Compounds and compositions for treating pathologies associated with STING activity

Abstract

The disclosure features chemical entities (e.g., compounds, or pharma- ceutically acceptable salts, and / or hydrates, and / or cocrystals, and / or combinations with drugs) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). The chemical entities are useful, for example, to treat conditions, diseases, or disorders in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). The disclosure also features compositions comprising same, as well as methods of using and making same. TIFF2025504415000110.tif24170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 298,893, filed January 12, 2022, which is incorporated by reference in its entirety herein.

[0002] Technical Field The disclosure features chemical entities (e.g., compounds, or pharma- ceutically acceptable salts, and / or hydrates, and / or cocrystals, and / or combinations with drugs) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). The chemical entities are useful, for example, to treat conditions, diseases, or disorders in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). The disclosure also features compositions comprising same, as well as methods of using and making same. [Background technology]

[0003] background 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. STING induces the production of type I interferons when cells are infected with intracellular pathogens, such as viruses, mycobacteria, and intracellular parasites. STING-mediated type I interferons protect infected cells and nearby cells from local infection in an autocrine and paracrine manner.

[0004] The STING pathway is crucial in mediating the recognition of cytosolic DNA. In this context, STING is a transmembrane protein localized in the endoplasmic reticulum (ER) that acts as a second messenger receptor for 2',3' cyclic GMP-AMP (hereafter cGAMP) produced by cGAS after dsDNA binding. In addition, STING can also function as a major pattern recognition receptor for bacterial cyclic dinucleotides (CDNs) and small molecule agonists. Recognition of endogenous or prokaryotic CDNs proceeds through the carboxy-terminal domain of STING, which faces the cytosol and forms a V-shaped binding pocket formed by STING homodimers. Ligand-induced activation of STING triggers its relocalization to the Golgi apparatus, a process essential to promote the interaction of STING with TBK1. This protein complex subsequently signals to induce type I interferons (IFNs) and other co-regulated antiviral factors via the transcription factor IRF-3. In addition, STING has been shown to cause activation of NF-κB and MAP kinases. After initiating signaling, STING is rapidly degraded, a step thought to be important in terminating the inflammatory response.

[0005] Excessive activation of STING is associated with a subset of monogenic autoinflammatory pathologies, the so-called type I interferonopathies. Examples of these diseases include the clinical syndrome called STING-associated vasculitis onset in infancy (SAVI), caused by gain-of-function mutations in TMEM173 (the gene for STING). Furthermore, STING has been linked to the pathogenesis of Aicardi-Goutières syndrome (AGS) and genetic forms of lupus. In contrast to SAVI, dysregulation of nucleic acid metabolism underlies the ongoing innate immune activity in AGS. Apart from these genetic disorders, emerging evidence points to a more general pathogenetic role for STING in various inflammation-related disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and cancer. Thus, small molecule-based pharmacological interventions in the STING signaling pathway hold great potential for treating a wide range of diseases. Summary of the Invention [Means for solving the problem]

[0006] overview The disclosure features chemical entities (e.g., compounds, or pharma- ceutically acceptable salts, and / or hydrates, and / or cocrystals, and / or combinations with drugs) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). The chemical entities are useful, for example, to treat conditions, diseases, or disorders in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). The disclosure also features compositions comprising same, as well as methods of using and making same.

[0007] "Antagonists" of STING include compounds that directly bind to or modify STING at the protein level, e.g., by inhibiting, blocking or attenuating agonist-mediated responses, altering distribution, or otherwise decreasing STING activity. STING antagonists include chemicals that interfere with or inhibit STING signaling.

[0008] In one embodiment, the compound of formula (I): TIFF2025504415000002.tif38170(in the formula, Q 1 , L A , Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 and W may be as defined anywhere herein. or a pharma- ceutically acceptable salt thereof.

[0009] In one aspect, the invention features a pharmaceutical composition that includes a chemical entity described herein (e.g., a compound generally or specifically described herein, or a pharma- ceutically acceptable salt thereof, or a composition containing same) and one or more pharma- ceutically acceptable excipients.

[0010] In one aspect, a method of inhibiting (e.g., antagonizing) STING activity is featured, comprising contacting STING with a chemical entity described herein (e.g., a compound generally or specifically described herein or a pharma- ceutically acceptable salt thereof, or a composition containing same). The method includes in vitro methods, e.g., contacting a sample comprising one or more cells (e.g., innate immune cells, e.g., mast cells, macrophages, dendritic cells (DCs), and natural killer cells) that contain STING with the chemical entity. The method can also include in vivo methods, e.g., administering the chemical entity to a subject (e.g., a human) having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease.

[0011] In one aspect, the present invention features a method of treating a condition, disease, or disorder in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human), or a condition, disease, or disorder that is alleviated by antagonizing STING. The method includes administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein or a pharma- ceutically acceptable salt thereof, or a composition comprising same).

[0012] Another aspect features a method of treating cancer, comprising administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein, or a pharma- ceutically acceptable salt thereof, or a composition comprising same) to a subject in need of such treatment.

[0013] Further aspects feature methods of treating other STING-associated conditions, such as type I interferonopathies (e.g., STING-associated vasculitis in infancy (SAVI)), Aicardi-Goutières syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis. The methods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein or a pharma- ceutically acceptable salt thereof, or a composition comprising same)

[0014] Another aspect features a method of inhibiting STING-dependent type I interferon production in a subject in need thereof, comprising administering to the subject an effective amount of a chemical entity described herein (e.g., a compound described generally or specifically herein, or a pharma- ceutically acceptable salt thereof, or a composition comprising same).

[0015] A further aspect features a method of treating a disorder in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the disease, comprising administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein or a pharma- ceutically acceptable salt thereof, or a composition comprising same)

[0016] In another aspect, the invention features a method of treatment comprising administering to a subject an effective amount of a chemical entity described herein (e.g., a compound described generally or specifically herein or a pharma- ceutically acceptable salt thereof, or a composition comprising either), wherein the subject has (or is susceptible to having) a disease in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the disease.

[0017] In a further aspect, a method of treatment includes administering to a subject a chemical entity described herein (e.g., a compound generally or specifically described herein or a pharma- ceutically acceptable salt thereof, or a composition comprising same), wherein the chemical entity is administered in an amount effective to treat a disease in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the disease, thereby treating the disease.

[0018] In another aspect, there is provided a compound as described herein, or a pharma- ceutically acceptable salt, or tautomer thereof, for use in the treatment of a disease, condition, or disorder that is modulated by inhibition of STING.

[0019] In another aspect, there is provided a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for use in the treatment of a condition, disease, or disorder associated with increased (e.g., excessive) STING activity.

[0020] In another aspect, there is provided a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for use in the treatment of cancer.

[0021] In another aspect, there is provided a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for use in the treatment of a cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma.

[0022] In another aspect, there is provided a compound as described herein, or a pharma- ceutically acceptable salt, or tautomer thereof, for use in the treatment of type I interferonopathy.

[0023] In another aspect, there is provided a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for use in the treatment of a type I interferonopathy selected from infantile-onset STING-associated vasculitis (SAVI), Aicardi-Goutières syndrome (AGS), genetic forms of lupus, and inflammation-related disorders such as systemic lupus erythematosus, and rheumatoid arthritis.

[0024] In another aspect, there is provided the use of a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, in the manufacture of a medicament for treating a condition, disease or disorder associated with increased (e.g., excessive) STING activity.

[0025] In another aspect, there is provided the use of a compound as described herein, or a pharma- ceutically acceptable salt, or tautomer thereof, in the manufacture of a medicament for treating cancer.

[0026] In another aspect, there is provided the use of a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, in the manufacture of a medicament for treating a cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma.

[0027] In another aspect, there is provided the use of a compound as described herein, or a pharma- ceutically acceptable salt, or tautomer thereof, in the manufacture of a medicament for treating type I interferonopathy.

[0028] In another aspect, there is provided the use of a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for use in the manufacture of a medicament for treating a type I interferonopathy selected from infantile-onset STING-associated vasculitis (SAVI), Aicardi-Goutières syndrome (AGS), genetic forms of lupus, and inflammation-related disorders such as systemic lupus erythematosus, and rheumatoid arthritis.

[0029] In another aspect, there is provided a use of a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for treating a disease, condition, or disorder modulated by inhibition of STING.

[0030] In another aspect, there is provided a use of a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for treating a condition, disease, or disorder associated with increased (e.g., excessive) STING activity.

[0031] In another aspect, there is provided the use of a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for the treatment of cancer.

[0032] In another aspect, there is provided a use of a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for treating a cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma.

[0033] In another aspect, there is provided the use of a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for treating type I interferonopathy.

[0034] In another aspect, there is provided a use of a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for treating a type I interferonopathy selected from infantile-onset STING-associated vasculitis (SAVI), Aicardi-Goutières syndrome (AGS), genetic forms of lupus, and inflammation-related disorders such as systemic lupus erythematosus, and rheumatoid arthritis.

[0035] Implementations may include one or more of the following features.

[0036] The chemical entity can be administered in combination with one or more additional therapeutic agents and / or regimens. For example, the method can further include administering one or more (e.g., 2, 3, 4, 5, 6, or more) additional agents.

[0037] The chemical entity can be administered in combination with one or more additional therapeutic agents and / or regimens useful for treating other STING-associated conditions, such as type I interferonopathies (e.g., STING-associated vasculitis in infancy (SAVI)), Aicardi-Goutières syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.

[0038] The chemical compound can be administered in combination with one or more additional cancer therapies (e.g., surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof, e.g., chemotherapy comprising administering one or more (e.g., 2, 3, 4, 5, 6, or more) additional chemotherapeutic agents. Non-limiting examples of additional chemotherapeutic agents include alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin); antimetabolites (e.g., azathioprine and / or mercaptopurine); terpenoids (e.g., vinca alkaloids and / or taxanes; e.g., vincristine, vinblastine, vinorelbine, and / or vindesine taxol, paclitaxel, and / or docetaxel); topoisomerase inhibitors (e.g., For example, type I topoisomerases and / or type 2 topoisomerases; camptothecins, such as irinotecan and / or topotecan; amsacrine, etoposide, etoposide phosphate and / or teniposide; cytotoxic antibiotics (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomas). isin; hormones (e.g., luteinizing hormone releasing hormone agonists; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, vedotin), canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; growth inhibitors; antiparasitic agents;and 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), galectin 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-CD4 0 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, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 selected from immune checkpoint inhibitors that target immune checkpoint receptors selected from the group consisting of adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1);

[0039] The subject may have cancer, for example, the subject has undergone and / or is undergoing and / or will undergo one or more cancer therapies.

[0040] Non-limiting examples of cancer include melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma. In certain embodiments, the cancer may be a refractory cancer.

[0041] The chemical entity can be administered intratumorally.

[0042] The method may further include identifying the subject.

[0043] Other embodiments may be described in the detailed description and / or claims.

[0044] Additional definitions In order to facilitate understanding of the disclosure described herein, some additional terms are defined below. In general, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry and pharmacology described herein 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 those skilled in the art to which this disclosure belongs. Each of the patents, applications, published applications and other publications referred to in this specification and the attached appendix is ​​incorporated herein by reference in its entirety.

[0045] As used herein, the term "STING" is meant to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homolog and / or ortholog STING molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0046] The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that it has no lasting detrimental effects on the overall health of the subject being treated.

[0047] "API" refers to active pharmaceutical ingredient.

[0048] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of a chemical substance administered that will relieve to some extent one or more symptoms of the disease or condition being treated. This result includes reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" used in treatment is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study.

[0049] The term "excipient" or "pharmaceutically acceptable excipient" means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. For example, Remington:The Science and Practice of Pharmacy,21st ed.;Lippincott Williams & Wilkins:Philadelphia,PA,2005;Handbook of Pharmaceutical Excipients,6th ed.;Rowe et al.,Eds.;The Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0050] The term "pharmaceutical acceptable salt" refers to a compound formulation that does not cause significant irritation to an organism to which it is administered and does not suppress the biological activity and properties of the compound. In certain examples, pharmaceutical acceptable salts are obtained by reacting a compound described herein with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In some examples, pharmaceutical acceptable salts are obtained by reacting a compound having an acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., calcium salt or magnesium salt), a salt of an organic base (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine), and a salt with an amino acid (e.g., arginine, lysine, etc.), or by other methods previously identified. There is no particular limit to the pharmacologically acceptable salt, so long as it 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 exemplified by the following acid addition salts: mineral 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; acidic amino acids such as aspartic acid and glutamic acid.

[0051] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickening agents (collectively referred to herein as "excipients"). A pharmaceutical composition facilitates administration of a compound to an organism. Many techniques of administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0052] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, such as a human.

[0053] In the context of treating a disease or disorder, the terms "treat," "treating," and "treatment" are meant to include reducing or eliminating the disorder, disease or condition, or one or more symptoms associated with the disorder, disease or condition, or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof. "Treatment of cancer" refers to one or more of the following effects: (1) inhibition to some extent of tumor growth, including (i) stasis, and (ii) complete cessation of growth; (2) reduction in the number of tumor cells; (3) maintenance of tumor size; (4) reduction in tumor size; (5) inhibition to some extent of (i) reduction, (ii) stasis, or (iii) complete prevention of tumor cell infiltration into surrounding organs; (6) inhibition to some extent of (i) reduction, (ii) stasis, or (iii) complete prevention of metastasis; (7) enhancement of an anti-tumor immune response, which may result in (i) maintenance of tumor size, (ii) reduction in tumor size, (iii) slowing of tumor growth, (iv) reduction, slowing, or prevention of invasiveness, and / or (8) reduction to some extent in the severity or number of symptoms of one or more symptoms associated with the disorder.

[0054] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0055] The term "alkyl" refers to a saturated acyclic hydrocarbon group, which may be straight or branched, containing the indicated number of carbon atoms. For example, C 1~10 indicates that there may be 1 to 10 (inclusive) carbon atoms in the group. Alkyl groups may be substituted or unsubstituted 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 there are only single bonds between the constituent carbon atoms and other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0056] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with an independently selected halo.

[0057] The term "alkoxy" refers to an -O-alkyl group (eg, -OCH3).

[0058] The term "alkylene" refers to a divalent alkyl group (eg, --CH.sub.2--).

[0059] The term "alkenyl" refers to an acyclic hydrocarbon chain, which may be straight or branched, having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2~6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups may be unsubstituted or substituted with one or more substituents.

[0060] The term "alkynyl" refers to an acyclic hydrocarbon chain, which may be straight or branched, having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2~6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups may be unsubstituted or substituted with one or more substituents.

[0061] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbons in which 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 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, dihydro-1H-indenyl, and the like.

[0062] 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, more preferably 3 to 12 ring carbons or 3 to 10 ring carbons or 3 to 6 ring carbons, where the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, etc. Cycloalkyl also includes spirocycles (e.g., spirobicycles in which two rings are joined through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, etc. As used in this context, the term "saturated" means that only single bonds exist between the constituent carbon atoms.

[0063] 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, more preferably 3 to 12 ring carbons or 3 to 10 ring carbons or 3 to 6 ring carbons, and the cycloalkenyl group may be optionally 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 may have any degree of unsaturation, provided that there is one or more double bonds in the ring, none of the rings in the ring system is aromatic, and the cycloalkenyl group as a whole is not fully saturated. The cycloalkenyl may include multiple fused and / or bridged and / or spiro rings.

[0064] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, or alternatively 5, 6, 9, 10, or 14 ring atoms, and having 6, 10, or 14 pi-electrons shared in a cyclic arrangement, in which 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 (although rings containing heteroatoms are not required, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can be substituted or unsubstituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, Examples include pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolinyl, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0065] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated ring system containing 3 to 16 ring atoms (e.g., a 5-8 membered monocyclic ring system, an 8-12 membered bicyclic ring system, or an 11-14 membered tricyclic ring system) having 1 to 3 heteroatoms in the monocyclic ring system, 1 to 6 heteroatoms in the bicyclic ring system, or 1 to 9 heteroatoms in the tricyclic or polycyclic ring system, the heteroatoms being selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms in the monocyclic, bicyclic, or tricyclic ring system, respectively), and 0, 1, 2, or 3 atoms of each ring may be optionally substituted with a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]pentanyl, 2-azabicyclo[1.1.1]pentanyl, 3-azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[ 3.2.1]octanyl, 2-oxabicyclo[1.1.0]butanyl, 2-oxabicyclo[2.1.0]pentanyl, 2-oxabicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[4.2.0]octanyl, 2-oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1]octanyl, etc. Heterocyclyl also includes spirocycles (e.g., spirobicycles in which the two rings are joined through only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7-diazaspiro[4.5]decanyl, and 7-azaspiro[4.5]decanyl. 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-oxaspiro[2.2]pentanyl, 4-oxaspiro[2.5]octanyl, 1-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, 1-oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl, and the like. As used in this context, the term "saturated" means that only single bonds exist between the constituent ring atoms and other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0066] As used herein, the term "heterocycloalkenyl" refers to a partially unsaturated cyclic ring system containing 3 to 16 ring atoms (e.g., a 5-8 membered monocyclic ring system, an 8-12 membered bicyclic ring system, or an 11-14 membered tricyclic ring system) having 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic, where the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms if monocyclic, bicyclic, or tricyclic, respectively), and 0, 1, 2, or 3 atoms of each ring may be optionally substituted with a substituent. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl. As a partially unsaturated cyclic group, a heterocycloalkenyl group can have any degree of unsaturation, provided that there is one or more double bonds within the ring, no ring in the ring system is aromatic, and the heterocycloalkenyl group as a whole is not fully saturated. Heterocycloalkenyls can include multiple fused and / or bridged and / or spiro rings.

[0067] As used herein, when a ring is described as being "aromatic", it means that said ring has a continuously delocalized pi-electron system. Usually, the number of out-of-plane pi-electrons corresponds to Huckel's rule (4n+2). Examples of such rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0068] As used herein, when a ring is described as "partially unsaturated," it is meant that the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation due to the ring itself; e.g., one or more double or triple bonds between the constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0069] For the avoidance of doubt, and unless otherwise stated, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) which contain a sufficient number of ring atoms to form bicyclic or higher ring systems (e.g., tricyclic ring systems, polycyclic ring systems), such rings and cyclic groups are also understood to include those which have fused rings, e.g., rings which have a fusion point at which the ring is fused to the ring at which the fusion point is formed. (i) adjacent ring atoms (e.g., a [xx0] ring system, where 0 represents a 0 atom bridge (e.g., TIFF2025504415000003.tif15170)); (ii) single ring atom (spiro-fused ring systems) (e.g., TIFF2025504415000004.tif19170), or (iii) an arrangement of adjacent ring atoms (bridged ring systems where all bridges have a length >0) (e.g., TIFF2025504415000005.tif15170) It will be understood that this includes those located above.

[0070] Additionally, atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. As used herein, isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include tritium and deuterium. 13 C and 14 Contains C.

[0071] In addition, the compounds disclosed generically or specifically herein are intended to include all tautomeric forms. Thus, by way of example, the moiety: Compound containing TIFF2025504415000006.tif17170, part: TIFF2025504415000007.tif19170 are included. Similarly, a pyridinyl or pyrimidinyl moiety that is described as optionally substituted with hydroxyl is included the tautomeric forms of a pyridone or pyrimidon.

[0072] As used herein, the phrase "optionally substituted" when used in conjunction with a structural moiety (e.g., alkyl) is intended to encompass both unsubstituted structural moieties (i.e., none of the substitutable hydrogen atoms are replaced with one or more non-hydrogen substituents) and substituted structural moieties that are substituted with the indicated range of non-hydrogen substituents. For example, "1 to 4 R a "C1-C4 alkyl optionally substituted with" means an unsubstituted C1-C4 alkyl and 1 to 4 R a and C1-C4 alkyl substituted with .

[0073] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] Detailed Description The disclosure features chemical entities (e.g., compounds, or pharma- ceutically acceptable salts, and / or hydrates, and / or cocrystals, and / or combinations with drugs) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). The chemical entities are useful, for example, to treat conditions, diseases, or disorders in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). The disclosure also features compositions comprising same, as well as methods of using and making same.

[0075] Compounds of Formula I In one aspect, the present disclosure provides a compound of formula (I): TIFF2025504415000008.tif37170 or a pharma- ceutically acceptable salt thereof or a tautomer thereof, wherein L A is -(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 -*, where * is Q 1 represents the attachment point to; a1, a2, a3, a4, and a5 each independently represent 0 or 1; However, a1+a2+a3+a4+a5≧1 is satisfied. L 1 , L 3 , and L 5 are -O-, -N(H)-, -N(R d )-, S(O) 0~2 and -C(=O)-; However, if one or both of a2 and a4 are 0, L 1 , L 3 , and L 5with the proviso that the combination of: L 2 and L 4 Each of the Each of them has 1 to 6 R b Optionally substituted linear C 1~6 Alkylene, linear C 2~6 Alkenylene or linear C 2~6 Alkynylene; Each of them has 1 to 3 R c Optionally substituted with C 3~10 Cycloalkylene or C 3~10 Cycloalkenylene, where Y 1 , Y 2 , and Y 3 provided that the C is not directly connected to a six-membered ring containing 3~10 Cycloalkylene or C 3~10 Cycloalkenylene; and Heterocyclylene or heterocycloalkenylene, each having 4 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is selected from 1 to 3 R c may be substituted with, provided that Y 1 , Y 2 , and Y 3 provided that the heterocyclylene or heterocycloalkenylene is not directly attached to a six-membered ring containing are independently selected from the group consisting of: Q 1 -R g and; Y 1 , Y 2 , and Y 3 CR 1 , C(=O), N, and NR 2 each independently selected from the group consisting of: X 1 are O, S, N, and NR2 , and C.R. 1 selected from the group consisting of; X 2 are O, S, N, and NR 4 , and C.R. 5 selected from the group consisting of; Each TIFF2025504415000009.tif9170 is independently a single bond or a double bond, provided that X 1 and X 2 is a heteroaryl; and Y 1 , Y 2 , and Y 3 provided that the six-membered ring containing is aryl or heteroaryl; Furthermore, L A Y 1 , Y 2 , and Y 3 provided that the cyclic group cannot contain a cyclic group directly attached to a six-membered ring containing R 1 and R 5 Each occurrence of H;R c ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 2 and R 4 Each occurrence of H;R d ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 6 is H;R d ; and R g selected from the group consisting of; W is Each of them has 1 to 6 R a2 or R g Optionally substituted with C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 Alkynyl; Each of which is oxo and R cC 3~12 Cycloalkyl or C 3~12 Cycloalkenyl; and Heteroaryl, heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl, heterocyclyl, or heterocycloalkenyl is selected from the group consisting of oxo and R c The heteroaryl, heterocyclyl or heterocycloalkenyl may be substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of However, when W is heteroaryl, heterocyclyl, or heterocycloalkenyl, it is C(=O)NR via a ring carbon atom. 6 provided that it is attached to a group; R a and R a2 Each occurrence of is -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); and cyano; R b and R c each occurrence of is selected from halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1~10 Alkyl;C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4alkyl);-S(O)(=NH)(C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)NR'R''; and -SF5; R d Each occurrence of is selected from 1 to 3 independently selected R a C which may be substituted with 1~6 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 independently selected from the group consisting of alkoxy; R e and R f Each occurrence of is H;NR'R'', -OH, halo, C 1~4 Alkoxy and C 1~4 C may be substituted by 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~6 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 independently selected from the group consisting of alkoxy; R g Each occurrence of Each of them is oxo, R c , and R h C 3~12 Cycloalkyl or C 3~12 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is oxo, R c , and R h The heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl with 5 to 12 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl is oxo, R c , and R h The heteroaryl, which may be substituted with 1 to 4 substituents independently selected from the group consisting of: Oxo, R c , and R h C 6~10 Aryl independently selected from the group consisting of: R h Each occurrence of Each of them has 1 to 4 R i Optionally substituted with C 3~12 Cycloalkyl or C 3~12 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of 1 to 4 R i the heterocyclyl or heterocycloalkenyl optionally substituted by Heteroaryl with 5 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d), O, and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R i the heteroaryl, optionally substituted with 1 to 4 R i Optionally substituted with C 6~10 Aryl independently selected from the group consisting of: R i Each occurrence of C 1~6 Alkyl;C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 Independently selected from the group consisting of haloalkoxy; and halo; L g Each occurrence of is -O-, -NH-, -NR d , -S(O) 0~2 , C(O), and 1 to 3 R a C which may be substituted with 1~3 independently selected from the group consisting of alkylene; each occurrence of bg is independently 1, 2, or 3; Each occurrence of R' and R'' is H; -OH; and C 1~4 alkyl.

[0076] Variable L A (-(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 -*(* is Q 1 represents the attachment point to In some embodiments, L A is a divalent moiety having a linear array of 1 to 6 (e.g., 2 to 6 (e.g., 2, 3, or 4)) substituted or unsubstituted carbon and / or heteroatoms. In some embodiments, L Ais a divalent moiety having a combination of cyclic moieties and a linear array of 1-6 (e.g., 2-6 (e.g., 2, 3, or 4)) substituted or unsubstituted carbon and / or heteroatoms, such as one cyclic moiety (e.g., C3-6, e.g., C4 cycloalkylene) and an acyclic moiety (e.g., O).

[0077] In some embodiments, L 4 Each of them has 1 to 6 R b Optionally substituted linear C 1~6 Alkylene, linear C 2~6 Alkenylene or linear C 2~6 Other than alkynylene.

[0078] In some embodiments, a2 is 1. In some embodiments, a2 is 0.

[0079] In a particular embodiment (where a2 is 1), L 2 Each of them has 1 to 6 R b Optionally substituted linear C 1~6 Alkylene, linear C 2~6 Alkenylene or linear C 2~6 It is alkynylene.

[0080] In certain of the foregoing embodiments, L 2 is 1 to 6 R b Optionally substituted linear C 1~6 It is alkylene.

[0081] In certain of the foregoing embodiments, L 2 1 to 3 R b Optionally substituted linear C 1~3 It is alkylene.

[0082] In certain embodiments, L 2 -CH2-, -CHR b - and -C(R b For example, L 2may be -CH2-.

[0083] Specific embodiments (L 2 However, 1 to 6 R b Optionally substituted linear C 1~6 In the case where the alkylene is used, L 2 1 to 3 R b Optionally substituted linear C 2~3 It is alkylene.

[0084] In certain of these embodiments, L 2 1 to 3 R b In certain of the foregoing embodiments, L is -CHCH-, -CHCH(R b )-*, and -CH2C(R b )2-*, where the asterisk is -(L 3 ) a3 - represents the point of attachment to the -. For example, L 2 may be -CH2CH2-.

[0085] In certain embodiments, L 2 1 to 3 R b For example, L 2 teeth, TIFF2025504415000010.tif16170, and the asterisk is -(L 3 ) a3 - represents the attachment point to.

[0086] In a particular embodiment (where a2 is 1), L 2 is 1 to 6 R b Optionally substituted linear C 2~6 In certain of these embodiments, L is alkenylene. 2 1 to 3 R b Optionally substituted linear C 2~4 Alkenylene. For example, L 2 teeth, TIFF2025504415000011.tif11170, and the asterisk is -(L 3 ) a3 - represents the attachment point to.

[0087] In a particular embodiment (where a2 is 1), L 2 teeth, Each of them has 1 to 3 R c Optionally substituted with C 3~10 Cycloalkylene or C 3~10 Cycloalkenylene; and Heterocyclylene or heterocycloalkenylene, each having 4 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is selected from 1 to 3 R c The heterocyclylene or heterocycloalkenylene may be optionally substituted by is selected from the group consisting of:

[0088] In certain of these embodiments, L 2 teeth, 1 to 3 R c Optionally substituted with C 3~8 Cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is selected from 1 to 3 R c The heterocyclylene may be substituted with is selected from the group consisting of:

[0089] In certain of the foregoing embodiments, L 2 1 to 2 R c may be substituted with TIFF2025504415000012.tif20170, where n1 and n2 are independently 0, 1, or 2; Q 2 , CH, CR c , or N; asterisk is -(L 3 ) a3 - represents the attachment point to.

[0090] In certain of these embodiments, Q 2 is CH.

[0091] Specific embodiments (L 2 As defined above, In the case where the image size is TIFF2025504415000013.tif20170), n1 and n2 are each 0.

[0092] Non-limiting examples (L 2 As defined above, TIFF2025504415000014.tif20170) as L 2 teeth TIFF2025504415000015.tif12170, where the asterisk is -(L 3 ) a3 -or- (L 1 ) a1 For example, a1 is 1 -(L 1 ) a1 For example, L 2 teeth, TIFF2025504415000016.tif12170, where the asterisk is -(L 1 ) a1 In certain of these embodiments, -(L 1 ) a1 is O. In certain such embodiments, each of a3, a4, and a5 is 0.

[0093] In some embodiments, a1 is 1. In some embodiments, a1 is 0.

[0094] In a particular embodiment (where a1 is 1), L 1 -O-, -N(H)-, -N(R d In certain of these embodiments, L is selected from the group consisting of -R-, ... 1 is -O-.

[0095] In some embodiments, a3 is 1. In some embodiments, a3 is 0.

[0096] In a particular embodiment (where a3 is 1), L 3 -O-, -N(H)-, -N(R d In certain of these embodiments, L is selected from the group consisting of -R-, ... 3 In certain other embodiments, L 3 is -N(H)- or -N(R d )-(e.g., -N(H)-).

[0097] In some embodiments, a4 is 1. In some embodiments, a4 is 0.

[0098] In a particular embodiment (where a4 is 1), L 4 1 to 3 R b Optionally substituted linear C 1~3 In certain of these embodiments, L 4 is -CH2-.

[0099] In a particular embodiment (where a4 is 1), L 4 teeth, 1 to 3 R c Optionally substituted with C 3~8 Cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is selected from 1 to 3 R cThe heterocyclylene may be substituted with is selected from the group consisting of:

[0100] In certain of these embodiments, L 4 1 to 2 R c may be substituted with TIFF2025504415000017.tif18170, and n3 and n4 are independently 0, 1, or 2; Q 3 , CH, CR c , or N; asterisk is -(L 5 ) a5 - represents the attachment point to.

[0101] Specific embodiments (L 4 but In the example (TIFF2025504415000018.tif18170), n3 and n4 are each 1. 4 but TIFF2025504415000019.tif18170) Q 3 is N.

[0102] As a non-limiting example of the above embodiment, L 4 teeth, TIFF2025504415000020.tif12170, where the asterisk is -(L 5 ) a5 - represents the attachment point to.

[0103] In some embodiments, a5 is 0.

[0104] -(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 - Non-limiting combinations of * In some embodiments, -(L 1 )a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 -* has a length of 1 to 8 atoms (as used herein, and for purposes of counting only, moieties such as CH2, C(O), CF2, whether present in an acyclic or cyclic moiety count as 1 atom); for example, 1 to 6 atoms, or 1 to 5 atoms, or 1 to 4 atoms; or 1 to 3 atoms; or 2 to 6 atoms; or 2 to 4 atoms.

[0105] In certain embodiments, one of a1, a3, and a5 is 1, and the other two of a1, a3, and a5 are 0. In certain embodiments, a1 is, for example, L 2 When is a cyclic group (eg, cycloalkylene), it is 1.

[0106] In certain embodiments, one of a2 and a4 is 1, and the other of a2 and a4 is 0 or 1.

[0107] In certain of the aforementioned embodiments, one of a1, a3, and a5 is 1, and the other two of a1, a3, and a5 are 0; One of a2 and a4 is 1, and the other of a2 and a4 is 0 or 1.

[0108] In certain embodiments, 1≦a1+a2+a3+a4+a5≦4. In certain of these embodiments, 1≦a1+a2+a3+a4+a5≦3.

[0109] In certain embodiments, a1 and a2 are each 1.

[0110] [AA1] In certain embodiments, a1 and a2 are each 1; L 1is -O-, -N(H)-, or -N(R d )-and; L 2 teeth, 1 to 3 R b Optionally substituted linear C 1~3 Alkylene; 1 to 3 R c Optionally substituted with C 3~8 Cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is selected from 1 to 3 R c The heterocyclylene may be substituted with is selected from the group consisting of:

[0111] [AA2] In certain embodiments, a1 and a2 are each 1; L 1 is -O-; L 2 1 to 3 R b Optionally substituted linear C 1~3 It is alkylene.

[0112] [AA3] In certain embodiments, a1 and a2 are each 1; L 1 is -O-; L 2 -CH2-, -CHR b - and -C(R b )2-.

[0113] [AA4] In certain embodiments, a1 and a2 are each 1; L 1 is -O-; L 2 1 to 3 R bOptionally substituted linear C 2~3 It is alkylene.

[0114] In certain embodiments of [AA4], L 2 1 to 3 R b As a non-limiting example of the foregoing embodiment, L 2 is -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is -(L 3 ) a3 - represents the point of attachment to the -. For example, L 2 may be -CH2CH2-.

[0115] [AA5] In certain embodiments, a1 and a2 are each 1; L 1 is -O-; L 2 teeth, 1 to 3 R c Optionally substituted with C 3~8 Cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is selected from 1 to 3 R c The heterocyclylene may be substituted with is selected from the group consisting of:

[0116] In certain embodiments of [AA5], L 2 1 to 2 R c may be substituted with TIFF2025504415000021.tif20170, where n1 and n2 are independently 0, 1, or 2; Q 2 , CH, CR c , or N; asterisk is -(L 3) a3 - represents the attachment point to.

[0117] In certain of these embodiments, n1 and n2 are independently 0 or 1, optionally 0; Q 2 For example, n1 and n2 may both be 0; Q 2 may be CH, for example, L 2 may be an optionally substituted cyclobutane-diyl, such as an optionally substituted cyclobutane-1,3-diyl.

[0118] In certain embodiments when a1 and a2 are each 1, a3, a4, and a5 are each 0.

[0119] In certain embodiments of [AA1], a3, a4, and a5 are each 0. In certain embodiments of [AA2], a3, a4, and a5 are each 0. In certain embodiments of [AA3], a3, a4, and a5 are each 0. In certain embodiments of [AA4], a3, a4, and a5 are each 0. In certain embodiments of [AA5], a3, a4, and a5 are each 0.

[0120] In certain embodiments when a1 and a2 are each 1, a3 and a5 are 0;

[0121] In certain embodiments of [AA1], a3 and a5 are 0; a4 is 1. In certain embodiments of [AA2], a3 and a5 are 0; a4 is 1. In certain embodiments of [AA3], a3 and a5 are 0; a4 is 1. In certain embodiments of [AA4], a3 and a5 are 0; a4 is 1. In certain embodiments of [AA5], a3 and a5 are 0; a4 is 1.

[0122] In a particular embodiment (where a1 and a2 are each 1, a3 and a5 are 0; and a4 is 1), L 4 teeth, 1 to 3 R c Optionally substituted with C 3~8 Cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is selected from 1 to 3 R c The heterocyclylene may be substituted with is selected from the group consisting of:

[0123] In certain of these embodiments, L 4 1 to 2 R c may be substituted with TIFF2025504415000022.tif20170, n3 and n4 are independently 0, 1, or 2; Q 3 , CH, CR c , or N; asterisk is -(L 5 ) a5 -represents a point of attachment to -. In certain of the foregoing embodiments, n3 and n4 are independently 0 or 1; Q 3 is N.

[0124] In certain embodiments, a1 is 0; and a2 is 1.

[0125] [BB1] In certain embodiments, a1 is 0; a2 is 1; L 2 is 1 to 6 R b Optionally substituted linear C 1~6 It is alkylene.

[0126] In certain embodiments of [BB1], L 2 1 to 3 R b Optionally substituted linear C 1~3 In certain of the above embodiments, L2 is -CH2-, -CHR b - and -C(R b For example, L2 may be -CH2-.

[0127] In certain embodiments of [BB1], L 2 1 to 3 R b Optionally substituted linear C 2~3 In certain of the foregoing embodiments, L 2 1 to 3 R b A non-limiting example of L is a straight chain C2 alkylene optionally substituted with 2 is -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is -(L 3 ) a3 - represents the point of attachment to the -. For example, L 2 may be -CH2CH2-.

[0128] In certain embodiments of [BB1], L 2 1 to 3 R b In certain of these embodiments, L is a straight chain C alkylene optionally substituted with 2 teeth, TIFF2025504415000023.tif16170, and the asterisk represents -(L 3 ) a3 - represents the attachment point to.

[0129] In a particular embodiment (where a1 is 0; a2 is 1), a3 is 0; and a4 is 0.

[0130] In specific embodiments of [BB1], a3 is 0; and a4 is 0.

[0131] In certain embodiments (where a1 is 0; a2 is 1), a3 is 1. In certain embodiments of [BB1], a3 is 1.

[0132] In certain embodiments (where a1 is 0; a2 is 1), or in certain embodiments of [BB1], a3 is 1; L 3 is -O-, -N(H)-, and -N(R d In certain of these embodiments, a3 is 1; L 3 In certain other embodiments, a3 is 1; L 3 is -N(H)- or -N(R d )-, optionally -N(H)-.

[0133] In certain embodiments (where a1 is 0; a2 is 1), or in certain embodiments of [BB1], a4 is 1; L 4 1 to 3 R b Optionally substituted linear C 1~3 In certain of these embodiments, a4 is 1; L 4 is -CH2-.

[0134] In certain embodiments (where a1 is 0; a2 is 1) or in certain embodiments of [BB1], a4 is 0.

[0135] In certain embodiments (where a1 is 0; a2 is 1) or in certain embodiments of [BB1], a5 is 0.

[0136] In certain embodiments (where a1 is 0; a2 is 1), or in certain embodiments of [BB1], L A is -CH2-O-CH2-.

[0137] [CC1] In certain embodiments, a1 is 0; a2 is 1; L 2 1 to 3 R b Optionally substituted linear C 2~4 It is alkenylene.

[0138] In certain embodiments of [CC1], L 2 teeth, TIFF2025504415000024.tif12170, and the asterisk represents -(L 3 ) a3 - represents the attachment point to.

[0139] In certain embodiments of [CC1], a3 is 0; and a4 is 0.

[0140] For the avoidance of doubt, if any one or more of a1, a2, a3, a4, and a5 is 0, the corresponding variable (L 1 ~L 5 ) is L A For example, if a3, a4, and a5 are each 0, then L A is the formula -L 1 -L 2 - means to have

[0141] In certain embodiments, L A -L 1 -L 2 -It is.

[0142] In certain embodiments, L A -L 2 -L 3 -It is.

[0143] In certain embodiments, L A -L 2 -L 3 -L 4 -It is.

[0144] In certain embodiments, L A may be -CH2CH2-O-*, where * is Q 1 Represents a point of attachment to

[0145] In certain embodiments, L A may be -O-CH2CH2-*, where * is Q 1 Represents a point of attachment to

[0146] In certain embodiments, L Amay be -CH2-O-CH2-.

[0147] In certain embodiments, L A teeth, TIFF2025504415000025.tif11170 (for example, TIFF2025504415000026.tif10170), where * is Q 1 Represents a point of attachment to

[0148] Variable Q 1 In some embodiments, Q 1 teeth, Heteroaryl with 5 to 12 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R c’ the heteroaryl, optionally substituted with 1 to 4 R c’ Optionally substituted with C 6~10 Aryl is selected from the group consisting of:

[0149] In certain of these embodiments, Q 1 teeth, Heteroaryl with 5-6 ring atoms, 1-4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 3 R c’ the heteroaryl, optionally substituted with 1 to 3 R c’ phenyl, optionally substituted with is selected from the group consisting of:

[0150] In certain of the aforementioned embodiments, Q 1 teeth, Heteroaryl having 6 ring atoms, 1 to 2 of which are ring nitrogen atoms, and the heteroaryl is c’ the heteroaryl, optionally substituted with 1 to 3 R c’ phenyl, optionally substituted with is selected from the group consisting of:

[0151] In certain embodiments, Q 1 1 to 3 R c’ In certain of these embodiments, Q is phenyl, optionally substituted with 1 teeth, TIFF2025504415000027.tif20170.

[0152] In certain embodiments, Q 1 is a heteroaryl of 6 ring atoms, 1 to 2 of which are ring nitrogen atoms, said heteroaryl being selected from the group consisting of 1 to 3 R c’ In certain of these embodiments, Q 1 1 to 3 R c’ In certain of the foregoing embodiments, Q is pyridyl, optionally substituted with 1 teeth, TIFF2025504415000028.tif17170.

[0153] In certain embodiments, Q 1 is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c’ may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0154] In certain of these embodiments, Q 1is a heterocyclyl of 4-10 ring atoms, 1-3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and heterocyclyl is an oxo or R c’ may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0155] In certain of the aforementioned embodiments, Q 1 is a heterocyclyl of 4-8 ring atoms, 1-2 of which are N, N(H), N(R d ), O, and S(O) 0~2 and each heteroatom is independently selected from the group consisting of: d ), Heterocyclyl is oxo and R c’ may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0156] As a non-limiting example of the above embodiment, Q 1 teeth, TIFF2025504415000029.tif17170, wherein m1 and m2 are each independently 0, 1, or 2; Q 1 1 to 2 R c’ For example, Q 1 teeth, TIFF2025504415000030.tif12170. As another non-limiting example, 1 teeth It may be TIFF2025504415000031.tif12170.

[0157] In certain embodiments, Q 1 For each R in d is -C(O)O(C 1~4 alkyl); and 1 to 3 independently selected R a C which may be substituted with 1~6 alkyl.

[0158] In certain of the aforementioned embodiments, Q 1 For each R in d C optionally substituted with 1 to 3 independently selected halo 1~6 It is an alkyl.

[0159] In certain of the aforementioned embodiments, Q 1 For each R in d is C substituted with 1 to 3 -F 1~4 In certain embodiments, Q is alkyl. 1 For each R in d is C substituted with 1 to 3 -F 2~3 It is an alkyl group. For example, Q 1 For each R in d may be -CH2CF3.

[0160] In certain embodiments, R c’ Each occurrence of is an independently selected R c It is.

[0161] In certain embodiments, R c’ each occurrence of c Optionally substituted with C 3~12 Cycloalkyl or C 3~12 (ii) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from 1 to 4 independently selected R c (iii) heteroaryl having 5 to 12 ring atoms, wherein 1 to 4 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R cthe heteroaryl, optionally substituted with (iv) 1 to 4 R c Optionally substituted with C 6~10 aryl.

[0162] In certain embodiments, R c’ each occurrence of c Optionally substituted with C 3~12 Cycloalkyl or C 3~12 (ii) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from 1 to 4 independently selected R c (iii) heteroaryl having 5 to 12 ring atoms, wherein 1 to 4 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R c the heteroaryl, optionally substituted with (iv) 1 to 4 R c Optionally substituted with C 6~10 an independently selected R independently selected from the group consisting of aryl; c and any combination of cyclic moieties.

[0163] In certain embodiments, the cyclic moiety is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 ring atoms are selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from 1 to 4 independently selected R c may be substituted with.

[0164] In certain embodiments, the cyclic moiety has 1 to 4 R c C which may be substituted with 6~10 It is aryl.

[0165] In certain embodiments, Q 1 For each R in c is halo;cyano;C 1~4 Alkoxy;C 1~4 haloalkoxy; and 1 to 6 independently selected R a C which may be substituted with 1~10 alkyl.

[0166] In certain embodiments, Q 1 For each R in c is halo;cyano;C 1~4 Alkoxy;C 1~4 haloalkoxy; and C optionally substituted with 1 to 6 independently selected halo. 1~6 alkyl.

[0167] In certain of the aforementioned embodiments, Q 1 For each R in c C optionally substituted with halo and 1 to 6 independently selected halo 1~3 alkyl.

[0168] In certain embodiments, Q 1 For each R in c is C optionally substituted with 1 to 6 -F 1~3 It is an alkyl group. For example, Q 1 For each R in c may be CF3.

[0169] In certain embodiments, Q 1 For each R in c is an independently selected halo (e.g., --F or --Cl).

[0170] Variable Y 1, Y 2 , Y 3 , X 1 , and X 2 In some embodiments, Y 1 CR 1 It is.

[0171] In some embodiments, Y 2 CR 1 It is.

[0172] In some embodiments, Y 3 CR 1 It is.

[0173] In certain embodiments, R 1 Each occurrence of is independently H or R c In certain of these embodiments, R 1 Each occurrence of is H.

[0174] In certain other embodiments, R 1 One or two occurrences of R c ;R 1 Each remaining occurrence of is H. For example, R 1 may be halo (e.g., -F or -Cl), and one occurrence of R 1 Each remaining occurrence of may be H.

[0175] In certain embodiments, Y 1 , Y 2 , and Y 3 are independently selected CRs 1 It is.

[0176] In certain embodiments, Y 1 , Y 2 , and Y 3 are CH, respectively.

[0177] In certain embodiments, Y 1 , Y 2 , and Y 3 One of them is CR c, optionally C-halo; the remaining two Y 1 , Y 2 and Y 3 Each of the is CH.

[0178] In some embodiments, X 1 is NR 2 In certain of these embodiments, X 1 is NH.

[0179] In some embodiments, X 2 CR 5 In certain of these embodiments, X 2 is CH.

[0180] In certain embodiments, X 1 is NR 2 ;X 2 CR 5 In certain of the above embodiments, X 1 is NH;X 2 is CH.

[0181] In certain embodiments, Y 1 , Y 2 , and Y 3 are independently selected CRs 1 ;X 1 is NR 2 ;X 2 CR 5 In certain of the above embodiments, Y 1 , Y 2 , and Y 3 are CH and X, respectively. 1 is NH;X 2 is CH.

[0182] Variable R 6 and W In some embodiments, R 6 is H.

[0183] In some embodiments, W is selected from the group consisting of 1 to 6 R a2Optionally substituted with C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 It is alkenyl.

[0184] In certain of these embodiments, W is 1 to 6 R a2 Optionally substituted with C 1~10 In certain of the foregoing embodiments, W is 1 to 6 R a2 Optionally substituted with C 1~6 It is an alkyl.

[0185] In some embodiments, W is selected from the group consisting of 1 to 6 R a2 or R g Optionally substituted with C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 It is alkenyl.

[0186] In certain of these embodiments, W is 1 to 6 R a2 or R g Optionally substituted with C 1~10 In certain of the foregoing embodiments, W is 1 to 6 R a2 or R g Optionally substituted with C 1~6 It is an alkyl.

[0187] In certain embodiments, W is selected from 1 to 6 R a2 or R g Optionally substituted with C 1~4 In certain embodiments, W is selected from 1 to 6 R a2 Optionally substituted with C 1~4 It is an alkyl.

[0188] In certain embodiments, W is selected from 1 to 6 R g Optionally substituted with C 1~4 It is an alkyl.

[0189] In certain embodiments, W is selected from the group consisting of one R gC replaced with 1~4 It is an alkyl.

[0190] In certain embodiments, W is It may be TIFF2025504415000032.tif23170.

[0191] In certain of the foregoing embodiments, W is an unsubstituted C 1~4 As a non-limiting example of the foregoing embodiment, W can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, and isobutyl. For example, W can be methyl or ethyl.

[0192] In certain embodiments, W is selected from 1 to 6 R a2 Replaced by C 1~4 It is an alkyl.

[0193] In certain of these embodiments, each R a2 -OH; -Halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl; and cyano. For example, each R a2 is halo;-OH;C 1~4 Alkoxy; and C 1~4 haloalkoxy can be independently selected from the group consisting of:

[0194] In certain embodiments, W is halo; -OH; 1~4 Alkoxy; and C 1~4 substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy; 1~4 As a non-limiting example, W is It may be TIFF2025504415000033.tif12170.

[0195] In some embodiments, W is Each of which is oxo and R c A monocyclic C 3~8 Cycloalkyl or C 3~8 Cycloalkenyl; and Monocyclic heterocyclyl or heterocycloalkenyl of 3 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c The heterocyclyl or heterocycloalkenyl may be substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0196] In certain of the foregoing embodiments, W is selected from the group consisting of oxo and R c A monocyclic C 3~8 Cycloalkyl or C 3~8 It is a cycloalkenyl.

[0197] In certain of these embodiments, W is selected from the group consisting of oxo and R c A monocyclic C 3~8 It is cycloalkyl.

[0198] In certain embodiments, W is an unsubstituted C 3~8 As a non-limiting example of the foregoing embodiment, W can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. For example, W can be cyclobutyl.

[0199] In some embodiments, W is Each of which is oxo and R c A bicyclic C ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of3~12 Cycloalkyl or C 3~12 Cycloalkenyl; and Bicyclic heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c The heterocyclyl or heterocycloalkenyl may be substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0200] In some embodiments, W is Each of which is oxo and R c A bicyclic C ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~10 Cycloalkyl or C 3~10 Cycloalkenyl; and Bicyclic heterocyclyl or heterocycloalkenyl of 3 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c The heterocyclyl or heterocycloalkenyl may be substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0201] In some embodiments, W is Each of which is oxo and R c A bicyclic C ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~8 Cycloalkyl or C 3~8 Cycloalkenyl; and Bicyclic heterocyclyl or heterocycloalkenyl of 3 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c The heterocyclyl or heterocycloalkenyl may be substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0202] In certain of the foregoing embodiments, W is selected from the group consisting of oxo and R c A bicyclic C ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~8 Cycloalkyl or C 3~8 It is a cycloalkenyl.

[0203] In certain of these embodiments, W is selected from the group consisting of oxo and R c A bicyclic C ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~8 It is cycloalkyl.

[0204] In certain embodiments, W is an unsubstituted bicyclic C 3~8 It is cycloalkyl.

[0205] In certain of these embodiments, W is selected from the group consisting of oxo and R c A bicyclic C ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~8 It is cycloalkyl.

[0206] In certain embodiments, W is an unsubstituted bicyclic C 3~8 It is cycloalkyl.

[0207] In certain of the foregoing embodiments, W is a bicyclic heterocyclyl or heterocycloalkenyl of 3 to 10 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O)0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c In certain of the foregoing embodiments, W is a bicyclic heterocyclyl or heterocycloalkenyl of 3 to 8 ring atoms, wherein 1 to 3 ring atoms are selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0208] In certain of the foregoing embodiments, W is a bicyclic heterocyclyl of 3 to 8 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0209] In certain of the foregoing embodiments, W is It may be TIFF2025504415000034.tif17170.

[0210] In certain embodiments, W is a heteroaryl of 3-12 ring atoms, where 1-3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0211] In certain embodiments, W is a heteroaryl of 3-10 ring atoms, where 1-3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and each heteroatom is independently selected from the group consisting of oxo and R c may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0212] In certain embodiments, W is a heteroaryl of 3-8 ring atoms, where 1-3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and each heteroatom is independently selected from the group consisting of oxo and R c may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0213] In certain embodiments, W is It may be TIFF2025504415000035.tif20170.

[0214] Non-limiting combinations In certain embodiments, the compound has formula (Ia): TIFF2025504415000036.tif35170 or a pharma- ceutically acceptable salt thereof, wherein L 1 is -O-, -N(H)-, and -N(R d )- selected from the group consisting of; L 2 teeth, 1 to 3 R b Optionally substituted linear C 1~3 Alkylene; 1 to 3 R c Optionally substituted with C 3~8 Cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2and the heterocyclylene is selected from 1 to 3 R c The heterocyclylene may be substituted with is selected from the group consisting of:

[0215] In certain embodiments of Formula (Ia), L 1 is -O-.

[0216] In certain embodiments of Formula (Ia), L 2 1 to 3 R b Optionally substituted linear C 1~3 It is alkylene.

[0217] In certain embodiments of Formula (Ia), L 2 -CH2-, -CHR b - and -C(R b )2-, and optionally, L 2 is -CH2-.

[0218] In certain embodiments of Formula (Ia), L 2 1 to 3 R b In certain of these embodiments, L is a straight chain C alkylene optionally substituted with 2 is -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is -Q 1 For example, L 2 may be -CH2CH2-.

[0219] In certain embodiments of Formula (Ia), L 2 1 to 3 R b It is a straight-chain C3 alkylene which may be substituted with.

[0220] In certain embodiments of Formula (Ia), L 2 1 to 2 R c may be substituted with TIFF2025504415000037.tif23170, where n1 and n2 are independently 0, 1, or 2; Q 2 , CH, CR c , or N; asterisk is Q 1 Represents a point of attachment to

[0221] In certain of these embodiments, n1 and n2 are independently 0 or 1, optionally 0; Q 2 For example, n1 and n2 may both be 0; Q 2 may be CH, for example, L 2 may be an optionally substituted cyclobutane-diyl, such as an optionally substituted cyclobutane-1,3-diyl.

[0222] In certain embodiments of Formula (Ia), L 1 is -O-;L 2 1 to 2 R c may be substituted with TIFF2025504415000038.tif18170, n1 and n2 are independently 0 or 1, optionally 0; Q 2 For example, n1 and n2 may both be 0; Q 2 may be CH, for example, L 2 may be optionally substituted cyclobutane-diyl, such as optionally substituted-1,3-cyclobutane-1,3-diyl, for example unsubstituted cyclobutane-diyl, such as unsubstituted cyclobutane-1,3-diyl.

[0223] In certain embodiments of Formula (Ia), L 1 is -O-;L 2 1 to 3 R b Optionally substituted linear C 2~3 It is alkylene.

[0224] In certain of the foregoing embodiments of formula (Ia), L 2 1 to 3 R bIt is a straight-chain C2 alkylene which may be substituted with.

[0225] In certain of the foregoing embodiments, L 2 is -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is -Q 1 For example, L 2 may be -CH2CH2-.

[0226] In certain embodiments of Formula (Ia), L 1 is -O-;L 2 -CH2-, -CHR b - and -C(R b For example, L 2 may be -CH2-.

[0227] In certain embodiments, the compound has formula (Ib): TIFF2025504415000039.tif35170 or a pharma- ceutically acceptable salt thereof, wherein L 2 Each of them has 1 to 6 R b Optionally substituted linear C 1~6 Alkylene or linear C 2~6 It is alkynylene.

[0228] In certain embodiments of Formula (Ib), L 2 1 to 3 R b Optionally substituted linear C 2~3 It is alkylene.

[0229] In certain embodiments of Formula (Ib), L 2 1 to 3 R b In certain of these embodiments, L is a straight chain C alkylene optionally substituted with 2 is -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b)2-*, where the asterisk is -Q 1 For example, L 2 may be -CH2CH2-.

[0230] In certain embodiments of Formula (Ib), L 2 1 to 3 R b In certain of these embodiments, L is a straight chain C alkylene optionally substituted with 2 teeth, TIFF2025504415000040.tif17170, and the asterisk represents -Q 1 For example, L 2 teeth, It may be TIFF2025504415000041.tif9170.

[0231] In certain embodiments of Formula (Ib), L 2 1 to 3 R b Optionally substituted linear C 2~4 It is alkenylene.

[0232] In certain of these embodiments, L 2 teeth, TIFF2025504415000042.tif11170, and the asterisk represents -Q 1 Represents a point of attachment to

[0233] In some embodiments, the compound has formula (Ic): TIFF2025504415000043.tif34170 or a pharma- ceutically acceptable salt thereof, wherein L 2 and L 4 is 1 to 6 R b and independently selected linear C 1~3 is alkylene; L 3 is -O-, -N(H)-, and -N(R d )-.

[0234] In certain embodiments of Formula (Ic), L 2 and L 4 -CH2-, -CHR b - and -C(R b In certain of these embodiments, L 2 and L 4 are -CH2-, respectively.

[0235] In certain embodiments of Formula (Ic), L 3 is -O-.

[0236] In certain embodiments of Formula (Ic), L 3 is -N(H)- or -N(R d )-. For example, L 3 may be -N(H)-.

[0237] In certain embodiments, the compound has formula (Id): TIFF2025504415000044.tif36170 or a pharma- ceutically acceptable salt thereof, wherein L 2 is 1 to 6 R b Optionally substituted linear C 1~3 is alkylene; L 3 is -O-, -N(H)-, and -N(R d )-.

[0238] In certain embodiments of formula (Id), L 2 -CH2-, -CHR b - and -C(R b ) 2.

[0239] In certain embodiments of formula (Id), L 2 1 to 3 R b In certain of these embodiments, L is a straight chain C alkylene optionally substituted with 2 is -CH2CH2-, -CH2CH(R b)-*, and -CH2C(R b )2-*, where the asterisk is -L 3 For example, L 2 may be -CH2CH2-.

[0240] In certain embodiments of formula (Id), L 3 is -O-.

[0241] In certain embodiments of formula (Id), L 3 is -N(H)- or -N(R d )-. For example, L 3 may be -N(H)-.

[0242] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, Heteroaryl with 5-6 ring atoms, 1-4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 3 R c’ the heteroaryl, optionally substituted with 1 to 3 R c’ phenyl, optionally substituted with

[0243] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, Heteroaryl having 6 ring atoms, 1 to 2 of which are ring nitrogen atoms, and the heteroaryl is c’ the heteroaryl, optionally substituted with 1 to 3 R c’ phenyl, optionally substituted with is selected from the group consisting of:

[0244] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q1 1 to 3 R c’ and n is 1 or 2, each of which may be substituted with phenyl or pyridyl.

[0245] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, The file is TIFF2025504415000045.tif20170.

[0246] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 1 to 3 R c’ phenyl or pyridyl, each of which may be substituted by Q 1 Each R in c is optionally substituted with halo and 1 to 6 independently selected halo; C 1~3 alkyl.

[0247] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, TIFF2025504415000046.tif17170;Q 1 Each R in c is independently selected from the group consisting of -F, -Cl, and -CF3.

[0248] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 is a heterocyclyl of 4 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and each heteroatom independently selected from the group consisting of oxo and R c’ may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0249] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q1 teeth, TIFF2025504415000047.tif21170, and m1 and m2 are each independently 0, 1, or 2.

[0250] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, The file is TIFF2025504415000048.tif14170.

[0251] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, TIFF2025504415000049.tif18170; Q 1 R exists in d is -C(O)O(C 1~4 alkyl); and 1 to 3 independently selected R a C which may be substituted with 1~6 is selected from the group consisting of alkyl; or Q 1 R exists in d is C substituted with 1 to 3 -F 2~3 It is an alkyl.

[0252] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, TIFF2025504415000050.tif12170; Q 1 R exists in d is -C(O)O(C 1~4 alkyl); and 1 to 3 independently selected R a C which may be substituted with 1~6 is selected from the group consisting of alkyl; or Q 1 R exists in d is C substituted with 1 to 3 -F 2~3 It is an alkyl.

[0253] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), R c’ is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from 1 to 4 independently selected R c may be substituted with.

[0254] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), R c’ is 1 to 4 R c C which may be substituted with 6~10 It is aryl.

[0255] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), each R 1 is H.

[0256] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), R 1 One occurrence of R c and the remaining R 1 is H.

[0257] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), R 2 is H;R 5 is H.

[0258] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is 1 to 6 R a2 Optionally substituted with C 1~6 It is an alkyl.

[0259] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is an unsubstituted C 1~4 For example, W can be methyl or ethyl.

[0260] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is 1 to 6 R a2 Replaced by C 1~4 It is an alkyl.

[0261] In certain of these embodiments, W is halo; -OH; 1~4 Alkoxy; and C 1~4 C substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy 1~4 It is an alkyl.

[0262] As a non-limiting example of the foregoing embodiment, W is It may be TIFF2025504415000051.tif13170.

[0263] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is 1 to 6 R g Optionally substituted with C 1~6 It is an alkyl.

[0264] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is 1 to 6 R g Replaced by C 1~4 It is an alkyl.

[0265] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is It may be TIFF2025504415000052.tif21170.

[0266] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is Each of which is oxo and R c C 3~12 Cycloalkyl or C 3~12 Cycloalkenyl; and Heteroaryl, heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl, heterocyclyl, or heterocycloalkenyl is selected from the group consisting of oxo and R c The heteroaryl, heterocyclyl or heterocycloalkenyl may be substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0267] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is Each of which is oxo and R c C 3~10 Cycloalkyl or C 3~10 Cycloalkenyl; and Heteroaryl, heterocyclyl or heterocycloalkenyl of 3 to 10 ring atoms, where 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl, heterocyclyl, or heterocycloalkenyl is selected from the group consisting of oxo and R c The heteroaryl, heterocyclyl or heterocycloalkenyl may be substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0268] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is Each of which is oxo and R c C 3~8 Cycloalkyl or C 3~8 Cycloalkenyl; and Heteroaryl, heterocyclyl or heterocycloalkenyl of 3 to 8 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl, heterocyclyl, or heterocycloalkenyl is selected from the group consisting of oxo and R c The heteroaryl, heterocyclyl or heterocycloalkenyl may be substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0269] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is selected from the group consisting of oxo and R c A monocyclic C 3~8 In certain of these embodiments, W is an unsubstituted C 3~8 For example, W can be cyclobutyl.

[0270] In certain embodiments of Formula (Ia), (Ib), (Ic), or (Id), W is a heteroaryl of 3 to 10 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and heteroaryl, heterocyclyl, or heterocycloalkenyl is selected from the group consisting of oxo and R c In certain embodiments, W is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: It may be TIFF2025504415000053.tif19170.

[0271] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), W is a heterocyclyl of 3 to 10 ring atoms in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2and heterocyclyl, heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c In certain embodiments, W is an unsubstituted heterocyclyl of 3 to 10 ring atoms, wherein 1 to 3 ring atoms are selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 In certain embodiments, W is a heteroatom independently selected from the group consisting of: It may be TIFF2025504415000054.tif12170.

[0272] Non-limiting exemplary compounds In some embodiments, the compound is selected from the group consisting of the compounds depicted in Table C1 or a pharma- ceutically acceptable salt thereof.

[0273] [Table C1] TIFF2025504415000056.tif196170TIFF2025504415000057.tif187170TIFF2025504415000058.tif211170TIFF2025504415000059.tif209170

[0274] Pharmaceutical Compositions and Administration overview In some embodiments, a chemical entity (e.g., a compound that inhibits (e.g., antagonizes) STING, or a pharma- ceutically acceptable salt, and / or hydrate, and / or cocrystal, and / or combination with a drug) is administered as a pharmaceutical composition that includes the chemical entity, one or more pharma- ceutically acceptable excipients, and, optionally, one or more additional therapeutic agents, as described herein.

[0275] In some embodiments, the chemical substance can 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 formulation administration such as Tween, poloxamer or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers and wool fat. Chemically modified derivatives such as cyclodextrins, such as α-, β-, and γ-cyclodextrin, or hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilized derivatives, may also be used to enhance delivery of the compounds described herein. Dosage forms or compositions may be prepared that contain 0.005%-100% of chemicals as described herein, with the remainder consisting of non-toxic excipients. Contemplated compositions may contain 0.001%-100%, in one embodiment 0.1-95%, in another embodiment 75-85%, and in a further embodiment 20-80% of chemicals provided herein. Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art and are described, for example, in Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0276] Route of Administration and Composition Components In some embodiments, the chemical entities described herein or pharmaceutical compositions thereof can be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, oral, cutaneous, intracervical, intrasinus, intratracheal, intraintestinal, epidural, intrainterstitial, intraperitoneal, intraarterial, intrabronchial, intracapsular, intracerebral, intracapsular, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intrathecal, intrasynovial, intratesticular, intraarachnoid, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal, nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0277] The composition can be formulated for parenteral administration, for example, for injection by intravenous, intramuscular, subcutaneous, or intraperitoneal route.Generally, such compositions can be prepared as injections, either as liquid solutions or suspensions, or as solid forms suitable for use in preparing solutions or suspensions by adding liquid prior to injection, or these preparations can be emulsified.The preparation of such formulations will be known to those skilled in the art in light of the present disclosure.

[0278] The pharmaceutical forms suitable for use in injections include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions.In all cases, the form must be sterile and fluid to the extent that it can be easily injected.It should also be stable under the conditions of manufacture and storage and preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0279] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, maintaining the required particle size in the case of dispersion, and by using surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of the injectable composition can be brought about by using an agent that delays absorption in the composition, for example, aluminum monostearate and gelatin.

[0280] Sterile injection solution is prepared by adding the active compound in the required amount to a suitable solvent together with various other components listed above as necessary, and then sterilizing by filtration.Generally, dispersion is prepared by adding various sterilized active components to a sterile vehicle that contains a basic dispersion medium and other desired components from the components listed above.In the case of sterile powder for preparing sterile injection solution, the preferred preparation method is vacuum drying and freeze-drying technique, which can obtain powder of active component and any other desired components from the solution that has been previously sterile-filtered.

[0281] Intratumoral injection is described, 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. 2006, 10, 788-795.

[0282] Pharmacologically acceptable excipients that may be used in rectal compositions as gels, creams, enemas, or suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, aerosols, papain in phenoxyethanol, and the like. Examples of the active ingredients include one or more of raven, methyl p-oxybenzoate sodium salt, propyl p-oxybenzoate sodium salt, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxymetabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamin A and vitamin E, and potassium acetate.

[0283] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum to release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

[0284] In other embodiments, the compounds described herein or pharmaceutical compositions thereof are suitable for localized delivery to the digestive or GI tract via oral administration (eg, in solid or liquid dosage form).

[0285] 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 pharma- ceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0286] In one embodiment, the composition takes the form of a unit dosage form such as a pill or tablet, and thus the composition may contain, together with the chemical entities provided herein, diluents such as lactose, sucrose, dicalcium phosphate, lubricants such as magnesium stearate, and binders such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated, such as capsules (or tablets in capsules) containing granules of each agent, bilayer tablets, bicompartment gelcaps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0287] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0288] In certain embodiments, the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not required for excipients of various oral dosage forms, such as tablets and capsules. USP / NF standards are usually sufficient.

[0289] In certain embodiments, the solid oral dosage form may further comprise one or more ingredients that chemically and / or structurally pretreat the composition so that the chemical is delivered to the stomach or lower GI (e.g., the ascending colon and / or the transverse colon and / or the distal colon and / or the 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.

[0290] Examples include upper GI targeting approaches such as the Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

[0291] Other examples include lower GI targeting approaches. Several enteric / pH-responsive coatings and excipients are available to target different regions of the intestinal tract. These materials are usually polymers designed to dissolve or erode at a specific pH range that is selected based on the GI region of desired drug release. These materials also function to protect acid-labile drugs from gastric juices or limit exposure if the active ingredient may irritate the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer) and Marcoat). Other approaches include dosage forms that respond to the local microflora in the GI tract, enteric pressure disintegrating colon delivery capsules and Pulsincap.

[0292] Ophthalmic compositions may include, but are not limited to, any one or more of the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymers), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (a stabilized oxychloro complex; Allergan, Inc.)).

[0293] Topical compositions can include ointments and creams. Ointments are generally semi-solid formulations based on petrolatum or other petroleum derivatives. Creams containing selected active agents are generally viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil. Cream bases are generally water-washable and contain an oil phase, an emulsified phase, and an aqueous phase. The oil phase, sometimes called the "internal" phase, is generally composed of petrolatum and a fatty alcohol (e.g., cetyl or stearyl alcohol), and the aqueous phase usually, although not necessarily, exceeds the oil phase in volume and generally contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. As with other carriers or vehicles, ointment bases must be inert, stable, non-irritating, and non-sensitizing.

[0294] In any of the foregoing embodiments, the pharmaceutical compositions described herein may include one or more of the following: lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0295] Dosage Dosage may vary depending on the patient's requirements, the severity of the condition being treated, and the specific compound being used. The appropriate dosage for a particular situation can be determined by those skilled in the medical field. The total daily dosage can be divided and administered in portions throughout the day, or by any means that achieves continuous delivery.

[0296] In some embodiments, the compounds described herein are administered at a dosage of about 0.001 mg / Kg to about 500 mg / Kg (e.g., about 0.01 mg / Kg to about 100 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 1 mg / Kg; about 0.01 mg / Kg to about 0.1 mg / Kg; about 0.1 mg / Kg to about 100 mg / Kg; about 0.1 mg / Kg to about 10 mg / Kg).

[0297] Regimen The aforementioned dosages can be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every second day, every third day, once a week, twice every few weeks, once every two weeks, once a month).

[0298] In some embodiments, the administration period of the compounds described herein is 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 more. In further embodiments, the period of time during which administration is suspended is 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 more. In one embodiment, the therapeutic compound is administered to the individual for one period of time, followed by administration to the individual for another period of time. In another embodiment, the therapeutic compound is administered for a first period of time and a second period of time following the first period of time, administration is suspended during the second period of time, followed by administration of the therapeutic compound for a third period of time, followed by administration being suspended for a fourth period of time following the third period of time. In one aspect of this embodiment, the period of administration of the therapeutic compound followed by the period of time during which administration is suspended is repeated for a set or indefinite period of time. In further embodiments, the administration period is 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 more. In further embodiments, the period during which administration is discontinued is 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 more.

[0299] Treatment method In some embodiments, methods are provided for treating a subject having a condition, disease or disorder in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., immune disorders, cancer).

[0300] Indications In some embodiments, the condition, disease or disorder is cancer. Non-limiting examples of cancer include melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancer include breast cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer or renal cancer, lung cancer including clear cell carcinoma, 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 cancer. cancer), gastrointestinal stromal tumors, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, theca cell tumor, androgenic tumor, hepatocellular carcinoma, hematologic malignancies including non-Hodgkin's lymphoma (NHL), multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, chronic myeloid leukemia, and acute hematologic malignancies, endometrial or uterine cancer, endometriosis, endometrial stromal sarcoma, fibrosarcoma, choriocarcinoma, salivary gland cancer, vulvar cancer, thyroid cancer, esophageal cancer, and 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, osteosarcoma, leiomyosarcoma, Ewing's sarcoma, peripheral primitive neuroectodermal tumor, urinary tract cancer, thyroid cancer, Wilms' tumor, and abnormal blood vessel proliferation associated with nevus syndrome, edema (e.g., associated with brain tumors), and Meigs' syndrome. In some cases, the cancer is melanoma.

[0301] 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 epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers disease; alternating hemiplegia; Alzheimer's disease; vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; hemangiomatosis; anoxia; aphasia; apraxia; arachnoid cyst; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger's syndrome; ataxia-telangiectasia. telegiectasia);attention deficit hyperactivity disorder;autism;autonomic dysfunction;back pain;Batten disease;Behcet's disease;Bell's palsy;benign idiopathic blepharospasm;benign focal;muscular atrophy;benign intracranial hypertension;Binswanger's disease;blepharospasm;Bloch-Sulzberger syndrome;brachial plexus injury;brain abscess;brain injury;brain tumor (including glioblastoma multiforme);spinal tumor;Brown-Séquard syndrome;Cavan disease;carpal tunnel syndrome;burning pain;central pain syndrome;central pontine myelinolysis;craniopathy;cerebral aneurysm;cerebral arteriosclerosis;cerebral atrophy;cerebral Gigantism;Cerebral palsy;Charcot-Marie-Tooth disease;Chemotherapy-induced neuropathy and neuropathic pain;Chiari malformation;Choreae;Chronic inflammatory demyelinating polyneuropathy;Chronic pain;Chronic regional pain syndrome;Coffin-Lowry syndrome;Coma including persistent vegetative state;Congenital facial paraplegia;Corticobasal degeneration;Cranial arteritis;Craniosynostosis;Creutzfeldt-Jakob disease;Cumulative trauma disease;Cushing's syndrome;Giant inclusion body disease;Cytomegalovirus infection;Dancing eyes-dancing feet syndrome eyes-dancing feet syndrome);Dandy-Walker syndrome;Dawson's disease;Domorsia syndrome;Dejerine-Klumke palsy;Dementia;Dermatomyositis;Diabetic neuropathy;Diffuse sclerosis;Autonomic neuropathy;Dysgraphia;Dyslexia;Dystonia;Early infantile epileptic encephalopathy;Empty Sella syndrome;Encephalitis;Encephalocele;Cerebral trigeminal region angiomatosis;Epilepsy;Erb's palsy;Essential tremor;Fabry disease;Fahr syndrome;syncope;familial spastic paraparesis;febrile convulsions;Fisher syndrome;Friedreich ataxia;frontotemporal dementia and other "tauopathies";Gaucher disease;Gerstmann syndrome;giant cell arteritis;giant cell inclusion disease;globoid cell leukodystrophy;Guillain-Barré syndrome;HTLV-1-associated myelopathy;Hallervorden-Spatz disease;head trauma;headache;hemifacial spasm;hereditary spastic paraplegia;hereditary polyneuropathic ataxia;herpes zoster oticus ;herpes zoster;Hirayama syndrome;HIV-associated dementia and neuropathy (also a neurological sign of AIDS);holoprosencephaly;Huntington's disease and other polyglutamine repeat diseases;hydranencephaly;hydrocephalus;corticosteroid hyperactivity;hypoxia;immune-mediated encephalomyelitis;inclusion body myositis;incontinentia pigmenti;pediatric phytanic acid storage disease;pediatric Refsum disease;infantile spasms;inflammatory myopathies;intracranial cysts;intracranial hypertension;Joubert syndrome;Kerns-Sayre syndrome;Kennedy disease Kinsbone syndrome;Klippel-Feil syndrome;Krabbe disease;Kugelberg-Welander disease;Kuru disease;Lafora disease;Lambert-Eaton myasthenic syndrome;Landau-Kleffner syndrome;Lateral medullary (Wallenberg) syndrome;Learning disabilities;Leigh disease;Lennox-Gastaut syndrome;Lesch-Nyhan syndrome;Leukodystrophy;Lewy body dementia;Lissencephaly;Lock-in syndrome;Lou Gehrig's disease (i.e. motor neuron disease or amyotrophic lateral sclerosis);Lyme disease - neurological sequelae;Macado-Joseph disease;Myelopathy;Megalencephaly;Melkersson-Rosenthal syndrome;Ménière's disease;Meningitis;Menkes disease;Metachromatic leukodystrophy;Microcephaly;Migraine;Miller-Fisher syndrome;Minor stroke;Mitochondrial myopathy;Mobius syndrome syndrome);monolithic muscular atrophy;motor neuron disease;moyamoya disease;mucopolysaccharidosis;multiple infarct dementia;multiple focal motor peripheral neuropathy;multiple sclerosis and other demyelinating disorders;multiple system atrophy with orthostatic hypotension;p muscular dystrophy;myasthenia gravis;myelin-destructive diffuse sclerosis;infantile myoclonus encephalopathy;myoclonus;myopathy;myotonia congenita;narcolepsy;neurofibromatosis;neuroleptic malignant syndrome;neurological manifestations of AIDS;neurological sequelae of lupus;neuromyotonia;neuronal ceroid lipofuscinosis;Neuronal migration disorders;Niemann-Pick disease;O'Sullivan-McLeod syndrome;Occipital neuralgia;Coccidal spinal dysraphism;Ohtahara syndrome;Olivopontocerebellar atrophy;Opsoclonus-myoclonus;Optic neuritis;Orthostatic hypotension;Overuse syndrome;Paresthesia;Parkinson's disease;Congenital paramyotonia;Paraneoplastic disorders;Seizures;Parry-Romberg syndrome;Pelizaeus-Merzbach disease;Periodic paralysis;Peripheral neuropathy;Painful neuropathy and neuropathic pain;Persistent vegetative state;Pervasive developmental disorder;Phosphotic sneeze reflex;Phytanic acid storage disease;Pick's disease;Compressed nerve;Pituitary tumor;Polymyositis;Porencephaly;Post-polio syndrome;Postherpetic neuralgia;Postinfectious encephalomyelitis;Orthostatic Hypotonia;Prader-Willi syndrome;Primary lateral sclerosis;Prion disease;Progressive facial hemimetrophy;Progressive multifocal leukoencephalopathy;Progressive sclerosing poliodystrophy;Progressive supranuclear palsy;Pseudotumor cerebri;Ramsay Hunt syndrome (types I and II);Rasmussen encephalitis;Reflex sympathetic dystrophy syndrome;Refsum disease;Repetitive movement disorder;Repetitive stress injury;Restless legs syndrome;Retroviral-associated myelopathy;Rett syndrome;Reye syndrome;Choreopathy;Sandhoff disease;Schilder's disease;Schisencephaly;Septo-optic dysplasia;Shaken baby syndrome;Valves;Shy-Drager syndrome;Sjogren's syndrome;Sleep apnea;Sotos syndrome syndrome);spasticity;spina bifida;spinal cord injury;spinal tumor;spinal muscular atrophy;stiff body syndrome;stroke;Sturge-Weber syndrome;subacute sclerosing panencephalitis;subcortical arteriosclerotic encephalopathy;Sydenham chorea;syncope;syringomyelia;tardive dyskinesia;Tay-Sachs disease;temporal arteritis;tethered spinal cord syndrome;Thomsen's disease;thoracic outlet syndrome;painful tics;Todd's palsy;Tourette's syndrome;transient ischemic attack;transmitting spongiform encephalopathy;transverse myelitis;traumatic brain injury;tremor;trigeminal neuralgia;tropical spastic paraparesis;tuberous sclerosis;vascular dementia (multi-infarct dementia);vasculitis including temporal arteritis;von Hippel-Lindau disease;Wallenberg syndrome;Werdnig-Hoffmann disease;West syndrome;whiplash injury;Williams syndrome;Wildon's disease amyotrophic lateral sclerosis and Zellweger syndrome;

[0302] In some embodiments, the condition, disease or disorder is a condition associated with STING, e.g., type I interferonopathy (e.g., STING-associated vasculitis in infancy (SAVI)), Aicardi-Goutières syndrome (AGS), genetic forms of lupus, and inflammation-related disorders such as systemic lupus erythematosus, and rheumatoid arthritis. In certain embodiments, the condition, disease or disorder is an autoimmune disease (e.g., an autoinflammatory disease induced by cytosolic DNA). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (IBD), including the polygenic susceptibility chronic inflammatory conditions Crohn's disease (CD) and ulcerative colitis (UC). In certain embodiments, the condition is inflammatory bowel disease. In certain embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by adoptive cell therapy treatment, colitis associated with one or more alloimmune diseases (such as graft-versus-host disease, such as acute graft-versus-host disease and chronic graft-versus-host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is an alloimmune disease (such as graft-versus-host disease, such as 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 (such as oral, esophageal, or intestinal mucositis).

[0303] In some embodiments, modulation of the immune system by STING is provided to treat diseases, including diseases caused by foreign pathogens. Exemplary infections by foreign pathogens that can be treated and / or prevented by the methods of the present invention include infections by bacteria (e.g., gram-positive or gram-negative bacteria), fungi, parasites, and viruses. In one embodiment of the present invention, the infection is a bacterial infection (e.g., infection by E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Staphylococcus aureus, Streptococcus spp., or vancomycin-resistant enterococcus), or sepsis. In another embodiment, the infection is a fungal infection (e.g., infection by mold, yeast, or higher fungi). In yet another embodiment, the infection is a parasitic infection (e.g., an infection caused by a unicellular or multicellular parasite, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondiz). In yet another embodiment, the infection is a viral infection (e.g., an infection caused by a virus associated with AIDS, avian influenza, chickenpox, herpes, the common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and lower or upper respiratory tract infections (e.g., respiratory syncytial virus)).

[0304] In some embodiments, the condition, disease, or disorder is Hepatitis B (see, e.g., WO 2015 / 061294).

[0305] In some embodiments, the condition, disease or disorder is selected from cardiovascular diseases (including, for example, myocardial infarction).

[0306] In some embodiments, the condition, disease or disorder is age-related macular degeneration.

[0307] In some embodiments, the condition, disease or disorder is mucositis, also known as stomatitis, which may occur as a result of damage caused by chemotherapy or radiation therapy, alone or in combination, as well as exposure to radiation outside the context of radiation therapy.

[0308] In some embodiments, the condition, disease, or disorder is uveitis, which is an inflammation of the uvea (e.g., anterior uveitis, e.g., iridocyclitis or iritis; intermediate uveitis (also known as pars planitis); posterior uveitis; or chorioretinitis, e.g., panuveitis).

[0309] 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.

[0310] Further examples include the indications discussed herein and below in the contemplated combination therapy regimens.

[0311] Combination therapy The present disclosure contemplates both monotherapy and combination therapy regimens.

[0312] In some embodiments, the methods described herein may further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of the compounds described herein.

[0313] In certain embodiments, the methods described herein may further comprise administering one or more additional cancer therapies.

[0314] The one or more additional cancer therapies can include, but are 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, and combinations thereof. Immunotherapy includes, but is not limited to, adoptive cell therapy, stem cell and / or dendritic cell induction, blood transfusions, lavage, and / or other therapies, such as, but not limited to, freezing the tumor.

[0315] In some embodiments, the one or more additional cancer therapies is chemotherapy and can include administering one or more additional chemotherapeutic agents.

[0316] In certain embodiments, the additional chemotherapeutic agent is an immunomodulatory moiety, such as an immune checkpoint inhibitor. In certain of these embodiments, the immune checkpoint inhibitor is 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), galectin 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, C D40L, 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, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Targeting immune checkpoint receptors selected from the group consisting of adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155; e.g., CTLA-4 or PD1 or PD-L1. See, e.g., Postow, MJ Clin. Oncol. 2015, 33, 1.

[0317] In certain of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of urelumab, PF-05082566, MEDI6469, TRX518, varlilumab, CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-L1), avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertib, urocupulumab, BKT140, bavituximab, CC-90002, bevacizumab, and MNRP1685A, and MGA271.

[0318] In certain embodiments, the additional chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because of their ability to alkylate many nucleophilic functional groups under conditions present in cells, including but not limited to cancer cells. In further embodiments, alkylating agents include, but are not limited to, cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin. In one embodiment, alkylating agents may function by forming covalent bonds with amino, carboxyl, sulfhydryl, and phosphate groups of biologically important molecules, thereby impairing cellular function, or by modifying the DNA of the cell. In further embodiments, the alkylating agent is synthetic, semi-synthetic, or derivative.

[0319] In certain embodiments, the additional chemotherapeutic agent is an antimetabolite. Antimetabolites act as purines or pyrimidines, which are building blocks of DNA, and generally block these substances from being incorporated into DNA during the "S" phase (of the cell cycle), halting normal development and division. Antimetabolites can also affect RNA synthesis. In one embodiment, the antimetabolite includes, but is not limited to, azathioprine and / or mercaptopurine. In further embodiments, the antimetabolite is synthetic, semi-synthetic, or derivative.

[0320] In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and / or a plant terpenoid. These alkaloids are derived from plants and generally block cell division by inhibiting the function of microtubules. In one embodiment, the plant alkaloid and / or plant terpenoid is a vinca alkaloid, a podophyllotoxin, and / or a taxane. Vinca alkaloids generally bind to specific sites on tubulin and inhibit the assembly of tubulin into microtubules, usually during the M phase of the cell cycle. In one embodiment, the vinca alkaloid is derived from, but is not limited to, Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). In one embodiment, the vinca alkaloid includes, but is not limited to, vincristine, vinblastine, vinorelbine, and / or vindesine. In one embodiment, the taxanes include, but are not limited to, taxol, paclitaxel, and / or docetaxel. In a further embodiment, the plant alkaloids or plant terpenoids are synthetic, semi-synthetic, or derivatives. In a further embodiment, the podophyllotoxins are, but are not limited to, etoposide and / or teniposide. In one embodiment, the taxanes are, but are not limited to, docetaxel and / or ortataxel. In one embodiment, the cancer therapeutic is a topoisomerase. Topoisomerases are essential enzymes that maintain DNA topology. Inhibition of type I or type II topoisomerases disrupts both DNA transcription and replication by disrupting proper DNA supercoiling. In a further embodiment, the topoisomerase is, but is not limited to, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, the type I topoisomerase inhibitor is, but is not limited to, camptothecin. In another embodiment, the camptothecin is, but is not limited to, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and / or ST 1481.In one embodiment, the type II topoisomerase inhibitor is, but is not limited to, epipodophyllotoxin. In further embodiments, the epipodophyllotoxin is, but is not limited to, amsacrine, etoposide, etoposide phosphate, and / or teniposide. In further embodiments, the topoisomerase is synthetic, semi-synthetic, or a derivative, including but not limited to, those found in nature, such as epipodophyllotoxin, a substance naturally occurring in the root of the American Mayapple (Podophyllum peltatum).

[0321] In certain embodiments, the additional chemotherapeutic agent is a stilbenoid. In further embodiments, the stilbenoid includes, but is not limited to, resveratrol, piceatannol, pinosylvin, pterostilbene, α-viniferin, ampelopsin A, ampelopsin E, diptoindonesin C, diptoindonesin F, ε-vinferin, flexosol A, gnetin H, hemsleyanol D, hopeaphenol, trans-diptoindonesin B, astringin, piceid, and diptoindonesin A. In further embodiments, the stilbenoid is synthetic, semi-synthetic, or derivative.

[0322] In certain embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. In one embodiment, the cytotoxic antibiotic is, but is not limited to, actinomycin, anthracenedione, anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and / or clofazimine. In one embodiment, the actinomycin is, but is not limited to, actinomycin D, bacitracin, colistin (polymyxin E), and / or polymyxin B. In another embodiment, the anthracenedione is, but is not limited to, mitoxantrone and / or pixantrone. In a further embodiment, the anthracycline is, but is not limited to, bleomycin, doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin, and / or valrubicin. In a further embodiment, the cytotoxic antibiotic is synthetic, semi-synthetic, or derivative.

[0323] In certain embodiments, the additional chemotherapeutic agent is endostatin, angiogenin, angiostatin, chemokine, angioarrestin, angiostatin (plasminogen fragment), antiangiogenic factor derived from basement membrane collagen (tumstatin, canstatin, or arrestin), antiangiogenic antithrombin III, signal transduction inhibitor, cartilage-derived inhibitor (CDI), CD59 complement fragment, fibronectin fragment, gro-β, heparinase, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon α / β / γ, interferon-inducible protein (I P-10), interleukin-12, kringle 5 (plasminogen fragment), metalloproteinase inhibitor (TIMP), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor 4 (PF4), prolactin 16 kD fragment, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth factor-β (TGF-β), vasculostatin, vasostatin (calreticulin fragment), and the like.

[0324] In certain embodiments, the additional chemotherapeutic agent is selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-L-proline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxel, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine Selected from dolastatins, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea taxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

[0325] In certain embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide and doxorubicin. Additional agents include mTOR (mammalian target of rapamycin) inhibitors, including but not limited to rapamycin, everolimus, temsirolimus, and deforolimus.

[0326] In still other embodiments, the additional chemotherapeutic agents can include those described in US Pat. No. 7,927,613, which is incorporated herein by reference in its entirety.

[0327] In some embodiments, the additional therapeutic agent and / or regimen is one that can be used to treat other STING-associated conditions, such as, for example, type I interferonopathies (e.g., infantile-onset STING-associated vasculitis (SAVI)), Aicardi-Goutières syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis.

[0328] Non-limiting examples of additional therapeutic agents and / or regimens for treating 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®), ABBV-599, Evobruxo, and the like. tinib, and sulfasalazine (Azulfidine®)), and biologics such as abatacept (Orencia®), adalimumab (Humira®), anakinra (Kineret®), certolizumab (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), infliximab (Remicade®), rituximab (Rituxan®), tocilizumab (Actemra®), bovalilizumab, sarilumab (Kevzara®), secukinumab, ABP 501, CHS-0214, ABC-3373, and tocilizumab (ACTEMRA®).

[0329] Non-limiting examples of additional therapeutic agents and / or regimens for treating 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), antimalarials (e.g., hydroxychloroquine (Plaquenil)), corticosteroids (e.g., prednisone) and immunomodulators (e.g., evobrutinib, iveldmide, voclosporin, cenerimod, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®). (Registered Trademarks), Gengraf®, and mycophenolate mofetil) baricitinib, iguratimod, filogotinib, GS-9876, rapamycin, and PF-06650833), and biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, obinutuzumab, bovalilizumab, lurizumab, amphetamine, rifapril ... These include tacicept, PF-06823859, and lupizole, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirorizumab, edoratide, IFN-α-kinoids, OMS721, RC18, RSLV-132, selalizumab, XmAb5871, and ustekinumab (Stelara®).For example, non-limiting treatments for systemic lupus erythematosus include nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarials (e.g., hydroxychloroquine (Plaquenil)), corticosteroids (e.g., prednisone) and immunomodulatory agents (e.g., ivedomide, voclosporin, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil, baric acid, and rifampicin. nibs, filogotinib, and PF-06650833), and biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, bovalilizumab, lurizumab, atacicept, PF-06823859, lupizole, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirorizumab, edoratides, IFN-α-kinoids, RC18, RSLV-132, ceralizumab, XmAb5871, and ustekinumab (Stelara®)). As another example, non-limiting examples of treatments for cutaneous lupus include steroids, immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®), GS-9876, filogotinib, and thalidomide (Thalomid®). Medications and regimens for treating drug-induced lupus and / or neonatal lupus may also be administered.

[0330] Non-limiting examples of additional therapeutic agents and / or regimens for treating infantile-onset STING-associated vasculitis (SAVI) include JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[0331] Non-limiting examples of additional therapeutic agents and / or regimens for treating 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, filgotinib, and baricitinib).

[0332] Non-limiting examples of additional therapeutic agents and / or regimens for treating IBD include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34-selected peripheral blood stem cell transplantation, azathioprine, bertilimumab, BI 655066, BMS-936557, certolizumab pegol (Cimzia®), cobitolimod, corticosteroids (e.g., prednisone, methylprednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbiota transplant, figlotinib, fingolimod, filategrast (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, HMPL-004 (Andrographis paniculata paniculata extract), IMU-838, infliximab, interleukin 2 (IL-2), Janus kinase (JAK) inhibitors, laquinimod, masitinib (AB1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mirikizumab (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peficitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab (MK 3222), TJ301, TNF-Kinoid®, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, batelizumab, VB-201, vedolizumab, and bidofludimus.

[0333] Non-limiting examples of additional therapeutic agents and / or regimens for treating irritable bowel syndrome include alosetron, bile acid sequestrants (e.g., cholestyramine, colestipol, colesevelam), chloride channel activators (e.g., lubiprostone), coated peppermint oil capsules, desipramine, dicyclomine, ebastine, eluxadoline, farnesoid X receptor agonists (e.g., obeticholic acid), fecal microbiota transplantation. , fluoxetine, gabapentin, guanylate cyclase-C agonists (e.g., linaclotide, plecanatide), ivodutant, imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, ondansetron, opioids, paroxetine, pinaverium, polyethylene glycol, pregabalin, probiotics, ramosetron, rifaximin, and tanpanor.

[0334] Non-limiting examples of additional therapeutic agents and / or regimens for treating 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®). ), Gengraf®), antithymocyte globulin, mycophenolate mofetil, intravenous immunoglobulin, rituximab, sirolimus, and alefecept), 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, prostanoids, and tyrosine kinase inhibitors (e.g., imatinib, nilotinib, and dasatinib).

[0335] Non-limiting examples of additional therapeutic agents and / or regimens for treating Crohn's disease (CD) include adalimumab, autologous CD34-selected peripheral blood stem cell transplantation, 6-mercaptopurine, azathioprine, certolizumab pegol (Cimzia®), corticosteroids (e.g., prednisone), etrolizumab, E6011, fecal microbiota transplantation, figlotinib, guselkumab, infliximab, IL-2, JAK inhibitors, matrix metalloproteinase 9 (MMP 9), and / or IL-2 inhibitors. 9) Inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, natalizumab, ozanimod, RHB-104, rifaximin, risankizumab, SHP647, sulfasalazine, thalidomide, upadacitinib, V565, and vedolizumab.

[0336] Non-limiting examples of additional therapeutic agents and / or regimens for treating UC include AbGn-168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, bertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol (Cimzia®), CP-690,550, corticosteroids (e.g., multimax budesonide (multimax budesonide), methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, fecal microbiota transplant, figlotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mirikizumab (LY3074828), RPC1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tofacitinib, ustekinumab, UTTR1147A, and vedolizumab.

[0337] Non-limiting examples of additional therapeutic agents and / or regimens for treating autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0338] Non-limiting examples of additional therapeutic agents and / or regimens for treating iatrogenic autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0339] Non-limiting examples of additional therapeutic agents and / or regimens for treating colitis induced by one or more chemotherapeutic agents include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0340] Non-limiting examples of additional therapeutic agents and / or regimens for treating colitis induced by adoptive cell therapy treatment include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0341] Non-limiting examples of additional therapeutic agents and / or regimens for treating colitis associated with one or more alloimmune diseases include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), sulfasalazine, and eicosapentaenoic acid.

[0342] Non-limiting examples of additional therapeutic agents and / or regimens for treating radiation enteritis include teduglutide, amifostine, angiotensin-converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril), probiotics, selenium administration, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin), sucralfate, and vitamin E.

[0343] Non-limiting examples of additional therapeutic agents and / or regimens for treating collagenous colitis include 6-mercaptopurine, azathioprine, bismuth subsalicate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0344] Non-limiting examples of additional therapeutic agents and / or regimens for treating lymphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), loperamide, mesalamine, methotrexate, and sulfasalazine.

[0345] Non-limiting examples of additional therapeutic agents and / or regimens for treating microscopic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), fecal microbiota transplant, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0346] Non-limiting examples of additional therapeutic agents and / or regimens for treating alloimmune disorders include intrauterine platelet transfusions, intravenous immunoglobulin, maternal steroids, abatacept, alemtuzumab, alpha 1-antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilizumab (d acilzumab, defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neiflizumab, pentostatin, pevonegistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0347] Non-limiting examples of additional therapeutic agents and / or regimens for treating multiple sclerosis (MS) include alemtuzumab (Lemtrada®), ALKS 8700, amiloride, ATX-MS-1467, azathioprine, baclofen (Lioresal®), beta interferons (e.g., IFN-β-1a, IFN-β-1b), cladribine, corticosteroids (e.g., methylprednisolone), daclizumab, dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), fluoxetine, rifampicin ... These include xetine, glatiramer acetate (Copaxone®), hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVax™, ocrelizumab, ofatumumab, pioglitazone, and RPC1063.

[0348] Non-limiting examples of additional therapeutic agents and / or regimens for treating graft-versus-host disease include abatacept, alemtuzumab, alpha 1-antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defibroblastoma, and the like. defribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neiflizumab, pentostatin, pevonegistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0349] Non-limiting examples of additional therapeutic agents and / or regimens for treating acute graft-versus-host disease include alemtuzumab, alpha-1-antitrypsin, antithymocyte globulin, basiliximab, brentuximab, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate mofetil, natalizumab, neiflizumab, pentostatin, photopheresis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.

[0350] Non-limiting examples of additional therapeutic agents and / or regimens for treating chronic graft-versus-host disease include abatacept, alemtuzumab, AMG592, antithymocyte globulin, basiliximab, bortezomib, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0351] Non-limiting examples of additional therapeutic agents and / or regimens for treating celiac disease include AMG 714, AMY01, Aspergillus niger prolyl endoprotease, BL-7010, CALY-002, GBR 830, Hu-Mik-β-1, IMGX003, KumaMax, larazotide acetate, Nexvan2®, pancrelipase, TIMP-GLIA, vedolizumab, and ZED1227.

[0352] Non-limiting examples of additional therapeutic agents and / or regimens for treating psoriasis include topical corticosteroids, topical crisaborole / AN2728, topical SNA-120, topical SAN021, topical tapinarof, topical tocafinib, topical IDP-118, topical M518101, topical calcipotriene and betamethasone dipropionate (e.g., MC2-01 cream and Taclonex®), topical P-3073, topical LEO90100 (Enstilar®), topical betamethasone dipropionate (Sernivo®), halobetasol propionate (Ultravate®), vitamin D analogs (e.g., calcipotriene (Dovonex®) and calcitriol (Vectical®)), anthralin (e.g., Dritho-scalp® and Dritho-creme®), topical retinoids (e.g., tazarotene (e.g., Tazorac® and Avage®), topical steroids (e.g., benzodiazepine (Benza®), ... )), calcineurin inhibitors (e.g., tacrolimus (Prograf®), and pimecrolimus (Elidel®)), salicylic acid, coal tar, moisturizers, phototherapy (e.g., sun exposure, UVB phototherapy, narrowband UVB phototherapy, Goeckerman therapy, psoralen ultraviolet A (PUVA) treatment, and excimer laser), retinoids (e.g., acitretin (Soriatane®)), methotrexate (Trexall®, Otrexup®, Rasuvo®), ), Rheumatrex®), Apo805K1, baricitinib, FP187, KD025, Prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (serlopitant), upadacitinib (ABT-494), aprmilast, tofacitinib, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biologics (e.g., etanercept (Enbrel®), entanercept-szzs (Elrezi®), infliximab (Remicade®), adalimumab (Humira®), adalimumab-adbm (Cyltezo®), ustekinumab (Stelara®), golimumab (Simponi®), apremilast (Otezla®), secukinumab (Cosentyx®), certolixumab pegolpegol), secukinumab, tildrakizumab-asmn, infliximab-dyyb, abatacept, ixekizumab (Taltz®), ABP 710, BCD-057, BI695501, bimekizumab (UCB4940), CHS-1420, GP2017, guselkumab (CNTO 1959), HD203, M923, MSB11022, mirikizumab (LY3074828), PF-06410293, PF-06438179, risankizumab (BI655066), SB2, SB4, SB5, siliq (brodalumab), namilumab (MT203, tildrakizumab (MK-3222), and ixekizumab (Taltz®)), thioguanine, and hydroxyurea (e.g., Droxia® and Hydrea®).

[0353] Non-limiting examples of additional therapeutic agents and / or regimens for treating cutaneous T-cell lymphoma include phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrowband UVB phototherapy, Goeckerman therapy, psoralen ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photopheresis, radiation therapy (e.g., spot irradiation and total skin electron beam therapy), stem cell transplantation, corticosteroids, imiquimod, bexarotene gel, topical bis-chloroethyl-nitrourea, mechlorethamine gel, vorinostat (Zolinza®), romidepsin (Istodax®), pralatrexate (Folotyn®), biologics (e.g., alemtuzumab (Campath®), brentuximab vedotin (SGN-35), mogamulizumab, and IPH4102).

[0354] Non-limiting examples of additional therapeutic agents and / or regimens for treating uveitis include corticosteroids (e.g., intravitreal triamcinolone acetonide injectable suspension), antibiotics, antivirals (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 (S imponi®), certolizumab (Cimzia®), rituximab (Rituxan®), abatacept (Orencia®), basiliximab (Simulect®), anakinra (Kineret®), canakinumab (Ilaris®), gevokixumab (XOMA052), tocilizumab (Actemra®), alemtuzumab (Campath®), efalizumab (Raptiva®), LFG316, sirolimus (Santen®), abatacept, sarilumab (Kevzara®), and daclizumab (Zenapax®)), cytotoxic drugs, surgical implants (e.g., fluocinolone inserts), and vitrectomy.

[0355] Non-limiting examples of additional therapeutic agents and / or regimens for treating mucositis include AG013, SGX942 (dasketide), amifostine (Ethyol®), cryotherapy, cepacol troches, capsaicin troches, mucoadhesives (e.g., MuGard®), oral diphenhydramine (e.g., Benadry® elixir), oral bioadhesives (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita (chamomilla recutita mouthwash, grape vegetal exosomes, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periodogard®), topical sedatives (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble beta-1,3 / 1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, granules containing vaccinium myrtillus extract, macleaya cordata alkaloids and echinacea angustifolia extract (e.g., SAMITAL®), and GI cocktail (gastric acid suppressants such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungals (e.g., nystatin), and pain relievers (e.g., hurricane liquid)).For example, non-limiting examples of treatments for oral mucositis include AG013, amifostine (Ethyol®), cryotherapy, cepacol troches, mucoadhesives (e.g., MuGard®), oral diphenhydramine (e.g., Benadry® elixir), oral bioadhesives (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita (chamomilla recutita mouthwash, grape vegetal exosomes, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periodogard®), topical sedatives (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (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 GI cocktails (gastric acid suppressants such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungals (e.g., nystatin), and painkillers (e.g., hurricane liquid)). As another example, a non-limiting example of a treatment for esophageal mucositis is xylocaine (e.g., gel viscous xylocaine 2%). As another example, a treatment for intestinal mucositis, a treatment for reducing intestinal mucositis, and a treatment for the signs and symptoms of intestinal mucositis include GI cocktails (gastric acid suppressants such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungals (e.g., nystatin), and painkillers (e.g., hurricane liquid)).

[0356] In certain embodiments, the subject is administered a second therapeutic agent or treatment regimen prior to contacting with or administering the chemical (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month).

[0357] In other embodiments, the subject is administered a second therapeutic agent or regimen at about the same time as contacting with or administering 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.

[0358] In yet other embodiments, a second therapeutic agent or treatment regimen is administered to the subject after contact with or administration of the chemical entity (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month).

[0359] Patient Selection In some embodiments, the methods described herein further include identifying a subject (e.g., a patient) in need of such treatment (e.g., by biopsy, endoscopy, or other conventional methods known in the art). In certain embodiments, STING protein can serve as a biomarker for certain types of cancer, such as colon and prostate cancer. In other embodiments, identifying the subject can include assaying whether the patient's tumor microenvironment is absent of T cells and / or has exhausted T cells (e.g., the patient has one or more non-inflammatory tumors). Such patients can also include patients who are resistant to treatment with checkpoint inhibitors. In certain embodiments, such patients can be treated with the chemical entities described herein, e.g., to recruit T cells to the tumor, and optionally, can be further treated with one or more checkpoint inhibitors, e.g., once T cells are exhausted.

[0360] In some embodiments, the chemical entities, methods, and compositions described herein can be administered to certain treatment-resistant patient populations (e.g., patients resistant to checkpoint inhibitors; e.g., patients with one or more non-inflammatory tumors, e.g., tumors lacking T cells or exhausted T cells).

[0361] Preparation of compounds As those skilled in the art will recognize, the method of synthesizing the compounds of the formula herein will be obvious to those skilled in the art.Synthetic chemical transformations and protective group techniques (protection and deprotection) useful for synthesizing the compounds described herein are known in the art, and include, for example, those described in R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TWGreene and RGM.Wuts, Protective Groups in Organic Synthesis, 2d.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 and can be prepared by known methods or are commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein may be interchangeable with alternative art-recognized equivalents. For example, in many reactions, triethylamine may be interchangeable with other bases, such as non-nucleophilic bases (e.g., diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

[0362] Those skilled in the art will appreciate that, for example, 1One will recognize the various analytical methods that can be used to characterize the compounds described herein, including H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of the characterization methods available to one of skill in the art and is not intended to be limiting.

[0363] To further illustrate the foregoing, the following non-limiting exemplary synthetic schemes are included. Variations of these examples within the scope of the claims are within the scope of those skilled in the art and are considered to be within the scope of the invention as described and claimed herein. The reader will recognize that the artisan armed with this disclosure and those skilled in the art can prepare and use the invention without the exhaustive examples. EXAMPLES

[0364] Chemical Abbreviations ADDP = 1,1'-(azodicarbonyl)-dipiperidine ACN = acetonitrile Boc2O = di-tert-butylpyrocarbonate DCM = dichloromethane DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide Dppf = bis(diphenylphosphino)ferrocene HPLC = High Performance Liquid Chromatography LC-MS = Liquid Chromatography Mass Spectrometry NMR=nuclear magnetic resonance RT=retention time TBUP = tri-n-butylphosphine TEA = trimethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran FA = formic acid Speedvac=Savant SC250EXP Speedvac concentrator DMSO = dimethyl sulfoxide Na2SO4 = Sodium sulfate

[0365] Materials and Methods LC-MS was recorded using one of the following methods:

[0366] Examples 1-2: LCMS Method A: Kinetex EVO C18 100A, 30*3mm, injection volume 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution was from 10% MPB to 95% in 2.00 min, held at 95% MPB for 0.30 min, and from 95% MPB to 10% in 0.10 min.

[0367] LCMS method B: HALOC18, 30*3mm, injection volume 0.5μL, flow rate 1.5mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 0.05%TFA and mobile phase B (MPB): acetonitrile / 0.05%TFA. Elution was from 5% MPB to 100% in 1.20min, held at 100% MPB for 0.60min, from 100% MPB to 5% in 0.02min, then equilibrated to 5% MPB for 0.18min.

[0368] NMR were recorded on a BRUKER NMR 300.03 Mz, DUL-CH, ULTRASHIELD™ 300, AVANCE II 300 B-ACS™ 120, or a BRUKER NMR 400.13 Mz, BBFO, ULTRASHIELD™ 400, AVANCE III 400, B-ACS™ 120.

[0369] Examples 3 to 24 Method A Equipment: Agilent LCMS system equipped with DAD and ELSD detectors. Ion mode: Positive Column: Waters X-Bridge C18, 50*2.1mm*5μm or equivalent Mobile phase: A: H2O (0.04%TFA); B: CH3CN (0.02%TFA) Gradient: 4.5 min gradient method, actual method depends on clogP of compound. Flow rate: 0.6mL / min or 0.8mL / min Column temperature: 40℃ or 50℃ UV: 220nm

[0370] Method B Equipment: Agilent LCMS system equipped with DAD and ELSD detectors. Ion mode: Positive Column: Waters X-Bridge ShieldRP18, 50*2.1mm*5μm or equivalent Mobile phase: A: H2O (0.05% NH3·H2O) or 10 mM ammonium bicarbonate; B: CH3CN Gradient: 4.5 min gradient method; actual method depends on the clogP of the compound. Flow rate: 0.6mL / min or 0.8mL / min Column temperature: 40℃ UV: 220nm

[0371] Preparative HPLC conditions device: 1. GILSON 281 and Shimadzu LCMS 2010A 2. GILSON 215 and Shimadzu LC-20AP 3. GILSON 215 Mobile phase: A: NH4OH / H2O=0.05% v / v; B: ACN A: FA / HO=0.225% v / v; B: ACN column Xtimate C18 150*25mm*5μm Flow rate: 25mL / min or 30mL / min Monitor wavelength: 220 and 254 nm Slope: Actual method depends on the clogP of the compound Detector: MS trigger or UV

[0372] Preparation Examples Schemes for preparing key intermediates: The schemes below show the preparation of key intermediates.

[0373] Scheme 1: Synthesis of intermediate 1 (5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-amine TFA salt) TIFF2025504415000060.tif86170 tert-Butyl N-(5-bromo-1H-indol-3-yl)carbamate (4.0 g, 12.8 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (20 mL) and water (4 mL), then Cs2CO3 (8.3 g, 25.7 mmol, 2.0 equiv.), Pd(dppf)Cl2 (0.9 g, 1.2 mmol, 0.1 equiv.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.7 g, 19.2 mmol, 1.2 equiv.) were added under nitrogen atmosphere. The reaction mixture was heated to 90° C. for 3 h, then cooled to ambient temperature and quenched by adding water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:1) to give tert-butyl (5-vinyl-1H-indol-3-yl)carbamate (2.0 g) as a brown solid. LCMS Method A: [M+H] + =259.

[0374] Step 2: tert-Butyl (5-(2-hydroxyethyl)-1H-indol-3-yl)carbamate tert-Butyl (5-vinyl-1H-indol-3-yl)carbamate (2.0 g, 7.7 mmol, 1.0 equiv.) was dissolved in THF (10 mL) and cooled to 0° C., then BH3-THF (1 M, 46.4 mL, 46.4 mmol, 6.0 equiv.) was added dropwise. After stirring at ambient temperature for 2 h, aqueous NaOH (1 M, 14 mL, 14.0 mmol, 2.0 equiv.) was added. This was followed by the addition of H2O2 (30% wt. in water, 2.6 mL, 23.2 mmol, 3.0 equiv.) and the reaction mixture was maintained at 0° C. The reaction mixture was stirred at 0° C. for an additional hour and then quenched by the addition of saturated aqueous NH4Cl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:1) to give tert-butyl (5-(2-hydroxyethyl)-1H-indol-3-yl)carbamate (605.0 mg) as a brown solid. LCMS Method A: [M+H] + =277.

[0375] Step 3: tert-Butyl N-(5-[2-[4-(trifluoromethyl)phenoxy]ethyl]-1H-indol-3-yl)carbamate tert-Butyl N-[5-(2-hydroxyethyl)-1H-indol-3-yl]carbamate (338.0 mg, 1.2 mmol, 1.0 equiv.) and 4-(trifluoromethyl)phenol (198.2 mg, 1.2 mmol, 1.0 equiv.) were dissolved in THF (10 mL), then ADDP (612.4 mg, 2.4 mmol, 2.0 equiv.) and TBUP (494.9 mg, 2.4 mmol, 2.0 equiv.) were added. The reaction mixture was heated to 70° C. for 5 h, then cooled to ambient temperature and quenched by adding water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give tert-butyl N-(5-[2-[4-(trifluoromethyl)phenoxy]ethyl]-1H-indol-3-yl)carbamate (260.0 mg) as a brown solid. LCMS Method A: [M+H] + =421.

[0376] Step 4: 5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-amine TFA salt tert-Butyl N-(5-{2-[4-(trifluoromethyl)phenoxy]ethyl}-1H-indol-3-yl)carbamate (260.0 mg, 0.6 mmol, 1.0 equiv) was dissolved in DCM (2 mL) and TFA (2 mL). The reaction mixture was stirred at ambient temperature for 30 min and then concentrated in vacuo to give 5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-amine TFA salt (350.0 mg) as a yellow solid. LCMS Method A: [M+H] + =321.

[0377] Example 1: 1-(Tetrahydrofuran-2-yl)-N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-yl)methanesulfonamide [Compound 125] TIFF2025504415000061.tif591705-[2-[4-(trifluoromethyl)phenoxy]ethyl]-1H-indol-3-amine trifluoroacetate (260.0 mg, 0.4 mmol, 1.0 equiv) and TEA (0.2 mL, 1.4 mmol, 3.0 equiv) were dissolved in DCM (5 mL) and then oxolan-2-ylmethanesulfonyl chloride (89.9 mg, 0.4 mmol, 1.0 equiv) was added. The reaction mixture was stirred at ambient temperature for 2 h and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:1) to give the first material which was further purified by preparative HPLC with the following conditions: Column: Sunfire preparative C18 column, 30*150, 5μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 45B to 75B in 7 min; 254 / 210nm; RT1: 6.42 min. This gave 1-(tetrahydrofuran-2-yl)-N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-yl)methanesulfonamide (12.9mg) as a white solid. LCMS Method B: [M+H] + =469. 1 H NMR(400MHz,DMSO-d6):δ 11.01(d,J=2.4Hz,1H),9.10(s,1H),7.64(d,J=8.8Hz,2H),7.57(s,1H),7.31(d,J=8.4Hz,1H),7.26(d,J=2.4Hz,1H),7.14-7.09(m,3H) ),4.30-4.21(m,3H),3.75-3.71(m,1H),3.64-3.62(m,1H),3.18-3.11(m,4H),2.05-2.01(m,1H),1.82-1.78(m,2H),1.64-1.59(m,1H).

[0378] TIFF2025504415000062.tif60170

[0379] Example 3: Synthesis of N-(5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-indol-3-yl)ethane-1-sulfonamide TIFF2025504415000063.tif31170 tert-Butyl 3-{[(tert-butoxy)carbonyl]amino}-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-indole-1-carboxylate (83.2 mg, 0.16 mmol, 1.0 equiv) was dissolved in DCM (2 mL) and then TFA (500 μl) was added to the solution. The mixture was heated at 30° C. for 2 h. The reaction mixture was concentrated in a Speedvac to give a residue. This residue and ethanesulfonyl chloride (41.0 mg, 0.32 mmol, 2.0 equiv) were then dissolved in DCM (2 mL) and then TEA (116 μl, 0.8 mmol, 5.0 equiv) was added. The mixture was heated at 30° C. for 16 h. The reaction mixture was concentrated in a Speedvac to give a residue that was purified by preparative HPLC to give N-(5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-indol-3-yl)ethane-1-sulfonamide (14.2 mg, 0.034 mmol) as a powder. MS-ESI, 413.2 [M+H + ]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.89(br s,1H),9.01(s,1H),7.68(br d,J=8.1Hz,2H),7.58(br d,J=8.0Hz,2H),7.28-7.12(m,3H),6.73(dd,J=8.7,2.4Hz,1H),4.19(t,J= 6.6Hz,2H),3.22-3.09(m,2H),2.92(q,J=7.4Hz,2H),1.22(t,J=7.3Hz,3H).

[0380] Example 4: Synthesis of N-(5-{2-[4-(trifluoromethyl)phenoxy]ethyl}-1H-indol-3-yl)ethane-1-sulfonamide TIFF2025504415000064.tif29170 tert-Butyl (5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-yl)carbamate (67.2 mg, 0.16 mmol, 1.0 equiv) was dissolved in DCM (2 mL) and then TFA (500 μl) was added to the solution. The mixture was heated at 30° C. for 2 h. The reaction mixture was concentrated in a Speedvac to give a residue. This residue and ethanesulfonyl chloride (41.0 mg, 0.32 mmol, 2.0 equiv) were then dissolved in DCM (2 mL) and then TEA (116 μl, 0.8 mmol, 5.0 equiv) was added. The mixture was heated at 30° C. for 16 h. The reaction mixture was concentrated in a Speedvac to give a residue that was purified by preparative HPLC to give N-(5-{2-[4-(trifluoromethyl)phenoxy]ethyl}-1H-indol-3-yl)ethane-1-sulfonamide (33.3 mg, 0.081 mmol) as a powder. MS-ESI, 413.2 [M+H + ]. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.03-10.95(m,1H),9.07(s,1H),7.63(d,J=8.8Hz,2H),7.55(s,1H),7.29(d,J=8.3Hz,1H),7.24(d,J=2.5Hz, 1H),7.14-7.06(m,3H),4.27(t,J=6.8Hz,2H),3.17-3.07(m,2H),2.93(q,J=7.4Hz,2H),1.23(t,J=7.4Hz,3H).

[0381] The compounds in the following table were prepared using the procedures of Examples 3 and 4 above with the appropriate starting materials.

[0382] TIFF2025504415000065.tif196170TIFF2025504415000066.tif200170TIFF2025504415000067.tif211170 TIFF2025504415000068.tif197170TIFF2025504415000069.tif210170TIFF2025504415000070.tif157170

[0383] Biological assays STING pathway activity by the compounds described herein was measured using THP1-Dual™ cells (KO-IFNAR2).

[0384] THP1-Dual™ KO-IFNAR2 cells (obtained from Invivogen) were maintained in RPMI, 10% FCS, 5ml P / S, 2mM L-glut, 10mM Hepes, and 1mM sodium pyruvate. Compounds were spotted by Echo to final concentrations of 0.0017-100μM onto empty 384-well tissue culture plates (Greiner 781182). Cells were plated at 2x10E6 cells / mL in 40μL per well on TC plates. For activation with STING ligand, 2'3'cGAMP (MW 718.38, obtained from Invivogen) was prepared in Optimem medium.

[0385] The following solutions were prepared for each of the 1x384 plates: Solution A: 2 mL of Optimem containing one of the following stimuli: ■ 10mM 2'3'cGAMP 60μL → Stock 150μM Solution B: 2 mL of Optimem containing 60 μL of Lipofectamine 2000 → Incubate at room temperature for 5 minutes

[0386] 2 mL of solution A and 2 mL of solution B were mixed and incubated at room temperature (RT) for 20 min. 20 μL of transfection solution (A+B) was added on top of the plated cells at a final concentration of 15 μM of 2'3'cGAMP. The plate was then immediately centrifuged at 340 g for 1 min and then incubated at 37° C., 5% CO2, >98% humidity for 24 h. Luciferase reporter activity was then measured. EC was assayed using standard methods known in the art. 50 values ​​were calculated.

[0387] Luciferase reporter assay: 10 μL of supernatant from the assay was transferred to a white 384 plate with flat bottom square wells. One QUANTI-Luc™ Plus pouch was dissolved in 25 mL of water. 100 μL of QLC stabilizer was added per 25 mL of QUANTI-Luc™ Plus solution. Then 50 μL of QUANTI-Luc™ Plus / QLC solution was added per well. Luminescence was measured on a plate reader (e.g., Spectramax I3X (Molecular Devices GF3637001)).

[0388] Luciferase reporter activity was then measured. EC 50 values ​​were calculated.

[0389] Table BA shows the activity of compounds in the STING reporter assay: <0.008 μM = "++++++"; ≧0.008 and <0.04 μM = "+++++"; ≧0.04 and <0.2 μM = "++++"; ≧0.2 and <1 μM = "+++"; ≧1 and <5 μM = "++"; ≧5 and <100 μM = "+".

[0390] [Table BA]

[0391] Numbered Sections The compounds, compositions, methods, and other subject matter described herein are further described in the numbered sections below.

[0392] 1. Formula (I): TIFF2025504415000072.tif40170 or a pharma- ceutically acceptable salt or tautomer thereof, wherein: L A But -(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4) a4 -(L 5 ) a5 -*, where * is Q 1 represents the attachment point to; a1, a2, a3, a4, and a5 each independently represent 0 or 1; However, a1+a2+a3+a4+a5≧1 is satisfied. L 1 , L 3 , and L 5 are -O-, -N(H)-, -N(R d )-, S(O) 0~2 and -C(=O)-; However, if one or both of a2 and a4 are 0, L 1 , L 3 , and L 5 with the proviso that the combination of: L 2 and L 4 Each of the Each of them has 1 to 6 R b Optionally substituted linear C 1~6 Alkylene, linear C 2~6 Alkenylene or linear C 2~6 Alkynylene; Each of them has 1 to 3 R c Optionally substituted with C 3~10 Cycloalkylene or C 3~10 Cycloalkenylene; and Heterocyclylene or heterocycloalkenylene, each having 4 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is selected from 1 to 3 R c The heterocyclylene or heterocycloalkenylene may be optionally substituted by independently selected from the group consisting of: Q1 But -R g and; Y 1 , Y 2 , and Y 3 But, CR 1 , C(=O), N, and NR 2 each independently selected from the group consisting of: X 1 But O, S, N, NR 2 , and C.R. 1 selected from the group consisting of; X 2 But O, S, N, NR 4 , and C.R. 5 selected from the group consisting of; Each TIFF2025504415000073.tif5170 are independently a single bond or a double bond, provided that X 1 and X 2 is a heteroaryl; and Y 1 , Y 2 , and Y 3 provided that the six-membered ring containing is aryl or heteroaryl; Furthermore, L A Y 1 , Y 2 , and Y 3 provided that the cyclic group cannot contain a cyclic group directly attached to a six-membered ring containing R 1 and R 5 Each occurrence of H;R c ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 2 and R 4 Each occurrence of H;R d ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 6 But H;R d ; and R g selected from the group consisting of; W, Each of them has 1 to 6 R a2 or R g Optionally substituted with C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 Alkynyl; Each of which is oxo and R c C 3~12 Cycloalkyl or C 3~12 Cycloalkenyl; and Heteroaryl, heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl, heterocyclyl, or heterocycloalkenyl is selected from the group consisting of oxo and R c The heteroaryl, heterocyclyl or heterocycloalkenyl may be substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of However, when W is heteroaryl, heterocyclyl, or heterocycloalkenyl, it is C(=O)NR via a ring carbon atom. 6 provided that it is attached to a group; R a and R a2 Each occurrence of is -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); and cyano; R b and R ceach occurrence of is selected from halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1~10 Alkyl;C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)NR'R''; and -SF5; R d Each occurrence of a C which may be substituted with 1~6 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 independently selected from the group consisting of alkoxy; R e and R f Each occurrence of is H;NR'R'', -OH, halo, C 1~4 Alkoxy and C 1~4 C may be substituted by 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~6 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 1~4independently selected from the group consisting of alkoxy; R g Each occurrence of Each of them is oxo, R c , and R h C 3~12 Cycloalkyl or C 3~12 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is oxo, R c , and R h The heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl with 5 to 12 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl is oxo, R c , and R h The heteroaryl, which may be substituted with 1 to 4 substituents independently selected from the group consisting of: Oxo, R c , and R h C 6~10 Aryl independently selected from the group consisting of: R h Each occurrence of Each of them has 1 to 4 R i Optionally substituted with C 3~12 Cycloalkyl or C 3~12 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(Rd ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of 1 to 4 R i the heterocyclyl or heterocycloalkenyl optionally substituted by Heteroaryl with 5 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R i the heteroaryl, optionally substituted with 1 to 4 R i Optionally substituted with C 6~10 Aryl independently selected from the group consisting of: R i Each occurrence of C 1~6 Alkyl;C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 Independently selected from the group consisting of haloalkoxy; and halo; L g Each occurrence of -O-, -NH-, -NR d , -S(O) 0~2 , C(O), and 1 to 3 R a C which may be substituted with 1~3 independently selected from the group consisting of alkylene; each occurrence of bg is independently 1, 2, or 3; Each occurrence of R' and R'' is H; -OH; and C 1~4 independently selected from the group consisting of alkyl, The compound or a pharma- ceutically acceptable salt thereof or a tautomer thereof.

[0393] 2. The compound according to item 1, wherein a2 is 1.

[0394] 3.L 2 However, each of them has 1 to 6 R b Optionally substituted linear C1~6 Alkylene, linear C 2~6 Alkenylene or linear C 2~6 Item 3. The compound according to item 1 or 2, which is alkynylene.

[0395] 4.L 2 However, 1 to 6 R b Optionally substituted linear C 1~6 Item 4. The compound according to any one of Items 1 to 3, wherein the alkylene is alkylene.

[0396] 5.L 2 But 1 to 3 R b Optionally substituted linear C 1~3 Item 5. The compound according to any one of items 1 to 4, wherein the alkylene is alkylene.

[0397] 6.L 2 -CH2-, -CHR b - and -C(R b 6. The compound according to any one of items 1 to 5, wherein the compound is selected from the group consisting of:

[0398] 7.L 2 The compound according to any one of items 1 to 6, wherein is -CH2-.

[0399] 8.L 2 But 1 to 3 R b Optionally substituted linear C 2~3 Item 5. The compound according to any one of items 1 to 4, wherein the alkylene is alkylene.

[0400] 9.L 2 But 1 to 3 R b Item 9. The compound according to any one of items 1 to 4 or 8, wherein the alkyl group is a straight-chain C2 alkylene optionally substituted with:

[0401] 10.L 2 -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is selected from the group consisting of -(L 3 ) a3- represents a point of attachment to the compound according to any one of items 1 to 4 or 8 to 9.

[0402] 11.L 2 The compound according to any one of items 1 to 4 or 8 to 10, wherein is -CH2CH2-.

[0403] 12.L 2 But 1 to 3 R b Item 9. The compound according to any one of items 1 to 4 or 8, wherein R is a straight-chain C3 alkylene optionally substituted with R.

[0404] 13.L 2 but, TIFF2025504415000074.tif18170, and the asterisk is -(L 3 ) a3 13. The compound according to any one of items 1 to 4, 8, or 12, wherein - represents a point of attachment to.

[0405] 14.L 2 However, 1 to 6 R b Optionally substituted linear C 2~6 The compound according to any one of items 1 to 3, which is alkenylene.

[0406] 15.L 2 But 1 to 3 R b Optionally substituted linear C 2~4 Item 15. The compound according to any one of items 1 to 3 or 14, which is alkenylene.

[0407] 16.L 2 but, TIFF2025504415000075.tif12170, and the asterisk is -(L 3 ) a3 - represents a point of attachment to the compound according to any one of items 1 to 3 or 14 to 15.

[0408] 17.L 2 but, Each of them has 1 to 3 R cOptionally substituted with C 3~10 Cycloalkylene or C 3~10 Cycloalkenylene; and Heterocyclylene or heterocycloalkenylene, each having 4 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is selected from 1 to 3 R c The heterocyclylene or heterocycloalkenylene may be optionally substituted by The compound according to item 1 or 2, selected from the group consisting of:

[0409] 18.L 2 but, 1 to 3 R c Optionally substituted with C 3~8 Cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is selected from 1 to 3 R c The heterocyclylene may be substituted with Item 18. The compound according to any one of items 1 to 2 or 17, selected from the group consisting of:

[0410] 19.L 2 But 1-2 R c may be substituted with TIFF2025504415000076.tif20170, n1 and n2 are independently 0, 1, or 2; Q 2 But, CH, CR c , or N; an asterisk is -(L 3 ) a3 - represents a point of attachment to the compound according to any one of items 1-2 or 17-18.

[0411] 20.Q2 Item 20. The compound according to item 19, wherein is CH.

[0412] 21. The compound according to item 19 or 20, wherein n1 and n2 are each 0.

[0413] 22.L 2 but, TIFF2025504415000077.tif11170, and the asterisk is -(L 3 ) a3 22. The compound according to any one of items 1 to 2 or 17 to 21, wherein - represents a bonding point to -.

[0414] 23. The compound according to item 1, wherein a2 is 0.

[0415] 24. The compound according to any one of items 1 to 23, wherein a1 is 1.

[0416] 25.L 1 -O-, -N(H)-, -N(R d 25. The compound according to any one of items 1 to 24, wherein the R is selected from the group consisting of -R-, ...

[0417] 26.L 1 26. The compound according to any one of items 1 to 25, wherein is -O-.

[0418] 27. The compound according to any one of items 1 to 23, wherein a1 is 0.

[0419] 28. The compound according to any one of items 1 to 27, wherein a3 is 1.

[0420] 29.L 3 -O-, -N(H)-, -N(R d 29. The compound according to any one of items 1 to 28, wherein the compound is selected from the group consisting of -S-, -R ...

[0421] 30.L 3 30. The compound according to any one of items 1 to 29, wherein is -O-.

[0422] 31.L 3 is -N(H)- or -N(R d 30. The compound according to any one of items 1 to 29, wherein the R is —N(H)—, and optionally —N(H)—.

[0423] 32. The compound according to any one of items 1 to 27, wherein a3 is 0.

[0424] 33. The compound according to any one of items 1 to 32, wherein a4 is 1.

[0425] 34.L 4 But 1 to 3 R b Optionally substituted linear C 1~3 Item 34. The compound according to any one of items 1 to 33, wherein the compound is alkylene.

[0426] 35.L 4 The compound according to any one of items 1 to 34, wherein is -CH2-.

[0427] 36.L 4 but, 1 to 3 R c Optionally substituted with C 3~8 Cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is selected from 1 to 3 R c The heterocyclylene may be substituted with The compound according to any one of items 1 to 33, selected from the group consisting of:

[0428] 37.L 4 But 1-2 R c may be substituted with TIFF2025504415000078.tif19170, and n3 and n4 are independently 0, 1, or 2; Q 3 But, CH, CR c, or N; an asterisk is -(L 5 ) a5 37. The compound according to any one of items 1 to 33 or 36, wherein - represents a point of attachment to.

[0429] 38. The compound according to item 37, wherein n3 and n4 are each 1.

[0430] 39.Q 3 is N. The compound according to item 37 or 38.

[0431] 40.L 4 but, TIFF2025504415000079.tif12170, and the asterisk is -(L 5 ) a5 - represents a point of attachment to the compound according to any one of items 1 to 33 or 36 to 39.

[0432] 41. The compound according to any one of items 1 to 32, wherein a4 is 0.

[0433] 42. The compound according to any one of items 1 to 41, wherein a5 is 0.

[0434] 43. The compound according to item 1, wherein one of a1, a3, and a5 is 1 and the other two are 0.

[0435] 44. The compound according to item 1 or 43, wherein one of a2 and a4 is 1, and the other is 0 or 1.

[0436] 45. The compound according to any one of items 1 or 43 to 44, wherein a1 and a2 are each 1.

[0437] 46. ​​a1 and a2 are each 1; L 1 is -O-, -N(H)-, or -N(R d )-and; L 2 but, 1 to 3 R b Optionally substituted linear C1~3 Alkylene; 1 to 3 R c Optionally substituted with C 3~8 Cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is selected from 1 to 3 R c The heterocyclylene may be substituted with Selected from the group consisting of: Item 46. The compound according to any one of items 1 or 43 to 45.

[0438] 47. a1 and a2 are each 1; L 1 is -O-; L 2 But 1 to 3 R b Optionally substituted linear C 1~3 is alkylene, Item 47. The compound according to any one of items 1 or 43 to 46.

[0439] 48. a1 and a2 are each 1; L 1 is -O-; L 2 -CH2-, -CHR b - and -C(R b )2-, Item 1 or the compound according to any one of items 43 to 47.

[0440] 49. a1 and a2 are each 1; L 1 is -O-; L 2 But 1 to 3 R b Optionally substituted linear C 2~3 is alkylene, Item 1 or the compound according to any one of items 43 to 47.

[0441] 50.L 2 But 1 to 3 R b Item 50. The compound according to item 49, wherein the alkylene is a straight chain C2 alkylene optionally substituted with.

[0442] 51.L 2 -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is selected from the group consisting of -(L 3 ) a3 51. The compound according to claim 49 or 50, wherein the - represents a point of attachment to

[0443] 52.L 2 52. The compound according to any one of items 49 to 51, wherein is -CH2CH2-.

[0444] 53. a1 and a2 are each 1; L 1 is -O-; L 2 but, 1 to 3 R c Optionally substituted with C 3~8 Cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is selected from 1 to 3 R c The heterocyclylene may be substituted with Selected from the group consisting of: Item 47. The compound according to any one of items 1 or 43 to 46.

[0445] 54.L 2 But 1-2 R c may be substituted with TIFF2025504415000080.tif21170, where n1 and n2 are independently 0, 1, or 2; Q 2 But, CH, CRc , or N; an asterisk is -(L 3 ) a3 54. The compound according to claim 53, which represents a point of attachment to -.

[0446] 55. n1 and n2 are independently 0 or 1, optionally 0; Q 2 is CH; optionally, n1 and n2 are 0, and Q 2 is CH; optionally, L 2 But 1-2 R c cyclobutane-diyl optionally substituted with L 2 But 1-2 R c cyclobutane-1,3-diyl optionally substituted by L 2 is unsubstituted cyclobutane-diyl; optionally, L 2 55. The compound according to item 54, wherein is unsubstituted cyclobutane-1,3-diyl.

[0447] 56. a3, a4, and a5 are each 0, and optionally, L A is -O-CH2CH2-*, or TIFF2025504415000081.tif12170 (for example TIFF2025504415000082.tif12170), where * is Q 1 56. The compound according to any one of items 43 to 55, wherein the compound represents a point of attachment to

[0448] 57. The compound according to any one of items 43 to 55, wherein a3 and a5 are 0; and a4 is 1.

[0449] 58.L 4 but, 1 to 3 R c Optionally substituted with C 3~8 Cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2and the heterocyclylene is selected from 1 to 3 R c The heterocyclylene may be substituted with 58. The compound according to claim 57, selected from the group consisting of:

[0450] 59.L 4 But 1-2 R c may be substituted with TIFF2025504415000083.tif19170, and n3 and n4 are independently 0, 1, or 2; Q 3 But, CH, CR c , or N; an asterisk is -(L 5 ) a5 59. The compound according to claim 57 or 58, which represents a point of attachment to -.

[0451] 60. n3 and n4 are independently 0 or 1; Q 3 is N. Item 60. The compound according to item 59,

[0452] 61. The compound according to any one of items 1 or 43 to 44, wherein a1 is 0; and a2 is 1.

[0453] 62. a1 is 0; a2 is 1; L 2 However, 1 to 6 R b Optionally substituted linear C 1~6 Item 62. The compound according to any one of items 1, 43 to 44, or 61, wherein the compound is alkylene.

[0454] 63.L 2 But 1 to 3 R b Optionally substituted linear C 1~3 Item 63. The compound according to item 61 or 62, which is alkylene.

[0455] 64.L 2 -CH2-, -CHR b - and -C(R b 64. The compound according to any one of items 61 to 63, wherein the compound is selected from the group consisting of:

[0456] 65.L 2 is -CH2-.

[0457] 66.L 2 But 1 to 3 R b Optionally substituted linear C 2~3 Item 64. The compound according to any one of items 61 to 63, wherein the compound is alkylene.

[0458] 67.L 2 But 1 to 3 R b Item 67. The compound according to any one of items 61 to 63 or 66, wherein the alkylene is a straight-chain C2 alkylene optionally substituted with

[0459] 68.L 2 -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is selected from the group consisting of -(L 3 ) a3 - represents a point of attachment to the compound according to any one of items 61 to 63 or 66 to 67.

[0460] 69.L 2 is -CH2CH2-.

[0461] 70.L 2 But 1 to 3 R b Item 67. The compound according to any one of items 61 to 63 or 66, wherein the alkylene is a straight-chain C3 alkylene optionally substituted with

[0462] 71.L 2 but, TIFF2025504415000084.tif17170, and the asterisk is -(L 3 ) a3 71. The compound according to any one of paragraphs 61 to 63, 66, or 70, wherein - represents a point of attachment to.

[0463] 72. The compound according to any one of clauses 61 to 71, wherein a3 is 0; a4 is 0; and a5 is 0.

[0464] 73. The compound according to any one of items 61 to 71, wherein a3 is 1.

[0465] 74.a3 is 1;L 3 -O-, -N(H)-, and -N(R d 74. The compound according to claim 73, wherein the compound is selected from the group consisting of:

[0466] 75.a3 is 1;L 3 Item 75. The compound according to item 73 or 74, wherein is -O-.

[0467] 76.a3 is 1;L 3 is -N(H)- or -N(R d 75. The compound according to any one of items 61 to 71 or 73 to 74, wherein the compound is —N(H)—, optionally —N(H)—.

[0468] 77.a4 is 1;L 4 But 1 to 3 R b Optionally substituted linear C 1~3 The compound according to any one of items 61 to 71 or 73 to 76, wherein the alkylene is alkylene.

[0469] 78.a4 is 1;L 4 The compound according to any one of items 61 to 71 or 73 to 77, wherein is -CH2-.

[0470] 79. a4 is 0; a5 is 0, and optionally, L A is -CH2CH2-O-*, * is Q 1 80. The compound according to any one of items 61 to 71 or 73 to 77, wherein the compound represents a point of attachment to

[0471] 80. a1 is 0; a2 is 1; L 2 But 1 to 3 R b Optionally substituted linear C 2~4Item 3. The compound according to item 1, which is alkenylene.

[0472] 81.L 2 but, TIFF2025504415000085.tif12170, and the asterisk is -(L 3 ) a3 81. The compound according to claim 80, which represents a point of attachment to -.

[0473] 82. The compound according to item 80 or 81, wherein a3 is 0; a4 is 0; and a5 is 0.

[0474] 83.Q 1 but, Heteroaryl with 5 to 12 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R c’ the heteroaryl, optionally substituted with 1 to 4 R c’ Optionally substituted with C 6~10 Aryl The compound according to any one of items 1 to 82, selected from the group consisting of:

[0475] 84.Q 1 but, Heteroaryl with 5-6 ring atoms, 1-4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 3 R c’ the heteroaryl, optionally substituted with 1 to 3 R c’ phenyl, optionally substituted with The compound according to any one of items 1 to 82, selected from the group consisting of:

[0476] 85.Q 1but, Heteroaryl having 6 ring atoms, 1 to 2 of which are ring nitrogen atoms, and the heteroaryl is c’ the heteroaryl, optionally substituted with 1 to 3 R c’ phenyl, optionally substituted with The compound according to any one of items 1 to 82, selected from the group consisting of:

[0477] 86.Q 1 But 1 to 3 R c’ 86. The compound according to any one of items 1 to 85, wherein the phenyl is optionally substituted with

[0478] 87.Q 1 but, 87. The compound according to any one of items 1 to 86, selected from the group consisting of TIFF2025504415000086.tif18170.

[0479] 88.Q 1 but, Heteroaryl of 6 ring atoms, 1-2 of which are ring nitrogen atoms, and 1-3 of which are R c’ The heteroaryl may be substituted with Item 86. The compound according to any one of items 1 to 85, wherein

[0480] 89.Q 1 But 1 to 3 R c’ 89. The compound according to any one of items 1 to 85 or 88, wherein the pyridyl is optionally substituted with

[0481] 90.Q 1 but, TIFF2025504415000087.tif18170. The compound according to any one of items 1 to 85 or 88 to 89, wherein the compound is selected from the group consisting of

[0482] 91.Q 1 but, Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c’ The heterocyclyl or heterocycloalkenyl may be substituted by 1 to 4 substituents independently selected from the group consisting of Item 83. The compound according to any one of items 1 to 82, wherein

[0483] 92.Q 1 but, Heterocyclyl of 4 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl is selected from the group consisting of oxo and R c’ The heterocyclyl may be substituted with 1 to 4 substituents independently selected from the group consisting of The compound according to any one of items 1 to 82 or 91, wherein

[0484] 93.Q 1 but, Heterocyclyl of 4 to 8 ring atoms, 1 to 2 of which are N, N(H), N(R d ), O, and S(O) 0~2 and each heteroatom is independently selected from the group consisting of: d ), The heterocyclyl is oxo and R c’ and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: The compound according to any one of items 1 to 82 or 91 to 92.

[0485] 94.Q 1 but, TIFF2025504415000088.tif21170, m1 and m2 are each independently 0, 1, or 2; Q 1 But 1-2 R c’ The compound according to any one of items 1 to 82 or 91 to 93, which may be substituted with

[0486] 95.Q 1 but, The compound according to any one of items 1 to 82 or 91 to 94, wherein the compound is TIFF2025504415000089.tif12170.

[0487] 96.Q 1 but, The compound according to any one of items 1 to 82 or 91 to 94, wherein the compound is TIFF2025504415000090.tif13170.

[0488] 97.Q 1 For each R in d But -C(O)O(C 1~4 alkyl); and 1 to 3 independently selected R a C which may be substituted with 1~6 97. The compound according to any one of items 91 to 96, wherein the compound is independently selected from the group consisting of alkyl.

[0489] 98.Q 1 For each R in d C optionally substituted with 1 to 3 independently selected halo 1~6 Item 98. The compound according to any one of items 91 to 97, wherein the compound is alkyl.

[0490] 99.Q 1 For each R in d but, i. C substituted with 1 to 3 -F 1~4 Alkyl; ii. C substituted with 1 to 3 -F 2~3 Alkyl; or iii.-CH2CF3 Item 99. The compound according to any one of items 91 to 98, wherein

[0491] 100.Q 1 Each R in c But, halo; cyano; C 1~4 Alkoxy;C 1~4 haloalkoxy; and 1 to 6 independently selected R a C which may be substituted with 1~10 Item 83. The compound according to any one of items 83 to 99, wherein the compound is independently selected from the group consisting of alkyl.

[0492] 101.Q 1 Each R in c But, halo; cyano; C 1~4 Alkoxy;C 1~4 haloalkoxy; and C optionally substituted with 1 to 6 independently selected halo. 1~6 Item 101. The compound according to any one of items 83 to 100, wherein the compound is independently selected from the group consisting of alkyl.

[0493] 102.Q 1 Each R in c C optionally substituted with halo and 1 to 6 independently selected halo 1~3 Item 83 to 101. The compound according to any one of items 83 to 101, wherein each of the compounds is independently selected from the group consisting of alkyl.

[0494] 103.Q 1 Each R in c but, i. C optionally substituted with 1 to 6 -F 1~3 Alkyl; or ii.CF3 Item 83. The compound according to any one of items 83 to 102, wherein

[0495] 104.Q 1 Each R in c is an independently selected halo, optionally -F or -Cl.

[0496] 105.Y 1 But, CR 1The compound according to any one of items 1 to 104, wherein

[0497] 106.Y 2 But, CR 1 The compound according to any one of items 1 to 105, wherein

[0498] 107.Y 3 But, CR 1 The compound according to any one of items 1 to 106, wherein

[0499] 108.R 1 Each occurrence of is independently H or R c The compound according to any one of items 1 to 107, wherein

[0500] 109.R 1 Each occurrence of is H.

[0501] 110.R 1 One or two occurrences of R c ;R 1 and each remaining occurrence of is H.

[0502] 111.R 1 is halo, optionally -F or -Cl; R 1 and each remaining occurrence of is H.

[0503] 112.Y 1 , Y 2 , and Y 3 are selected independently 1 The compound according to any one of items 1 to 111, wherein

[0504] 113.Y 1 , Y 2 , and Y 3 and each are CH. The compound according to any one of items 1 to 107 or 112,

[0505] 114.Y 1 , Y 2 , and Y 3 One of them is CR c , optionally C-halo; the remaining two Y 1 , Y 2 , and Y 3 Each of the formulas 1 to 107 and 112 is CH.

[0506] 115.X 1 But NR 2 The compound according to any one of items 1 to 114, wherein

[0507] 116.X 1 The compound according to any one of items 1 to 115, wherein is NH.

[0508] 117.X 2 But, CR 5 The compound according to any one of items 1 to 116, wherein

[0509] 118.X 2 The compound according to any one of items 1 to 117, wherein is CH.

[0510] 119.X 1 But NR 2 ;X 2 But, CR 5 The compound according to any one of items 1 to 114, wherein

[0511] 120.X 1 is NH;X 2 Item 119. The compound according to any one of items 1 to 114 or 119, wherein is CH.

[0512] 121.Y 1 , Y 2 , and Y 3 are selected independently 1 ;X 1 But NR 2 ;X 2 But, CR 5The compound according to any one of items 1 to 104, wherein

[0513] 122.Y 1 , Y 2 , and Y 3 are CH and X, respectively. 1 is NH;X 2 Item 122. The compound according to any one of items 1 to 104 or 121, wherein is CH.

[0514] 123.R 6 is H. The compound according to any one of items 1 to 122.

[0515] 124.W, each of which has 1 to 6 R a2 or R g Optionally substituted with C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 The compound according to any one of items 1 to 123, wherein the compound is alkenyl.

[0516] 125.W has 1 to 6 R a2 Optionally substituted with C 1~10 Item 125. The compound according to any one of items 1 to 124, wherein the compound is alkyl.

[0517] 126.W has 1 to 6 R a2 Optionally substituted with C 1~6 The compound according to any one of items 1 to 125, wherein the compound is alkyl.

[0518] 127.W has 1 to 6 R a2 Optionally substituted with C 1~4 The compound according to any one of items 1 to 126, wherein the compound is alkyl.

[0519] 128.W is unsubstituted C 1~4 The compound according to any one of items 1 to 127, wherein the compound is alkyl.

[0520] 129. The compound according to any one of clauses 1 to 128, wherein W is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, and isobutyl.

[0521] 130. The compound according to any one of paragraphs 1 to 129, wherein W is methyl or ethyl.

[0522] 131. W has 1 to 6 R a2 C replaced with 1~4 The compound according to any one of items 1 to 126, wherein the compound is alkyl.

[0523] 132.Each R a2 but, i.-OH;-Halo;-NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl); and cyano; or ii. Halo; -OH; C 1~4 Alkoxy; and C 1~4 Haloalkoxy Independently selected from the group consisting of: The compound according to any one of items 1 to 126 or 131.

[0524] 133.W, i.Halo;-OH;C 1~4 Alkoxy; and C 1~4 C substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy 1~4 is alkyl; or ii.W TIFF2025504415000091.tif12170, The compound according to any one of items 1 to 126 or 131 to 132.

[0525] 134.W, Each of which is oxo and R cC 3~12 Cycloalkyl or C 3~12 Cycloalkenyl; and Heteroaryl, heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl, heterocyclyl, or heterocycloalkenyl is selected from the group consisting of oxo and R c The heteroaryl, heterocyclyl or heterocycloalkenyl may be substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of However, when W is heteroaryl, heterocyclyl, or heterocycloalkenyl, it is C(=O)NR via a ring carbon atom. 6 provided that the group is bonded to The compound according to any one of items 1 to 123.

[0526] 135. W is an oxo or R c C 3~12 Cycloalkyl or C 3~12 Item 135. The compound according to any one of items 1 to 123 or 134, which is cycloalkenyl.

[0527] 136.W is oxo and R c C 3~12 The compound according to any one of items 1 to 123 or 134 to 135, which is cycloalkyl.

[0528] 137.W is unsubstituted C 3~12 The compound according to any one of items 1 to 123 or 134 to 136, which is cycloalkyl.

[0529] 138. The compound according to any one of paragraphs 1 to 123 or 134 to 137, wherein W is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0530] 139. The compound according to any one of paragraphs 1 to 123 or 134 to 138, wherein W is cyclobutyl.

[0531] 140. The compound according to any one of paragraphs 1 to 123, wherein W is H.

[0532] 141. Formula (Ia): TIFF2025504415000092.tif36170 or a pharma- ceutically acceptable salt thereof, wherein L 1 -O-, -N(H)-, and -N(R d )- selected from the group consisting of; L 2 but, 1 to 3 R b Optionally substituted linear C 1~3 Alkylene; 1 to 3 R c Optionally substituted with C 3~8 Cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is selected from 1 to 3 R c The heterocyclylene may be substituted with Selected from the group consisting of: Item 1. The compound according to item 1.

[0533] 142.L 1 Item 142. The compound according to item 141, wherein is -O-.

[0534] 143.L 2 But 1 to 3 R b Optionally substituted linear C 1~3Item 143. The compound according to item 141 or 142, which is alkylene.

[0535] 144.L 2 -CH2-, -CHR b - and -C(R b )2-, and optionally, L 2 is -CH2-.

[0536] 145.L 2 But 1 to 3 R b 144. The compound according to any one of items 141 to 143, wherein the alkylene is a straight-chain C2 alkylene optionally substituted with.

[0537] 146.L 2 -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is selected from the group consisting of -Q 1 146. The compound according to any one of items 141 to 143 or 145, wherein said compound represents a point of attachment to

[0538] 147.L 2 Item 147. The compound according to item 146, wherein is -CH2CH2-.

[0539] 148.L 2 But 1 to 3 R b 144. The compound according to any one of items 141 to 143, wherein the alkylene is a straight-chain C3 alkylene optionally substituted with.

[0540] 149.L 2 But 1-2 R c may be substituted with TIFF2025504415000093.tif19170, where n1 and n2 are independently 0, 1, or 2; Q 2 But, CH, CR c or N; an asterisk is Q 1 143. The compound according to claim 141 or 142, which represents a point of attachment to

[0541] 150. n1 and n2 are independently 0 or 1, optionally 0; Q 2 is CH; optionally, n1 and n2 are 0, and Q 2 is CH; optionally, L 2 But 1-2 R c cyclobutane-diyl optionally substituted with L 2 But 1-2 R c cyclobutane-1,3-diyl optionally substituted by L 2 But 1-2 R c cyclobutane-diyl optionally substituted with L 2 is unsubstituted cyclobutane-diyl; optionally, L 2 Item 149. The compound according to item 149, wherein is unsubstituted cyclobutane-1,3-diyl.

[0542] 151.L 1 is -O-;L 2 But 1 to 3 R b Optionally substituted linear C 2~3 Item 142. The compound according to item 141, which is alkylene.

[0543] 152.L 2 but, i. 1 to 3 R b is a linear C2 alkylene optionally substituted with ii. -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is selected from the group consisting of -Q 1 represents a point of attachment to; or iii. -CH2CH2-; Item 152. The compound according to item 151.

[0544] 153.L 1 is -O-;L 2 but, i. -CH2-, -CHR b - and -C(R b )2-; or ii. -CH2-; Item 142. The compound according to item 141.

[0545] 154.Formula (Ib): TIFF2025504415000094.tif35170 or a pharma- ceutically acceptable salt thereof, wherein L 2 However, each of them has 1 to 6 R b Optionally substituted linear C 1~6 Alkylene or linear C 2~6 Item 3. The compound according to item 1, which is alkenylene.

[0546] 155.L 2 But 1 to 3 R b Optionally substituted linear C 2~3 Item 155. The compound according to item 154, which is alkylene.

[0547] 156.L 2 But 1 to 3 R b Item 156. The compound according to item 154 or 155, which is a straight-chain C2 alkylene optionally substituted with:

[0548] 157.L 2 -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is selected from the group consisting of -Q 1 represents the point of attachment to 2 is -CH2CH2-.

[0549] 158.L 2 But 1 to 3 R b 156. The compound according to items 154 to 155, wherein the alkylene is a straight-chain C3 alkylene optionally substituted with.

[0550] 159.L 2 but, TIFF2025504415000095.tif19170, and the asterisk is selected from the group consisting of -Q 1represents the point of attachment to 2 but, Item 154. The compound according to any one of items 154 to 155 or 158, wherein the compound is TIFF2025504415000096.tif10170.

[0551] 160.L 2 But 1 to 3 R b Optionally substituted linear C 2~4 Item 155. The compound according to item 154, which is alkenylene.

[0552] 161.L 2 but, TIFF2025504415000097.tif10170, and the asterisk is selected from the group consisting of -Q 1 161. The compound according to claim 154 or 160, which represents a point of attachment to

[0553] 162.Formula (Ic): TIFF2025504415000098.tif36170 or a pharma- ceutically acceptable salt thereof, wherein L 2 and L 4 However, 1 to 6 R b and independently selected linear C 1~3 is alkylene; L 3 -O-, -N(H)-, and -N(R d Item 2. The compound according to item 1, wherein the compound is selected from the group consisting of:

[0554] 163.L 2 and L 4 -CH2-, -CHR b - and -C(R b Item 163. The compound according to item 162, wherein the compound is independently selected from the group consisting of:

[0555] 164.L 2 and L 4 and each is -CH2-.

[0556] 165.L 3 The compound according to any one of items 162 to 164, wherein is -O-.

[0557] 166.L 3 is -N(H)- or -N(R d 165. The compound according to any one of items 162 to 164, wherein the R is -N(H)-, optionally -N(H)-.

[0558] 167. Formula (Id): TIFF2025504415000099.tif35170 or a pharma- ceutically acceptable salt thereof, wherein L 2 However, 1 to 6 R b Optionally substituted linear C 1~3 is alkylene; L 3 -O-, -N(H)-, and -N(R d Item 2. The compound according to item 1, wherein the compound is selected from the group consisting of:

[0559] 168.L 2 -CH2-, -CHR b - and -C(R b Item 168. The compound according to item 167, selected from the group consisting of:

[0560] 169.L 2 But 1 to 3 R b Item 168. The compound according to item 167, wherein the C2 alkylene is optionally substituted with a straight chain C2 alkylene.

[0561] 170.L 2 -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is selected from the group consisting of -L 3 represents the point of attachment to 2 Item 169. The compound according to item 167 or 169, wherein is -CH2CH2-.

[0562] 171.L 3171. The compound according to any one of items 167 to 170, wherein is -O-.

[0563] 172.L 3 is -N(H)- or -N(R d 171. The compound according to any one of items 167 to 170, wherein the R is —N(H)—, optionally —N(H)—.

[0564] 173.Q 1 but, Heteroaryl with 5-6 ring atoms, 1-4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 3 R c’ the heteroaryl, optionally substituted with 1 to 3 R c’ phenyl, optionally substituted with The compound according to any one of items 141 to 172, selected from the group consisting of:

[0565] 174.Q 1 but, Heteroaryl having 6 ring atoms, 1 to 2 of which are ring nitrogen atoms, and the heteroaryl is c’ the heteroaryl, optionally substituted with 1 to 3 R c’ phenyl, optionally substituted with The compound according to any one of items 141 to 173, selected from the group consisting of:

[0566] 175.Q 1 but, i. 1 to 3 R c’ phenyl or pyridyl, each of which may be substituted by ii. TIFF2025504415000100.tif21170; iii.Q 1 For each R in cis optionally substituted with halo and 1 to 6 independently selected halo, 1~3 any of the groups i or ii, independently selected from the group consisting of alkyl; or iv.Q 1 Each R in c any group of i or ii, independently selected from the group consisting of -F, -Cl, and -CF3; The compound according to any one of items 141 to 174, wherein

[0567] 176.Q 1 but, Heterocyclyl of 4 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl is selected from the group consisting of oxo and R c’ The heterocyclyl may be substituted with 1 to 4 substituents independently selected from the group consisting of Item 173. The compound according to any one of items 141 to 172, wherein

[0568] 177.Q 1 but, i. TIFF2025504415000101.tif20170 (wherein m1 and m2 are each independently 0, 1, or 2); ii. TIFF2025504415000102.tif12170; iii.Q 1 R exists in d But -C(O)O(C 1~4 alkyl); and 1 to 3 independently selected R a C which may be substituted with 1~6 any of the groups i or ii selected from the group consisting of alkyl; or iv.Q 1 R exists in d C substituted with 1 to 3 -F 2~3 any group i or ii which is alkyl The compound according to any one of items 141 to 172 or 176, wherein

[0569] 178.R 1 is H. The compound according to any one of items 141 to 177.

[0570] 179.R 1 One occurrence of R c and the remaining R 1 is H. The compound according to any one of items 141 to 177.

[0571] 180.R 2 is H;R 5 is H.

[0572] 181.W has 1 to 6 R a2 Optionally substituted with C 1~6 181. The compound according to any one of items 141 to 180, wherein the compound is alkyl.

[0573] 182.W is unsubstituted C 1~4 Item 141. The compound according to any one of items 141 to 181, wherein the compound is alkyl.

[0574] 183. The compound according to any one of paragraphs 141 to 182, wherein W is methyl or ethyl.

[0575] 184.W has 1 to 6 R a2 Replaced by C 1~4 Item 141. The compound according to any one of items 141 to 181, wherein the compound is alkyl.

[0576] 185.W, i.Halo;-OH;C 1~4 Alkoxy; and C 1~4 C substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy 1~4 is alkyl; or ii.W TIFF2025504415000103.tif11170, The compound according to any one of items 141 to 181 or 184.

[0577] 186.W, Each of which is oxo and R c A monocyclic C 3~8 Cycloalkyl or C 3~8 Cycloalkenyl; and Monocyclic heterocyclyl or heterocycloalkenyl of 3 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c The heterocyclyl or heterocycloalkenyl may be substituted by 1 to 4 substituents independently selected from the group consisting of The compound according to any one of items 141 to 181, selected from the group consisting of:

[0578] 187.W is oxo and R c A monocyclic C 3~8 The compound according to any one of items 141 to 181 or 186, which is cycloalkyl.

[0579] 188.W, i.Unsubstituted C 3~8 cycloalkyl; or ii. Cyclobutyl The compound according to any one of items 141 to 181 or 186 to 187,

[0580] 189. The compound according to item 1, selected from the group consisting of the compounds shown in Table C1 and pharma- ceutically acceptable salts thereof.

[0581] 190. A pharmaceutical composition comprising a compound according to any one of items 1 to 189 and one or more pharma- ceutically acceptable excipients.

[0582] 191. A method for inhibiting STING activity, comprising contacting STING with a compound as defined in any one of paragraphs 1 to 126 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined in paragraph 190.

[0583] 192. The method of claim 191, wherein inhibiting comprises antagonizing STING.

[0584] 193. The method according to any one of paragraphs 191 to 192, which is carried out in vitro.

[0585] 194. The method of claim 193, comprising contacting a sample containing one or more cells containing STING with a compound.

[0586] 195. The method of claim 193 or 194, wherein the one or more cells are one or more cancer cells.

[0587] 196. The method of paragraph 194 or 195, wherein the sample further comprises one or more cancer cells, and the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma.

[0588] 197. The method of paragraph 191 or 192, which is carried out in vivo.

[0589] 198. The method of claim 197, comprising administering the compound to a subject having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease.

[0590] 199. The method of claim 198, wherein the subject is a human.

[0591] 200. The method according to claim 199, wherein the disease is cancer.

[0592] 201. The method of claim 200, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma.

[0593] 202. The method according to paragraph 200 or 201, wherein the cancer is a refractory cancer.

[0594] 203. The method of paragraph 198, wherein the compound is administered in combination with one or more additional cancer therapies.

[0595] 204. The method of paragraph 203, wherein the one or more additional cancer therapies include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

[0596] 205. The method of claim 204, wherein the chemotherapy comprises administering one or more additional chemotherapeutic agents.

[0597] 206. The one or more further chemotherapeutic agents are alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); antimetabolites (e.g., azathioprine and / or mercaptopurine); terpenoids (e.g., vinca alkaloids and / or taxanes; e.g., vincristine, vinblastine, vinorelbine and / or vindesine taxol, paclitaxel and / or docetaxel); topoisomerase (e.g., type I topoisomerase and / or type 2 topoisomerase; e.g., camptothecins such as irinotecan and / or topotecan; amsacrine, etoposide, etoposide phosphate and / or teniposide; cytotoxic antibiotics (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); hormones (e.g., luteinizing hormone releasing hormone agonists; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, vedotin), canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; growth inhibitors; antiparasitic agents;and 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), galectin 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-CD4 0 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, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 206. The method of claim 205, wherein the immune checkpoint inhibitor is selected from an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1);

[0598] 207. The method of any one of paragraphs 198 to 206, wherein the compound is administered intratumorally.

[0599] 208. A method for treating cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of paragraphs 1 to 189, or a pharmaceutical composition as defined in paragraph 190.

[0600] 209. The method of claim 208, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma.

[0601] 210. The method according to item 208 or 209, wherein the cancer is a refractory cancer.

[0602] 211. The method of clause 208, wherein the compound is administered in combination with one or more additional cancer therapies.

[0603] 212. The method of paragraph 211, wherein the one or more additional cancer therapies comprise surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

[0604] 213. The method of clause 212, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.

[0605] 214. The one or more further chemotherapeutic agents are alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); antimetabolites (e.g., azathioprine and / or mercaptopurine); terpenoids (e.g., vinca alkaloids and / or taxanes; e.g., vincristine, vinblastine, vinorelbine and / or vindesine taxol, paclitaxel and / or docetaxel); topoisomerases (e.g., type I topoisomerase and / or type 2 topoisomerase; e.g., camptothecins such as irinotecan and / or topotecan; amsacrine, etoposide, etoposide phosphate and / or teniposide; cytotoxic antibiotics (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); hormones (e.g., luteinizing hormone releasing hormone agonists; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, vedotin), canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; growth inhibitors; antiparasitic agents;and 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), galectin 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-CD4 0 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, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 213. The method of claim 212, wherein the immune checkpoint inhibitor is selected from an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1);

[0606] 215. The method of any one of clauses 208 to 214, wherein the compound is administered intratumorally.

[0607] 216. A method for inducing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of a compound as defined in any one of clauses 1 to 189, or a pharmaceutical composition as defined in clause 190.

[0608] 217. The method of claim 216, wherein the subject has cancer.

[0609] 218. The method of claim 217, wherein the subject has undergone and / or is undergoing and / or will undergo one or more cancer therapies.

[0610] 219. The method of claim 217, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma.

[0611] 220. The method according to any one of items 217 to 219, wherein the cancer is a refractory cancer.

[0612] 221. The method of clause 219, wherein the immune response is an innate immune response.

[0613] 222. The method of paragraph 221, wherein the at least one cancer therapy comprises surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

[0614] 223. The method of clause 222, wherein the chemotherapy comprises administering one or more further chemotherapeutic agents.

[0615] 224. The one or more further chemotherapeutic agents are alkylating agents (e.g. cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); antimetabolites (e.g. azathioprine and / or mercaptopurine); terpenoids (e.g. vinca alkaloids and / or taxanes; e.g. vincristine, vinblastine, vinorelbine and / or vindesine taxol, paclitaxel and / or docetaxel); topoisomerases (e.g. type I topoisomerase and / or type 2 topoisomerase; e.g. camptothecins such as irinotecan and / or topotecan; amsacrine, etoposide, etoposide phosphate and / or teniposide; cytotoxic antibiotics (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); hormones (e.g., luteinizing hormone releasing hormone agonists; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, vedotin), canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; growth inhibitors; antiparasitic agents;and 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), galectin 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-CD4 0 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, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 224. The method of claim 223, wherein the immune checkpoint inhibitor is selected from an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1);

[0616] 225. A method for treating a disease in which increased (e.g. excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of paragraphs 1 to 189, or a pharmaceutical composition as defined in paragraph 190.

[0617] 226. A method of treatment comprising administering to a subject having a disease in which increased (e.g. excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease an effective amount of a compound as defined in any one of paragraphs 1 to 189, or a pharmaceutical composition as defined in paragraph 190.

[0618] 227. A method of treatment comprising administering to a subject a compound as defined in any one of clauses 1 to 189, or a pharmaceutical composition as defined in clause 190, wherein the compound or composition is administered in an amount effective to treat a disease in which increased (e.g. excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease, thereby treating the disease.

[0619] 228. The method according to any one of clauses 225 to 227, wherein the disease is cancer.

[0620] 229. The method of claim 228, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma.

[0621] 230. The method according to item 228 or 229, wherein the cancer is a refractory cancer.

[0622] 231. The method of any one of clauses 228 to 230, wherein the compound is administered in combination with one or more additional cancer therapies.

[0623] 232. The method of paragraph 231, wherein the one or more additional cancer therapies comprise surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

[0624] 233. The method of claim 232, wherein chemotherapy comprises administering one or more further chemotherapeutic agents.

[0625] 234. The one or more further chemotherapeutic agents are alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); antimetabolites (e.g., azathioprine and / or mercaptopurine); terpenoids (e.g., vinca alkaloids and / or taxanes; e.g., vincristine, vinblastine, vinorelbine and / or vindesine taxol, paclitaxel and / or docetaxel); topoisomerases (e.g., type I topoisomerase and / or type 2 topoisomerase; e.g., camptothecins such as irinotecan and / or topotecan; amsacrine, etoposide, etoposide phosphate and / or teniposide; cytotoxic antibiotics (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); hormones (e.g., luteinizing hormone releasing hormone agonists; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, vedotin), canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; growth inhibitors; antiparasitic agents;and 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), galectin 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-CD4 0 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, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 234. The method of claim 233, wherein the immune checkpoint inhibitor is selected from an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1);

[0626] 235. The method of any one of clauses 225 to 234, wherein the compound is administered intratumorally.

[0627] 236. A method for treating a disease, disorder or condition associated with STING, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1 to 189, or a pharmaceutical composition as defined in clause 190.

[0628] 237. The method of clause 236, wherein the disease, disorder, or condition is selected from type I interferonopathy, Aicardi-Goutières syndrome (AGS), genetic forms of lupus, inflammation-related disorders, and rheumatoid arthritis.

[0629] 238. The method of claim 237, wherein the disease, disorder, or condition is type I interferonopathy (e.g., STING-associated vasculitis in infancy (SAVI)).

[0630] 239. The method of claim 238, wherein the type I interferon syndrome is STING-associated vasculitis in infancy (SAVI).

[0631] 240. The method of claim 237, wherein the disease, disorder, or condition is Aicardi-Goutières Syndrome (AGS).

[0632] 241. The method of clause 237, wherein the disease, disorder, or condition is a genetic form of lupus.

[0633] 242. The method of claim 237, wherein the disease, disorder, or condition is an inflammation-related disorder.

[0634] 243. The method of claim 242, wherein the inflammation-related disorder is systemic lupus erythematosus.

[0635] 244. The method of any one of paragraphs 191 to 243, further comprising identifying the subject.

[0636] 245. A combination comprising a compound as defined in any one of paragraphs 1 to 126 or a pharma- ceutically acceptable salt or tautomer thereof, and one or more therapeutically active agents.

[0637] 246. A compound as defined in any one of paragraphs 1 to 189 or a pharma- ceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in paragraph 190, for use as a medicament.

[0638] 247. A compound as defined in any one of paragraphs 1 to 189 or a pharma- ceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in paragraph 190, for use in the treatment of a disease, condition or disorder modulated by inhibiting STING.

[0639] 248. A compound as defined in any one of paragraphs 1 to 189 or a pharma- ceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in paragraph 190, for use in treating a disease as defined in any one of paragraphs 191 to 244.

[0640] 249. Use of a compound as defined in any one of paragraphs 1 to 189 or a pharma- ceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in paragraph 190, in the manufacture of a medicament for treating a disease as referred to in any one of paragraphs 191 to 244.

Claims

[Claim 1] Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein L Ａ But, -(L １ ) ａ１ - (L ２ ) ａ２ - (L ３ ) ａ３ - (L ４ ) ａ４ - (L ５ ) ａ５ -* and * is Q １ represents a point of attachment to a1, a2, a3, a4, and a5 each independently represent 0 or 1; However, it is subject to the condition that a1+a2+a3+a4+a5≧1. L １ , L ３ , and L ５ are each -O-, -N(H)-, -N(R ｄ ) -, S(O) ０～２ independently selected from the group consisting of -C(=O)-; However, when one or both of a2 and a4 is 0, L １ , L ３ , and L ５ The combination is O-O, N-O, N-N, O-S, S-S, or N-S(O) ０ provided that they are unable to form bonds, L ２ and L ４ Each of the ・Each of them has 1 to 6 R ｂ a linear C １～６ Alkylene, linear C ２～６ Alkenylene or linear C ２～６ Alkynylene; ・Each of them has 1 to 3 R ｃ optionally substituted with C ３～１０ Cycloalkylene or C ３～１０ cycloalkenylene, provided that Y １ , Y ２ , and Y ３ provided that C is not directly connected to a 6-membered ring containing ３～１０ Cycloalkylene or C ３～１０ cycloalkenylene; and heterocyclylene or heterocycloalkenylene, each having 4 to 10 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R ｄ ), O, and S(O) ０～２ and the heterocyclylene or heterocycloalkenylene is selected from the group consisting of 1 to 3 R ｃ may be substituted with, provided that Y １ , Y ２ , and Y ３ provided that the heterocyclylene or heterocycloalkenylene is not directly attached to a 6-membered ring containing are independently selected from the group consisting of Furthermore, L Ａ But Y １ , Y ２ , and Y ３ provided that the cyclic group cannot contain a cyclic group directly attached to a six-membered ring containing Q １ But, -R ｇ and Y １ , Y ２ , and Y ３ But, CR １ , C(═O), N, and NR ２ are each independently selected from the group consisting of: X １ But O, S, N, NR ２ , and C.R. １ selected from the group consisting of: X ２ But O, S, N, NR ４ , and C.R. ５ selected from the group consisting of: Each 【Chemistry 2】 are independently a single bond or a double bond, provided that X １ and X ２ is a heteroaryl; and Y １ , Y ２ , and Y ３ is aryl or heteroaryl; R １ and R ５ Each occurrence of H;R ｃ ;R ｇ and -(L ｇ ) ｂｇ -R ｇ are independently selected from the group consisting of: R ２ and R ４ Each occurrence of H;R ｄ ;R ｇ and -(L ｇ ) ｂｇ -R ｇ are independently selected from the group consisting of: R ６ But H;R ｄ and R ｇ selected from the group consisting of: W is, ・Each of them has 1 to 6 R ａ２ or R ｇ optionally substituted with C １～１０ Alkyl, C ２～１０ Alkenyl, or C ２～１０ Alkynyl; - each of which is oxo and R ｃ C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of ３～１２ Cycloalkyl or C ３～１２ cycloalkenyl; and Heteroaryl, heterocyclyl, or heterocycloalkenyl of 3 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R ｄ ), O, and S(O) ０～２ and the heteroaryl, heterocyclyl, or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ The heteroaryl, heterocyclyl, or heterocycloalkenyl may be substituted with 1 to 4 substituents independently selected from the group consisting of: is selected from the group consisting of However, when W is heteroaryl, heterocyclyl, or heterocycloalkenyl, it is C(═O)NR via a ring carbon atom. ６ provided that it is attached to a group; R ａ and R ａ２ each occurrence of is -OH; -halo; -NR ｅ R ｆ ; C １～４ Alkoxy; C １～４ Haloalkoxy; —C(═O)O(C １～４ alkyl); -C(=O)(C １～４ alkyl); -C(=O)OH; -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); and cyano; R ｂ and R ｃ each occurrence of ａ C optionally substituted with １～１０ Alkyl; C ２～６ Alkenyl; C ２～６ Alkynyl; C １～４ Alkoxy; C １～４ Haloalkoxy; -S(O) １～２ (C １～４ alkyl); -S(O)(=NH)(C １～４ alkyl); -NR ｅ R ｆ ;-OH;-S(O) １～２ NR'R'';-C １～４ Thioalkoxy; -NO ２ -C(=O)(C １～１０ alkyl); -C(=O)O(C １～４ alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF ５ are independently selected from the group consisting of: R ｄ each occurrence of ａ C optionally substituted with １～６ 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 independently selected from the group consisting of alkoxy; R ｅ and R ｆ each occurrence of is H; NR'R'', -OH, halo, C １～４ Alkoxy, and C １～４ C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy １～６ 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 independently selected from the group consisting of alkoxy; R ｇ Each occurrence of -Each of them is oxo, R ｃ , and R ｈ C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of ３～１２ Cycloalkyl or C ３～１２ cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R ｄ ), O, and S(O) ０～２ and the heterocyclyl or heterocycloalkenyl is oxo, R ｃ , and R ｈ the heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl of 5 to 12 ring atoms, 1 to 4 of which are N, N(H), N(R ｄ ), O, and S(O) ０～２ and the heteroaryl is oxo, R ｃ , and R ｈ the heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ・Oxo, R ｃ , and R ｈ C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of ６～１０ Aryl are independently selected from the group consisting of: R ｈ Each occurrence of ・Each of them has 1 to 4 R ｉ optionally substituted with C ３～１２ Cycloalkyl or C ３～１２ cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R ｄ ), O, and S(O) ０～２ and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of 1 to 4 R ｉ the heterocyclyl or heterocycloalkenyl optionally substituted by Heteroaryl of 5 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R ｄ ), O, and S(O) ０～２ and the heteroaryl is selected from 1 to 4 R ｉ the heteroaryl, optionally substituted with ・1 to 4 R ｉ optionally substituted with C ６～１０ Aryl are independently selected from the group consisting of: R ｉ Each occurrence of C １～６ Alkyl; C １～４ Haloalkyl; C １～４ Alkoxy; C １～４ Independently selected from the group consisting of haloalkoxy; and halo; L ｇ each occurrence of is -O-, -NH-, -NR ｄ , -S(O) ０～２ , C(O), and 1 to 3 R ａ C optionally substituted with １～３ independently selected from the group consisting of alkylene; each occurrence of bg is independently 1, 2, or 3; Each occurrence of R' and R'' is selected from the group consisting of H; -OH; and C １～４ independently selected from the group consisting of alkyl, The compound or a pharmaceutically acceptable salt thereof or a tautomer thereof.

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