Oxalamide compounds and compositions for treating conditions 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 combination drugs) that inhibit (e.g., antagonize) STING (Stimulator of Interferon Gene). The chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., enhanced) STING activation (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 containing the chemical entities, as well as methods of using and making the chemical entities.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 135,303, filed January 8, 2021, each of which is incorporated by reference in its entirety herein.

[0002] Technical Field The disclosure features chemical entities (compounds or pharma- ceutically acceptable salts and / or hydrates and / or cocrystals and / or combination drugs) that inhibit (e.g., antagonize) STING (Stimulator of Interferon Gene). The chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., enhanced) STING activation (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 containing the chemical entities, as well as methods of using and making the chemical entities. [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 type I interferon production when cells are infected with intracellular pathogens such as viruses, mycobacteria, and intracellular parasites. STING-mediated type I interferon protects infected 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, a transmembrane protein localized to the endoplasmic reticulum (ER), 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 into the cytosol and creates a V-shaped binding pocket formed by STING homodimers. Ligand-induced activation of STING triggers its relocalization to the Golgi, a process essential for promoting the interaction of STING with TBK1. This protein complex then signals through the transcription factor IRF-3 to induce type I interferon (IFN) and other co-regulated antiviral factors. In addition, STING has been shown to induce activation of NF-κB and MAP kinases. After initiation of signaling, STING is rapidly degraded, a step that is thought to be important in terminating the inflammatory response.

[0005] Hyperactivation of STING is associated with a subset of monogenic autoinflammatory conditions, the so-called type I interferonopathies. Examples of these diseases include the clinical syndrome termed STING-associated vasculitis with infantile onset (SAVI), caused by gain-of-function mutations in TMEM173 (the gene name for STING). Furthermore, STING is involved in the pathogenesis of Aicardi-Goutières syndrome (AGS) and inherited forms of lupus. In contrast to SAVI, it is dysregulation of nucleic acid metabolism that underlies the continuous innate immune activation in AGS. Apart from these inherited disorders, emerging evidence points to a more universal pathogenetic role of STING in a wide range of inflammation-related disorders, e.g., systemic lupus erythematosus, rheumatoid arthritis, and cancer. Therefore, small molecule-based pharmacological interventions in the STING signaling pathway hold significant potential for the treatment of a wide range of diseases. Summary of the Invention

[0006] overview The disclosure features chemical entities (compounds or pharma- ceutically acceptable salts and / or hydrates and / or cocrystals and / or combination drugs) that inhibit (e.g., antagonize) STING (Stimulator of Interferon Gene). The chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., enhanced) STING activation (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 containing the chemical entities, as well as methods of using and making the chemical entities.

[0007] "Antagonists" of STING include compounds that directly bind to or modify STING at the protein level such that the activity of STING is reduced, for example, by inhibition, blocking or attenuating agonist-mediated responses, altering distribution, or otherwise. STING antagonists include chemical entities that interfere with or inhibit STING signaling.

[0008] In one aspect, the compound of formula (I): TIFF2024502473000001.tif40128, or a pharma- ceutically acceptable salt thereof, wherein Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 3 , Q 1 , L A , a1, Q 2 , W, and A may be as defined anywhere herein.

[0009] In one aspect, a pharmaceutical composition is featured that includes a chemical entity described herein (e.g., a compound described generically or specifically 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 for inhibiting (e.g., antagonizing) STING activity is featured, comprising contacting STING with a chemical entity described herein (e.g., a compound generically or specifically described herein or a pharma- ceutically acceptable salt thereof or a composition containing same). The method includes an in vitro method, e.g., an in vitro method, in which a sample comprising one or more cells (e.g., innate immune cells, e.g., mast cells, macrophages, dendritic cells (DCs), and natural killer cells) comprising STING is contacted with the chemical entity. The method can further include an in vivo method, e.g., an in vivo method, in which the chemical entity is administered to a subject (e.g., a human) having a disease in which increased (e.g., enhanced) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease.

[0011] In one aspect, a method of treating a condition, disease, or disorder that is ameliorated by antagonizing STING is featured, e.g., a condition, disease, or disorder in which increased (e.g., enhanced) STING activation (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 method includes administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generically or specifically described herein or a pharma- ceutically acceptable salt thereof, or a composition containing same).

[0012] In another aspect, a method of treating cancer is featured that includes administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein, or a pharma- ceutically acceptable salt thereof, or a composition containing same).

[0013] In a further aspect, a method for treating other STING-associated conditions, such as type I interferonopathies (e.g., STING-associated vasculitis with infantile onset (SAVI)), Aicardi-Goutières syndrome (AGS), inherited forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus and rheumatoid arthritis, is featured. 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 generically or specifically described herein or a pharma- ceutically acceptable salt thereof, or a composition containing the same).

[0014] In another aspect, a method is featured for suppressing STING-dependent type I interferon production in a subject, the method including administering to a subject in need thereof an effective amount of a chemical entity described herein (e.g., a compound generically or specifically described herein, or a pharma- ceutically acceptable salt thereof, or a composition containing same).

[0015] In a further aspect, a method of treating a disease in which increased (e.g., enhanced) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the disease is featured. 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 generically or specifically described herein or a pharma- ceutically acceptable salt thereof, or a composition containing same).

[0016] In another aspect, a method of treatment is featured, comprising administering to a subject an effective amount of a chemical entity described herein (e.g., a compound generically or specifically described herein, or a pharma- ceutically acceptable salt thereof, or a composition containing same), wherein the subject has (or is predisposed to have) a disease in which increased (e.g., enhanced) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the disease.

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

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

[0019] Another aspect is a compound described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for use in treating a condition, disease, or disorder associated with increased (e.g., enhanced) STING activation.

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

[0021] Another aspect is a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in treating a cancer 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, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma.

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

[0023] Another aspect is a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for use in the treatment of type I interferonopathies selected from STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutieres syndrome (AGS), genetic forms of lupus, and inflammation-related disorders, such as systemic lupus erythematosus and rheumatoid arthritis.

[0024] Another aspect is the use of a compound described herein, or a pharma- ceutically acceptable salt or tautomer thereof, in the manufacture of a medicament for the treatment of a condition, disease, or disorder associated with increased (e.g., enhanced) STING activation.

[0025] Another aspect is the use of a compound described herein, or a pharma- ceutically acceptable salt or tautomer thereof, in the manufacture of a medicament for the treatment of cancer.

[0026] Another aspect is the use of a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a medicament for the treatment of a cancer 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, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma.

[0027] Another aspect is the use of a compound described herein, or a pharma- ceutically acceptable salt or tautomer thereof, in the manufacture of a medicament for the treatment of type I interferonopathy.

[0028] Another aspect is 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 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.

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

[0030] Another aspect is the use of a compound described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for treating a condition, disease, or disorder associated with increased (e.g., enhanced) STING activation.

[0031] Another aspect is the use of a compound described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for treating cancer.

[0032] Another aspect is the use of a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, to treat a cancer 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, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma.

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

[0034] Another aspect is the use of a compound as described herein, or a pharma- ceutically acceptable salt or tautomer thereof, for treating type I interferonopathies 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] Embodiments can 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 entities can be administered in combination with one or more additional therapeutic agents and / or regimens useful for treating other STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculitis with onset in infancy (SAVI)), Aicardi-Goutières syndrome (AGS), inherited forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus and rheumatoid arthritis.

[0038] The chemical entity 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 including 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), and the like. Taxol, paclitaxel, and / or docetaxel), topoisomerases (e.g., type I topoisomerases and / or type 2 topoisomerases, 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, bica lutamide, flutamide, and / or nilutamide), antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumab, ranibizumab, rituximab, tocilizumab, tositumomab, and / or trastuzumab), antiangiogenic agents, cytokines, thrombotic agents, growth inhibitors, antihelminthic agents, andand an immune checkpoint inhibitor that targets an immune checkpoint receptor, the immune checkpoint receptor being selected from 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), and 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-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 NKG2 A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

[0039] The subject can 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 cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma. In certain embodiments, the cancer may be a refractory cancer.

[0041] The chemical entity may be administered intratumorally.

[0042] The method may further comprise the step of identifying the subject.

[0043] Other aspects include those described in the detailed description and / or claims.

[0044] Additional definitions In order to facilitate understanding of the disclosure described herein, a number of additional terms are defined below. Generally, the academic terms used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. Unless otherwise defined, all scientific and technical 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 mentioned throughout this specification and the appendix is ​​incorporated herein in its entirety by reference.

[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, homologous and / or orthologous 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 component means having no lasting adverse effects on the general 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 entity being administered that relieves to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is 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 aspect, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without undue 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 preparation of a compound that does not cause significant irritation to the organism to which it is administered and does not interfere with the biological activity and properties of the compound. In certain cases, pharmaceutical acceptable salts can be 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, and salicylic acid. In some cases, pharmaceutical acceptable salts can be 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, such as a sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, an organic base, such as a salt of dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and an amino acid, such as arginine, and lysine, or by other methods previously determined. There is no particular limit to the pharmacologically acceptable salt, as long as it can be used in medicine. Examples of the salts that the compounds described herein form with bases include their salts with inorganic bases, such as sodium, potassium, magnesium, calcium, and aluminum, their salts with organic bases, such as methylamine, ethylamine, and ethanolamine, their salts with basic amino acids, such as lysine and ornithine, and ammonium salts.The salt may be an acid addition salt, which is particularly exemplified by the acid addition salts with 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, and acidic amino acids, such as aspartic acid and glutamic acid.

[0051] The term "pharmaceutical composition" refers to a mixture of the compounds described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickening agents. Pharmaceutical compositions facilitate the administration of a compound to an organism. Multiple 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, for example, a human.

[0053] The terms "treat," "treating," and "treatment" in the context of treatment of a disease or disorder are meant to include alleviating or preventing the disorder, disease, or condition, or one or more of the symptoms associated with said disorder, disease, or condition, or to include 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 of tumor growth to any extent, including (i) slowing 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 of tumor cell invasion into peripheral organs, including (i) reduction, (ii) slowing, or (iii) complete prevention; (6) inhibition of metastasis, including (i) reduction, (ii) slowing, or (iii) complete prevention; (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 invasion; and / or (8) reduction to any extent in the severity or number 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 specified number of carbon atoms. For example, C 1-10 indicates that the group may have 1 to 10 (inclusive) carbon atoms in it. Alkyl groups may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term "saturated" as used in this context means that only single bonds exist 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 (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 2 to 6 (inclusive) carbon atoms in it. An alkenyl group can 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 2-6indicates that the group may have 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can be unsubstituted or substituted with one or more substituents.

[0061] The term "aryl" refers to a 6-20 carbon monocyclic, bicyclic, tricyclic, or polycyclic group 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 with a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, dihydro-1H-indenyl, and the like.

[0062] The term "cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon group, for example 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, 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. Cycloalkyls may contain 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 spirocyclic rings (e.g., spirocyclic bicycles in which two rings are joined by only one carbon). 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. The term "saturated" as used in this context means that only single bonds exist between the constituent carbon atoms.

[0063] The term "cycloalkenyl" as used herein means 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, which cycloalkenyl groups 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 one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group as a whole is not fully saturated. Cycloalkenyls may contain multiple fused and / or bridged and / or spirocyclic rings.

[0064] The term "heteroaryl" as used herein refers to a monocyclic, bicyclic, tricyclic or polycyclic group having 5-20 ring atoms, or 5, 6, 9, 10, or 14 ring atoms, with 6, 10, or 14 pi electrons shared in a cyclic array, where 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 it is not necessary for the ring to contain a heteroatom, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can be unsubstituted or substituted 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, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b ... and the like. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl, 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 (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 3-16 ring atoms (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S, respectively, in the case of a monocyclic, bicyclic, or tricyclic ring system) with 1-3 heteroatoms selected from O, N, or S in the case of a tricyclic or polycyclic ring system, in which 0, 1, 2, or 3 atoms of each ring may be substituted by 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, and the like. Heterocyclyl also includes spirocyclic rings (eg, spirocyclic bicycles in which the two rings are joined by only one carbon).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, 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]nonanyl, 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, etc. The term "saturated" as used in this context means that only single bonds exist between the constituent ring atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0066] The term "heterocycloalkenyl" as used herein refers to a partially unsaturated cyclic ring system (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 3-16 ring atoms (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S, respectively, in the case of monocyclic, bicyclic, or tricyclic rings), having 1-3 heteroatoms selected from O, N, or S in the case of monocyclic, bicyclic, or tricyclic rings, in the case of tricyclic or polycyclic rings, in which 0, 1, 2, or 3 atoms of each ring may be substituted by 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 one or more double bonds are present 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 spirocyclic rings.

[0067] When a ring is described herein as being "aromatic", it means that the ring has a continuous delocalized π-electron system. Typically, the number of out-of-plane π-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, etc.

[0068] When a ring is described herein as being "partially unsaturated," it is meant that the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributable 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, unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form a bicyclic or higher order ring system (e.g., tricyclic, polycyclic ring system), such rings and cyclic groups are not limited to those having fused rings, e.g., those in which the points of fusion are (i) located on adjacent ring atoms (e.g., [xx0] ring systems where 0 represents no atom bridge). TIFF2024502473000002.tif13128), (ii) located on a single ring atom (spiro-fused ring systems). TIFF2024502473000003.tif19128, or (iii) located on an array of contiguous ring atoms (bridged ring systems with a bridge length >0). TIFF2024502473000004.tif14128 is understood to encompass the file.

[0070] In addition, the atoms constituting the compounds of this embodiment are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include atoms having the same atomic number but different mass numbers. By way of non-limiting general examples, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include tritium and deuterium. 13 C and 14 C is an example.

[0071] In addition, the compounds disclosed generically or specifically herein are intended to include all tautomers. Thus, by way of example, the moiety: The compound TIFF2024502473000005.tif14128 contains the moiety: TIFF2024502473000006.tif17128 are encompassed by tautomers containing the formula: TIFF2024502473000006.tif17128. Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxyl are encompassed by pyridone or pyrimidone tautomers.

[0072] 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

[0073] Detailed Description The disclosure features chemical entities (compounds or pharma- ceutically acceptable salts and / or hydrates and / or co-crystals and / or combination drugs) that inhibit (e.g., antagonize) STING (Stimulator of Interferon Gene). The chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., enhanced) STING activation (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 containing the chemical entities, as well as methods of using and making the chemical entities.

[0074] Compounds of Formula I In one aspect, the present disclosure provides a compound of formula (I): TIFF2024502473000007.tif40128, or a pharma- ceutically acceptable salt or tautomer thereof, During the ceremony, Y 1 , Y 2 , and Y3 is CR 1 , C(=O), N, and NR 2 independently selected from the group consisting of: X 1 O, S, N, NR 2 , and C.R. 1 selected from the group consisting of; X 2 O, S, N, NR 4 , and C.R. 5 selected from the group consisting of; each TIFF2024502473000008.tif2128 is independently a single bond or a double bond, except that X 1 and X 2 is a heteroaryl, and Y 1 , Y 2 , and Y 3 is an aryl or heteroaryl; R 1 and R 5 Each occurrence of H;R c ;R h ; and -(L 1 ) b1 -R h independently selected from the group consisting of: R 2 and R 4 Each occurrence of H;R d ;R g ; and -(L 2 ) b2 -R g independently selected from the group consisting of: R 3 is H;R d ; and R h selected from the group consisting of; Q 1 is the following: Oxo, R c , and R h Each of the substituents may be substituted with 1 to 4 substituents independently selected from the group consisting of 3-12 Cycloalkylene or C 3-12 Cycloalkenylene; Heterocyclylene or heterocycloalkenylene 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 heterocyclylene or heterocycloalkenylene is oxo, R c , and R h a heterocyclylene or heterocycloalkenylene optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroarylenes 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 heteroarylene is R c and R h Heteroarylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ·R c and R h C 6-10 Arylene selected from the group consisting of; Each L A is 1 to 2 R a1 C which may be substituted with 1-3 Alkylene; -O-; -NH-; -NR d ; -S(O) 0-2 and C(O); a1 is 0, 1, 2, 3, or 4; However, -(L A ) a1 - cannot contain bonds between O, N, or S(O) atoms, unless an N-N bond is further connected to a C(O); Q 2 is R g and; WA is either (AA) or (BB) as follows: (AA) W is -N(H)- or -N(R d )- and; A is the following: ·H; 1 to 6 R b C which may be substituted with 1-10 Alkyl; and -(Y A1 ) nA -Y A2 wherein: nA is 0 or 1; Y A1 1 to 3 R b C which may be substituted with 1-6 alkylene; and Y A2 is the following: Each of which is oxo and R c and 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 heterocyclyl or heterocycloalkenyl is oxo and R c a monocyclic heterocyclyl or heterocycloalkenyl, optionally substituted by 1 to 4 substituents independently selected from the group consisting of: or (BB) W and A, taken together, Form TIFF2024502473000009.tif15128; and Ring E is a saturated or partially unsaturated ring of 3-16 ring atoms, where 0-3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2and the ring is selected from the group consisting of oxo, R c , R h , and -(L g ) bg -R h and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: R a , R a1 , and R b 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 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 1-4 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 independently selected from the group consisting of: -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 1-6Alkyl; -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, and R i C which may be substituted with 1 to 3 substituents each independently selected from the group consisting of 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 , R h , and -(L g ) bg -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 heterocyclyl or heterocycloalkenyl is oxo, R c , R h , and -(L g ) bg -R ha 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 3 of which are N, N(H), N(R d ), O, and S(O) 0-2 and heteroaryl is R c , R h , and -(L g ) bg -R h Heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ·R c , R h , and -(L g ) bg -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 3-8 Cycloalkyl or C 3-8 Cycloalkenyl; 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 one to four R i heterocyclyl or heterocycloalkenyl, optionally substituted with Heteroaryl with 5-6 ring atoms, 1-3 of which are N, N(H), N(R d ), O, and S; and heteroaryl is 1 to 4 R i heteroaryl, optionally substituted with 1 to 4 R i C6 aryl optionally substituted with 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 1 , L 2 , and 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 alkylene; b1, b2, and bg are each independently 1, 2, or 3; and Each occurrence of R' and R'' is H; -OH; and C 1-4 alkyl.

[0075] For the avoidance of doubt, -(L A ) a1 - does not contain "a bond between an O, N, or S(O) atom unless an N-N bond further connects to a C(O)", -(L A ) a1 - is -N(H)-O-, -N(R d )-O, -OO-, -S(O)0-O-, -S(O)0-N(H)-, S(O)0-N(R d ), or -S(O)0-S(O)0-; and A ) a1 - means -N(H)-N(H)- or -N(H)-N(C(O)) unless they are further linked to C(O). 1-3 It cannot contain a divalent moiety such as alkyl-.

[0076] Variable symbol Q 1 In some embodiments, Q1 is a heteroarylene 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 heteroarylene is R c and R h and the heteroarylene is optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0077] In certain of these embodiments, Q 1 is a heteroarylene of 5-6 ring atoms, 1-3 of which are N, N(H), N(R d ), O, and S; and heteroarylene is R c and R h and the heteroarylene is optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

[0078] In certain of the aforementioned embodiments, Q 1 is a heteroarylene of 5-6 ring atoms, 1-3 of which are N, N(H), N(R d ), O, and S; and the heteroarylene is one to three R c and heteroarylene, optionally substituted with

[0079] In certain embodiments, Q 1 is a heteroarylene of 5 ring atoms, 1 to 3 (e.g., 2 to 3) of which are N, N(H), N(R d ), O, and S; and the heteroarylene is one to two R c and heteroarylene, optionally substituted with

[0080] In certain of these embodiments, Q 1 is 1 to 2 R c and optionally substituted pyrazolylene.

[0081] As a non-limiting example of the above embodiment, Q 1 is 1 to 2 R c may be substituted with TIFF2024502473000010.tif19128, where aa is -(L A ) a1 -Q 2 For example, Q 1 teeth It could be TIFF2024502473000011.tif19128.

[0082] As a further non-limiting example, 1 1 to 2 R c wherein Q is an optionally substituted pyrazolylene; 1 Each of them has 1 to 2 R c may be substituted (e.g., unsubstituted) TIFF2024502473000012.tif20128, where aa is -(L A ) a1 -Q 2 Represents a point of attachment to

[0083] Variables a1 and Q 2 In some embodiments, a1 is 0. In some embodiments, a1 is 1.

[0084] In some embodiments, Q 2 teeth, 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 heteroaryl is R c , R h , and -(L g ) bg -R h Heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ·R c, R h , and -(L g ) bg -R h C 6-10 Aryl is selected from the group consisting of:

[0085] In certain of these embodiments, Q 2 teeth, Heteroaryl with 5-6 ring atoms, 1-3 of which are N, N(H), N(R d ), O, and S; and heteroaryl is 1 to 4 R cq2 heteroaryl, optionally substituted with 1 to 4 R cq2 C which may be substituted with 6-10 Aryl is selected from the group consisting of Here, each R cq2 are independently selected R c It is.

[0086] In certain of the aforementioned embodiments, Q 2 teeth, 1 to 4 R cq2 phenyl optionally substituted with; and Heteroaryl having 6 ring atoms, 1 to 3 of which are ring nitrogen atoms, and the heteroaryl has 1 to 4 R cq2 Heteroaryl, optionally substituted with is selected from the group consisting of Here, each R cq2 are independently selected R c It is.

[0087] As a non-limiting example of the above embodiment, Q 2 is 1 to 2 R cq2 wherein each R cq2 are independently selected R c It is.

[0088] In certain embodiments, Q 2 is the following formula: I have TIFF2024502473000013.tif18128, where A , Q B , Q C , Q D , and Q E CH, CR cq2 and N, where Q A ~Q E Two or less of are N, and Q A ~Q E 2 or less is CR cq2 where each R cq2 are independently selected R c It is.

[0089] In certain of these embodiments, Q A , Q B , Q C , Q D , and Q E are independently CH or CR cq2 However, Q A ~Q E 2 or less is CR cq2 It is.

[0090] In certain embodiments, (Q 2 is the following formula: TIFF2024502473000014.tif18128), Q A and Q E is CH; and Q B , Q C , and Q D are independently CH or CR cq2 However, Q A ~Q E 2 or less is CR cq2 It is.

[0091] In certain of these embodiments, Q B and Q D is CH; and Q C is CR cq2 It is.

[0092] In certain other embodiments, Q B and Q C is CH; and Q D is CR cq2 It is.

[0093] In certain other embodiments, Q B , Q C , and Q D are CH, respectively.

[0094] In certain embodiments, (Q 2 is the following formula: TIFF2024502473000015.tif19128), Q A is CR cq2 And Q B , Q C , Q D , and Q E are CH, respectively.

[0095] As a non-limiting example, Q 2 is unsubstituted phenyl, TIFF2024502473000016.tif22128, wherein each R cq2 are independently selected R c It is.

[0096] In certain embodiments, (Q 2 is the following formula: TIFF2024502473000017.tif18128), Q A ~Q E 1 to 2 are N; and Q A ~Q E The remaining one of each is CH or CR cq2 However, Q A ~Q E 2 or less is CR cq2 It is.

[0097] In some embodiments, Q 2 Each of them is oxo and R cq2C 3-12 Cycloalkyl or C 3-12 cycloalkenyl, where each R cq2 are independently selected R c It is.

[0098] In certain of these embodiments, Q 2 is oxo and R cq2 C 3-6 (e.g., C3, C4, C5, or C6) cycloalkyl (e.g., each of which is one to two R cq2 TIFF2024502473000018.tif12128), where each R cq2 are independently selected R c It is.

[0099] In certain embodiments, each R cq2 is halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1-6 Alkyl;C 1-4 Alkoxy;C 1-4 haloalkoxy; and -C 1-4 thioalkoxy.

[0100] In certain of these embodiments, each R cq2 is halo;cyano;C 1-6 Alkyl (e.g., C 1-3 alkyl (e.g., ethyl); 1 to 6 independently selected R a C replaced with 1-6 Alkyl;C 1-4 Alkoxy;C 1-4 haloalkoxy (e.g., -OCF3 or -OCH2CF3); and -C 1-4 thioalkoxy.

[0101] In certain of the aforementioned embodiments, each Rcq2 is halo;cyano;C 1-6 Alkyl (e.g., C 1-3 alkyl (e.g., ethyl);-halo, C 1-3 C substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy, -OH, 1-6 Alkyl (e.g., -CF3, -CH2CF3, or -CH2OMe); C 1-4 Alkoxy;C 1-4 haloalkoxy (e.g., -OCF3 or -OCH2CF3); and -C 1-4 thioalkoxy.

[0102] Variable symbol Y 1 , Y 2 , Y 3 , X 1 , X 2 , and R 3 In some embodiments, Y 1 is CR 1 It is.

[0103] In some embodiments, Y 2 is CR 1 It is.

[0104] In some embodiments, Y 3 is CR 1 It is.

[0105] In some embodiments, Y 1 is CR 1 And;Y 2 is CR 1 and Y 3 is CR 1 It is.

[0106] In some embodiments, R 1 Each occurrence of is H or R c It is.

[0107] In certain of these embodiments, R 1 Each occurrence of is H.

[0108] In certain embodiments, R 1 1 or 2 (e.g. 1) occurrences of R c and R 1 Each remaining occurrence of is H.

[0109] In certain embodiments, R 1 is halo (e.g., -F or -Cl); and R 1 Each remaining occurrence of is H.

[0110] In certain embodiments, Y 1 , Y 2 , and Y 3 are independently selected CR 1 It is.

[0111] In certain of these embodiments, Y 1 , Y 2 , and Y 3 are CH, respectively.

[0112] In certain embodiments, Y 1 , Y 2 , and Y 3 One of them is CR c (e.g., C-halo); and the remaining two Y 1 , Y 2 , and Y 3 Each of the is CH.

[0113] In some embodiments, X 1 is NR 2 In certain of these embodiments, X 1 is NH.

[0114] In some embodiments, X 2 is CR 5 In certain of these embodiments, X 2 is CH.

[0115] In certain embodiments, X 1 is NR 2 and X 2 is CR 5In certain of these embodiments, X 1 is NH; and X 2 is CH.

[0116] In some embodiments, R 3 is H.

[0117] In certain embodiments, X 1 is NH;X 2 is CH; and R 3 is H.

[0118] Variable symbol WA In some embodiments, WA is defined according to (AA).

[0119] In certain of these embodiments, W is -N(H)-.

[0120] In certain embodiments, W is -N(R d )-(e.g., -N(C 1-3 alkyl)-(e.g., -N(Me)-)).

[0121] In certain embodiments, A is -H.

[0122] In certain embodiments, A is 1 to 6 R b C which may be substituted with 1-10 It is an alkyl.

[0123] In certain embodiments, A is selected from 1 to 6 R b C which may be substituted with 1-6 (e.g., C1, C2, C3, or C4) alkyl.

[0124] In certain of these embodiments, A is C 1-6 For example, A can be methyl, ethyl, propyl, isopropyl, or isobutyl.

[0125] In certain embodiments, A is -OH; -halo; -NR e R f (For example, -N(C 1-3alkyl)2 or NHC(O)O(C 1-4 Alkyl));C 1-4 Alkoxy (e.g., -OMe); C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl);-C(=O)(C 1-4 substituted with 1 to 6 substituents each independently selected from the group consisting of alkyl, aryl, aryloxy ... 1-6 It is an alkyl.

[0126] In certain of these embodiments, A is C substituted with 1 to 6 independently selected halo (e.g., -F). 1-6 For example, A can be -CH2CF3, -CH2CH2CF3, or -CH2CHF2.

[0127] In certain embodiments, A is C 1-4 Alkoxy or C 1-4 Haloalkoxy substituted C 1-6 For example, A can be -CH2CH2OMe.

[0128] In certain embodiments, A is -(Y A1 ) nA -Y A2 It is.

[0129] In certain of these embodiments, nA is 0.

[0130] In certain embodiments, nA is 1. In certain of these embodiments, Y A1 1 to 3 R b C which may be substituted with 1-3 For example, Y A1 can be CH2.

[0131] In certain embodiments, Y A2 Each of them is oxo and R c and a monocyclic C 3-8 Cycloalkyl or C 3-8It is a cycloalkenyl.

[0132] In certain of these embodiments, Y A2 is oxo and R c and a monocyclic C 3-8 Cycloalkyl (e.g., C 3-6 cycloalkyl).

[0133] As a non-limiting example of the above embodiment, Y A2 Each of them has 1 to 2 R c and cyclopentyl, each of which may be independently selected from the group consisting of: cyclopropyl; cyclobutyl; and cyclopentyl, each of which may be substituted with .

[0134] In certain embodiments, Y A2 is a 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 heterocyclyl or heterocycloalkenyl is oxo and R c and is a monocyclic heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of:

[0135] In certain of these embodiments, Y A2 is a monocyclic heterocyclyl of 4-6 ring atoms, 1-2 of which are N, N(H), N(R d ), O, and S(O) 0-2 and heterocyclyl is oxo and R c and is a monocyclic heterocyclyl optionally substituted by 1 to 2 substituents independently selected from the group consisting of:

[0136] As a non-limiting example of the above embodiment, Y A2 is 1 to 2 R cIt may be oxetanyl or tetrahydrofuranyl, each of which may be optionally substituted with

[0137] In certain embodiments, A is Y A2 or -CH2-Y A2 where Y A2 teeth, Oxo and R c and a monocyclic C 3-6 Cycloalkyl; and Monocyclic heterocyclyl of 4 to 6 ring atoms, 1 to 2 of which are N, N(H), N(R d ), O, and S(O) 0-2 and heterocyclyl is oxo and R c and a monocyclic heterocyclyl optionally substituted by 1 to 2 substituents independently selected from the group consisting of is selected from the group consisting of:

[0138] In some embodiments, WA is defined according to (BB).

[0139] In certain of these embodiments, W and A together represent: Form TIFF2024502473000019.tif14128; and Ring E is a saturated or partially unsaturated ring of 3-8 ring atoms, where 0-2 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and the ring is oxo, R c , R h , and -(L g ) bg -R h It may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0140] In certain embodiments, W and A together represent: Form TIFF2024502473000020.tif14128; and Ring E is a saturated ring of 3-8 ring atoms, where 0-2 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and the ring is oxo and R c It may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0141] In certain embodiments, W and A together represent: TIFF2024502473000021.tif15128, where m1 and m2 are independently 0, 1, or 2, and where W 1 is CH2, CH(R c ), C(R c )2, NH, or N(R d ).

[0142] In certain embodiments, W and A taken together are TIFF2024502473000022.tif15128), m1 and m2 are independently 0 or 1.

[0143] In certain embodiments, W and A taken together are TIFF2024502473000023.tif15128), W 1 is CH2 or N(R d ) (e.g., CH2 or -NC(=O)(C 1-3 alkyl)-).

[0144] Non-limiting combinations In certain embodiments, the compound has formula (Ia): TIFF2024502473000024.tif52128, or a pharma- ceutically acceptable salt thereof.

[0145] In certain embodiments of formula (Ia), Q 2is the following formula: I have TIFF2024502473000025.tif18128, where A , Q B , Q C , Q D , and Q E CH, CR cq2 and N, where Q A ~Q E Two or less of are N, and Q A ~Q E 2 or less is CR cq2 where each R cq2 are independently selected R c It is.

[0146] In certain embodiments of formula (Ia), (Q 2 is the following formula: TIFF2024502473000026.tif18128), Q A , Q B , Q C , Q D , and Q E are independently CH or CR cq2 However, Q A ~Q E 2 or less is CR cq2 It is.

[0147] In certain embodiments of formula (Ia), (Q 2 is the following formula: TIFF2024502473000027.tif18128), Q A and Q E is CH; and Q B , Q C , and Q D are independently CH or CR cq2 However, Q A ~Q E 2 or less is CR cq2 It is.

[0148] In certain of these embodiments, Q B and Q D is CH; and QC is CR cq2 It is.

[0149] In certain embodiments, Q B and Q C is CH; and Q D is CR cq2 It is.

[0150] In certain embodiments, Q B , Q C , and Q D are CH, respectively.

[0151] In certain embodiments of formula (Ia), (Q 2 is the following formula: TIFF2024502473000028.tif18128), Q A is CR cq2 And Q B , Q C , Q D , and Q E are CH, respectively.

[0152] In certain embodiments of formula (Ia), Q 2 is unsubstituted phenyl, TIFF2024502473000029.tif22128, wherein each R cq2 are independently selected R c It is.

[0153] In certain embodiments of formula (Ia), (Q 2 is the following formula: TIFF2024502473000030.tif18128), Q A ~Q E 1 to 2 are N; and Q A ~Q E The remaining one of each is CH or CR cq2 However, Q A ~Q E 2 or less is CR cq2 It is.

[0154] In certain embodiments of formula (Ia), Q 2 is oxo and R cq2 C 3-12 cycloalkyl, where each R cq2 are independently selected R c It is.

[0155] In certain embodiments of Formula (Ia), each R cq2 is halo;cyano;C 1-6 Alkyl (e.g., C 1-3 alkyl (e.g., ethyl);-halo, C 1-3 C substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy, -OH, 1-6 Alkyl (e.g., -CF3, -CH2CF3, or -CH2OMe); C 1-4 Alkoxy;C 1-4 haloalkoxy (e.g., -OCF3 or -OCH2CF3); and -C 1-4 thioalkoxy.

[0156] In certain embodiments of formula (Ia), Y 1 , Y 2 , and Y 3 are independently selected CR 1 For example, Y 1 , Y 2 , and Y 3 Each of Y can be CH. As another non-limiting example, Y 1 , Y 2 , and Y 3 One of them is CR c (e.g., C-halo); and the remaining two Y 1 , Y 2 , and Y 3 Each of may be CH.

[0157] In certain embodiments of formula (Ia), R 2 is H.

[0158] In certain embodiments of formula (Ia), R5 is H.

[0159] In certain embodiments of formula (Ia), R 3 is H.

[0160] In certain embodiments of formula (Ia), WA is defined according to (AA).

[0161] In certain embodiments of Formula (Ia), W is -N(H)-.

[0162] In certain embodiments of formula (Ia), W is -N(C 1-3 alkyl)-.

[0163] In certain embodiments of Formula (Ia), A is H.

[0164] In certain embodiments of formula (Ia), A is C 1-6 For example, A can be methyl, ethyl, propyl, isopropyl, or isobutyl.

[0165] In certain embodiments of formula (Ia), A is -OH; -halo; -NR e R f (For example, -N(C 1-3 alkyl)2 or NHC(O)O(C 1-4 Alkyl));C 1-4 Alkoxy (e.g., -OMe); C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl);-C(=O)(C 1-4 substituted with 1 to 6 substituents each independently selected from the group consisting of alkyl, aryl, aryloxy ... 1-6 It is an alkyl.

[0166] As a non-limiting example of the above embodiment, A is C substituted with 1 to 6 independently selected halo. 1-6 It can be alkyl (e.g., A is -CH2CF3, -CH2CH2CF3, or -CH2CHF2). As a further non-limiting example, A can be C 1-4 Alkoxy or C1-4 Haloalkoxy substituted C 1-6 It can be alkyl (eg, A is -CH2CH2OMe).

[0167] In certain embodiments of formula (Ia), A is Y A2 or -CH2-Y A2 where Y A2 teeth, Oxo and R c and a monocyclic C 3-6 Cycloalkyl; and Monocyclic heterocyclyl of 4 to 6 ring atoms, 1 to 2 of which are N, N(H), N(R d ), O, and S(O) 0-2 and heterocyclyl is oxo and R c and a monocyclic heterocyclyl optionally substituted by 1 to 2 substituents independently selected from the group consisting of is selected from the group consisting of:

[0168] In certain embodiments of formula (Ia), WA is defined according to (BB).

[0169] In certain embodiments of Formula (Ia), W and A together represent: Form TIFF2024502473000031.tif14128; and Ring E is a saturated ring of 3-8 ring atoms, where 0-2 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and the ring is oxo and R c It may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0170] In certain embodiments of Formula (Ia), W and A together represent: TIFF2024502473000032.tif15128, where m1 and m2 are independently 0, 1, or 2, and where W 1 is CH2, CH(R c ), C(R c )2, NH, or N(R d ).

[0171] In certain of these embodiments, m1 and m2 are independently 0 or 1.

[0172] In certain embodiments, W and A taken together are TIFF2024502473000033.tif15128), W 1 is CH2 or N(R d ).

[0173] In certain embodiments, W and A taken together are TIFF2024502473000034.tif15128), m1 and m2 are independently 0 or 1; and W 1 is CH2 or N(R d ).

[0174] Non-limiting exemplary compounds In some embodiments, the compound is selected from the group consisting of the compounds set forth in Table C1, or a pharma- ceutically acceptable salt thereof.

[0175] [Table C1] TIFF2024502473000036.tif196113TIFF2024502473000037.tif192113TIFF2024502473 000038.tif224113TIFF2024502473000039.tif214113TIFF2024502473000040.tif92128

[0176] Pharmaceutical Compositions and Administration overview In some embodiments, the 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 drug thereof) is administered as a pharmaceutical composition comprising the chemical entity, one or more pharma- ceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0177] In some embodiments, chemical entities 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 pharmaceutical dosage forms, such as Tween, poloxamer or other similar polymeric 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, potassium 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 hydroxyalkyl cyclodextrins, 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 containing within the range of 0.005%-100% of the chemical entities as described herein, with the remainder being composed 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 the chemical entities provided herein. Actual methods of preparing such dosage forms will be known or apparent to those skilled in the art and may be found, for example, in Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0178] Route of Administration and Composition Components In some aspects, the chemical entities described herein or pharmaceutical compositions thereof can be administered to a subject in need thereof by any approved route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, endosinusial, intratracheal, enteral, epidural, interstitial, intraabdominal, intraarterial, intrabronchial, intrasynovial, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intraductal, intratumor, intrauterine, intravascular, intravenous, intranasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the preferred route of administration is parenteral (eg, intratumoral).

[0179] The composition can be formulated for parenteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal route.Typically, such compositions can be prepared as injectable liquid, either as liquid solution or suspension, and also can be prepared in solid form suitable for use in preparing solution or suspension by adding liquid before injection, and the preparation can also be emulsified.The preparation of such formulations is known to those skilled in the art in light of the present disclosure.

[0180] Suitable pharmaceutical forms for injectable use include sterile aqueous solutions or dispersions, formulations containing sesame oil, peanut oil, or aqueous propylene glycol, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.In all cases, the form must be sterile and must be fluid to the extent that it can be easily injected.It should also be stable under the conditions of production and storage, and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0181] 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 the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. 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 the use of agents that delay absorption, for example, aluminum monostearate and gelatin in the composition.

[0182] Sterile injectable solution is prepared by incorporating the active compound in the required amount in a suitable solvent together with various other components listed above as required, followed by sterilization filtration.Generally, dispersion is prepared by incorporating various sterilized active components into a sterile medium that contains basic dispersion medium and other components listed above as required.For the preparation of sterile powder for sterile injectable solution, the preferred method of preparation is vacuum drying and freeze-drying technology, which produces a powder of active component and any additional desired components from the solution that has been previously sterilized and filtered.

[0183] Intratumoral injection is discussed, for example, in Lammers, et al., "Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems" Neoplasia. 2006, 10, 788-795.

[0184] Pharmacologically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (such as PEG ointment), glycerin, glycerin gelatin, hydrogenated vegetable oils, poloxamers, 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, parabens in aerosols, phenoxyethanol, methyl p-oxybenzoate ... In some embodiments, the additives and / or preservatives may include, but are not limited to, any one or more of: sodium stearate, sodium p-oxybenzoate, propyl sodium p-oxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, disodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0185] 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 thus melt in the rectum to release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

[0186] 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 (e.g., solid or liquid dosage forms).

[0187] The solid dosage form for oral administration includes 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 starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) wetting agents, such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, and the like. , potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as 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 form may also contain buffering agents. A similar type of solid composition can also be used as a filler in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols.

[0188] In one embodiment, the composition is in the form of a unit dosage form such as a pill or tablet, so that the composition may contain, together with the chemical entities provided herein, a diluent such as lactose, sucrose, or dicalcium phosphate, a lubricant such as magnesium stearate, and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, or cellulose derivatives. 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 envisioned, such as capsules (or tablets in capsules) with granules of each drug, bilayer tablets, bicompartment gelcaps, and the like. Enteric coating or delayed release oral dosage forms are also envisioned.

[0189] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives that are specifically useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0190] In certain embodiments, the excipients are sterile and generally free of undesirable substances.These compositions can be sterilized by conventional well-known sterilization techniques.For excipients of various oral dosage forms such as tablets and capsules, sterility is not required.USP / NF standards are usually sufficient.

[0191] In certain embodiments, the solid oral dosage form can further comprise one or more components that provide the composition with a chemical and / or structural predisposition for delivery of chemical entities to the stomach or lower GI, for example, 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.

[0192] Examples include upper GI targeting technologies such as the Accordion Pill (Intec Pharma), floating capsules, and materials that can adhere to mucosal walls.

[0193] Other examples include lower GI targeting technology. Several enteric / pH-responsive coatings and excipients are available to target different regions in the intestinal tract. These materials are typically polymers designed to dissolve or erode at a specific pH range 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 when the active ingredient may be irritating to the upper GI (e.g., hydroxypropylmethylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer), and Marcoat). Other technologies include dosage forms that respond to local flora in the GI tract, pressure-controlled colonic delivery capsules, and Pulsincap.

[0194] 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 (stabilized oxychloro complex, Allergan, Inc.)).

[0195] External compositions can include ointments and creams. Ointments are semi-solid preparations typically based on petrolatum or other petroleum derivatives. Creams containing selected active agents are typically viscous liquids or semi-solid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes called the "internal" phase, generally contains petrolatum and a fatty alcohol, e.g., cetyl or stearyl alcohol, and the aqueous phase usually, but not necessarily, exceeds the oil phase in volume and generally contains a humectant. Emulsifiers in cream formulations are generally non-ionic, anionic, cationic, or amphoteric surfactants. As with other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing.

[0196] In any of the foregoing embodiments, the pharmaceutical compositions described herein can comprise one or more of: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particles supporting lipid bilayers.

[0197] Dosage Dosage may vary depending on the needs of the patient, the severity of the condition being treated, and the specific compound being used. The determination of the appropriate dosage for a specific situation can be determined by those skilled in the medical field. The total daily dosage may be divided or administered in portions throughout the day, or by any means that provides continuous delivery.

[0198] 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).

[0199] Regimen The dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or off-daily (e.g., every other day, every second day, every third day, once a week, twice a week, once every two weeks, once a month).

[0200] In some embodiments, the duration of administration 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 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 a period of time, followed by a separate period of time. In another embodiment, the therapeutic compound is administered for a first period of time, and for a second period of time after the first period of time during which administration is suspended during the second period of time, followed by a third period of time during which administration of the therapeutic compound is initiated, and then a fourth period of time after the third period of time during which administration is suspended. 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 determined or undetermined period of time. In further embodiments, the duration of administration 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 for 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.

[0201] Treatment methods In some aspects, methods are provided for treating a subject having a condition, disease, or disorder (e.g., immune disorder, cancer) in which increased (e.g., enhanced) STING activity (e.g., STING signaling, etc.) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder.

[0202] 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 or renal cancer, clear cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung cancer including adenocarcinoma of the lung and squamous carcinoma of the lung, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), cervical cancer, ovarian cancer, prostate cancer, prostate neoplasms, liver cancer, bladder cancer, peritoneal cancer, hepatocellular carcinoma, gastric or esophageal cancer including gastrointestinal cancer. tomach cancer, gastrointestinal stromal tumors, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, theca cell tumor, arenoblastoma, hepatoma, non-Hodgkin's lymphoma (NHL), multiple myeloma, myelodysplastic disorder, myeloproliferative disorder, chronic myeloid leukemia, and hematological malignancies including acute hematological malignancies, endometrial or uterine cancer, endometriosis, endometrial stromal sarcoma, fibrosarcoma, choriocarcinoma, salivary gland cancer, vulvar cancer, thyroid cancer Cancers of the esophagus, liver, anus, penis, nasopharyngeal, laryngeal, Kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin cancer, schwannoma, oligodendroglioma, neuroblastoma, neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, Ewing's sarcoma, peripheral primitive neuroectodermal tumor, urinary tract cancer, thyroid carcinoma, Wilms' tumor, as well as 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.

[0203] In some embodiments, the condition, disease, or disorder is a neurological disorder, including disorders involving the central nervous system (brain, brain stem, and cerebellum), the peripheral nervous system (including the cranial nerves), and the autonomic nervous system (parts of which are located in both the central and peripheral nervous systems). Non-limiting examples of neurological disorders include acquired epileptic aphasia, acute powder-borne encephalomyelitis, adrenoleukodystrophy, age-related macular degeneration, dysgenesis of the corpus callosum, agnosia, Ecardi's syndrome, Alexander's disease, Alpers' disease, alternating hemiplegia, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis, anencephaly, Angelman's syndrome, hemangiomatosis, anoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Anronl-Chiari malformation, arteriovenous malformations, Asperger's syndrome, ataxia telegiectasia, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Batten's disease, Behcet's disease, Bell's palsy, benign essential blepharospasm, benign focal glaucoma, and glaucoma. focal), muscle 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, Canavan disease, carpal tunnel syndrome, causal pain, central pain syndrome, central pontine myelinolysis, head injury, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, Charcot-Marie-Tooth disease, chemotherapy-induced neuropathy and neuropathic pain, Chiari malformation, chorea, chronic inflammatory demyelinating polyneuropathy, chronic pain, chronic regional pain syndrome, Coffin-Lowry syndrome, coma including persistent vegetative state, congenital facial diplegia, corticobasal ganglia degeneration encephalopathy, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion disease, cytomegalovirus infection, dancing eyes-dancing feet syndrome, Dandy-Walker syndrome, Dawson's disease, Domorsia syndrome, Degerines-Klumke palsy, dementia, dermatomyositis, diabetic neuropathy, diffuse sclerosis, autonomic dysfunction, dysgraphia, dyslexia, dystonia, early infantile epileptic encephalopathy, empty sella syndrome, encephalitis, cerebral herniation, cerebral trigeminal angiomatosis, epilepsy, Erb's palsy, essential tremor, Fabry's disease, Fahr's syndrome, syncope, familial spastic paralysis, febrile seizures,Fisher syndrome, Friedreich's ataxia, frontotemporal dementia and other "tauopathies", Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, Guillain-Barré syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, head injury, headache, hemifacial spasm, hereditary spastic paraplegia, polyneuropathy hereditary ataxia, herpes zoster oticus, hereditary ataxia, herpes zoster oticus Herpes simplex, Hirayama syndrome, HIV-associated dementia and neuropathy (also a neurological manifestation of AIDS), holoprosencephaly, Huntington's disease and other polyglutamine repeat diseases, hydrocephalus, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum's disease, infantile spasms, inflammatory myopathy, intracranial cysts, intracranial hypertension, Joubert's disease Syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbone syndrome, Klippel-Feil syndrome, Krabbe disease, Kugelberg-Welander disease, Kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, Lateral bulbar (Wallenberg) syndrome, Learning disabilities, Leigh disease, Lennox-Gustaut syndrome, Lesch-Nyhan syndrome, Leukodystrophies, Dementia with Lewy bodies, Lissencephaly, Locked-in syndrome, Lou Gehrig's disease (i.e. motor neuron disease or amyotrophic lateral sclerosis), Lumbar discopathy, Lyme disease - neurological sequelae, Machado-Joseph disease, Macrencephaly, Megalencephaly, Melkersson-Rosenthal syndrome, Meniere's disease disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, migraine, Miller Fisher syndrome, mini stroke, mitochondrial myopathy, Moebius syndrome, single limb muscular atrophy, motor neuron disease, Moyamoya disease, mucopolysaccharidoses, milti-infarct dementia, multifocal motor neuropathy, multiple sclerosis and other demyelinating disorders, multiple system atrophy with orthostatic hypotension, p muscular dystrophy, myasthenia gravis, myelinoclastic diffuse sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy,Congenital myotonia, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, neurological symptoms of AIDS, neurological sequelae of lupus, neurogenic myotonia, neuronal ceroid lipofuscinosis, neuronal migration disorder, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occult neuralgia, occult spinal dysraphism sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus, optic neuritis, orthostatic hypotension, overuse syndrome, paresthesias, Parkinson's disease, congenital paramyotonia, paraneoplastic disorders disease, seizures, Paley-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralysis, peripheral neuropathy, painful neuropathy and neuropathic pain, persistent vegetative state, pervasive developmental disorder, photophobia, phytanic acid storage disease, Pick's disease, pinched nerve nerve), pituitary tumor, polymyositis, porencephaly, post-polio syndrome, post-herpetic neuralgia, post-infectious encephalomyelitis, orthostatic hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion disease, progressive hemifacial atrophy, 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's disease, repetitive movement disorder, repetitive stress injury, restless legs syndrome, retrovirus-associated myelopathy, Rett's syndrome, Reye's syndrome, chorea, Sandhoff's disease, Schilder's disease, schizencephaly, septo-optic dysplasia, shaken baby syndrome, herpes zoster, Shy-Drager syndrome, Sjogren's syndrome, sleep apnea, Sotos syndrome, spasticity, spina bifida, spinal cord injury, spinal tumor, spinal muscular atrophy, stiff person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, Sydenham's chorea, syncope, syringomyelia, tardive dyskinesia, Tay-Sachs disease, temporal arteritis, tethered spinal cord syndrome, Thomsen's disease, thoracic outlet syndrome, trigeminal neuralgia, Todd's palsy, Tourette's syndrome, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraplegia, tuberous sclerosis, vascular dementia (multi-infarct dementia), vasculitis including temporal arteritis, von Hippel-Lindau disease,These include Wallenberg syndrome, Werdnig-Hoffmann disease, West syndrome, whiplash injury, Williams syndrome, Wildon's disease, amyotrophic lateral sclerosis, and Zellweger syndrome.

[0204] In some embodiments, the condition, disease, or disorder is a STING-associated condition, for example, type I interferonopathy (e.g., STING-associated vasculitis with infantile onset (SAVI)), Aicardi-Goutières syndrome (AGS), hereditary forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus and rheumatoid arthritis. In certain embodiments, the condition, disease, or disorder is an autoimmune disease (e.g., cytosolic DNA-induced autoinflammatory disease). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. 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 treatment with adoptive cell therapy, colitis associated with one or more alloimmune diseases (e.g., graft-versus-host disease, e.g., 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 (e.g., graft-versus-host disease, e.g., acute graft-versus-host disease and chronic graft-versus-host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis, or intestinal mucositis).

[0205] In some embodiments, modulation of the immune system by STING provides treatment of diseases, including diseases caused by foreign agents. Exemplary infections by foreign agents that may 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., an 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., an infection caused by a mold, yeast, or higher fungus). 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, cold sores, common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and lower or upper respiratory tract infections (e.g., respiratory syncytial virus)).

[0206] In some embodiments, the condition, disease, or disorder is Hepatitis B (see, e.g., WO 2015 / 061294).

[0207] In some embodiments, the condition, disease, or disorder is selected from cardiovascular disease (including, for example, myocardial infarction).

[0208] In some aspects, the condition, disease, or disorder is age-related macular degeneration.

[0209] In some aspects, the condition, disease, or disorder is mucositis, also known as stomatitits, which can occur as a result of damage caused by chemotherapy or radiation therapy, either alone or in combination, as well as exposure to radiation outside the context of radiation therapy.

[0210] In some aspects, 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).

[0211] In some embodiments, the condition, disease, or disorder is selected from the group consisting of cancer, a neurological disorder, an autoimmune disease, hepatitis B, uveitis, cardiovascular disease, age-related macular degeneration, and mucositis.

[0212] Further examples may include the indications discussed below herein and the contemplated combination therapy regimens.

[0213] Combination therapy The present disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[0214] In some embodiments, the methods described herein can 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.

[0215] In certain aspects, the methods described herein can further comprise the step of administering one or more additional cancer therapies.

[0216] 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, as well as 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 treatments, including, but not limited to, freezing the tumor.

[0217] In some embodiments, the one or more additional cancer therapies is chemotherapy, which can include administering one or more additional chemotherapeutic agents.

[0218] In certain embodiments, the additional chemotherapeutic agent is an immune modulating moiety, e.g., an immune checkpoint inhibitor. In certain of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor, which 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, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-C D160, 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 NK G2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155, e.g., CTLA-4 or PD1 or PD-L1).See, e.g., Postow, MJ Clin. Oncol. 2015, 33, 1.

[0219] In certain of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of urelumab, PF-05082566, MEDI6469, TRX518, valilumab, 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.

[0220] 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 can function by impairing cell function by forming covalent bonds with amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules, or they can act by modifying the DNA of cells. In further embodiments, alkylating agents are synthetic, semi-synthetic, or derivatives.

[0221] In certain embodiments, the additional chemotherapeutic agent is an antimetabolite. Antimetabolites masquerade as purines or pyrimidines, the building blocks of DNA, and generally prevent 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, antimetabolites include, but are not limited to, azathioprine and / or mercaptopurine. In further embodiments, antimetabolites are synthetic, semi-synthetic, or derivatives.

[0222] In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and / or terpenoid. These alkaloids are derived from plants and generally block cell division by preventing microtubule function. In one embodiment, the plant alkaloid and / or 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, generally 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 terpernoids 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 agent is a topoisomerase. Topoisomerases are essential enzymes that maintain DNA topology. Inhibition of type I or type II topoisomerases interferes with 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 a further embodiment, the epipodophyllotoxin is, but is not limited to, amsacrine, etoposid, etoposide phosphate, and / or teniposide. In a further embodiment, the topoisomerase is synthetic, semi-synthetic, or a derivative, including those found in nature, such as, but not limited to, epipodophyllotoxin, a substance naturally occurring in the root of the American mayapple (Podophyllum peltatum).

[0223] 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, epsilon-vinferin, flexuosol 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.

[0224] 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 chlofazimine. 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 aspect, the cytotoxic antibiotic is synthetic, semi-synthetic, or a derivative.

[0225] In certain embodiments, the additional chemotherapeutic agent is endostatin, angiogenin, angiostatin, chemokine, angioarrestin, angiostatin (plasminogen fragment), basement membrane collagen-derived antiangiogenic factor (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 inhibitors (TIMPs), 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, and vasostatin (calreticulin fragment).

[0226] 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'-norbin-caleukoblastine, docetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine Selected from dolastatins, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyureataxanes, 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.

[0227] 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 inhibitors of mTOR (mammalian target of rapamycin), including, but not limited to, rapamycin, everolimus, temsirolimus, and deforolimus.

[0228] In still other embodiments, the additional chemotherapeutic agent can be selected from those described in detail in US Pat. No. 7,927,613, which is incorporated herein by reference in its entirety.

[0229] In some embodiments, the additional therapeutic agents and / or regimens are those that can be used to treat other STING-associated conditions, such as type I interferonopathies (e.g., STING-associated vasculitis with onset in infancy (SAVI)), Aicardi-Goutières syndrome (AGS), inherited forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus and rheumatoid arthritis.

[0230] 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, evobrutinib, 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®).

[0231] 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®, Gengraf®, (Trademark), and mycophenolate mofetil) baricitinib, iguratimod, filgotinib, GS-9876, rapamycin, and PF-06650833), and biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, obinutuzumab, bovalilizumab, lulizumab, izumab), atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirorizumab, edoratides, 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 immunomodulators (e.g., iveldmide, voclosporin, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycobacterial agents (e.g., cefotaxime ... phenolate mofetil, baricitinib, filgotinib, and PF-06650833), and biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, bovalilizumab, lurizumab, atacicept, PF-06823859, lupzole, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirorizumab, edorazide, IFN-α-kinoid, 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, filgotinib, and thalidomide (Thalomid®). Agents and regimens for treating drug-induced and / or neonatal lupus may also be administered.

[0232] 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).

[0233] Non-limiting examples of additional therapeutic agents and / or regimens for treating Aicardi-Goutières Syndrome (AGS) include physical therapy, treatment for 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).

[0234] 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 microbial transplant, filgotinib, fingolimod, filategrast (SB-683699) (formerly known as 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, vatelizumab, VB-201, vedolizumab, and vidofludimus.

[0235] Non-limiting examples of additional therapeutic agents and / or regimens for treating irritable bowel syndrome include alosetron, bile acid sequestrants, sequesterants (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 transplants, fluoxetine, gabapentin, guanylate cyclase-C agonists (e.g., linaclotide, plecanatide), ibodutant, imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, ondansetron, opioids, paroxetine, pinaverium, polyethylene glycol, pregabalin, probiotics, ramosetron, rifaximin, and tenapanor.

[0236] 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 alefacept), 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).

[0237] 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 transplant, 6-mercaptopurine, azathioprine, certolizumab pegol (Cimzia®), corticosteroids (e.g., prednisone), etrolizumab, E6011, fecal microbiota transplant, filgotinib, guselkumab, infliximab, IL-2, JAK inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, natalizumab, ozanimod, RHB-104, rifaximin, risankizumab, SHP647, sulfasalazine, thalidomide, upadacitinib, V565, and vedolizumab.

[0238] 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 microbial transplant, filgotinib, 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] Non-limiting examples of additional therapeutic agents and / or regimens for treating colitis induced by treatment with adoptive cell therapy 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.

[0243] 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.

[0244] 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 supplementation, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin), sucralfate, and vitamin E.

[0245] 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.

[0246] Non-limiting examples of additional therapeutic agents and / or regimens for treating lyphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), loperamide, mesalamine, methotrexate, and sulfasalazine.

[0247] 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 microbial transplants, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0248] Non-limiting examples of additional therapeutic agents and / or regimens for treating alloimmune diseases 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, dacilzumab, defibrotide (d efribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonegistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0249] 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, and fluoxetine. These include cetin, glatiramer acetate (Copaxone®), hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVax™, ocrelizumab, ofatumumab, pioglitazone, and RPC1063.

[0250] 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, baricitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisolone, prednisone), cyclosporine, daclizumab, defibrotide, These include denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, nemolizumab, pentostatin, pevonegistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0251] 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., methylprednisolone, prednisone), cyclosporine, daclizumab, defibrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate mofetil, natalizumab, nemolizumab, pentostatin, photopheresis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.

[0252] 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., methylprednisolone, prednisone), cyclosporine, daclizumab, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0253] 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-Beta-1, IMGX003, KumaMax, larazotide acetate, Nexvan2®, pancrelipase, TIMP-GLIA, vedolizumab, and ZED1227.

[0254] 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 LEO 90100 (Enstilar®), topical betamethasone dipropionate, topical serotoninib ... dipropriate) (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®)), calcineurin inhibitors (e.g., tacrolimus (Prograf®) and pimecrolimus (Elidel®)), salicylic acid, coal tar, moisturizers, phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrowband UVB phototherapy, Goeckerman therapy, solar radiation therapy, solar eczema ... Treatment with cyclosporine plus ultraviolet A (PUVA) therapy, 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®), etanercept-szzs (Elrezi®), infliximab (Remicade®), adalimumab (Humira®), adalimumab-adbm (Cyltezo®), ustekinumab (Stelara®), golimumab (Simponi®), apremilast (Otezla®), secukinumab (Cosentyx®), certolixumab pegol, 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®).

[0255] 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 plus ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photopheresis, radiation therapy (e.g., spot radiation and total body 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).

[0256] 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 (Actem®), These include rituximab (Raptiva®), alemtuzumab (Campath®), efalizumab (Raptiva®), LFG316, sirolimus (Santen®), abatacept, sarilumab (Kevzara®), and daclizumab (Zenapax®), cytotoxic drugs, surgical implants (e.g., fluocinolone inserts), and vitrectomy.

[0257] Non-limiting examples of additional therapeutic agents and / or regimens for treating mucositis include AG013, SGX942 (dusquetide), amifostine (Ethyol®), cryotherapy, cepacol lozenges, capsaicin lozenges, mucoadhesives (e.g., MuGard®), oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita (Citroenac), cepacol lozenges, capsaicin lozenges, mucoadhesives (e.g., MuGard®), oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita) mouthwash, edible grape plant exosomes, antiseptic mouthwashes (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol), corticosteroids (e.g., prednisone), pain killers (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 angustifolia extract (e.g., SAMITAL®), and a gastrointestinal cocktail (acid reducers, 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, cepacor lozenges, 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®), cafosol, chamomilla recta mouthwash, grape plant exosomes, antiseptic mouthwashes (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol), corticosteroids (e.g., prednisone), pain killers (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, and gastrointestinal cocktails (acid reducers, e.g., aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungals (e.g., nystatin), and analgesics (e.g., hurricane liquid)). As another example, non-limiting examples of treatments for esophageal mucositis include xylocaine (e.g., gel viscous xylocaine 2%). As another example, treatments for, modifying, and the signs and symptoms of intestinal mucositis include gastrointestinal cocktails (acid reducers, e.g., aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungals (e.g., nystatin), and pain relievers (e.g., hurricane liquid)).

[0258] In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering 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).

[0259] In other embodiments, the second therapeutic agent or regimen is administered to the subject at approximately the same time as the chemical entity is contacted or administered.For example, the second therapeutic agent or regimen and the chemical entity are simultaneously provided to the subject in the same dosage form.For another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject in parallel in separate dosage forms.

[0260] In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering 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).

[0261] Patient Selection In some embodiments, the methods described herein further comprise identifying a subject (e.g., a patient) in need of such treatment (e.g., via 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 cancer and prostate cancer. In other embodiments, identifying the subject can comprise assaying the patient's tumor microenvironment, e.g., a patient with one or more cold tumors, for the absence of T cells and / or the presence of exhausted T cells. Such patients can include patients who are resistant to treatment with checkpoint inhibitors. In certain embodiments, such patients can be treated with chemical entities herein, e.g., to recruit T cells to the tumor, and in some cases, can be further treated with one or more checkpoint inhibitors, e.g., once T cells are exhausted.

[0262] In some aspects, 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 having one or more cold tumors, e.g., tumors lacking T cells or exhausted T cells).

[0263] compound preparation As can be recognized by those skilled in the art, the method of synthesizing the compounds of the formula herein is clear to those skilled in the art.The synthetic chemistry transformations and protective group methodologies (protection and deprotection) useful in 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); TW Greene 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 preparing the compounds of the present invention are known, made by known methods, or commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein can be interchanged with alternative equivalents recognized in the art. For example, in many reactions, triethylamine can be interchanged with other bases, such as non-nucleophilic bases (e.g., diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

[0264] Those of skill in the art will recognize the various analytical methods that can be used to characterize the compounds described herein, including, for example, 1 Characterization methods include 1 H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The above list is a subset of the characterization methods available to one of skill in the art and is not intended to be limiting.

[0265] To further illustrate the above, the following non-limiting exemplary synthetic schemes are included. Variations of these examples that are within the scope of the claims are within the scope of one of ordinary skill in the art and are considered to fall within the scope of the invention as described and claimed in this application. The reader will recognize that one of ordinary skill in the art, armed with this disclosure and the skill in the art, can make and use the invention without the exhaustive examples.

[0266] Abbreviation ACN = acetonitrile Ac = acetyl Bu = Butyl DCM = dichloromethane DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide DPPA = diphenyl azidophosphate HPLC = High Performance Liquid Chromatography LCMS = Liquid Chromatography-Mass Spectrometry Me = methyl NMR = nuclear magnetic resonance Pd(dppf)Cl2 = dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium Py = pyridine TEA = triethylamine TFA = trifluoroacetic acid THF = Tetrahydrofuran T3P = 2,4,6-tripropyl-2,4,6-trioxo-1,3,5,2,4,6-trioxatriphosphorinane Dioxane = 1,4-dioxane K3PO4 = Potassium phosphate XPhos Pd G3 = methanesulfonato(2-dicyclohexylphosphino2,4,6-tri-i-propyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) T3P = 2,4,6-tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide FA = formic acid SpeedVac = Savant SC250EXP SpeedVac Concentrator Pd(CH3CN)2Cl2 = bis(acetonitrile)palladium(II) chloride SPhos = 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl K2CO3 = Potassium Carbonate CuI = copper(I) iodide Na2SO4 = Sodium sulfate H2O = Water Parallel synthesizer = ZHCHENG ZWY-113H40 NaOH = Sodium Hydroxide MeNH2-HCl = methylamine hydrochloride T3P = 2,4,6-tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide XPhos Pd G3 = methanesulfonato(2-dicyclohexylphosphino2,4,6-tri-i-propyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) MeOH = methanol EtOAc = ethyl acetate EXAMPLES

[0267] Materials and Methods LCMS was recorded using one of the following methods.

[0268] LCMS method A: Kinetex EVO C18 100A, 30*3mm, injection 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 10%MPB~95% / 2.0min, hold at 95%MPB for 0.3min, 95%MPB~10% / 0.1min.

[0269] LCMS method B: Xselect CSH C18, 50*3mm, injection 1.0μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 0.1%FA and mobile phase B (MPB): acetonitrile / 0.1%FA. Elute 5%MPB-100% / 2.00min, hold at 100%MPB for 0.7min, 100%MPB-5% / 0.05min, then equilibrate to 5%MPB for 0.15min.

[0270] LCMS Method C: XBridge Shield RP18, 50*4.6mm, injection 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 0.04%NH4OH and mobile phase B (MPB): acetonitrile. Elute 10%MPB-95% / 2.00min, hold at 95%MPB for 0.79min, 95%MPB-10% / 0.06min, then equilibrate to 10%MPB for 0.15min.

[0271] LCMS Method D: Shim-pack XR-ODS, 50*3mm, injection 0.3μL, flow rate 1.2mL / 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. Elute 5%MPB-100% / 1.10min, hold at 100%MPB for 0.60min, 100%MPB-5% / 0.05min, then equilibrate to 5%MPB for 0.25min.

[0272] LCMS Method E: kinetex 2.6um EVO, 50*3mm, injection 0.5μL, flow rate 1.2mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elute 10%MPB-95% / 2.00min, hold at 95%MPB for 0.70min, 95%MPB-10% / 0.05min, then equilibrate to 10%MPB for 0.25min.

[0273] LCMS method F: Titank C18, 50*3mm, injection 0.5μL, flow rate 1.5mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution 10%MPB-95% / 1.80min, hold at 95%MPB for 0.80min, 95%MPB-10% / 0.15min, then equilibrate to 10%MPB for 0.25min.

[0274] LCMS method G: Shim-pack Scepter C18, 30*3mm, injection 0.5μL, flow rate 1.5mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 0.04%NH4OH and mobile phase B (MPB): acetonitrile. Elute 10%MPB-95% / 2.00min, hold at 95%MPB for 0.60min, 95%MPB-10% / 0.20min, then equilibrate to 10%MPB for 0.20min.

[0275] Method B.A. Equipment: Agilent LCMS system, 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 the clogP of the compound. Flow rate: 0.6mL / min or 0.8mL / min Column temperature: 40℃ or 50℃ UV: 220nm

[0276] Method BB Equipment: Agilent LCMS system, 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 will vary depending on the clogP of the compound. Flow rate: 0.6mL / min or 0.8mL / min Column temperature: 40℃ UV: 220nm

[0277] 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 vol%; B: ACN A: FA / HO = 0.225 vol%; B: ACN column Xtimate C18 150*25mm*5μm Flow rate: 25mL / min or 30mL / min Monitor wavelength: 220&254nm Slope: Actual method depends on the clog P of the compound Detector: MS Trigger or UV

[0278] 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.

[0279] Preparation of Exemplary Intermediates Synthesis of intermediate 1 (methyl 2-((5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)amino)-2-oxoacetate) TIFF2024502473000041.tif92141Step 1: 5-Bromo-1H-indole-3-carbonyl azide 5-Bromo-1H-indole-3-carboxylic acid (5.0 g, 20.8 mmol, 1.0 equiv) was dissolved in THF (30 mL) and then TEA (8.6 mL, 62.4 mmol, 3.0 equiv) and DPPA (8.6 g, 31.2 mmol, 1.5 equiv) were added. The reaction mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure to give 5-bromo-1H-indole-3-carbonyl azide (4.1 g) as a white solid which was used without further purification. LCMS Method A: [M+H] + = 265.

[0280] Step 2: tert-Butyl N-(5-bromo-1H-indol-3-yl)carbamate 5-Bromo-1H-indole-3-carbonyl azide (4.0 g, 15.1 mmol, 1.0 equiv) was dissolved in t-BuOH (30 mL). The reaction mixture was heated at 90° C. for 16 h, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18; mobile phase, ACN / water (5 mM NH4HCO3), 0% to 100% gradient / 15 min; detector, UV 254 nm. This gave tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate (2.2 g) as a white solid. LCMS Method A: [M+H] + = 311.

[0281] Step 3: tert-Butyl (5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)carbamate Tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate (500.0 mg, 1.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (20 mL) and water (2 mL), then 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (479.1 mg, 1.6 mmol, 1.0 equiv.), Cs2CO3 (1.0 g, 3.2 mmol, 2.0 equiv.) and Pd(dppf)Cl2 (235.1 mg, 0.3 mmol, 0.2 equiv.) were added under nitrogen atmosphere. The reaction mixture was heated at 100° C. overnight under nitrogen atmosphere, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography using the following conditions: column, C18; mobile phase, ACN / water (5 mM NH4HCO3), 0% to 100% gradient / 15 min; detector, UV 254 nm. This gave tert-butyl (5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)carbamate (170.5 mg) as a white solid. LCMS Method B: [M+H] + = 403

[0282] Step 4: 5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-amine hydrochloride tert-Butyl (5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)carbamate (160.0 mg, 0.4 mmol, 1.0 equiv) was dissolved in HCl / 1,4-dioxane (4 M, 6 mL). The reaction mixture was stirred at ambient temperature for 2 h and then concentrated under reduced pressure to give 5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-amine hydrochloride (103.5 mg) as a white solid. LCMS Method C: [M+H] + = 303.

[0283] Step 5: ([5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-yl]carbamoyl)methyl formate 5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-amine hydrochloride (100.0 mg, 0.3 mmol, 1.0 equiv) and TEA (0.1 mL, 0.6 mmol, 2.0 equiv) were dissolved in DCM (10 mL) and cooled to 0° C. Methyl oxalochloridate (0.03 mL, 0.3 mmol, 1.0 equiv) was then added while maintaining the reaction mixture at 0° C. The reaction mixture was stirred at ambient temperature for 1 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl ([5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-yl]carbamoyl)formate (170.2 mg) as a crude white solid, which was used without further purification. LCMS Method D: [M+H] + = 389.

[0284] Synthesis of intermediate 2 (2-oxo-2-((5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)amino)acetic acid) TIFF2024502473000042.tif92154 Step 1: tert-Butyl N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]carbamate tert-Butyl N-(5-bromo-1H-indol-3-yl)carbamate (5.0 g, 16.1 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (80 mL), then bis(pinacolato)diboron (8.2 g, 32.1 mmol, 2.0 equiv.), AcOK (3.2 g, 32.1 mmol, 2.0 equiv.) and Pd(dppf)Cl2 (1.2 g, 1.6 mmol, 0.1 equiv.) were added under nitrogen atmosphere. The reaction mixture was heated at 90° C. for 16 h, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to give tert-butyl N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]carbamate (4.8 g) as a brown solid. LCMS Method A: [M+H] += 359.

[0285] Step 2: tert-Butyl N-(5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)carbamate Tert-butyl N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]carbamate (3.8 g, 10.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (50 mL) and water (5 mL), then 4-bromo-1-[4-(trifluoromethyl)phenyl]pyrazole (3.7 g, 12.8 mmol, 1.2 equiv.), Cs2CO3 (6.9 g, 21.3 mmol, 2.0 equiv.) and Pd(dppf)Cl2 (1.6 g, 2.1 mmol, 0.2 equiv.) were added under nitrogen atmosphere. The reaction mixture was heated at 90° C. overnight under nitrogen atmosphere, then cooled to ambient temperature 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-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)carbamate (1.5 g) as a brown solid. LCMS Method A: [M+H] + = 443.

[0286] Step 3: N-(5-bromo-1H-indol-3-yl)carbamic acid tert-butyl TFA salt tert-Butyl N-(5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)carbamate (1.5 g, 3.3 mmol, 1.0 equiv) was dissolved in DCM (10 mL) and then TFA (5 mL) was added. The resulting solution was stirred at ambient temperature for 2 h and then concentrated under reduced pressure to give crude 5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-amine TFA salt (1.4 g) as a brown solid. LCMS Method A: [M+H] + =343.

[0287] Step 4: Ethyl [(5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)carbamoyl]formate 5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-amine TFA salt (1.4 g, 4.1 mmol, 1.0 equiv) and TEA (1.1 mL, 8.2 mmol, 2.0 equiv) were dissolved in DCM (20 mL) and cooled to 0° C. Ethyl chloroglyoxylate (0.6 mL, 6.1 mmol, 1.5 equiv) was then added while maintaining the solution at 0° C. The reaction mixture was stirred at ambient temperature overnight and then quenched with water. The resulting solution was extracted with DCM, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography column on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give ethyl [(5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)carbamoyl]formate (611.2 mg) as a brown solid. LCMS Method A: [M+H] + = 443.

[0288] Step 5: [(5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)carbamoyl]formic acid Ethyl [(5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)carbamoyl]formate (610.0 mg, 1.4 mmol, 1.0 equiv) was dissolved in MeOH (15 mL) and water (15 mL) and then NaOH (300.0 mg, 7.5 mmol, 5.4 equiv) was added. The reaction mixture was stirred at ambient temperature for 2 h and then concentrated under reduced pressure. The residue was diluted with water and then adjusted to pH=5 with aqueous HCl (1M). The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give [(5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)carbamoyl]formate (560.0 mg) as a brown solid, which was used without further purification. LCMS Method A: [M+H] + = 415.

[0289] Synthesis of intermediate 3 (1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole) TIFF2024502473000043.tif64140Step 1: 4-Bromo-1-(4-ethylphenyl)-1H-pyrazole 4-Ethylphenylboronic acid (10.0 g, 66.7 mmol, 1.0 equiv) and 4-bromopyrazole (9.8 g, 66.7 mmol, 1.0 equiv) were dissolved in DCM (300 mL), then Cu(OAc)2 (24.2 g, 133.4 mmol, 2.0 equiv) and pyridine (2.1 mL, 26.7 mmol, 2.0 equiv) were added under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature overnight and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:10) to give 4-bromo-1-(4-ethylphenyl)pyrazole (9.5 g) as a white solid. LCMS Method E: [M+H] + = 251.

[0290] Step 2: 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 4-Bromo-1-(4-ethylphenyl)pyrazole (9.5 g, 37.8 mmol, 1.0 equiv.) was dissolved in dioxane (200.0 ml) and then bis(pinacolato)diboron (9.6 g, 37.8 mmol, 1.0 equiv.), AcOK (7.4 g, 75.7 mmol, 2.0 equiv.) and Pd(dppf)Cl2 (5.5 g, 7.6 mmol, 0.2 equiv.) were added under nitrogen atmosphere. The reaction mixture was heated at 80° C. overnight, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:4) to give 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.0 g) as a yellow solid. LCMS method D:[M+H] + = 299.

[0291] Synthesis of intermediate 4 (4-bromo-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole) TIFF2024502473000044.tif44128 The title compound was prepared using the method described for Intermediate 3, Step 1. LCMS: Method C, [M+H] + = 291.

[0292] Example 1: N'-[5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-yl]-N-methylethanediamide (Compound 123) TIFF2024502473000045.tif25152 ([5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-yl]carbamoyl)methyl formate (100.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and then CH3NH2·HCl (172.6 mg, 2.0 mmol, 10.0 equiv.) was added. The reaction mixture was heated at 80 °C for 4 h, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC with the following conditions: Column: XBridge Prep OBD C18 column, 30*150mm 5μm; Mobile phase A: water (10 mM NH4HCO3), Mobile phase B: ACN; Flow rate: 50 mL / min; Gradient: 70 B to 70 B / 8 min; 220 nm. This gave N'-[5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-yl]-N-methylethanediamide as a white solid. LCMS Method F: [M+H] + = 388. TIFF2024502473000046.tif27149

[0293] Example 2 was prepared using the method described for Example 1. TIFF2024502473000047.tif79143

[0294] Example 3: N-[trans-3-methoxycyclobutyl]-N'-(5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)ethanediamide (Compound 101) TIFF2024502473000048.tif46144 [(5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)carbamoyl]formic acid (340.0 mg, 0.8 mmol, 1.0 equiv) was dissolved in THF (40 mL) and then trans-3-methoxycyclobutan-1-amine (498.0 mg, 4.9 mmol, 6.0 equiv), T3P (50 wt% in ethyl acetate, 1.0 mL, 1.6 mmol, 2.0 equiv) and TEA 0.6 mL, 4.1 mmol, 5.0 equiv) were added. The reaction mixture was stirred at ambient temperature for 16 h and then quenched by the addition of 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 preparative HPLC with the following conditions: Column: XBridge Shield RP18 OBD column, 19*250mm, 10μm; Mobile phase A: Water (10mM NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 25%B~70%B / 8min; 220 / 254nm. This gave N-[trans-3-methoxycyclobutyl]-N'-(5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)ethanediamide as a white solid. LCMS Method E: [M+H] + = 498. TIFF2024502473000049.tif27148

[0295] Example 4 was prepared using the method described for Example 3. TIFF2024502473000050.tif92144

[0296] Example 5: N 1 -(5-(1-(2-chlorophenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-N 2 Synthesis of -methyloxalamide (compound 121) TIFF2024502473000051.tif79155Step 1: Synthesis of 2-((5-bromo-1H-indol-3-yl)amino)-2-oxoethyl acetate 5-Bromo-1H-indol-3-amine (18.0 g, 86.0 mmol, 1.0 equiv) was dissolved in THF (200 mL) and cooled to 0° C. A solution of 2-chloro-2-oxoethyl acetate (11.7 g, 86.0 mmol, 1.0 equiv) in THF (50 mL) was then added dropwise over 5 min while maintaining the reaction mixture at 0° C. TEA (30.7 mL, 215 mmol, 2.5 equiv) was then added to the reaction mixture. The mixture was stirred at 25° C. for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to provide 2-((5-bromo-1H-indol-3-yl)amino)-2-oxoethyl acetate (12.0 g, 38.0 mmol), which was used in the next step without further purification.

[0297] Step 2: Synthesis of 2-((5-bromo-1H-indol-3-yl)amino)-2-oxoacetic acid Ethyl 2-((5-bromo-1H-indol-3-yl)amino)-2-oxoacetate (12.0 mg, 38.0 mmol, 1 equiv) was dissolved in MeOH (200 mL). 2M aqueous NaOH (28.5 mL, 57.0 mmol, 1.5 equiv) was then added to the reaction mixture. The mixture was stirred at 30° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove MeOH and adjusted to pH 4 by dropwise addition of 2M HCl. The resulting solid was collected by filtration and washed with water to give 2-((5-bromo-1H-indol-3-yl)amino)-2-oxoacetic acid (7.5 g, 27.0 mmol).

[0298] Stage 3: N 1 -(5-Bromo-1H-indol-3-yl)-N 2 Synthesis of -methyloxalamide 2-((5-Bromo-1H-indol-3-yl)amino)-2-oxoacetic acid (7.5 g, 27.0 mmol, 1.0 equiv) and MeNH2·HCl (1.8 g, 27.0 mmol, 1.0 equiv) were dissolved in ACN (100 mL). T3P (50 wt% in EtOAc, 54 mL, 93.2 mmol, 3.5 equiv) and TEA (7.8 mL, 54.0 mmol, 2.0 equiv) were then added. The mixture was heated at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (30 mL) and then HO (100 mL) was added. The resulting solid was collected by filtration, washed with water and purified by filtration with N 1 -(5-Bromo-1H-indol-3-yl)-N 2 -Methyloxalamide (7.0 g, 23.7 mmol) was obtained.

[0299] Stage 4: N 1 -(5-(1-(2-chlorophenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-N 2 Synthesis of -methyloxalamide N 1 -(5-Bromo-1H-indol-3-yl)-N 2 -Methyloxalamide (74.0 mg, 0.25 mmol, 1.0 equiv) and (1-(2-chlorophenyl)-1H-pyrazol-4-yl)boronic acid (83.4 mg, 0.38 mmol, 1.5 equiv) were dissolved in 1,4-dioxane (3.0 mL). Then, 2M aqueous K3PO4 solution (0.25 mL, 0.5 mmol, 2.0 equiv) and XPhos Pd G3 (10.2 mg, 0.012 mmol, 0.05 equiv) were added under nitrogen atmosphere. The mixture was shaken at 120 °C for 16 h. Water (3 mL) was added to the reaction mixture, which was then extracted with EtOAc. The combined organic layers were concentrated in a Speedvac. The residue was purified by preparative HPLC to give N 1 -(5-(1-(2-chlorophenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-N 2 -methyloxalamide was obtained. MS-ESI, 394.2 [M+H + ]. TIFF2024502473000052.tif19153

[0300] The following compounds were prepared using the methods described for Example 5 above. TIFF2024502473000053.tif186148

[0301] Example 10: N 1 -(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-N 2 Synthesis of -(2,2,2-trifluoroethyl)oxalamide (Compound 114) TIFF2024502473000054.tif118153 Step 1: Synthesis of 4-bromo-1-(4-ethylphenyl)pyrazole 1-Ethyl-4-iodo-benzene (25 g, 107.73 mmol, 1 eq.) and 4-bromo-1H-pyrazole (31.67 g, 215.46 mmol, 2.0 eq.) were dissolved in DMSO (500 mL). Then K2CO3 (29.78 g, 215.46 mmol, 2 eq.), (2S)-pyrrolidine-2-carboxylic acid (2.48 g, 21.55 mmol, 0.2 eq.) and CuI (2.05 g, 10.77 mmol, 0.1 eq.) were added under nitrogen atmosphere. The mixture was heated at 90° C. under nitrogen atmosphere for 16 h. The mixture was added to 500 mL H2O and then extracted with 800 mL ethyl acetate. The solids were filtered off and then the aqueous phase was extracted with ethyl acetate. The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 0-6%) to give 4-bromo-1-(4-ethylphenyl)pyrazole (18.5 g, 73.7 mmol) as a white solid. MS-ESI, 250.9, 252.9 [M+H + ].

[0302] Step 2: Synthesis of 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 4-Bromo-1-(4-ethylphenyl)pyrazole (18.5 g, 73.7 mmol, 1 equiv.) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (89.57 g, 699.86 mmol, 101.55 mL, 9.5 equiv.) were dissolved in toluene (500 mL), then TEA (174.96 mmol, 24.35 mL, 2.4 equiv.), Pd(CH3CN)2Cl2 (907.82 mg, 3.50 mmol, 0.05 equiv.) and SPhos (4.31 g, 10.50 mmol, 0.14 equiv.) were added under nitrogen atmosphere. The mixture was heated at 90 °C for 16 h. The solution was added to 500 mL of H2O. The aqueous layer was extracted with ethyl acetate, then the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 0% to 6%) to give 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (16.16 g, 54.22 mmol) as a yellow solid. MS-ESI, 299.1 [M+H + ].

[0303] Stage 3: N 1 -(5-Bromo-1H-indol-3-yl)-N 2 Synthesis of -(2,2,2-trifluoroethyl)oxalamide 2-((5-Bromo-1H-indol-3-yl)amino)-2-oxoacetic acid (113 mg, 0.40 mmol, 1.0 equiv) and 2,2,2-trifluoroethanamine (118 mg, 1.20 mmol, 3.0 equiv) were dissolved in ACN (4.0 mL), then triethylamine (221 μl, 1.60 mmol, 4.0 equiv) and T3P (50 wt% in EtOAc, 800 μl, 1.38 mmol, 3.45 equiv) were added to the mixture. The mixture was heated at 100° C. for 16 h, then 6 mL of saturated aqueous Na2CO3 was added and extracted with EtOAc. The combined organic layers were concentrated in a Speedvac and diluted with N 1 -(5-Bromo-1H-indol-3-yl)-N 2 -(2,2,2-trifluoroethyl)oxalamide was obtained, which was used in the next step without further purification.

[0304] Stage 4: N 1 -(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-N 2 Synthesis of -(2,2,2-trifluoroethyl)oxalamide N 1 -(5-Bromo-1H-indol-3-yl)-N 2 The residue of -(2,2,2-trifluoroethyl)oxalamide (0.4 mmol, 1.0 equiv.) and 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (155 mg, 0.52 mmol, 1.3 equiv.) were dissolved in 1,4-dioxane (4.0 mL). XPhos Pd G3 (16.9 mg, 0.02 mmol, 0.05 equiv.) and 0.6 mL 2M aqueous K3PO4 (1.20 mmol, 3.0 equiv.) were then added to the mixture under nitrogen atmosphere. The mixture was heated at 120° C. for 16 h, then 6 mL of H2O was added and extracted with EtOAc. The combined organic layers were concentrated in a Speedvac and the residue was purified by preparative HPLC to give a 1:1 ratio of 1:1 with 1:1 hexanes. 1 -(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-N 2 -(2,2,2-trifluoroethyl)oxalamide was obtained. MS-ESI, 456.2 [M+H + ]. TIFF2024502473000055.tif27153

[0305] The following compounds were prepared using the methods described for Example 10 above. TIFF2024502473000056.tif82155TIFF2024502473000057.tif216155TIFF20245024730 00058.tif176155TIFF2024502473000059.tif223155TIFF2024502473000060.tif135155

[0306] Bioassay STING pathway activation by the compounds described herein was measured using THP1-Dual™ cells (KO-IFNAR2).

[0307] 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 onto empty 384-well tissue culture plates (Greiner 781182) at final concentrations of 0.0017-100μM. Cells were seeded at 40μL / well, 2x10E6 cells / mL in TC plates. For activation with STING ligand, 2'3'cGAMP (MW 718.38, obtained from Invivogen) was prepared in Optimem medium.

[0308] The following solutions were prepared for each 1x384 plate: - Solution A: 2mL Optimem and one of the following stimulants: 60 μL of 10 mM 2'3' cGAMP → 150 μM stock - Solution B: 2mL Optimem and 60μL Lipofectamine 2000 → Incubate at room temperature for 5 minutes

[0309] 2 mL of solution A and 2 ml of solution B were mixed and incubated for 20 min at room temperature (RT). 20 μL of transfection solution (A+B) was added on top of the seeded cells with a final 2'3'cGAMP concentration of 15 μM. The plate was then immediately centrifuged at 340 g for 1 min and then incubated at 37°C, 5% CO2, and humidity >98% for 24 h. Luciferase reporter activity was then measured. EC 50 Values ​​were calculated using standard methods known in the art.

[0310] Luciferase reporter assay: 10 μL of supernatant from the assay was transferred to a flat bottom square well white 384 plate. One packet of QUANTI-Luc™ Plus was dissolved in 25 mL of water. 100 μL of QLC Stabilizer / 25 mL of QUANTI-Luc™ Plus solution was added. Then 50 μL of QUANTI-Luc™ Plus / QLC solution / well was added. Luminescence was measured in a plate reader (e.g., Spectramax I3X (Molecular Devices GF3637001)).

[0311] Luciferase reporter activity was then measured. 50 Values ​​were calculated using standard methods known in the art.

[0312] Table BA shows the activity of compounds in the STING reporter assay: <0.008 μM = "++++++"; ≥0.008~<0.04 μM = "+++++"; ≥0.04~<0.2 μM = "++++"; ≥0.2~<1 μM = "+++"; ≥1~<5 μM = "++"; ≥5~<100 μM = "+".

[0313] [Table BA]

[0314] Numbered Items The compounds, compositions, methods, and other subjects described herein are further described in the following numbered paragraphs: 1. A compound of formula (I): TIFF2024502473000062.tif39128, or a pharma- ceutically acceptable salt or tautomer thereof, During the ceremony, Y 1 , Y 2 , and Y 3 But, CR 1a , C(=O), N, and NR 2 independently selected from the group consisting of: X 1But 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 TIFF2024502473000063.tif2128 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 is an aryl or heteroaryl; R 1 and R 5 Each occurrence of H;R c ;R h ; and -(L 1 ) b1 -R h independently selected from the group consisting of: R 2 and R 4 Each occurrence of H;R d ;R g ; and -(L 2 ) b2 -R g independently selected from the group consisting of: R 3 But H;R d ; and R h selected from the group consisting of; Q 1 But the following: Oxo, R c , and R h Each of the substituents may be substituted with 1 to 4 substituents independently selected from the group consisting of 3-12 Cycloalkylene or C 3-12 Cycloalkenylene; Heterocyclylene or heterocycloalkenylene having 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0-2and the heterocyclylene or heterocycloalkenylene is oxo, R c , and R h a heterocyclylene or heterocycloalkenylene optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroarylenes 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 heteroarylene is R c and R h Heteroarylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ·R c and R h C 6-10 Arylene selected from the group consisting of; Each L A But 1-2 R a1 C which may be substituted with 1-3 Alkylene; -O-; -NH-; -NR d ; -S(O) 0-2 and C(O); a1 is 0, 1, 2, 3, or 4; However, -(L A ) a1 - cannot contain bonds between O, N, or S(O) atoms, unless an N-N bond is further connected to a C(O); Q 2 But R g and; WA is (AA) or (BB) of the following: (AA) W is -N(H)- or -N(R d )- and; A is the following: ·H; 1 to 6 R bC which may be substituted with 1-10 Alkyl; and -(Y A1 ) nA -Y A2 wherein the compound is selected from the group consisting of: nA is 0 or 1; Y A1 However, 1 to 3 R b C which may be substituted with 1-6 alkylene; and Y A2 But the following: Each of which is oxo and R c and 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 a monocyclic heterocyclyl or heterocycloalkenyl, optionally substituted by 1 to 4 substituents independently selected from the group consisting of: or (BB) W and A, taken together, Form TIFF2024502473000064.tif14128; and Ring E is a saturated or partially unsaturated ring of 3 to 16 ring atoms, where 0 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and the ring is oxo, R c , R h , and -(L g ) bg -Rh and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: is defined according to R a , R a1 , and R b 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 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 1-4 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 independently selected from the group consisting of: -alkyl; -C(=O)OH; -C(=O)NR'R''; and -SF5; R d Each occurrence of is one to three 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, and R i C which may be substituted with 1 to 3 substituents each independently selected from the group consisting of 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 , R h , and -(L g ) bg -R h C 3-12 Cycloalkyl or C 3-12 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 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 heterocyclyl or heterocycloalkenyl is oxo, R c , R h , and -(L g ) bg -R h a 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 3 of which are N, N(H), N(R d ), O, and S(O) 0-2and the heteroaryl is R c , R h , and -(L g ) bg -R h Heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ·R c , R h , and -(L g ) bg -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 3-8 Cycloalkyl or C 3-8 Cycloalkenyl; 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 1 to 4 R i heterocyclyl or heterocycloalkenyl, optionally substituted with Heteroaryl with 5-6 ring atoms, 1-3 of which are N, N(H), N(R d ), O, and S; and the heteroaryl is selected from 1 to 4 R i heteroaryl, optionally substituted with 1 to 4 R i C6 aryl optionally substituted with independently selected from the group consisting of: R i Each occurrence of C 1-6 Alkyl;C 1-4Haloalkyl;C 1-4 Alkoxy;C 1-4 Independently selected from the group consisting of haloalkoxy; and halo; L 1 , L 2 , and 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 alkylene; b1, b2, and bg are each independently 1, 2, or 3; and 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 or tautomer thereof. 2. Q 1 is a heteroarylene having 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 heteroarylene is R c and R h The compound according to item 1, which is a heteroarylene optionally substituted with 1 to 4 substituents independently selected from the group consisting of: 3. Q 1 is a heteroarylene having 5-6 ring atoms, 1-3 of which are N, N(H), N(R d ), O, and S; and the heteroarylene is R c and R h The compound according to item 1 or 2, which is a heteroarylene optionally substituted with 1 to 3 substituents independently selected from the group consisting of: 4. Q 1 is a heteroarylene having 5-6 ring atoms, 1-3 of which are N, N(H), N(R d), O, and S; and the heteroarylene is selected from 1 to 3 R c The compound according to any one of items 1 to 3, wherein the heteroarylene is optionally substituted with 5. Q 1 is a heteroarylene of 5 ring atoms, in which 1 to 3 (e.g., 2 to 3) ring atoms are N, N(H), N(R d ), O, and S; and the heteroarylene is selected from 1 to 2 R c The compound according to any one of items 1 to 4, wherein the heteroarylene is optionally substituted with 6. Q 1 But 1-2 R c 6. The compound according to any one of items 1 to 5, which is a pyrazolylene optionally substituted by: 7. Q 1 But 1-2 R c may be substituted with TIFF2024502473000065.tif19128, wherein aa is -(L A ) a1 -Q 2 7. The compound according to any one of paragraphs 1 to 6, wherein 8. Q 1 However, each of them has 1 to 2 R c may be substituted (e.g., unsubstituted) TIFF2024502473000066.tif20128, wherein aa is -(L A ) a1 -Q 2 7. The compound according to any one of paragraphs 1 to 6, wherein 9. The compound according to any one of items 1 to 8, wherein a1 is 0. 10. The compound according to any one of items 1 to 8, wherein a1 is 1. 11. Q 2 But the following: 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 R c , R h , and -(L g ) bg -R h Heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ·R c , R h , and -(L g ) bg -R h C 6-10 Aryl The compound according to any one of items 1 to 10, selected from the group consisting of: 12. Q 2 but, Heteroaryl with 5-6 ring atoms, 1-3 of which are N, N(H), N(R d ), O, and S; and the heteroaryl is selected from 1 to 4 R cq2 heteroaryl, optionally substituted with 1 to 4 R cq2 C which may be substituted with 6-10 Aryl is selected from the group consisting of Here, each R cq2 is an independently selected R c 12. The compound according to any one of items 1 to 11, wherein 13. Q 2 But the following: 1 to 4 R cq2 phenyl optionally substituted with; and Heteroaryl having 6 ring atoms, 1 to 3 of which are ring nitrogen atoms, and the heteroaryl is selected from the group consisting of 1 to 4 R cq2 Heteroaryl, optionally substituted with is selected from the group consisting of Here, each R cq2 is an independently selected Rc 13. The compound according to any one of items 1 to 12, wherein 14. Q 2 But 1-2 R cq2 phenyl, optionally substituted with cq2 are independently selected R c 14. The compound according to any one of items 1 to 13, wherein 15. Q 2 But the following formula: I have TIFF2024502473000067.tif18128, where A , Q B , Q C , Q D , and Q E But, CH, CR cq2 and N, where Q A ~Q E Two or less of the following are N and Q A ~Q E Two or less of the above are CR cq2 where each R cq2 are independently selected R c 14. The compound according to any one of items 1 to 13, wherein 16. Q A , Q B , Q C , Q D , and Q E However, CH or CR independently cq2 However, Q A ~Q E Two or less of the above are CR cq2 Item 16. The compound according to item 15, wherein 17. Q A and Q E is CH; and Q B , Q C , and Q D However, independently CH or CR cq2 However, Q A ~Q E Two or less of the above are CR cq2 17. The compound according to item 15 or 16, wherein 18. Q B and Q Dis CH; and Q C But, CR cq2 Item 18. The compound according to item 17, wherein 19. Q B and Q C is CH; and Q D But, CR cq2 Item 18. The compound according to item 17, wherein 20. Q B , Q C , and Q D and each is CH. 21. Q A But, CR cq2 And Q B , Q C , Q D , and Q E and each is CH. 22. Q 2 unsubstituted phenyl; TIFF2024502473000068.tif22128, wherein each R cq2 is an independently selected R c 16. The compound according to any one of items 1 to 15, 23. Q A ~Q E One or two of are N; and Q A ~Q E The remaining one of each is CH or CR cq2 However, Q A ~Q E Two or less of the above are CR cq2 Item 16. The compound according to item 15, wherein 24. Q 2 Each of which is oxo and R cq2 C 3-12 Cycloalkyl or C 3-12 cycloalkenyl, where each R cq2 are independently selected R c The compound according to any one of items 1 to 10, 25. Q 2 However, oxo and Rcq2 C 3-6 (e.g., C3, C4, C5, or C6) cycloalkyl, e.g., each of which is selected from 1 to 2 R cq2 TIFF2024502473000069.tif12128, wherein each R is optionally substituted with cyclopropyl or cyclopentyl. cq2 are independently selected R c 25. The compound according to any one of items 1 to 10 or 24, wherein 26. Each R cq2 halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1-6 Alkyl;C 1-4 Alkoxy;C 1-4 haloalkoxy; and -C 1-4 16. The compound according to any one of items 12 to 15, independently selected from the group consisting of thioalkoxy. 27. Each R cq2 But, halo; cyano; C 1-6 Alkyl, e.g., ethyl, etc. 1-3 alkyl; 1 to 6 independently selected R a C replaced with 1-6 Alkyl;C 1-4 Alkoxy;C 1-4 haloalkoxy, for example, -OCF3 or -OCH2CF3; and -C 1-4 27. The compound according to any one of items 12 to 26, independently selected from the group consisting of thioalkoxy. 28. Each R cq2 But, halo; cyano; C 1-6 Alkyl, e.g., ethyl, etc. 1-3 Alkyl; -Halo, C 1-3 C substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy, -OH, 1-6 Alkyl (e.g., -CF3, -CH2CF3, or -CH2OMe); C 1-4 Alkoxy;C 1-4haloalkoxy, for example, -OCF3 or -OCH2CF3; and -C 1-4 28. The compound according to any one of items 12 to 27, independently selected from the group consisting of thioalkoxy. 29. Y 1 But, CR 1 29. The compound according to any one of items 1 to 28, wherein 30. Y 2 But, CR 1 30. The compound according to any one of items 1 to 29, wherein 31. Y 3 But, CR 1 The compound according to any one of items 1 to 30, wherein 32. R 1 Each occurrence of is H or R c 32. The compound according to any one of items 1 to 31, wherein 33. R 1 The compound according to any one of paragraphs 1 to 32, wherein each occurrence of is H. 34. R 1 1 or 2 occurrences, e.g. 1 occurrence, of R c and R 1 and each remaining occurrence of is H. 35. R 1 is halo, e.g., -F or -Cl; and R 1 The compound according to any one of paragraphs 1 to 32 or 34, wherein each remaining occurrence of is H. 36. Y 1 , Y 2 , and Y 3 are selected independently 1 32. The compound according to any one of items 1 to 31, wherein 37. Y 1 , Y 2 , and Y 3 and R are each CH. 38. Y 1 , Y 2 , and Y 3 One of them is CR c, e.g., C-halo; and the remaining two Y 1 , Y 2 , and Y 3 Each of is CH. 39. X 1 But NR 2 39. The compound according to any one of items 1 to 38, wherein 40. X 1 The compound according to any one of items 1 to 39, wherein is NH. 41. X 2 But, CR 5 41. The compound according to any one of items 1 to 40, wherein 42. X 2 The compound according to any one of items 1 to 41, wherein is CH. 43. X 1 But NR 2 and X 2 But, CR 5 39. The compound according to any one of items 1 to 38, wherein 44. X 1 is NH; and X 2 The compound according to any one of paragraphs 1 to 38 or 43, wherein is CH. 45. R 3 The compound according to any one of items 1 to 44, wherein 46. ​​The compound according to any one of items 1 to 45, wherein WA is defined according to (AA). 47. The compound according to any one of items 1 to 46, wherein W is -N(H)-. 48. W is -N(R d )-, for example, -N(Me)-, etc. 1-3 47. The compound according to any one of items 1 to 46, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 2 49. The compound according to any one of items 1 to 48, wherein A is H. 50. A is 1 to 6 R b C which may be substituted with 1-10 49. The compound according to any one of items 1 to 48, wherein the compound is alkyl. 51. A is 1 to 6 Rb C which may be substituted with 1-6 51. The compound according to any one of paragraphs 1 to 48 or 50, wherein the alkyl is (e.g., C1, C2, C3, or C4) alkyl. 52. A is C 1-6 The compound according to any one of items 1-48 or 50-51, wherein A is alkyl, for example A is methyl, ethyl, propyl, isopropyl, or isobutyl. 53. A is -OH; -halo; -NR e R f , for example, -N(C 1-3 alkyl)2 or NHC(O)O(C 1-4 alkyl);C 1-4 Alkoxy, for example, -OMe; 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl);-C(=O)(C 1-4 substituted with 1 to 6 substituents each independently selected from the group consisting of alkyl, aryl, aryloxy ... 1-6 The compound according to any one of items 1 to 48 or 50 to 51, wherein the compound is alkyl. 54. C in which A is substituted with 1 to 6 independently selected halo. 1-6 54. The compound according to any one of paragraphs 1 to 48, 50 to 51, or 53, wherein A is alkyl, for example, A is -CH2CF3, -CH2CH2CF3, or -CH2CHF2. 55. A is C 1-4 Alkoxy or C 1-4 Haloalkoxy substituted C 1-6 54. The compound according to any one of items 1 to 48, 50 to 51, or 53, wherein A is alkyl, for example, A is -CH2CH2OMe. 56. A is -(Y A1 ) nA -Y A2 49. The compound according to any one of items 1 to 48, wherein 57. The compound according to item 56, wherein nA is 0. 58. The compound according to item 56, wherein nA is 1. 59. Y A1 However, 1 to 3 Rb C which may be substituted with 1-3 59. The compound according to item 56 or 58, which is alkylene. 60. Y A1 The compound according to any one of items 56 or 58-59, wherein is CH2. 61. Y A2 However, each of them is oxo and R c and a monocyclic C 3-8 Cycloalkyl or C 3-8 The compound according to any one of items 56 to 60, which is cycloalkenyl. 62. Y A2 However, oxo and R c and a monocyclic C 3-8 Cycloalkyl, e.g., C 3-6 The compound according to any one of items 56 to 61, which is cycloalkyl. 63. Y A2 However, each of them has 1 to 2 R c 63. The compound according to any one of items 56 to 62, wherein each of the aryl groups is independently selected from the group consisting of cyclopropyl; cyclobutyl; and cyclopentyl, each of which may be substituted with . 64. Y A2 is a 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 compound according to any one of items 56 to 60, which is a monocyclic heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: 65. Y A2 is a monocyclic heterocyclyl having 4 to 6 ring atoms, 1 to 2 of which are N, N(H), N(R d ), O, and S(O) 0-2and heterocyclyl is oxo and R c The compound according to any one of items 56 to 60 or 64, which is a monocyclic heterocyclyl, optionally substituted with 1 to 2 substituents independently selected from the group consisting of: 66. Y A2 But 1-2 R c The compound according to any one of items 56 to 60 or 64 to 65, which is oxetanyl or tetrahydrofuranyl, each of which may be substituted with 67. A is Y A2 or -CH2-Y A2 where Y A2 But the following: Oxo and R c and a monocyclic C 3-6 Cycloalkyl; and Monocyclic heterocyclyl of 4 to 6 ring atoms, 1 to 2 of which are N, N(H), N(R d ), O, and S(O) 0-2 and heterocyclyl is oxo and R c and a monocyclic heterocyclyl optionally substituted by 1 to 2 substituents independently selected from the group consisting of 57. The compound according to any one of items 1 to 48 or 56, selected from the group consisting of: 68. The compound according to any one of paragraphs 1 to 45, wherein WA is defined according to (BB). 69. W and A, together, Form TIFF2024502473000070.tif14128; and Ring E is a saturated or partially unsaturated ring of 3-8 ring atoms, where 0-2 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and the ring is oxo, R c , Rh , and -(L g ) bg -R h 69. The compound according to any one of items 1 to 45 or 68, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: 70. W and A, together, Form TIFF2024502473000071.tif14128; and Ring E is a saturated ring of 3-8 ring atoms, where 0-2 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and the ring is oxo and R c The compound according to any one of items 1 to 45 or 68 to 69, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: 71. W and A, together, TIFF2024502473000072.tif15128, where m1 and m2 are independently 0, 1, or 2, and where W 1 However, CH2, CH(R c ), C(R c )2, NH, or N(R d 71. The compound according to any one of items 1 to 45 or 68 to 70, wherein 72. The compound according to item 71, wherein m1 and m2 are independently 0 or 1. 73. W 1 is CH2 or N(R d ), e.g., CH2 or NC(=O)(C 1-3 73. The compound according to item 71 or 72, wherein R is an alkyl group. 74. Compound of formula (Ia): TIFF2024502473000073.tif52128, or a pharma- ceutically acceptable salt thereof. 75. Q 2 is the following formula: I have TIFF2024502473000074.tif18128, whereA , Q B , Q C , Q D , and Q E But, CH, CR cq2 and N, where Q A ~Q E Two or less of the following are N and Q A ~Q E Two or less of the above are CR cq2 where each R cq2 are independently selected R c 75. The compound according to item 74, wherein 76. Q A , Q B , Q C , Q D , and Q E However, independently CH or CR cq2 However, Q A ~Q E Two or less of the above are CR cq2 76. The compound according to item 75, wherein 77. Q A and Q E is CH; and Q B , Q C , and Q D However, independently CH or CR cq2 However, Q A ~Q E Two or less of the above are CR cq2 77. The compound according to item 75 or 76, wherein 78. Q B and Q D is CH; and Q C But, CR cq2 78. The compound according to item 77, wherein 79. Q B and Q C is CH; and Q D But, CR cq2 78. The compound according to item 77, wherein 80. Q B , Q C , and Q D and each is CH. 81. QA But, CR cq2 And Q B , Q C , Q D , and Q E and each is CH. 82. Q 2 unsubstituted phenyl; TIFF2024502473000075.tif22128, wherein each R cq2 are independently selected R c 77. The compound according to item 74 or 76, wherein 83. Q A ~Q E One or two of are N; and Q A ~Q E The remaining one of each is CH or CR cq2 However, Q A ~Q E Two or less are CR cq2 76. The compound according to item 75, wherein 84. Q 2 However, oxo and R cq2 C 3-12 cycloalkyl, where each R cq2 is an independently selected R c 75. The compound according to item 74, wherein 85. Each R cq2 But, halo; cyano; C 1-6 Alkyl, e.g., ethyl, etc. 1-3 Alkyl; -Halo, C 1-3 C substituted with 1 to 6 substituents independently selected from the group consisting of alkoxy, -OH, 1-6 Alkyl (e.g., -CF3, -CH2CF3, or -CH2OMe); C 1-4 Alkoxy;C 1-4 haloalkoxy, for example, -OCF3 or -OCH2CF3; and -C 1-4 85. The compound according to any one of items 74 to 84, independently selected from the group consisting of: thioalkoxy. 86. Y1 , Y 2 , and Y 3 are selected independently 1 86. The compound according to any one of items 74 to 85, wherein 87. Y 1 , Y 2 , and Y 3 and each is CH. 88. Y 1 , Y 2 , and Y 3 One of them is CR c , e.g., C-halo; and the remaining two Y 1 , Y 2 , and Y 3 Each of the following is CH. 89. R 2 The compound according to any one of items 74 to 88, wherein is H. 90. R 5 The compound according to any one of items 74 to 89, wherein is H. 91. R 3 The compound according to any one of items 74 to 90, wherein 92. The compound according to any one of items 74 to 91, wherein WA is defined according to (AA). 93. The compound according to any one of items 74 to 92, wherein W is -N(H)-. 94. W is -N(C 1-3 The compound according to any one of items 74 to 92, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 95. The compound according to any one of items 74 to 94, wherein A is H. 96. A is C 1-6 The compound according to any one of items 74 to 94, wherein A is alkyl, for example A is methyl, ethyl, propyl, isopropyl, or isobutyl. 97. A is -OH;-halo;-NR e R f , for example, -N(C 1-3 alkyl)2 or NHC(O)O(C 1-4 alkyl);C1-4 Alkoxy, for example, -OMe; 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl);-C(=O)(C 1-4 substituted with 1 to 6 substituents each independently selected from the group consisting of alkyl, aryl, aryloxy ... 1-6 The compound according to any one of items 74 to 94, wherein the compound is alkyl. 98. A is a C group substituted with 1 to 6 independently selected halo. 1-6 alkyl, for example, A is -CH2CF3, -CH2CH2CF3, or -CH2CHF2, or A is C 1-4 Alkoxy or C 1-4 Haloalkoxy substituted C 1-6 The compound according to any one of paragraphs 74 to 94 or 97, wherein A is alkyl, for example, A is -CH2CH2OMe. 99. A is Y A2 or -CH2-Y A2 where Y A2 But the following: Oxo and R c and a monocyclic C 3-6 Cycloalkyl; and Monocyclic heterocyclyl of 4 to 6 ring atoms, 1 to 2 of which are N, N(H), N(R d ), O, and S(O) 0-2 and heterocyclyl is oxo and R c and a monocyclic heterocyclyl optionally substituted by 1 to 2 substituents independently selected from the group consisting of The compound according to any one of items 74 to 94, selected from the group consisting of: 100. The compound according to any one of items 74 to 91, wherein WA is defined according to (BB). 101. W and A, together, Form TIFF2024502473000076.tif14128; and Ring E is a saturated ring of 3-8 ring atoms, where 0-2 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and the ring is oxo and R c The compound according to any one of items 74 to 91 or 100, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: 102. W and A, together, TIFF2024502473000077.tif15128, where m1 and m2 are independently 0, 1, or 2, and where W 1 However, CH2, CH(R c ), C(R c )2, NH, or N(R d ) The compound according to any one of items 74 to 91 or 100 to 101, 103. The compound according to item 102, wherein m1 and m2 are independently 0 or 1. 104. W 1 The compound according to item 102 or 103, wherein is CH2. 105. W 1 But N(R d 104. The compound according to item 102 or 103, wherein 106. The compound according to item 1, selected from the group consisting of the compounds listed in Table C1 and pharma- ceutically acceptable salts thereof. 107. A compound according to item 1, selected from the group consisting of: N'-[5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-yl]-N-methylethanediamide (123); N 1 -(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)oxalamide (124); N-[trans-3-methoxycyclobutyl]-N'-(5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl)ethanediamide (101); N 1 -(oxetan-3-yl)-N 2 -(5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)oxalamide (102); N 1 -(5-(1-(2-chlorophenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-N 2 -Methyloxalamide (121); N 1 -(5-(1-(3-chlorophenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-N 2 -Methyloxalamide (119); N 1 -Methyl-N 2 -(5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)oxalamide (118); N 1 -(5-(1-cyclopentyl-1H-pyrazol-4-yl)-1H-indol-3-yl)-N 2 -Methyloxalamide (122); N 1 -(5-(3-cyclopropylphenyl)-1H-indol-3-yl)-N 2 -Methyloxalamide (117); N 1 -(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-N 2 -(2,2,2-trifluoroethyl)oxalamide (114); N'-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}-N-(propan-2-yl)ethanediamide (110); N-(2,2-difluoroethyl)-N'-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}ethanediamide (116); N-Cyclobutyl-N'-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}ethanediamide (113); N'-cyclopentyl-N-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}ethanediamide (104); N'-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}-N-[(1r,3r)-3-methoxycyclobutyl]ethanediamide (109); N-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}-N'-(oxolan-3-yl)ethanediamide (108); N'-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}-N-(2-methoxyethyl)ethanediamide (120); N'-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}-N-(3,3,3-trifluoropropyl)ethanediamide (103); N'-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}-N,N-dimethylethanediamide (112); 2-(azetidin-1-yl)-N-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}-2-oxoacetamide (107); N-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}-2-oxo-2-(pyrrolidin-1-yl)acetamide (115); N'-(cyclopentylmethyl)-N-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}ethanediamide (106); N-(cyclopropylmethyl)-N'-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}ethanediamide (105); and 2-(4-Acetylpiperazin-1-yl)-N-{5-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]-1H-indol-3-yl}-2-oxoacetamide (111). 108. A pharmaceutical composition comprising a compound according to any one of items 1 to 107 and one or more pharma- ceutically acceptable excipients. 109. A method for inhibiting STING activity, comprising contacting STING with a compound defined in any one of items 1 to 107 or a pharma- ceutically acceptable salt thereof; or a pharmaceutical composition defined in item 108. 110. The method of item 109, wherein inhibiting STING comprises antagonizing STING. 111. The method of any one of items 109 to 110, which is carried out in vitro. 112. The method of item 111, comprising contacting a sample containing one or more cells containing STING with a compound. 113. The method of item 111 or 112, wherein the one or more cells are one or more cancer cells. 114. The method of item 112 or 113, wherein the sample further comprises one or more cancer cells, 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 cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma. 115. The method of items 109 or 110, which is carried out in vivo. 116. The method of item 115, comprising administering the compound to a subject having a disease in which increased (e.g., enhanced) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease. 117. The method of item 116, wherein the subject is a human. 118. The method according to item 117, wherein the disease is cancer. 119. The method of item 118, 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 cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma. 120. The method according to item 118 or 119, wherein the cancer is a refractory cancer. 121. The method of item 116, wherein the compound is administered in combination with one or more additional cancer therapies. 122. The method of item 121, wherein the one or more additional cancer therapies comprise surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof. 123. The method of item 122, wherein the chemotherapy comprises administering one or more additional chemotherapeutic agents. 124. The one or more additional chemotherapeutic agents are selected from the group consisting of: 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, toposide 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., leuprorelin, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, canakinumab, cetuximab, certolizumab pegol (Ceertolizumab pegol), daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumuab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; growth inhibitors; anthelmintics;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 (MHC class III), and IL-10. RasII-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PD L2-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, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD 86-An immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of CTLA, CD80-CD28, CD39, CD73 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); The method according to item 123, wherein the method is selected from the group consisting of 125. The method of any one of items 116 to 124, wherein the compound is administered intratumorally. 126. A method for the treatment of cancer, comprising administering to a subject in need of such treatment an effective amount of a compound defined in any one of items 1 to 107, or a pharmaceutical composition defined in item 108. 127. The method of item 126, 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 cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma. 128. The method according to item 126 or 127, wherein the cancer is a refractory cancer. 129. The method of item 126, wherein the compound is administered in combination with one or more additional cancer therapies. 130. The method of item 129, wherein the one or more additional cancer therapies comprise surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof. 131. The method of item 130, wherein the chemotherapy comprises administering one or more additional chemotherapeutic agents. 132. The one or more additional chemotherapeutic agents are selected from the group consisting of: 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, toposide 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., leuprorelin, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, canakinumab, cetuximab, certolizumab pegol (Ceertolizumab pegol), daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumuab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; growth inhibitors; anthelmintics;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 (MHC class III), and IL-10. RasII-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PD L2-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, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD 86-An immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of CTLA, CD80-CD28, CD39, CD73 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); The method according to item 130, wherein the method is selected from the group consisting of 133. The method of any one of items 126 to 132, wherein the compound is administered intratumorally. 134. A method for inducing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of a compound defined in any one of items 1 to 107, or a pharmaceutical composition defined in item 108. 135. The method of item 134, wherein the subject has cancer. 136. The method according to item 135, wherein the subject has undergone and / or is undergoing and / or will undergo one or more cancer therapies. 137. The method of item 135, 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 cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma. 138. The method according to any one of items 135 to 137, wherein the cancer is a refractory cancer. 139. The method of item 134, wherein the immune response is an innate immune response. 140. The method according to item 139, wherein the at least one or more cancer therapies include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof. 141. The method of item 140, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents. 142. The one or more additional chemotherapeutic agents are selected from the group consisting of: 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, toposide 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., leuprorelin, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, canakinumab, cetuximab, certolizumab pegol (Ceertolizumab pegol), daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumuab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; growth inhibitors; anthelmintics;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 (MHC class III), and IL-10. RasII-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PD L2-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, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD 86-An immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of CTLA, CD80-CD28, CD39, CD73 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); Item 142. The method of item 141, wherein the method is selected from the group consisting of 143. A method for treating a disease in which increased (e.g. enhanced) 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 items 1 to 107, or a pharmaceutical composition as defined in item 108. 144. A method of treatment comprising administering to a subject having a disease in which increased (e.g., enhanced) 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 items 1 to 107, or a pharmaceutical composition as defined in item 108. 145. A method of treatment comprising administering to a subject an effective amount of a compound as defined in any one of items 1 to 107, or a pharmaceutical composition as defined in item 108, wherein the compound or composition is administered in an amount effective to treat a disease in which increased (e.g. enhanced) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease, thereby treating the disease. 146. The method according to any one of items 143 to 145, wherein the disease is cancer. 147. The method of item 146, 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 cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma. 148. The method according to item 146 or 147, wherein the cancer is a refractory cancer. 149. The method of any one of paragraphs 146 to 148, wherein the compound is administered in combination with one or more additional cancer therapies. 150. The method of item 149, wherein the one or more additional cancer therapies comprise surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof. 151. The method of item 150, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents. 152. The one or more additional chemotherapeutic agents are selected from the group consisting of: 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, toposide 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., leuprorelin, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, canakinumab, cetuximab, certolizumab pegol (Ceertolizumab pegol), daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumuab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; growth inhibitors; anthelmintics;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 (MHC class III), and IL-10. RasII-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PD L2-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, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD 86-An immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of CTLA, CD80-CD28, CD39, CD73 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); Item 152. The method of item 151, wherein the method is selected from the group consisting of 153. The method of any one of items 143 to 152, wherein the compound is administered intratumorally. 154. A method for the treatment of 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 items 1 to 107, or a pharmaceutical composition as defined in item 108. 155. The method of item 154, wherein the disease, disorder, or condition is selected from type I interferonopathy, Aicardi-Goutières syndrome (AGS), inherited forms of lupus, inflammation-related disorders, and rheumatoid arthritis. 156. The method of item 155, wherein the disease, disorder, or condition is type I interferonopathy (e.g., infantile-onset STING-associated vasculitis (SAVI)). 157. The method according to item 156, wherein the type I interferonopathy is STING-associated vasculitis in infancy (SAVI). 158. The method of item 155, wherein the disease, disorder, or condition is Aicardi-Goutières syndrome (AGS). 159. The method of item 155, wherein the disease, disorder, or condition is a genetic form of lupus. 160. The method of item 155, wherein the disease, disorder, or condition is an inflammation-related disorder. 161. The method according to item 160, wherein the inflammation-related disorder is systemic lupus erythematosus. 162. The method of any one of items 109 to 161, further comprising a step of identifying a subject. 163. A combination of a compound as defined in any one of items 1 to 107 or a pharma- ceutically acceptable salt or tautomer thereof with one or more therapeutically active agents. 164. A compound as defined in any one of items 1 to 107 or a pharma- ceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in item 108, for use as a medicament. 165. A compound as defined in any one of items 1 to 107, or a pharma- ceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in item 108, for use in the treatment of a disease, condition or disorder modulated by STING inhibition. 166. A compound as defined in any one of items 1 to 107 or a pharma- ceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in item 108, for use in the treatment of a disease as referred to in any one of items 109 to 162 (e.g., any one of items 114, 118 to 120, 127 to 128, 135, 137, 138, 143 to 148, or 154 to 161). 167. Use of a compound as defined in any one of items 1 to 107 or a pharma- ceutically acceptable salt or tautomer thereof, or a pharmaceutical composition as defined in item 108, in the manufacture of a medicament for the treatment of a disease as referred to in any one of items 109 to 162 (e.g., any one of items 114, 118 to 120, 127 to 128, 135, 137, 138, 143 to 148, or 154 to 161).

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof or a tautomer thereof, During the ceremony, Y 1 , Y 2 , and Y 3 But, CR 1a , C(=O), N, and NR 2 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 an aryl or heteroaryl; R 1 and R 5 For each occurrence, H;R c ;R h ; and -(L 1 ) b1 -R h independently selected from the group consisting of: R 2 and R 4 For each occurrence, H;R d ;R g ; and -(L 2 ) b2 -R g independently selected from the group consisting of: R 3 But H;R d and R h selected from the group consisting of: Q 1 but the following: ・Oxo, R c , and R h C 3-12 Cycloalkylene or C 3-12 Cycloalkenylene; Heterocyclylene or heterocycloalkenylene 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 heterocyclylene or heterocycloalkenylene is oxo, R c , and R h a heterocyclylene or heterocycloalkenylene, optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroarylene 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 heteroarylene is R c and R h heteroarylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ・R c and R h C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of 6-10 Arylene selected from the group consisting of: Each L A But one or two R a1 C which may be substituted with 1-3 Alkylene; -O-; -NH-; -NR d ； -S(O) 0-2 and C(O); a1 is 0, 1, 2, 3, or 4; However, -(L A ) a1 - represents O, N, or S(O), unless an NN bond further connects to a C(O). 0 It cannot contain bonds between atoms; Q 2 But R g and WA is (AA) or (BB) of the following: (AA) W is -N(H)- or -N(R d )-and A is the following: ・H； ・1 to 6 R b C which may be substituted with 1-10 Alkyl; and ·-(AND A1 ) nA -AND A2 wherein: nA is 0 or 1; ・Y A1 But 1 to 3 R b C which may be substituted with 1-6 alkylene; and ・Y A2 but the following: - each of which is oxo and R c and a monocyclic C 3-8 Cycloalkyl or C 3-8 cycloalkenyl; and Monocyclic 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 heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c a monocyclic heterocyclyl or heterocycloalkenyl, optionally substituted by 1 to 4 substituents independently selected from the group consisting of: or (BB) W and A, taken together, 【Chemistry 3】 and Ring E is a saturated or partially unsaturated ring of 3 to 16 ring atoms, where 0 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and the ring is oxo, R c , R h , and -(L g ) bg -R h and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: is defined according to R a , R a1 , and R b -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 c Each occurrence represents 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; -NO 2 ;-C(=O)(C 1-10 alkyl); -C(=O)O(C 1-4 -C(=O)OH; -C(=O)NR'R''; and -SF 5 independently selected from the group consisting of: R d Each occurrence of represents one to three 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 is H; NR'R'', -OH, and R i C which may be substituted with 1 to 3 substituents each independently selected from the group consisting of 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 For each occurrence: Each of them is oxo, R c , R h , and -(L g ) bg -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, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and the heterocyclyl or heterocycloalkenyl is oxo, R c , R h , and -(L g ) bg -R h heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl of 5 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 is R c , R h , and -(L g ) bg -R h heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ・R c , R h , and -(L g ) bg -R h C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of 6-10 Aryl independently selected from the group consisting of: R h For each occurrence: ・Each of them has 1 to 4 R i Optionally substituted with C 3-8 Cycloalkyl or C 3-8 Cycloalkenyl; 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 heterocyclyl or heterocycloalkenyl is selected from 1 to 4 R i heterocyclyl or heterocycloalkenyl, optionally substituted with Heteroaryl of 5 to 6 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S; and the heteroaryl is selected from 1 to 4 R i heteroaryl, optionally substituted with ・1 to 4 R i C which may be substituted with 6 Aryl independently selected from the group consisting of: R i For each occurrence, 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 1 , L 2 , and L g 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 alkylene; b1, b2, and bg are each independently 1, 2, or 3; and R' and R'' are, at each occurrence, H; -OH; and C 1-4 independently selected from the group consisting of alkyl, The compound, or a pharma- ceutically acceptable salt or tautomer thereof.

2. Q 1 is a heteroarylene 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 heteroarylene is R c and R h The compound of claim 1, which is a heteroarylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

3. Q 1 is a heteroarylene of 5 to 6 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S; and the heteroarylene is R c and R h The compound according to claim 1 or 2, which is a heteroarylene, optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

4. Q 1 But one or two R c may be substituted with 【Chemistry 4】 wherein aa is -(L A ) a1 -Q 2 represents a point of attachment to; or Q 1 However, each of them has one or two R c may be substituted with 【Chemistry 5】 wherein aa is -(L A ) a1 -Q 2 4. The compound of any one of claims 1 to 3, wherein the compound represents an attachment point to

5. Q 2 but the following: Heteroaryl of 5 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 is R c , R h , and -(L g ) bg -R h heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ・R c , R h , and -(L g ) bg -R h C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of 6-10 Aryl The compound according to any one of claims 1 to 4, selected from the group consisting of:

6. Q 2 But one or two R cq2 phenyl, optionally substituted with cq2 are independently selected R c and optionally, where each R cq2 is halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1-6 Alkyl; C 1-4 Alkoxy; C 1-4 haloalkoxy; and -C 1-4 6. The compound of any one of claims 1 to 5, independently selected from the group consisting of thioalkoxy.

7. Q 2 unsubstituted phenyl; 【Chemistry 6】 where each R cq2 are independently selected R c and optionally, where each R cq2 is halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1-6 Alkyl; C 1-4 Alkoxy; C 1-4 haloalkoxy; and -C 1-4 7. The compound of any one of claims 1 to 6, independently selected from the group consisting of: thioalkoxy.

8. Y 1 , Y 2 , and Y 3 are selected independently 1 and Optionally, R 1 is H for each occurrence, or Optionally, R 1 is a halo; and R 1 The compound of any one of claims 1-7, wherein each remaining occurrence of is H.

9. X 1 NR 2 and X 2 CR 5 9. The compound according to any one of claims 1 to 8, wherein

10. X 1 is NH; and X 2 The compound of any one of claims 1 to 9, wherein is CH.

11. The compound of any one of claims 1 to 10, wherein WA is defined according to (AA).

12. W is -N(H)-; or W is -N(R d 12. The compound according to any one of claims 1 to 11, wherein

13. A is H; or A is 1 to 6 R b C which may be substituted with 1-10 The compound of any one of claims 1 to 12, which is alkyl.

14. A is -(Y A1 ) nA -Y A2 13. The compound of any one of claims 1 to 12, wherein

15. Y A2 Each of which is oxo and R c and a monocyclic C 3-8 Cycloalkyl or C 3-8 is cycloalkenyl; or Y A2 is a 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 compound of any one of claims 1 to 12 or 14, which is a monocyclic heterocyclyl or heterocycloalkenyl, optionally substituted with one to four substituents independently selected from the group consisting of:

16. 11. The compound of any one of claims 1 to 10, wherein WA is defined according to (BB).

17. W and A, taken together, 【Chemistry 7】 and Ring E is a saturated or partially unsaturated ring of 3 to 8 ring atoms, where 0 to 2 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and the ring is oxo, R c , R h , and -(L g ) bg -R h 17. The compound of any one of claims 1 to 10 or 16, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

18. Compound of formula (Ia): 【Chemistry 8】 2. The compound of claim 1, which is:

19. 2. The compound of claim 1, selected from the group consisting of the compounds set forth in Table C1, or a pharma- ceutically acceptable salt thereof.

20. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

21. A method for inhibiting STING activity, comprising contacting STING with a compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof; or a pharmaceutical composition of claim 20.

22. 20. A pharmaceutical composition for inducing an immune response in a subject in need thereof, comprising an effective amount of a compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof.

23. 20. A pharmaceutical composition for treating a STING-associated disease, disorder, or condition, such as a disease, disorder, or condition in which increased STING signaling, such as excessive STING signaling, contributes to the pathology and / or symptoms and / or progression of the disease, such as cancer, comprising an effective amount of a compound according to any one of claims 1 to 19, or a pharma- ceutical acceptable salt thereof.

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