR 1 R 2 Where R is H or C 1-4 Alkyl; or R a1 and R a2 Together with the ring atoms to which they are attached, they form C3-C6 cycloalkyl groups or 4- to 7-membered saturated heterocyclic groups; R b1 and R b2 H and C independently 1-6 Alkyl, -OC 1-6 Alkyl, Halogenated -C 1-6 Alkyl, -O-halogen-C 1-6 Alkyl, (OH)-halogenated-C 1-6 Alkyl, halogen, -C 1-6 alkylene -OH, -C 1-6 Alkylene-NR c R d -C(=O)-NR c R d -NR c R d -CN or -OH, C3-C6 cycloalkyl, phenyl, oxo group, SO2NR 1 R 2 S(O)(NH)NR 1 R 2 NR-CO-NR 1 R 2 NRSO2 NR 1 R 2 Where R is H or C 1-4 Alkyl; or R b1 and R b2 Together with the ring atoms to which they are attached, they form C3-C6 cycloalkyl groups or 4- to 7-membered saturated heterocyclic groups; R c and R d H and C independently 1-6 Alkyl, C 3-8 Cycloalkyl, -C(=O)-C 1-6 Alkyl group, or -S(=O)2-C 1-6 Alkyl, or, R c and R d They can be optionally connected to each other to communicate with R. c and R d The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be surrounded by one or two R atoms. e replace; R e It is C 1-6 Alkyl, -OC 1-6 Alkyl or halogen; R 1 H, or C which can be substituted. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 4- to 7-membered saturated heterocyclic groups, optionally substituted phenyl groups, or optionally substituted heteroaryl groups; R 2 Is it by one or two Rs 3 Replacement C 1-6 Alkyl group, with one or two R 4 Replacement C 3-8 cycloalkyl, with one or two R 5 The substituted 4- to 7-membered saturated heterocyclic group, or the group replaced by one or two R groups. 6 Substituted phenyl; or R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be fused with a phenyl or a 5- to 6-membered heteroaryl group, and the heterocyclic group and / or the fused phenyl group may optionally be surrounded by one to three R groups. 7 replace; Each R 3 Independently -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C) 1-6 Alkyl group 2, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkylene -OH, -NH-S(=O)2-C 1-6 Alkylenes -C(=O)-OH, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, C3-C6 cycloalkyl, or -S(=O)(=NH)-C 1-6 alkyl; Each R 4 Independently -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C) 1-6 Alkyl group 2, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, or C3-C6 cycloalkyl, -S(=O)(=NH)-C 1-6 alkyl; Each R 5 It can be -OH, oxo group, or imino group independently; Each R 6 Independently, it is a halogenated group, -C(=O)-OH, -S(=O)2-NH2, or -S(=O)2-C 1-6 Alkyl group, -S(=O)(=NH)-C 1-6 Alkyl, C3-C6 cycloalkyl, or -NH-S(=O)2-C 1-6 alkyl; Each R 7 Independently, it is a halogenated group, C 1-6 Alkyl, -C 1-6 Alkylene-OH, Halogenated-C 1-6 Alkyl, -C 1-6 alkylene-C(=O)-OH, C 3-8 cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)(=NH)-C 1-6 Alkyl, -C(=O)-OH, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C) 1-6 Alkyl group, oxo group, imino group, -C 1-6 Alkylene-C3-C6 cycloalkyl, C3-C6 cycloalkyl, phenyl, or optionally C 1-6 Alkyl groups or 4- to 7-membered saturated heterocyclic groups substituted with one or two oxo groups; and, L represents -O-, -S-, -NH-, -N(C) 1-6 Alkyl group, -S(=O)2-, -C(=O)-, -NH-C(=O)-, -C(=O)NH-, C 1-6 Alkylene, -NHSO2-, -SO2NH-, -NHS(O)NR)-, -NRS(O)NH)-, -OC 1-6 alkylene, or C 1-6 Alkylene-O-.

2. The compound or a salt thereof according to claim 1, wherein, L is -O-.

3. The compound or a salt thereof according to claim 1, wherein, L is -S-.

4. The compound or a salt thereof according to claim 1, wherein, L stands for -NH-.

5. The compound or a salt thereof according to claim 1, wherein, L is -N(C) 1-6 alkyl)-.

6. The compound or a salt thereof according to claim 1, wherein, L is -S(=O)2-.

7. The compound or a salt thereof according to claim 1, wherein, L is -C(=O)-.

8. The compound or a salt thereof according to claim 1, wherein, L is -NH-C(=O)-.

9. The compound or a salt thereof according to claim 1, wherein, L is C 1-6 alkyl.

10. The compound or a salt thereof according to any one of claims 1-9, wherein, Ring B is a phenyl group, a 6-membered heteroaryl group containing one or two nitrogen atoms, or a pyrazolyl group; R a1 and R a2 H and C independently 1-6 Alkyl, halogen, halogenated -C 1-6 Alkyl or -O-halogenated -C 1-6 alkyl; R b1 and R b2 Independently, it is H, halogenated-C 1-6 Alkyl or -C 1-6 Alkylene-NR c R d ; R c and R d Independently, it is H or C 1-6 Alkyl; or, R c and R d They can be optionally connected to each other to communicate with R. c and R d The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be surrounded by one or two R atoms. e replace; R 1 It is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclic groups, optionally substituted phenyl or optionally substituted heteroaryl groups; R 2 Is it by one or two Rs 3 Replacement C 1-6 Alkyl group, with one or two R 4 Replacement C 3-8 cycloalkyl, with one or two R 5 The substituted 4- to 7-membered saturated heterocyclic group, or the group replaced by one or two R groups. 6 Substituted phenyl; or, R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be fused with a phenyl group, and the heterocyclic group and / or the fused phenyl group may optionally be surrounded by one or two R atoms. 7 replace; Each R 3 Independently, it is -OH, -C(=O)-NH2, -NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl groups or -S(=O)2-NH2; Each R 4 Independently, it is -OH, -C(=O)-NH2, -NH-C(=O)-C 1-6 Alkyl group, -NH-S(=O)2-C 1-6 Alkyl groups or -S(=O)2-NH2; Each R 5 It can be either -OH or an oxo group; Each R 6 Independently, it is -C(=O)-OH or -S(=O)2-NH2; and Each R 7 C is independent 1-6 Alkyl, -C 1-6 alkylene -OH, -C 1-6 alkylene-C(=O)-OH, C 3-8 Cycloalkyl, -OH, -NH2, -C(=O)-OH, -C(=O)-NH2, oxo, imino, or 4- to 7-membered saturated heterocyclic groups that may optionally be substituted with one or two oxo groups.

11. The compound or a salt thereof according to any one of claims 1-10, wherein, Ring A is a phenyl group, a 6-membered heteroaryl group containing one or two nitrogen atoms, a pyrazolyl group, or a 6-membered saturated or partially unsaturated heterocyclic group. Ring B is equation (V): X is CH or N. R 1 It is H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4- to 7-membered saturated heterocyclic groups, phenyl, or optionally substituted heteroaryl groups, R 2 Is it by one or two Rs 3 Replacement C 1-6 Alkyl group, with one or two R 4 Replacement C 3-8 cycloalkyl, or with one or two R 5 Substituted 4- to 7-membered saturated heterocyclic groups, or, R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be surrounded by one or two R atoms. 7 replace, R 4 It is -OH. The premise is R a1 R a2 R b1 or R b2 At least one of them is not H.

12. The compound or a salt thereof according to any one of claims 1-11, wherein, R b1 It's H. R b2 It is halogenated-C 1-6 Alkyl groups, and R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may optionally be surrounded by one or two R atoms. 7 replace.

13. The compound or a salt thereof according to any one of claims 1-12, wherein, Ring A is a phenyl group. R a1 R a2 and R b1 It's H. R b2 It is halogenated-C 1-6 alkyl, R 1 It's H. R 2 Is it by one or two Rs 3 Replacement C 1-6 Alkyl, or, R 1 and R 2 Connect to each other to R 1 and R 2 The attached nitrogen atoms together form an azahexacyclic butyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl group, wherein the azahexacyclic butyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl group may optionally be surrounded by one or two R groups. 7 replace, Each R 3 Independently, it is -OH or -C(=O)-NH2, and Each R 7 Independently is -C 1-6 Alkylene groups -OH, -OH, -C(=O)-NH2, oxo groups, or imino groups.

14. The compound or a salt thereof according to any one of claims 1-13, wherein, The compound is selected from the compounds in Table A or their pharmaceutically acceptable salts.

15. A pharmaceutical composition comprising a compound or a salt thereof according to any one of claims 1-14 and one or more pharmaceutically acceptable excipients.

16. A STING inhibitor comprising a compound or a salt thereof according to any one of claims 1-14.

17. The pharmaceutical composition according to claim 15, wherein, The pharmaceutical composition is a pharmaceutical composition for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases.

18. Use of the compound or salt thereof according to any one of claims 1-14 for the manufacture of a pharmaceutical composition for the treatment of autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases.

19. Use of the compound or salt thereof according to any one of claims 1-14 for the treatment of autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases.

20. The compound or salt thereof according to any one of claims 1-14, for use in the treatment of autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases.

21. A method for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases, comprising administering to a subject an effective amount of the compound or a salt thereof according to any one of claims 1-14.

Images