Compounds and compositions for treating pathologies associated with STING activity

Abstract

The disclosure features chemical entities (e.g., compounds, or pharma- ceutically acceptable salts, and / or hydrates, and / or cocrystals, and / or combinations with drugs) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). The chemical entities are useful, for example, to treat conditions, diseases, or disorders in which increased (e.g., excessive) STING 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 same and methods of using and making same. TIFF2025503675000309.tif24144

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 298,987, filed January 12, 2022, which is incorporated herein by reference in its entirety.

[0002] Technical Field The present disclosure features chemical compounds (e.g., compounds, or pharmaceutically acceptable salts, and / or hydrates, and / or cocrystals, and / or combinations with drugs) that inhibit (e.g., antagonize) stimulator of interferon genes (STING). The chemical compounds are useful, for example, to treat conditions, diseases, or disorders in which increased (e.g., excessive) 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 present disclosure also features compositions containing the same and methods of using and making the same. [Background technology]

[0003] background STING, also known as transmembrane protein 173 (TMEM173) and MPYS / MITA / ERIS, is a protein encoded by the TMEM173 gene in humans. STING has been shown to play a role in innate immunity. STING induces the production of type I interferons when cells are infected with intracellular pathogens, such as viruses, mycobacteria, and intracellular parasites. STING-mediated type I interferons protect infected cells and nearby cells from local infection in an autocrine and paracrine manner.

[0004] The STING pathway is crucial for mediating the recognition of cytosolic DNA. In this context, STING, a transmembrane protein localized in the endoplasmic reticulum (ER), acts as a second messenger receptor for 2',3' cyclic GMP-AMP (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 via the carboxy-terminal domain of STING, which faces the cytosol and forms a V-shaped binding pocket formed by STING homodimers. Ligand-induced STING activation triggers its relocalization to the Golgi apparatus, a process essential for promoting the interaction of STING with TBK1. This protein complex then signals via the transcription factor IRF-3 to induce type I interferon (IFN) and other co-regulated antiviral factors. Additionally, STING has been shown to cause activation of NF-κB and MAP kinases. After initiating signaling, STING is rapidly degraded, a step thought to be important for terminating the inflammatory response.

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

[0006] overview The present disclosure features chemical compounds (e.g., compounds, or pharmaceutically acceptable salts, and / or hydrates, and / or cocrystals, and / or combinations with drugs) that inhibit (e.g., antagonize) stimulator of interferon genes (STING). The chemical compounds are useful, for example, to treat conditions, diseases, or disorders in which increased (e.g., excessive) 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 present disclosure also features compositions containing the same and methods of using and making the same.

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

[0008] In one embodiment, a compound of formula (I): TIFF2025503675000002.tif35151, or a pharmaceutically acceptable salt thereof, wherein Q 1 , L A , Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 and W may be as defined anywhere herein.

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

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

[0011] One aspect features a method of treating a condition, disease, or disorder that is alleviated by antagonizing STING, e.g., treating a condition, disease, or disorder in which increased (e.g., excessive) 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 generally or specifically described herein or a pharmaceutically acceptable salt thereof, or a composition comprising same).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0038] The chemical compound can be administered in combination with one or more additional cancer therapies (e.g., surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof, e.g., chemotherapy comprising administering one or more (e.g., 2, 3, 4, 5, 6, or more) additional chemotherapeutic agents. Non-limiting examples of additional chemotherapeutic agents include alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin). antimetabolites (e.g., azathioprine and / or mercaptopurine); terpenoids (e.g., vinca alkaloids and / or taxanes; e.g., vincristine, vinblastine, vinorelbine and / or vindesine taxol, paclitaxel and / or docetaxel); topoisomerases (e.g., type I topoisomerase and / or type 2 topoisomerase; e.g., camptothecins such as irinotecan and / or topotecan; amsacrine, etoposide, etoposide phosphate and / or teniposide); cytotoxic anticancer drugs Biologics (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, tuzumab, brentuximab vedotin, canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agents; cytokines; thrombotic agents; growth inhibitors; antiparasitic agents;and CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC Class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-C selected from immune checkpoint inhibitors that target immune checkpoint receptors selected from the group consisting of TLA, 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 may have cancer, for example, the subject has undergone and / or is undergoing and / or will undergo one or more cancer therapies.

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

[0041] The chemical may be administered intratumorally.

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

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

[0044] Additional definitions To facilitate understanding of the disclosure set forth herein, some additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications mentioned in this specification and the accompanying appendices is incorporated herein by reference in its entirety.

[0045] As used herein, the term "STING" is meant to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, 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 ingredient means that it does not have a lasting adverse effect on the overall health of the subject being treated.

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

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

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

[0050] The term "pharmaceutically acceptable salt" refers to a compound formulation that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain examples, pharmaceutically 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, salicylic acid, etc. In some examples, pharmaceutically acceptable salts can be obtained by reacting a compound having an acidic group described herein with a base to form salts such as ammonium salts, alkali metal salts (e.g., sodium salts or potassium salts), alkaline earth metal salts (e.g., calcium salts or magnesium salts), salts of organic bases (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine), and salts with amino acids (e.g., arginine, lysine, etc.), or by other methods previously identified. Pharmacologically acceptable salts are not particularly limited, as long as they can be used in pharmaceutical preparations. Examples of salts formed by the compounds described herein with bases include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, specifically exemplified by the following acid addition salts: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

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

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

[0053] In relation to the treatment of a disease or disorder, the terms "treat," "treating," and "treatment" are meant to include reducing or eliminating the disorder, disease, or condition or one or more symptoms associated with the disorder, disease, or condition, or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof. "Treatment of cancer" refers to one or more of the following effects: (1) inhibition to some extent of tumor growth, including (i) stasis, and (ii) complete cessation of growth; (2) reduction in the number of tumor cells; (3) maintenance of tumor size; (4) reduction in tumor size; (5) inhibition to some extent of tumor cell infiltration into surrounding organs, including (i) reduction, (ii) stasis, or (iii) complete prevention; (6) inhibition to some extent of metastasis, including (i) reduction, (ii) stasis, or (iii) complete prevention; (7) enhancement of the 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 some 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 indicated number of carbon atoms. For example, C 1~10 indicates that there may be 1 to 10 (inclusive) carbon atoms in the group. Alkyl groups may be substituted or unsubstituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. When used in this context, the term "saturated" means that there are only single bonds between the constituent carbon atoms and that 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 (e.g., -OCH3).

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

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

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

[0061] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbons, in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system), and 0, 1, 2, 3, or 4 atoms in each ring can be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, dihydro-1H-indenyl, and the like.

[0062] As used herein, the term "cycloalkyl" refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons, 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. The cycloalkyl group 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 spirocycles (e.g., spirocyclic bicycles in which the two rings are joined through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, etc. As used in this context, the term "saturated" means that only single bonds exist between the constituent carbon atoms.

[0063] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons, 3 to 10 ring carbons, or 3 to 6 ring carbons; the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As a partially unsaturated cyclic hydrocarbon group, the cycloalkenyl group may have any degree of unsaturation, provided that one or more double bonds are present in the ring, none of the rings in the ring system is aromatic, and the cycloalkenyl group as a whole is not fully saturated. The cycloalkenyl may include multiple fused and / or bridged and / or spiro rings.

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

[0065] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated ring system containing 3 to 16 ring atoms (e.g., a 5- to 8-membered monocyclic ring system, an 8- to 12-membered bicyclic ring system, or an 11- to 14-membered tricyclic ring system), having 1 to 3 heteroatoms in the monocyclic ring, 1 to 6 heteroatoms in the bicyclic ring, or 1 to 9 heteroatoms in the tricyclic or polycyclic ring, wherein the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms in the monocyclic, bicyclic, or tricyclic ring, respectively), and 0, 1, 2, or 3 atoms in each ring can be substituted by substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. A heterocyclyl can include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]pentanyl, 2-azabicyclo[1.1.1]pentanyl, 3-azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[ 3.2.1]octanyl, 2-oxabicyclo[1.1.0]butanyl, 2-oxabicyclo[2.1.0]pentanyl, 2-oxabicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[4.2.0]octanyl, 2-oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1]octanyl, etc. Heterocyclyl also includes spirocycles (e.g., spirobicycles in which the two rings are joined through only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-oxa ... .2]pentanyl, 4-oxaspiro[2.5]octanyl, 1-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, 1-oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl, etc. When used in this context, the term "saturated" 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] As used herein, the term "heterocycloalkenyl" refers to a partially unsaturated cyclic ring system containing 3 to 16 ring atoms (e.g., a 5- to 8-membered monocyclic ring system, an 8- to 12-membered bicyclic ring system, or an 11- to 14-membered tricyclic ring system) having 1 to 3 heteroatoms in the monocyclic ring, 1 to 6 heteroatoms in the bicyclic ring, or 1 to 9 heteroatoms in the tricyclic or polycyclic ring, wherein the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms in the monocyclic, bicyclic, or tricyclic ring, respectively), and 0, 1, 2, or 3 atoms in each ring can be substituted by substituents. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl. As a partially unsaturated cyclic group, a heterocycloalkenyl group can have any degree of unsaturation, provided that there is one or more double bonds within the ring, no ring within the ring system is aromatic, and the heterocycloalkenyl group as a whole is not fully saturated. A heterocycloalkenyl can include multiple fused and / or bridged and / or spiro rings.

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

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

[0069] For the avoidance of doubt, and unless otherwise stated, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form bicyclic or higher ring systems (e.g., tricyclic ring systems, polycyclic ring systems), such rings and cyclic groups are not limited to those having fused rings, e.g., rings that are fused at the point of fusion. (i) adjacent ring atoms (e.g., a [xx0] ring system, where 0 represents a 0 atom bridge (e.g., TIFF2025503675000003.tif15154)); (ii) single ring atoms (spiro-fused ring systems) (e.g., TIFF2025503675000004.tif19152) or (iii) adjacent ring atom arrangements (bridged ring systems where all bridge lengths are >0) (e.g., TIFF2025503675000005.tif15149) It will be understood that this includes those located above.

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

[0071] Additionally, compounds disclosed generically or specifically herein are intended to include all tautomeric forms. Thus, by way of example, the moiety: The compound containing TIFF2025503675000006.tif16155 is part TIFF2025503675000007.tif17150. Similarly, a pyridinyl or pyrimidinyl moiety described as being optionally substituted with hydroxyl includes the tautomeric forms of pyridone or pyrimidone.

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

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

[0074] Detailed Description The present disclosure features chemical compounds (e.g., compounds, or pharmaceutically acceptable salts, and / or hydrates, and / or cocrystals, and / or combinations with drugs) that inhibit (e.g., antagonize) stimulator of interferon genes (STING). The chemical compounds are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., excessive) 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 present disclosure also features compositions containing the same and methods of using and making the same.

[0075] Compounds of Formula I In one aspect, the present disclosure provides a compound of formula (I): TIFF2025503675000008.tif35149 or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: L A is -(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 -*, where * is Q 1 represents the attachment point to; a1, a2, a3, a4, and a5 each independently represent 0 or 1; However, a1+a2+a3+a4+a5≧1, L 1 , L 3 and L 5 are -O-, -N(H)-, -N(R d )-, S(O) 0~2 and -C(=O)-; However, if one or both of a2 and a4 are 0, L 1 , L 3 and L 5cannot form an OO, NO, NN, OS, SS or NS(O) bond; and Furthermore, however, L A is Y 1 , Y 2 and Y 3 cannot contain cyclic groups directly attached to a six-membered ring containing L 2 and L 4 Each of the Each of them has 1 to 6 R b Optionally substituted with linear C 1~6 Alkylene, linear C 2~6 Alkenylene or linear C 2~6 Alkynylene; Each of them has 1 to 3 R c optionally substituted with C 3~10 Cycloalkylene or C 3~10 Cycloalkenylene, provided that Y 1 , Y 2 and Y 3 is not directly linked to a 6-membered ring containing 3~10 Cycloalkylene or C 3~10 cycloalkenylene; and Heterocyclylene or heterocycloalkenylene, each having 4 to 10 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is selected from the group consisting of 1 to 3 R c and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with Y 1 , Y 2 and Y 3 the heterocyclylene or heterocycloalkenylene is not directly linked to a 6-membered ring containing independently selected from the group consisting of: Q 1 -R g and; Y 1 , Y 2 and Y3 is CR 1 , C(═O), N and NR 2 each independently selected from the group consisting of: X 1 are O, S, N, and NR 2 and CR 1 selected from the group consisting of: X 2 are O, S, N, and NR 4 and CR 5 selected from the group consisting of: Each TIFF2025503675000009.tif5159 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 Each occurrence of H;R c ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 2 and R 4 Each occurrence of H;R d ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 6 is H;R d ; and R g selected from the group consisting of: W is (i) TIFF2025503675000010.tif28154In the formula, ring B1 is a heteroarylene of five ring atoms, and 1 to 4 of the ring atoms are N, NH, N(R d ), heteroatoms independently selected from the group consisting of O and S; heteroarylene in ring B1 is oxo and R cand optionally substituted with 1 to 2 substituents independently selected from the group consisting of: 6 is attached to a group; Each L AA is 1 to 2 R a C optionally substituted with 1~3 Alkylene; -O-; -NH-; -NR d ;-S(O) 0~2 and C(O); aa1 is 0, 1 or 2; Ring C1 is Oxo, R c and (L AA ) aa1 -R g C, each of which 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, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is oxo, R c and (L AA ) aa1 -R g the heterocyclylene or heterocycloalkenylene optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroarylene of 5 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heteroarylene is R c and (L AA ) aa1 -R g the heteroarylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ·R cand (L AA ) aa1 -R g C 6~10 Arylene selected from the group consisting of: R 7 is R g and -(L 7 ) b7 -R g selected from the group consisting of: Each L 7 is 1 to 2 R a1 C optionally substituted with 1~3 Alkylene; -O-; -NH-; -NR d ;-S(O) 0~2 and C(O); and b7 is 1, 2 or 3; (ii) TIFF2025503675000011.tif28149In the formula, ring B2 is a heteroarylene of five ring atoms, and 1 to 4 of the ring atoms are N, NH, N(R d ), heteroatoms independently selected from the group consisting of O and S, and the heteroarylene of ring B is oxo and R c and optionally substituted with 1 to 2 substituents independently selected from the group consisting of: 6 is attached to a group; Each L AB is 1 to 4 R a1 C optionally substituted with 1~3 Alkylene; -O-; -NH-; -NR d ;-S(O) 0~2 and C(O); aa2 is 0, 1, 2 or 3; Ring C2 is Oxo and R c C, each of which may be 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, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and wherein the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c the heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl of 5 to 12 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R c the heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl selected from the group consisting of: (iii) Heteroaryl of 5 ring atoms, wherein 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R c provided that said heteroaryl is substituted via a ring carbon atom with C(=O)NR 6 the heteroaryl being bound to a group; (iv) TIFF2025503675000012.tif20170, P 1 , P 2 , P 3 , P 4 and P 5 are N, NH, and NR d , N.R. 71 , C.H., C.R. c , C.R. 71 and C(=O), with the proviso that P 2 , P 3 and P4 1 to 3 of the above, for example, 1 is CR 71 or NR 71 and; R 71 Each occurrence of is independently -(L AC ) aa3 -R 8 and Each L AC is 1 to 4 R a C optionally substituted with 1~3 Alkylene; -O-; -NR N ;-S(O) 0~2 ;C(O);C(O)O;OC(O);NR N C(O);C(O)NR N ;NR N C(O)NR N ;NR N C(O)O; and OC(O)NR N independently selected from the group consisting of: aa3 is 0, 1, 2 or 3; R 8 Each occurrence of is independently R g , or 1 to 6 R a1 C optionally substituted with 1~10 is alkyl; R N Each occurrence of is independently H or R d What is; (v) a bicyclic or polycyclic ring system, Oxo, R c and -(L AD ) bB -R g a bicyclic or polycyclic C ring, each of which may be substituted with 1 to 4 substituents independently selected from the group consisting of 5~15 Cycloalkyl or C 5~15 cycloalkenyl; Bicyclic or polycyclic heterocyclyl or heterocycloalkenyl of 7 to 15 ring atoms, in which 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo, R c and -(L AD ) bB -R g the bicyclic or polycyclic heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Bicyclic or polycyclic heteroaryl of 8 to 15 ring atoms, in which 1 to 6 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is oxo, R c and -(L AD ) bB -R g the bicyclic or polycyclic heteroaryl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Oxo, R c and -(L AD ) bB -R g a bicyclic or polycyclic C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 8~15 Aryl is selected from the group consisting of However, bicyclic or polycyclic heterocycles are not bonded via a ring carbon atom to C(=O)NR 6 is attached to a group; L AD Each occurrence of is -O-, -NH-, -NR d , -S(O) 0~2 , C(O) and 1 to 3 R a C optionally substituted with 1~3 alkylene; and bB is 0, 1, 2 or 3; and (vi) TIFF2025503675000013.tif32170, L AE teeth, Each of them has 1 to 6 R aoptionally substituted with C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Alkynylene; Each of which is oxo and R c a monocyclic C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~8 Cycloalkylene or C 3~8 cycloalkenylene; and Monocyclic heterocyclylene or heterocycloalkenylene having 3 to 8 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is selected from the group consisting of oxo and R c and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C(═O)NR 6 the monocyclic heterocyclylene or heterocycloalkenylene bonded to a group selected from the group consisting of: Each L AF is 1 to 4 R a1 C optionally substituted with 1~3 Alkylene; -O-; -NH-; -NR d ;-S(O) 0~2 and C(O); aa4 is 0, 1, 2 or 3; Ring C4 is R g Something that is selected from the group consisting of: R a Each occurrence of is -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1~2 NR'R'';-S(O)1~2 (C 1~4 alkyl); and cyano; R b and R c each occurrence of is selected from halo; cyano; 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Alkoxy;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);-NR e R f ;-OH;-S(O) 1~2 NR'R'';-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)NR'R''; and -SF5; R d Each occurrence of is selected from 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 independently selected from the group consisting of alkoxy; R e and R f Each occurrence of is H;NR'R'', -OH, halo, C 1~4 Alkoxy and C 1~4 C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O)1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 independently selected from the group consisting of alkoxy; R g Each occurrence of Each of them is oxo, R c and R h C 3~12 Cycloalkyl or C 3~12 cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo, R c and R h the heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl of 5 to 12 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is oxo, R c and R h the heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Oxo, R c and R h C 6~10 Aryl independently selected from the group consisting of: R h Each occurrence of Each of them has 1 to 4 R i optionally substituted with C 3~12 Cycloalkyl or C 3~12 cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of 1 to 4 R i the heterocyclyl or heterocycloalkenyl optionally substituted by Heteroaryl of 5 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R i the heteroaryl, optionally substituted with 1 to 4 R i C optionally substituted with 6~10 Aryl independently selected from the group consisting of: R i Each occurrence of C 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 Independently selected from the group consisting of haloalkoxy; and halo; L g Each occurrence of is -O-, -NH-, -NR d , -S(O) 0~2 , C(O) and 1 to 3 R a C optionally substituted with 1~3 independently selected from the group consisting of alkylene; each occurrence of bg is independently 1, 2, or 3; Each occurrence of R' and R'' is H; -OH; and C 1~4 alkyl.

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

[0077] In some embodiments, L is 0, provided that a3 is 0; and a4 is 1. 4 Each of them has 1 to 6 R b Optionally substituted with linear C 1~6 Alkylene, linear C 2~6 Alkenylene or linear C 2~6 Other than alkynylene.

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

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

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

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

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

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

[0084] In certain of these embodiments, L2 is selected from 1 to 3 R b In certain of the foregoing embodiments, L is a straight chain C alkylene optionally substituted with -CHCH-, -CHCH(R b )-* and -CH2C(R b )2-*, where the asterisk represents -(L 3 ) a3 - represents the point of attachment to the -. For example, L 2 can be -CH2CH2-.

[0085] In certain embodiments, L 2 is 1 to 3 R b For example, L 2 teeth, TIFF2025503675000014.tif20170, and the asterisk represents -(L 3 ) a3 - represents the point of attachment to

[0086] In certain embodiments (where a2 is 1), L2 is 1 to 6 R b Optionally substituted linear C 2~6 In certain of these embodiments, L 2 is 1 to 3 R b Optionally substituted linear C 2~4 Alkenylene. For example, L 2 teeth, TIFF2025503675000015.tif20170, and the asterisk represents -(L 3 ) a3 - represents the point of attachment to

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

[0088] In certain of these embodiments, L 2 teeth, 1 to 3 R c C optionally substituted with 3~8 cycloalkylene; and Heterocyclylenes having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene is a ring heteroatom independently selected from the group consisting of 1 to 3 R cthe heterocyclylene optionally substituted by is selected from the group consisting of:

[0089] In certain of the foregoing embodiments, L 2 is 1 to 2 R c may be substituted with TIFF2025503675000016.tif20170, and n1 and n2 are independently 0, 1, or 2; Q 2 , CH, CR c or N; an asterisk represents -(L 3 ) a3 - represents the point of attachment to

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

[0091] Specific embodiments (L 2 As defined above, In the case where the image is TIFF2025503675000017.tif20170, n1 and n2 are 0 each.

[0092] Non-limiting examples (L 2 As defined above, TIFF2025503675000018.tif20170) as L 2 teeth, TIFF2025503675000019.tif20170, and the asterisk is -(L 3 ) a3 -or-(L 1 ) a1 , for example, a1 is 1 - (L 1 ) a1 represents the point of attachment to the 2 teeth, TIFF2025503675000020.tif20170, and the asterisk is -(L 1 ) a1 In certain of these embodiments, -(L 1 ) a1is O. In certain such embodiments, each of a3, a4, and a5 is 0.

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

[0094] In certain embodiments (where a1 is 1), L 1 -O-, -N(H)-, -N(R d In certain of these embodiments, L 1 is -O-.

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

[0096] In certain embodiments (where a3 is 1), L 3 -O-, -N(H)-, -N(R d In certain of these embodiments, L 3 is —O—. In certain other embodiments, L 3 is -N(H)- or -N(R d )-(e.g., -N(H)-).

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

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

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

[0100] In certain of these embodiments, L 4 is 1 to 2 R c may be substituted with TIFF2025503675000021.tif20170, and n3 and n4 are independently 0, 1, or 2; Q 3 , CH, CR c or N; an asterisk represents -(L 5 ) a5 - represents the point of attachment to

[0101] Specific embodiments (L 4 but In the example (TIFF2025503675000022.tif20170), n3 and n4 are each 1. 4 but TIFF2025503675000023.tif20170) Q 3 is N.

[0102] As a non-limiting example of the aforementioned embodiment, L 4 teeth, TIFF2025503675000024.tif20170, and the asterisk is -(L 5 ) a5 - represents the point of attachment to

[0103] In some embodiments, a5 is 0.

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

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

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

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

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

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

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

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

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

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

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

[0115] [AA5] In certain embodiments, a1 and a2 are each 1; L 1 is -O-; L 2 teeth, 1 to 3 R c optionally substituted with C 3~8 cycloalkylene; and Heterocyclylenes having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene is a ring heteroatom independently selected from the group consisting of 1 to 3 R c the heterocyclylene optionally substituted by is selected from the group consisting of:

[0116] In certain embodiments of [AA5], L 2 is 1 to 2 R c may be substituted with TIFF2025503675000025.tif20170, and n1 and n2 are independently 0, 1, or 2; Q 2 , CH, CR c or N; an asterisk represents -(L 3 ) a3 - represents the point of attachment to

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

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

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

[0120] In certain embodiments where a1 and a2 are each 1, a3 and a5 are 0; and a4 is 1.

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

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

[0123] In certain of these embodiments, L 4 is 1 to 2 R c may be substituted with TIFF2025503675000026.tif20170, and n3 and n4 are independently 0, 1, or 2; Q 3 , CH, CR c or N; an asterisk represents -(L 5 ) a5 In certain of the foregoing embodiments, n3 and n4 are independently 0 or 1; Q 3 is N.

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

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

[0126] In certain embodiments of [BB1], L 2 is 1 to 3 R b Optionally substituted linear C1~3 In certain of the foregoing embodiments, L is -CH-, -CHR b - and -C(R b )2-. For example, L 2 can be -CH2-.

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

[0128] In certain embodiments of [BB1], L 2 is 1 to 3 R b In certain of these embodiments, L 2 teeth, TIFF2025503675000027.tif20170, and the asterisk represents -(L 3 ) a3 - represents the point of attachment to

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

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

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

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

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

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

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

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

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

[0138] In certain embodiments of [CC1], L 2 teeth, TIFF2025503675000028.tif20170, and the asterisk represents -(L 3 ) a3 - represents the point of attachment to

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

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

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

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

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

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

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

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

[0147] In certain embodiments, L A teeth, TIFF2025503675000029.tif20170 (e.g., TIFF2025503675000030.tif13170), and * indicates Q 1 Represents a point of attachment to

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

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

[0150] In certain of the foregoing embodiments, Q 1 teeth, A heteroaryl having six ring atoms, one to two of which are ring nitrogen atoms, and the heteroaryl is c’ the heteroaryl, optionally substituted with 1 to 3 R c’ phenyl optionally substituted with is selected from the group consisting of:

[0151] In certain embodiments, Q 1 is 1 to 3 R c’ In certain of these embodiments, Q is phenyl optionally substituted with 1 teeth, TIFF2025503675000031.tif20170.

[0152] In certain embodiments, Q 1 is a heteroaryl of 6 ring atoms, 1 to 2 of which are ring nitrogen atoms, and the heteroaryl is a heteroaryl of 1 to 3 R c’ In certain of these embodiments, Q 1 is 1 to 3 R c’ In certain of the foregoing embodiments, Q is pyridyl optionally substituted with 1 teeth, TIFF2025503675000032.tif20170.

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

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

[0155] In certain of the foregoing embodiments, Q 1 is a heterocyclyl of 4 to 8 ring atoms, in which 1 to 2 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and wherein one ring atom is a heteroatom independently selected from the group consisting of N(R d ) wherein the heterocyclyl is selected from oxo and R c’ and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0156] As a non-limiting example of the foregoing embodiment, Q 1 teeth, TIFF2025503675000033.tif20170, wherein m1 and m2 are each independently 0, 1, or 2; Q 1 is 1 to 2 R c’ For example, Q 1 teeth, TIFF2025503675000034.tif20170. As another non-limiting example, 1 teeth, It could be TIFF2025503675000035.tif20170.

[0157] As another non-limiting example of the above embodiment, Q 1 is 1 to 2 R c’ may be substituted with TIFF2025503675000036.tif20170 (e.g., TIFF2025503675000037.tif20170). Another non-limiting example is Q 1 teeth, TIFF2025503675000038.tif20170 (e.g., TIFF2025503675000039.tif20170).

[0158] In certain embodiments, Q 1 Each R in d is -C(O)O(C 1~4 alkyl); and 1 to 3 independently selected R a C optionally substituted with 1~6 alkyl.

[0159] In certain of the foregoing embodiments, Q 1 Each R in d C optionally substituted with 1 to 3 independently selected halo 1~6 It is alkyl.

[0160] In certain of the foregoing embodiments, Q 1 Each R in d is C substituted with 1 to 3 -F 1~4 In certain embodiments, Q is alkyl. 1 Each R in d is C substituted with 1 to 3 -F 2~3 It is an alkyl group. For example, Q 1 Each R in d can be —CH2CF3.

[0161] In certain embodiments, R c’ Each occurrence of is an independently selected R c is.

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

[0163] In certain embodiments, R c’ each occurrence of (i) is selected from 1 to 4 independently selected R c optionally substituted with C 3~12 Cycloalkyl or C 3~12 (ii) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from 1 to 4 independently selected R c (iii) heteroaryl having 5 to 12 ring atoms, wherein 1 to 4 ring atoms are selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R cand (iv) one to four R c C optionally substituted with 6~10 an independently selected R independently selected from the group consisting of aryl; c and any combination of cyclic moieties.

[0164] In certain embodiments, the cyclic moiety is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 ring atoms are selected from N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is a heteroatom each independently selected from the group consisting of 1 to 4 independently selected R c may be substituted with.

[0165] In certain embodiments, the cyclic moiety is one to four R c C optionally substituted with 6~10 It is aryl.

[0166] In certain embodiments, Q 1 Each R in c is halo; cyano; C 1~4 Alkoxy;C 1~4 haloalkoxy; and 1 to 6 independently selected R a C optionally substituted with 1~10 alkyl.

[0167] In certain embodiments, Q 1 Each R in c is halo; cyano; C 1~4 Alkoxy;C 1~4 haloalkoxy; and C optionally substituted with 1 to 6 independently selected halo 1~6 alkyl.

[0168] In certain of the foregoing embodiments, Q 1 Each R in cC optionally substituted with halo and 1 to 6 independently selected halo 1~3 alkyl.

[0169] In certain embodiments, Q 1 Each R in c C optionally substituted with 1 to 6 -F 1~3 It is an alkyl group. For example, Q 1 Each R in c can be CF3.

[0170] In certain embodiments, Q 1 Each R in c is an independently selected halo (e.g., —F or —Cl).

[0171] Variable Y 1 , Y 2 , Y 3 , X 1 and X 2 In some embodiments, Y 1 is CR 1 is.

[0172] In some embodiments, Y 2 is CR 1 is.

[0173] In some embodiments, Y 3 is CR 1 is.

[0174] In certain embodiments, R 1 Each occurrence of is independently H or R c In certain of these embodiments, R 1 Each occurrence of is H.

[0175] In certain other embodiments, R 1 One or two occurrences of R c and;R 1 Each remaining occurrence of is H. For example, R 1One occurrence of may be halo (e.g., —F or —Cl), and R 1 Each remaining occurrence of may be H.

[0176] In certain embodiments, Y 1 , Y 2 and Y 3 are independently selected CRs 1 is.

[0177] In certain embodiments, Y 1 , Y 2 and Y 3 are CH, respectively.

[0178] In certain embodiments, Y 1 , Y 2 and Y 3 One of them is CR c , optionally C-halo; the remaining two Y 1 , Y 2 and Y 3 Each of the is CH.

[0179] In some embodiments, X 1 is NR 2 In certain of these embodiments, X 1 is NH.

[0180] In some embodiments, X 2 is CR 5 In certain of these embodiments, X 2 is CH.

[0181] In certain embodiments, X 1 is NR 2 and X 2 is CR 5 In certain of the foregoing embodiments, X 1 is NH;X 2 is CH.

[0182] In certain embodiments, Y 1 , Y 2 and Y 3are independently selected CRs 1 and X 1 is NR 2 and X 2 is CR 5 In certain of the foregoing embodiments, Y 1 , Y 2 and Y 3 are CH and X, respectively. 1 is NH;X 2 is CH.

[0183] Variable R 6 and W In some embodiments, R 6 is H.

[0184] [1] In some embodiments, W is a group represented by formula (A-1): TIFF2025503675000040.tif32170, wherein Ring B1 is a heteroarylene of five ring atoms, and 1 to 4 of the ring atoms are N, NH, N(R d ), heteroatoms independently selected from the group consisting of O and S; heteroarylene in ring B1 is oxo and R c and optionally substituted with 1 to 2 substituents independently selected from the group consisting of: 6 is attached to a group; Each L AA is 1 to 2 R a C optionally substituted with 1~3 Alkylene; -O-; -NH-; -NR d ;-S(O) 0~2 and C(O); aa1 is 0, 1 or 2; Ring C1 is Oxo, R c and (L AA ) aa1 -R g C, each of which may be substituted with 1 to 4 substituents independently selected from the group consisting of 3~12 Cycloalkylene or C3~12 cycloalkenylene; Heterocyclylene or heterocycloalkenylene of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is oxo, R c and (L AA ) aa1 -R g the heterocyclylene or heterocycloalkenylene optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroarylene of 5 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heteroarylene is R c and (L AA ) aa1 -R g the heteroarylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ·R c and (L AA ) aa1 -R g C 6~10 Arylene selected from the group consisting of: R 7 is R g and -(L 7 ) b7 -R g selected from the group consisting of: Each L 7 is 1 to 2 R a1 C optionally substituted with 1~3 Alkylene; -O-; -NH-; -NR d ;-S(O) 0~2 and C(O); and b7 is 1, 2 or 3.

[0185] Variable ring B1 In some embodiments, Ring B1 is a heteroarylene of 5 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms independently selected from the group consisting of N, NH, O, and S, and the heteroarylene of Ring B1 is selected from 1 to 2 R cB each R cB are independently selected R c is.

[0186] In some embodiments, Ring B1 is a heteroarylene of 5 ring atoms, wherein 2-3 of the ring atoms are N, NH, N(R d ), a heteroatom independently selected from the group consisting of O and S, and the heteroarylene of ring B1 is 1 to 2 R cB each R cB are independently selected R c is.

[0187] In some embodiments, Ring B1 is a heteroarylene of 5 ring atoms, 2 to 3 of which are heteroatoms independently selected from the group consisting of N and NH, and the heteroarylene of Ring B1 is selected from 1 to 2 R cB each R cB are independently selected R c As a non-limiting example of the foregoing embodiment, ring B1 may contain one R cB The alkyl group is selected from the group consisting of imidazolylene, pyrazolylene, or triazolylene (eg, 1,2,3-triazolylene), optionally substituted with

[0188] In certain embodiments, ring B1 contains one R cB and imidazolylene which may be substituted by.

[0189] In certain embodiments, ring B1 contains one R cB may be substituted with TIFF2025503675000041.tif20170, and aa is (L AA )aa1 It is the connection point to

[0190] In certain embodiments, ring B1 contains one R cB may be substituted with TIFF2025503675000042.tif20170, and aa is (L AA ) aa1 It is the connection point to

[0191] In certain embodiments, ring B1 contains one R cB and optionally substituted triazolylene (for example, 1,2,3-triazolylene).

[0192] In certain embodiments, ring B1 contains one R cB may be substituted with TIFF2025503675000043.tif20170, and aa is (L AA ) aa1 It is the connection point to

[0193] In certain embodiments, ring B1 contains one R cB and optionally substituted pyrazolylene.

[0194] In certain embodiments, rings B1 each contain one R cB may be substituted with TIFF2025503675000044.tif20170, and aa is (L AA ) aa1 It is the connection point to

[0195] In certain embodiments, rings B1 each contain one R cB may be substituted with TIFF2025503675000045.tif26170, and aa is (L AA ) aa1 It is the connection point to

[0196] In certain embodiments, each R cBis independently halo or optionally 1 to 3 independently selected R a (e.g., 1 to 3 independently selected halo) 1~3 It is alkyl.

[0197] In some embodiments, ring B1 has one R cB isoxazolylene, oxadiazolylene, oxazolylene, thiazolylene, isothiazolylene or thiadiazolylene, optionally substituted with

[0198] In certain embodiments, rings B1 each contain one R cB may be substituted with TIFF2025503675000046.tif26170, and aa is (L AA ) aa1 It is the connection point to

[0199] In certain embodiments, rings B1 each contain one R cB may be substituted with TIFF2025503675000047.tif26170, and aa is (L AA ) aa1 It is the connection point to

[0200] In certain embodiments, rings B1 each contain one R cB may be substituted with TIFF2025503675000048.tif26170, and aa is (L AA ) aa1 It is the connection point to

[0201] In certain embodiments, ring B1 contains one R cB may be substituted with TIFF2025503675000049.tif26170, and aa is (L AA ) aa1 It is the connection point to

[0202] In certain embodiments, rings B1 each contain one R cB may be substituted with TIFF2025503675000050.tif26170, and aa is (L AA ) aa1 It is the connection point to

[0203] In certain embodiments, rings B1 each contain one R cB may be substituted with TIFF2025503675000051.tif26170, and aa is (L AA ) aa1 It is the connection point to

[0204] In certain embodiments, each R cB is independently halo or optionally 1 to 3 independently selected R a (e.g., 1 to 3 independently selected halo) 1~3 It is alkyl.

[0205] Variables aa1 and L AA In some embodiments, aa1 is 0. In some other embodiments, aa1 is 1.

[0206] In some embodiments, L AA is 1 to 2 R a1 C optionally substituted with 1~3 In certain of these embodiments, L AA is CH2 or CH(Me), for example CH2.

[0207] In some embodiments, aa1 is 1; L AA is 1 to 2 R a1 C optionally substituted with 1~3 In certain of these embodiments, L AA is CH2 or CH(Me), for example CH2.

[0208] Variable ring C1 In some embodiments, ring C1 is Heteroarylene of 5 to 10 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heteroarylene is R cC and R hC the heteroarylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ·R cC and R hC C 6~10 arylene, wherein each R cC are independently selected R c and each R hC are independently selected R h C 6~10 Arylene is selected from the group consisting of:

[0209] In certain of these embodiments, ring C1 is Heteroarylene of 5 to 6 (e.g., 6) ring atoms, of which 1 to 3 (e.g., 1 to 2) ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heteroarylene is R cC the heteroarylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ·R cC C6 arylene optionally substituted with 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0210] In certain embodiments (wherein ring C1 is a heteroarylene of 5 to 10 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O and S(O) 0~2and the heteroarylene is R cC and R hC The heteroarylene; R cC and R hC C 6~10 arylene, wherein each R cC are independently selected R c and each R hC are independently selected R h C 6~10 arylene), ring C1 is ·R cC pyridylene optionally substituted with 1 to 3 (e.g., 1) substituents independently selected from the group consisting of: ·R cC C6 arylene optionally substituted with 1 to 4 (for example, 1 to 2) substituents independently selected from the group consisting of is selected from the group consisting of:

[0211] In certain embodiments, ring C1 has the following formula: TIFF2025503675000052.tif20170 is the basis, Q 1 , Q 2 , Q 3 and Q 4 One each of N, CH and CR cC bb is independently selected from the group consisting of R 7 are the attachment points to each R cC are independently selected R c is.

[0212] In certain embodiments, Q 1 , Q 2 , Q 3 and Q 4 each one of is independently CH or CR cC In certain other embodiments, Q 1 , Q 2 , Q3 and Q 4 One to two (e.g., one) of the 1 , Q 2 , Q 3 and Q 4 each remaining one of is independently CH or CR cC is.

[0213] In certain embodiments, Q 2 is CH. In certain embodiments, Q 3 is CH. In certain embodiments, Q 4 is N. In certain embodiments, Q 1 is CH. In certain other embodiments, Q 1 is CR cC is.

[0214] In certain embodiments, ring C1 is TIFF2025503675000053.tif20170, for example, The file is TIFF2025503675000054.tif20170.

[0215] In certain embodiments, each R cC is -halo and 1 to 6 independently selected R a (e.g., 1 to 6 independently selected halo, e.g., —F) 1~6 (For example, C 1~3 ) alkyl.

[0216] In certain embodiments, each R cC is independently halo, for example -Cl or -F, for example -F.

[0217] Variable R 7 In some embodiments, R 7 is R g is.

[0218] In some embodiments, R 7 teeth, Oxo, Rc7 , R h7 and -(L g ) bg -R h7 C 3~12 cycloalkyl; and Heterocyclyl of 4 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is oxo, R c7 , R h7 and -(L g ) bg -R h7 and each R c7 are independently selected R c and;R h7 are independently selected R h The heterocyclyl is selected from the group consisting of:

[0219] In certain of these embodiments, R 7 teeth, Oxo, R c7 and R h7 C 4~8 (e.g., C4, C5, or C6)cycloalkyl; and Heterocyclyl of 4 to 8 (e.g., 4, 5, or 6) ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is oxo, R c7 and R h7 The heterocyclyl may be substituted with 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0220] In certain of the foregoing embodiments, R7 teeth, ·R c7 C6 cycloalkyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heterocyclyl of 6 ring atoms, in which 1 to 2 (e.g., 1) ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is R c7 The heterocyclyl may be substituted with 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0221] In certain of these embodiments, R 7 is the following formula: TIFF2025503675000055.tif26170 is the base, X 7 , CH, CR c7 or N, for example CH or N. In certain embodiments (R 7 but TIFF2025503675000056.tif26170) in two R c7 There is a group.

[0222] In certain embodiments, R 7 is the following formula: TIFF2025503675000057.tif26170 is the base, X 7 is N or CH; each R c7 are independently selected R c In certain embodiments, R 7 teeth, TIFF2025503675000058.tif26170, X 7 is N or CH; for example, The file is TIFF2025503675000059.tif26170.

[0223] In certain of the foregoing embodiments, R 7 teeth, ·Rc7 C4 cycloalkyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heterocyclyl of four ring atoms, in which one to two (e.g., one) ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is R c7 The heterocyclyl may be substituted with 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0224] In certain of these embodiments, R 7 is the following formula: TIFF2025503675000060.tif26170 is the base, X 7 , CH, CR c7 or N, for example CH or N. In certain embodiments (R 7 but TIFF2025503675000061.tif26170) in two R c7 There is a group.

[0225] In certain embodiments, R 7 is the following formula: TIFF2025503675000062.tif26170 is the base, X 7 is N or CH; each R c7 are independently selected R c In certain embodiments, R 7 teeth, TIFF2025503675000063.tif26170, X 7 is N or CH; for example, The file is TIFF2025503675000064.tif26170.

[0226] In certain embodiments, R 7 Each of them has 1-2 R c7tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2-azabicyclo[2.2.1]heptanyl, optionally substituted with R 7 teeth, It could be TIFF2025503675000065.tif20170.

[0227] In certain embodiments, each R c7 is an independently selected halo or 1 to 6 R a (e.g., 1 to 6 independently selected halo) 1~3 In certain of these embodiments, each R c7 are independently halo, e.g., -F.

[0228] In some embodiments, R 7 teeth, ·R c7 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 4~5 cycloalkyl; and Heterocyclyl of 5-6 ring atoms, in which 1-2 (e.g., 1) ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is R c7 The heterocyclyl may be substituted with 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0229] In certain embodiments, R 7 is the following formula: TIFF2025503675000066.tif20170 is the base, X 7 , CH, CR c7 or N, for example CH or N.

[0230] In certain embodiments, R 7 is the following formula: TIFF2025503675000067.tif26170 is the base, R d is one to three independently selected R a C optionally substituted with 1~6 alkyl.

[0231] In certain embodiments, R 7 Each of them has 1-2 R c7 tetrahydropyranyl, morpholinyl, 5-azaspiro[2.5]octanyl, or 2-azabicyclo[2.2.1]heptanyl, optionally substituted with R 7 teeth, It could be TIFF2025503675000068.tif58170.

[0232] [2] In some embodiments, W is a group represented by formula (A-2): TIFF2025503675000069.tif32170, wherein Ring B2 is a heteroarylene of five ring atoms, and 1 to 4 of the ring atoms are N, NH, N(R d ), heteroatoms independently selected from the group consisting of O and S, and the heteroarylene of ring B is oxo and R c and optionally substituted with 1 to 2 substituents independently selected from the group consisting of: 6 is attached to a group; Each L AB is 1 to 4 R a1 C optionally substituted with 1~3 Alkylene; -O-; -NH-; -NR d ;-S(O) 0~2 and C(O); aa2 is 0, 1, 2 or 3; Ring C2 is Oxo and R c C, each of which may be substituted with 1 to 4 substituents independently selected from the group consisting of 3~12 Cycloalkyl or C 3~12cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and wherein the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c the heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl of 5 to 12 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R c the heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl is selected from the group consisting of:

[0233] Variable ring B2 In some embodiments, ring B2 is a heteroarylene of 5 ring atoms, 2-3 of which are N, NH, N(R d ), a heteroatom independently selected from the group consisting of O and S, and the heteroarylene of ring B2 is 1 to 2 R c provided that ring B2 may be substituted with C(=O)NR via a ring carbon atom. 6 is bonded to the group.

[0234] In certain of these embodiments, ring B2 is selected from the group consisting of: c and the ring nitrogen may be substituted with R d oxazolylene; triazolylene, for example 1,2,3-triazolylene or 1,2,4-triazolylene; isoxazolylene; and isothiazolylene, optionally substituted by

[0235] As a non-limiting example of the foregoing embodiment, ring B2 may each be R c and the ring nitrogen may be substituted with R d The group may be pyrazolylene; imidazolylene; 1,2,3-thiazolylene; or 1,2,4-triazolylene, each of which may be substituted with

[0236] In some embodiments, ring B2 has formula B1a or B2a: TIFF2025503675000070.tif32170, B 4 is C or N; B 1 , B 2 and B 3 are independently CH, CR c , NH, N(R d ), N, O or S; However, B 1 , B 2 and B 3 0 to 2 are CR c and; aa is (L A ) a1 is the attachment point to; Each TIFF2025503675000071.tif6170 are independently a single bond or a double bond, provided that B 1 -B 4 A ring containing is heteroaryl.

[0237] In certain embodiments, ring B2 has the formula B1a:

[0238] In certain embodiments of (B1a), B 4 is N.

[0239] In certain embodiments, ring B2 is TIFF2025503675000072.tif20170. For example, ring B2 is It could be TIFF2025503675000073.tif20170.

[0240] In certain embodiments, ring B2 is TIFF2025503675000074.tif26170, B 1 and B 2 are independently CH, CR c , NH, N(R d ), N, O or S.

[0241] In certain of these embodiments, ring B2 is TIFF2025503675000075.tif26170.

[0242] In certain embodiments, ring B2 is TIFF2025503675000076.tif26170, B 2 and B 3 are independently CH, CR c Or N.

[0243] In certain of these embodiments, ring B2 is TIFF2025503675000077.tif26170. As a non-limiting example of the foregoing embodiment, ring B2 is TIFF2025503675000078.tif26170. As a further non-limiting example, ring B2 can be: TIFF2025503675000079.tif26170. For example, ring B2 can be TIFF2025503675000080.tif26170. As a further non-limiting example, ring B2 can be: TIFF2025503675000081.tif26170. For example, ring B2 can be It could be TIFF2025503675000082.tif26170.

[0244] In certain embodiments of (B1a), B 4 is C.

[0245] In certain embodiments, ring B2 is TIFF2025503675000083.tif26170, B 1 and B 2 One of them is NH, NR d , O or S; B 1 and B 2 Another of B is N. In certain of these embodiments, B 3 is CH or CR c As a non-limiting example of these embodiments, ring B2 is c may be further substituted (e.g., may not be further substituted) with It could be TIFF2025503675000084.tif26170.

[0246] In certain embodiments, ring B2 is TIFF2025503675000085.tif26170, B 1 and B 3 One of them is NH, NR d , O or S; B 1 and B 3 The other of the rings is N, and ring B2 is R c It may be further substituted with.

[0247] In certain embodiments, ring B2 is TIFF2025503675000086.tif26170, B 2 and B 3 One of them is NH, NR d , O or S; B 2 or B 3 The other of the rings is N, and ring B2 is R c It may be further substituted with.

[0248] As a non-limiting example, ring B2 can be any ring selected from the group consisting of R c optionally substituted (e.g., unsubstituted) with It could be TIFF2025503675000087.tif26170.

[0249] In certain embodiments, ring B2 has the formula (B2a). In certain embodiments of (B2a), B 4 is N. As a non-limiting example of the foregoing embodiment, ring B2 is c optionally substituted (e.g., unsubstituted) with The file is TIFF2025503675000088.tif20170.

[0250] In certain embodiments, each R c The substituents are independently -OH; 1~3 alkyl; C optionally substituted with 1 to 6 independently selected halo 1~3 Alkyl;Halo;Cyano;C 1~4 Alkoxy; or C 1~4 It is haloalkoxy.

[0251] Variable L AB and aa2 In some embodiments, a1 is 0. In some embodiments, a1 is 1.

[0252] In some embodiments, L AB is 1 to 4 R a1 C optionally substituted with 1~3 In certain of these embodiments, L AB is 1 to 2 R a1 In certain embodiments, L AB is 1 to 4 R a1 C(H)Me, which may be substituted with, for example, L AB is C(H)Me. In certain embodiments, L AB is CH2CH2.

[0253] In some embodiments, aa2 is 1; L AB is 1 to 4 R a1 C optionally substituted with 1~3 In certain of these embodiments, L A is 1 to 2 Ra1 In certain embodiments, L AB is 1 to 4 R a1 C(H)Me, which may be substituted with, for example, L A is C(H)Me. In certain embodiments, L AB is CH2CH2.

[0254] In certain embodiments, aa2 is 2; (L AB ) aa2 -L A1 -L A2 and L A1 and L A2 are independently selected L A and L A2 is the point of attachment to ring C2. In certain of these embodiments, L A1 is 1 to 4 R a1 C optionally substituted with 1~3 alkylene, for example CH, C(H)Me, or CHCH. In certain of the foregoing embodiments, L A2 is -O-.

[0255] Variable ring C2 In some embodiments, ring C2 is Heteroaryl of 5 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R c the heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl is selected from the group consisting of:

[0256] In some embodiments, ring C2 is Heteroaryl of 5-6 ring atoms, of which 1-3 (e.g., 1-2) ring atoms are N, N(H), N(R d ), O and S(O)0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R c the heteroaryl, optionally substituted with 1 to 4 R c phenyl optionally substituted with is selected from the group consisting of:

[0257] In certain embodiments, ring C2 is TIFF2025503675000089.tif20170, and Q 1 , Q 2 , Q 3 , Q 4 and Q 5 are independently CH, CR c or N, where Q 1 ~Q 5 At least two of the following are CH:

[0258] In certain of these embodiments, Q 3 is CR c In certain embodiments, Q 1 , Q 2 , Q 4 and Q 5 each one of is independently CH or CR c As a non-limiting example of the foregoing embodiment, ring C2 is: TIFF2025503675000090.tif26170, for example, TIFF2025503675000091.tif26170. In certain embodiments, R c is a C1-C4 haloalkyl (eg, fluoroalkyl or perfluoroalkyl), for example, a C1-C2 haloalkyl (eg, fluoroalkyl or perfluoroalkyl), for example, a C1 haloalkyl (eg, fluoroalkyl or perfluoroalkyl), for example, CF3.

[0259] In certain embodiments, Q 1 and Q 2 One of them is N;Q 1 , Q2 , Q 4 and Q 5 each remaining one of is independently CH or CR c As a non-limiting example of the foregoing embodiment, ring C2 is: The file is TIFF2025503675000092.tif26170.

[0260] In certain embodiments, Q 2 is CR c In certain of these embodiments, Q 1 , Q 3 , Q 4 and Q 5 each one of is independently CH or CR c As a non-limiting example of the foregoing embodiment, ring C2 is: TIFF2025503675000093.tif26170, for example, It could be TIFF2025503675000094.tif26170.

[0261] In certain embodiments, Q 2 is CR c and;Q 1 and Q 3 One of the following (e.g., Q 1 ) is N;Q 1 , Q 3 , Q 4 and Q 5 each remaining one of is independently CH or CR c In certain of these embodiments, Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is CH (ie, ring C2 is unsubstituted phenyl).

[0262] In certain embodiments, Q 1 and Q 2 One of them is N;Q 1 , Q 2 , Q 3 , Q 4 and Q 5and each remaining one of is CH, for example, ring C2 is TIFF2025503675000095.tif20170, or ring C2 is The file is TIFF2025503675000096.tif20170.

[0263] In some embodiments, ring C2 is Oxo and R c C, each of which may be substituted with 1 to 4 substituents independently selected from the group consisting of 3~12 Cycloalkyl or C 3~12 cycloalkenyl; and Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and wherein the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c The heterocyclyl or heterocycloalkenyl may be substituted with 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0264] In certain of these embodiments, ring C2 is 1 to 4 R c C optionally substituted with 3~6 cycloalkyl, and Heterocyclyl of 4 to 6 ring atoms, in which 1 to 2 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is selected from the group consisting of 1 to 4 R c the heterocyclyl optionally substituted by is selected from the group consisting of:

[0265] In certain embodiments, ring C2 contains 1 to 2 R c C optionally substituted with 3~6cycloalkyl, e.g., ring C2 is cyclohexyl; or R 6 is 1 to 2 R c (eg, halo) substituted cyclohexyl.

[0266] In certain embodiments, each R c The substituents are halo; cyano; C 1~6 Alkyl; 1 to 6 R a C replaced with 1~6 Alkyl; C 1~4 Alkoxy; and C 1~4 In certain of these embodiments, R in Ring C is selected from the group consisting of haloalkoxy. c One occurrence of the substituent is C 1~6 Alkyl or 1 to 6 R a C replaced with 1~6 alkyl, e.g., C substituted with 1 to 6 independently selected halo, e.g., -F; 1~6 It is alkyl.

[0267] [3] In some embodiments, W is a heteroaryl of 5 ring atoms, wherein 1-4 of the ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is a heteroatom independently selected from the group consisting of 1 to 4 R c wherein said heteroaryl may be substituted via a ring carbon atom with C(=O)NR 6 The heteroaryl is bonded to a group.

[0268] In certain embodiments, W is thienyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, or tetrazolyl, such as thiazolyl.

[0269] In certain of the foregoing embodiments, the 5 ring atom heteroaryl is unsubstituted.

[0270] In certain of the foregoing embodiments, a heteroaryl of 5 ring atoms has 1 to 4 (e.g., 1 to 3, 1 to 2, or 1) R c may be substituted with.

[0271] [4] In some embodiments, W is a group represented by formula (A-3): TIFF2025503675000097.tif26170, wherein P 1 , P 2 , P 3 , P 4 and P 5 are N, NH, and NR d , N.R. 71 , C.H., C.R. c , C.R. 71 and C(=O), with the proviso that P 2 , P 3 and P 4 1 to 3 of the above, for example, 1 is CR 71 or NR 71 and; R 71 Each occurrence of is independently -(L AC ) aa3 -R 8 and Each L AC is 1 to 4 R a C optionally substituted with 1~3 Alkylene; -O-; -NR N ;-S(O) 0~2 ;C(O);C(O)O;OC(O);NR N C(O);C(O)NR N ;NR N C(O)NR N ;NR N C(O)O; and OC(O)NR N independently selected from the group consisting of: aa3 is 0, 1, 2 or 3; R 8 Each occurrence of is independently R g , or 1 to 6 R a1 C optionally substituted with 1~10 is alkyl; R N Each occurrence of is independently H or R d is.

[0272] In some embodiments, W is a group represented by formula (A-3-1): TIFF2025503675000098.tif26170, P 1 , P 2 , P 3 , P 4 and P 5 are N, NH, and NR d , N.R. 71 , C.H., C.R. c , C.R. 71 and C(═O); R 71 Each occurrence of is independently -(L AC ) aa3 -R 8 and Each L AC is 1 to 4 R a C optionally substituted with 1~3 Alkylene; -O-; -NR N ;-S(O) 0~2 ;C(O);C(O)O;OC(O);NR N C(O);C(O)NR N ;NR N C(O)NR N ;NR N C(O)O; and OC(O)NR N independently selected from the group consisting of: aa3 is 0, 1, 2 or 3; R 8 Each occurrence of is independently R g , or 1 to 6 R a1 C optionally substituted with 1~10 is alkyl; R N Each occurrence of is independently H or R d is.

[0273] Variable P 1 , P 2 , P 3 , P4 and P 5 In some embodiments, P 1 and P 5 are independently CH or CR c And ;P 2 , P 3 and P 4 are independently CH, CR c or CR 7 is.

[0274] In some embodiments, P 1 , P 2 , P 3 , P 4 and P 5 is N. In some embodiments, P 1 , P 2 , P 3 , P 4 and P 5 The two are N.

[0275] In some embodiments, P 2 , P 3 and P 4 One of them is CR 71 is.

[0276] In certain embodiments, P 3 is CR 71 In certain of these embodiments, P 4 is N. In certain other embodiments, P 4 is CH or CR c In certain of the foregoing embodiments, P 1 is N. In certain other embodiments, P 1 is CH or CR c In certain embodiments, P 2 and P 5 are independently CH or CR c is.

[0277] In certain embodiments, P 3 is CR 7 And ;P 1 , P 2 , P4 and P 5 are independently CH or CR c is.

[0278] In certain embodiments, The TIFF2025503675000099.tif26170 part has the formula: TIFF2025503675000100.tif14170, where n7 is 0, 1, or 2; c7 are independently selected R c ,for example, The file is TIFF2025503675000101.tif26170.

[0279] In certain embodiments, P 3 is CR 7 And ;P 4 is N;P 1 , P 2 and P 5 are independently CH or CR c is.

[0280] In certain embodiments, The TIFF2025503675000102.tif19170 part has the formula: TIFF2025503675000103.tif20170, where n7 is 0, 1, or 2; c7 are independently selected R c ,for example, The file is TIFF2025503675000104.tif20170.

[0281] In certain embodiments, P 3 is CR 7 And ;P 4 and P 1 is N;P 2 and P 5 are independently CH or CR c is.

[0282] In certain embodiments, The TIFF2025503675000105.tif20170 part has the formula: TIFF2025503675000106.tif20170, where n7 is 0, 1, or 2; c7 are independently selected R c ,for example, The file is TIFF2025503675000107.tif20170.

[0283] In some embodiments, P 4 is CR 71 In certain embodiments, P 3 is N. In certain other embodiments, P 3 is CH or CR c In certain embodiments, P 1 , P 2 and P 5 are independently CH or CR c is.

[0284] In certain embodiments, P 4 is CR 71 And ;P 3 is CH or CR c And ;P 1 , P 2 and P 5 are independently CH or CR c is.

[0285] In certain embodiments, The TIFF2025503675000108.tif20170 part has the formula: TIFF2025503675000109.tif26170, where n7 is 0, 1, or 2; c7 are independently selected R c ,for example, The file is TIFF2025503675000110.tif26170.

[0286] In certain embodiments, P 4 is CR 71 And ;P 3 is N;P1 , P 2 and P 5 are independently CH or CR c is.

[0287] In certain embodiments, The TIFF2025503675000111.tif26170 part has the formula: TIFF2025503675000112.tif26170, where n7 is 0, 1, or 2; c71 are independently selected R c ,for example, The file is TIFF2025503675000113.tif26170.

[0288] In certain embodiments, The TIFF2025503675000114.tif26170 part has the formula: TIFF2025503675000115.tif51170; where n7 is 0, 1, or 2; each R c7 are independently selected R c is.

[0289] In certain embodiments, R c7 Each occurrence of is halo; cyano; C 1~3 Alkyl; C 1~4 Alkoxy;C 1~4 haloalkoxy; and C substituted with 1 to 6 independently selected halo, e.g., -F 1~3 alkyl.

[0290] In certain embodiments, The part of TIFF2025503675000116.tif20170 is TIFF2025503675000117.tif20170.

[0291] Variable L AC , aa3 and R 8 In some embodiments, aa3 is 0. In some embodiments, aa3 is 1. In some embodiments, aa3 is 2. In some embodiments, aa3 is 3.

[0292] In some embodiments, L AC is -O-, -NH- or -CH2-, for example, L AC In certain embodiments (when aa3 is 1), L AC is -O-, -NH- or -CH2-, for example, L AC In certain embodiments, aa3 is 1; L AC is -O-.

[0293] In certain embodiments, aa31 is 2; -(L AC ) aa3 -L A1 -L A2 and L A1 and L A2 are independently selected L AC and;L A2 is R 8 In certain of these embodiments, L A1 is -O-;L A2 is 1 to 2 R a C optionally substituted with 1~3 alkylene, for example, L A1 is -O-;L A2 is CH2.

[0294] In certain embodiments, aa3 is 3; -(L AC ) aa3 -L A1 -L A2 -L A3 and L A1 , L A2 and L A3 are independently selected L AC and;L A3 is R 8 In certain of these embodiments, L A1 and LA3 are each independently one to two R a C optionally substituted with 1~3 In certain embodiments, L A2 is NR N C(O)O or OC(O)NR N is.

[0295] In some embodiments, R 8 is 1 to 4 R a C optionally substituted with 1~10 It is alkyl.

[0296] In certain embodiments, R 8 is C 1~10 Alkyl, e.g., C 1~7 Alkyl, for example C1, C2, C3, C4, C5, C6 or C7 alkyl, for example ethyl or isopropyl.

[0297] In certain embodiments, R 8 is 1 to 6 R a C replaced with 1~10 Alkyl, e.g., 1 to 6 R a In certain embodiments, R is a C1, C2, C3, C4, C5, C6, or C7 alkyl substituted with 1 is halo, e.g. -F; -OH; C 1~4 Alkoxy; and C 1~4 haloalkoxy.

[0298] In certain embodiments, R 8 is a C substituted with 1 to 6 independently selected halo groups; 1~10 alkyl, for example, C, C, C, C, C, C, or C alkyl substituted with 1 to 6 independently selected halo. 8 is C substituted with 1 to 6 -F 1~10 Alkyl, for example C1, C2, C3, C4, C5, C6 or C7 alkyl substituted with 1 to 6 -F, for example The file is TIFF2025503675000118.tif39170.

[0299] In certain embodiments, R 8 is C substituted with -OH 1~10 Alkyl, C 1~4 Alkoxy or C 1~4 haloalkoxy, e.g., 1 to 6 independently selected C 1~4 C1, C2, C3, C4, C5, C6 or C7 alkyl substituted with alkoxy, for example The file is TIFF2025503675000119.tif15170.

[0300] In some embodiments, R 8 is R g is.

[0301] In certain embodiments, R 8 teeth, Each of them is oxo, R c , R h and -(L g ) bg -R h C 3~8 Cycloalkyl or C 3~8 cycloalkenyl; and Heterocyclyl or heterocycloalkenyl of 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo, R c , R h and -(L g ) bg -R h The heterocyclyl or heterocycloalkenyl may be substituted with 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0302] In certain embodiments, R 8 teeth, Oxo and Rc C 3~8 cycloalkyl; and Heterocyclyl of 4 to 8 ring atoms, in which 1 to 2 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is selected from the group consisting of oxo and R c The heterocyclyl may be substituted with 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0303] In certain embodiments, R 8 teeth, substituted with 1 to 2 (e.g., 2) independently selected halo (e.g., -F), and oxo and R c C may be further substituted with 1 to 2 substituents independently selected from the group consisting of 3~8 cycloalkyl; and Heterocyclyl of 4 to 8 ring atoms, in which 1 to 2 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is substituted with 1 to 2 (e.g., 2) independently selected halo (e.g., -F), and oxo and R c The heterocyclyl may be further substituted with 1 to 2 substituents independently selected from the group consisting of is selected from the group consisting of:

[0304] As a non-limiting example of the foregoing embodiment, R 8 Each of these is substituted with two -F and one to two R c piperidinyl, pyrrolidinyl, azetidinyl, azaspiro[3.3]heptanyl, cyclobutyl, cyclopentyl and cyclohexyl, optionally further substituted by, for example TIFF2025503675000120.tif26170.

[0305] Another non-limiting example is R 8 is an optionally substituted 3-azabicyclo[3.1.0]hexane, for example: It could be TIFF2025503675000121.tif77170.

[0306] In certain embodiments, R 8 teeth, C such as cyclopropyl, cyclohexyl, cyclobutyl, or cyclopentyl 3~8 cycloalkyl; C 1~4 Alkoxy;C 1~4 Haloalkoxy;C 1~4 Alkoxy or C 1~4 Haloalkoxy-substituted C 1~4 Alkoxy;C 1~4 haloalkyl; and 1 to 6 independently selected halo, C 1~4 Alkoxy or C 1~4 Haloalkoxy-substituted C 1~6 alkyl, and one to two R c may be further substituted with C 3~8 cycloalkyl; Heterocyclyl of 4 to 8 ring atoms, in which 1 to 2 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 The heterocyclyl is a heteroatom independently selected from the group consisting of: TIFF2025503675000122.tif26170; and Heterocyclyl of 4 to 8 ring atoms, in which 1 to 2 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heteroatoms are each independently selected from the group consisting of: 1~4 Alkoxy;C 1~4 Haloalkoxy;C 1~4Alkoxy or C 1~4 Haloalkoxy-substituted C 1~4 Alkoxy;C 1~4 haloalkyl; and 1 to 6 independently selected halo, C 1~4 Alkoxy or C 1~4 Haloalkoxy-substituted C 1~6 alkyl, and the heterocyclyl is substituted with one to two R c The heterocyclyl may be further substituted by, for example, TIFF2025503675000123.tif64170.

[0307] In certain embodiments, R 8 is a C such as cyclopropyl, cyclohexyl, cyclobutyl or cyclopentyl 3~8 It is cycloalkyl.

[0308] In certain embodiments, R 8 is C 1~4 Alkoxy;C 1~4 Haloalkoxy;C 1~4 Alkoxy or C 1~4 Haloalkoxy-substituted C 1~4 Alkoxy;C 1~4 haloalkyl; and 1 to 6 independently selected halo, C 1~4 Alkoxy or C 1~4 Haloalkoxy-substituted C 1~6 alkyl, and one to two R c C which may be further substituted with 3~8 It is cycloalkyl.

[0309] In certain embodiments, R 8 is a heterocyclyl of 4 to 8 ring atoms, in which 1 to 2 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 The heterocyclyl is a heteroatom independently selected from the group consisting of: The file is TIFF2025503675000124.tif26170.

[0310] In certain embodiments, R 8 is a heterocyclyl of 4 to 8 ring atoms, in which 1 to 2 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heteroatoms are each independently selected from the group consisting of: 1~4 Alkoxy;C 1~4 Haloalkoxy;C 1~4 Alkoxy or C 1~4 Haloalkoxy-substituted C 1~4 Alkoxy;C 1~4 haloalkyl; and 1 to 6 independently selected halo, C 1~4 Alkoxy or C 1~4 Haloalkoxy-substituted C 1~6 alkyl, and the heterocyclyl is substituted with one to two R c The heterocyclyl may be further substituted by, for example, TIFF2025503675000125.tif64170.

[0311] In certain embodiments, R 8 teeth, Heteroaryl with 5-6 ring atoms, 1-3 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R c the heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl, e.g., phenyl is selected from the group consisting of:

[0312] In certain embodiments, aa3 is 0; R 8 teeth, substituted with 1 to 2 (e.g., 2) independently selected halo (e.g., -F), and oxo and R c C may be further substituted with 1 to 2 substituents independently selected from the group consisting of 3~8 cycloalkyl; and Heterocyclyl of 4 to 8 ring atoms, in which 1 to 2 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is substituted with 1 to 2 (e.g., 2) independently selected halo (e.g., -F), and oxo and R c The heterocyclyl may be further substituted with 1 to 2 substituents independently selected from the group consisting of is selected from the group consisting of:

[0313] As a non-limiting example of the foregoing embodiment, R 8 Each of these is substituted with two -F and one to two R c piperidinyl, pyrrolidinyl, azetidinyl, azaspiro[3.3]heptanyl, cyclobutyl, cyclopentyl and cyclohexyl, optionally further substituted by, for example TIFF2025503675000126.tif32170.

[0314] Another non-limiting example is R 8 is an optionally substituted 3-azabicyclo[3.1.0]hexane, for example: It could be TIFF2025503675000127.tif77170.

[0315] In certain embodiments, aa3 is 0; R 8 is a C substituted with 1 to 6 independently selected halo groups; 1~10 alkyl, for example, C, C, C, C, C, C, or C alkyl substituted with 1 to 6 independently selected halo. 8 is C substituted with 1 to 6 -F1~10 Alkyl, for example C1, C2, C3, C4, C5, C6 or C7 alkyl substituted with 1 to 6 -F, for example It could be TIFF2025503675000128.tif32170.

[0316] In certain embodiments, aa3 is 1; L AC is -O- or -NH-; R 8 is a C substituted with 1 to 6 independently selected halo groups; 1~10 alkyl, for example, C, C, C, C, C, C, or C alkyl substituted with 1 to 6 independently selected halo. In certain of these embodiments, R 8 is C substituted with 1 to 6 -F 1~10 Alkyl, for example C1, C2, C3, C4, C5, C6 or C7 alkyl substituted with 1 to 6 -F, for example TIFF2025503675000129.tif32170. In certain embodiments, L A is -O-.

[0317] In certain embodiments, aa3 is 1; L AC is -O-, -NH- or -CH2-; R 8 teeth, substituted with 1 to 2 (e.g., 2) independently selected halo (e.g., -F), and oxo and R c C may be further substituted with 1 to 2 substituents independently selected from the group consisting of 3~8 cycloalkyl; and Heterocyclyl of 4 to 8 ring atoms, in which 1 to 2 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is substituted with 1 to 2 (e.g., 2) independently selected halo (e.g., -F), and oxo and R c The heterocyclyl may be further substituted with 1 to 2 substituents independently selected from the group consisting of is selected from the group consisting of:

[0318] In certain of these embodiments, R 8 is substituted with one to two (e.g., two) independently selected halo (e.g., -F), and is substituted with oxo and R c C may be further substituted with 1 to 2 substituents independently selected from the group consisting of 3~8 Cycloalkyl, e.g., each of which is substituted with two -F and one to two R c cyclobutyl, cyclopentyl and cyclohexyl, which may be further substituted by, for example, TIFF2025503675000130.tif15170.

[0319] In certain of the foregoing embodiments, L AC is -O-.

[0320] [5] In some embodiments, W is Oxo, R c and -(L AD ) bB -R g a bicyclic or polycyclic C ring, each of which may be substituted with 1 to 4 substituents independently selected from the group consisting of 5~15 Cycloalkyl or C 5~15 cycloalkenyl; Bicyclic or polycyclic heterocyclyl or heterocycloalkenyl of 7 to 15 ring atoms, in which 1 to 4 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, R c and -(L AD ) bB -R g the bicyclic or polycyclic heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Bicyclic or polycyclic heteroaryl of 8 to 15 ring atoms, in which 1 to 6 ring atoms are N, N(H), N(Rd ), O and S(O) 0~2 and the heteroaryl is oxo, R c and -(L AD ) bB -R g the bicyclic or polycyclic heteroaryl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Oxo, R c and -(L AD ) bB -R g a bicyclic or polycyclic C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 8~15 Aryl is selected from the group consisting of However, bicyclic or polycyclic heterocycles are not bonded via a ring carbon atom to C(=O)NR 6 is attached to a group; L AD Each occurrence of is -O-, -NH-, -NR d , -S(O) 0~2 , C(O) and 1 to 3 R a C optionally substituted with 1~3 alkylene; and bB is 0, 1, 2 or 3 and is a bicyclic or polycyclic ring system.

[0321] In some embodiments, W is Bicyclic or polycyclic heteroaryl of 8 to 15 (e.g., 9, 10, 11, or 12) ring atoms, of which 1 to 6 (e.g., 1, 2 to 3, or 3 to 4) ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is R c and -(L B ) bB -R h the bicyclic or polycyclic heteroaryl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ·R c and -(LB ) bB -R h a bicyclic or polycyclic C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 8~15 (e.g., C9, C 10 , C 11 or C 12 ) Aryl wherein W is selected from the group consisting of C(=O)NR via a ring carbon atom. 6 is bonded to the group.

[0322] In some embodiments, W is a group represented by formula (B-1): TIFF2025503675000131.tif32170, wherein T 3 and T 4 are independently C or N; T 5 , T 6 , T 7 and T 8 are independently N, CH or CR B and; T 1 and T 2 are independently N, NH, and NR d , N.R. B , C.H., C.R. B , O or S; R B Each occurrence of is independently R c Or -(L B ) bB -R h and; Each TIFF2025503675000132.tif5170 are independently a single bond or a double bond, provided that T 1 ~T 4 A five-membered ring containing T is heteroaryl. 3 ~T 8 is an aryl or heteroaryl; Furthermore, however, T 1 ~T 8 Not more than four of R B There is a group.

[0323] In certain of these embodiments, T 1 ~T 4 The five-membered ring containing is thiophene, thiazole, oxazole, imidazole or pyrazole.

[0324] In certain embodiments, W is TIFF2025503675000133.tif45170.

[0325] In certain embodiments, W is TIFF2025503675000134.tif39170, and each R B are independently c Or -(L B ) bB -R h and m1 is 0, 1, or 2 (e.g., 1 or 2). As a non-limiting example of the foregoing embodiment, W is It could be TIFF2025503675000135.tif20170.

[0326] In some embodiments, W is a group represented by formula (B-2): TIFF2025503675000136.tif26170, wherein T 3 and T 4 are independently C or N; T 1 and T 2 are independently N, NH, and NR d , N.R. B , C.H., C.R. B , O or S; T 9 is -O-, S(O) 0~2 , CH2, CHR B , C(R B )2, NH, NR d or NR B and; nB is 0, 1, 2 or 3; mB is 1 or 2; Each R Bare independently c Or -(L B ) bB -R h and; m1 is 0, 1 or 2 (e.g., 1 or 2); Each TIFF2025503675000137.tif6170 are independently a single bond or a double bond, provided that T 1 ~T 4 is heteroaryl, provided that there are no more than four R B There is a group.

[0327] In certain of these embodiments, T 3 is N. In certain embodiments, T 1 ~T 4 The five-membered ring containing is pyrazole or imidazole.

[0328] In certain embodiments, W is TIFF2025503675000138.tif20170, and each R B are independently c Or -(L B ) bB -R h and m1 is 0, 1 or 2 (e.g., 1 or 2).

[0329] In certain embodiments, W is TIFF2025503675000139.tif77170, and each R B are independently c Or -(L B ) bB -R h and m1 is 0, 1 or 2 (e.g., 1 or 2).

[0330] In certain embodiments, W is TIFF2025503675000140.tif20170 or TIFF2025503675000141.tif20170, and each R Bare independently c Or -(L B ) bB -R h and m1 is 0, 1 or 2 (e.g., 1 or 2).

[0331] In certain embodiments, W is TIFF2025503675000142.tif20170, and each R B are independently c Or -(L B ) bB -R h and m1 is 0, 1 or 2 (e.g., 1 or 2).

[0332] In some embodiments, W is a group represented by formula (B-3): TIFF2025503675000143.tif26170, wherein P 3 and P 4 are independently C or N; P 1 and P 2 are independently N, NH, and NR d , N.R. B , C.H., C.R. B , O or S; P 5 , P 6 , P 7 and P 8 are independently N, CH or CR B and; Each R B are independently c Or -(L B ) bB -R h and; Each TIFF2025503675000144.tif6170 are independently a single bond or a double bond, provided that P 1 ~P 4 is a heteroaryl, and P 3 ~P 8 is an aryl or heteroaryl, with the further proviso that P 1 ~P8 Not more than four of R B There is a group.

[0333] In certain of these embodiments, P 3 is C. In certain embodiments, P 4 is C. In certain of the foregoing embodiments, P 3 is C;P 4 is C. In certain embodiments, P 1 is N;P 2 is NR B (e.g., N-(L B ) bB -R h In certain embodiments, P 1 is N;P 2 is NH. In certain embodiments, P 5 , P 6 , P 7 and P 8 each one of is independently N, CH or CR B For example, P 6 is CR B (e.g., CR c ) and ;P 5 , P 7 and P 8 is CH.

[0334] In certain embodiments of (B-3), P 1 ~P 4 A five-membered ring containing is a pyrazole.

[0335] In certain embodiments, W is TIFF2025503675000145.tif83170, and each R B are independently c Or -(L B ) bB -R h and m1 is 0, 1 or 2 (e.g., 1 or 2).

[0336] In certain embodiments, W is TIFF2025503675000146.tif26170.

[0337] In certain embodiments, W is TIFF2025503675000147.tif45170; Each R B are independently c Or -(L B ) bB -R h m1 is 0, 1, or 2 (e.g., 0); each R hB are independently selected R h For example, W is The file is TIFF2025503675000148.tif26170.

[0338] In certain embodiments, W is TIFF2025503675000149.tif26170, and each R B are independently c Or -(L B ) bB -R h and m1 is 0, 1 or 2 (e.g., 0).

[0339] As a non-limiting example of the foregoing embodiment, W may be: It could be TIFF2025503675000150.tif39170.

[0340] In certain embodiments of (B3), P 1 ~P 4 The five-membered ring containing is imidazole.

[0341] In certain of these embodiments, W is TIFF2025503675000151.tif45170, and each R B are independently c Or -(L B ) bB -R hand m1 is 0, 1 or 2 (e.g., 0).

[0342] In certain embodiments, W is TIFF2025503675000152.tif51170, and each R B are independently c Or -(L B ) bB -R h m1 is 0, 1 or 2 (e.g., 0), for example, The file is TIFF2025503675000153.tif26170.

[0343] In some embodiments, W is a group of formula (B4): TIFF2025503675000154.tif32170, wherein P 3 and P 4 are independently C or N; P 1 and P 2 are independently N, NH, and NR d , N.R. B , C.H., C.R. B , O or S; Q 9 is -O-, S(O) 0~2 , CH2, CHR B , C(R B )2, NH, NR d or NR B and; nB is 0, 1, 2 or 3; mB is 1 or 2; R B Each occurrence of is independently R c Or -(L B ) bB -R h and; m1 is 0, 1 or 2 (e.g., 1 or 2); Each TIFF2025503675000155.tif6170 are independently a single bond or a double bond, provided that P 1 ~P 4A five-membered ring containing B There is a group.

[0344] In certain of these embodiments, P 1 ~P 4 The five-membered ring containing is pyrazole, thiophene or imidazole.

[0345] In certain embodiments, W is TIFF2025503675000156.tif45170, and each R B are independently c Or -(L B ) bB -R h and m1 is 0, 1 or 2 (e.g., 0).

[0346] In some embodiments, W is a group represented by formula (B5) or (B6): TIFF2025503675000157.tif32170, wherein BA is a ring of 5-8 ring atoms, with 0-3 ring atoms being N, NH, or NR d , O, and S; and BA is one to two R B may be substituted with; Each R B are independently c Or -(L B ) bB -R h and m1 is 0, 1 or 2 (e.g., 0).

[0347] In certain of these embodiments, W is a non-aromatic ring of 5 to 8 ring atoms, of which 0 to 3 ring atoms are N, NH, NR d , O, and S; and BA is one to two R B may be substituted with.

[0348] As a non-limiting example of the foregoing embodiment, W may be: TIFF2025503675000158.tif20170, R B are independently c Or -(L B ) bB -R h is.

[0349] In certain embodiments of (B5) or (B6), BA is a 5-membered heteroaromatic ring in which 1 to 2 ring atoms are selected from N, NH, NR d , O, and S; and BA is one to two R B For example, BA may be substituted with R B In certain of these embodiments, Ring B is a pyrazole optionally substituted with TIFF2025503675000159.tif32170, where R hB are independently selected R h is.

[0350] In some embodiments, W is a group of formula (B7): TIFF2025503675000160.tif20170, wherein BB is an aromatic ring of 5-6 ring atoms, 0-3 of which are N, NH, or NR d , O, and S; and BB is one to two R B may be substituted with; Each R B are independently c Or -(L B ) bB -R h m1 is 0, 1 or 2 (e.g., 0), and for example, ring B is The file is TIFF2025503675000161.tif20170.

[0351] In some embodiments, W is a spirocyclic ring (e.g., a [4.4.1], [5.4.1], or [5.5.1] spiro ring). As a non-limiting example, ring B is: It could be TIFF2025503675000162.tif32170.

[0352] In some embodiments, W is a bridged ring. As a non-limiting example, ring B is: It could be TIFF2025503675000163.tif20170.

[0353] In certain embodiments, each R B is halo; cyano; C 1~4 alkyl, e.g., methyl; C substituted with 1 to 6 independently selected halo, e.g., —CF or —CHCHCF 1~4 Alkyl; C 1~4 Alkoxy, such as methoxy, ethoxy or isopropoxy; and C 1~4 independently selected from the group consisting of haloalkoxy, for example, -OCF3, -OCHF2, or -OCH2CF3.

[0354] In certain embodiments, L B is CH2.

[0355] In certain embodiments, each R of ring B h Substituents, such as R hB teeth, Heteroaryl with 5-6 ring atoms, 1-3 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 3 R i the heteroaryl, optionally substituted with 1 to 2 R i C6 aryl optionally substituted with, for example, R g1 1 to 4 R i phenyl optionally substituted with are independently selected from the group consisting of:

[0356] [6] In some embodiments, W is a group represented by formula (A-4): TIFF2025503675000164.tif32170, L AE teeth, Each of them has 1 to 6 R a optionally substituted with C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Alkynylene; Each of which is oxo and R c a monocyclic C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~8 Cycloalkylene or C 3~8 cycloalkenylene; Monocyclic heterocyclylene or heterocycloalkenylene having 3 to 8 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is selected from the group consisting of oxo and R c and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C(═O)NR 6 the monocyclic heterocyclylene or heterocycloalkenylene bonded to a group selected from the group consisting of: Each L AF is 1 to 4 R a1 C optionally substituted with 1~3 Alkylene; -O-; -NH-; -NR d ;-S(O) 0~2 and C(O); aa4 is 0, 1, 2 or 3; Ring C4 is R g is.

[0357] Variable L AE In some embodiments, L AE Each of them has 1 to 6 R a1 optionally substituted with C1~6 Alkylene, C 2~6 Alkenylene or C 2~6 It is alkynylene.

[0358] In certain embodiments, L AE is 1 to 6 R a1 C optionally substituted with 1~6 In certain embodiments, L AE is CH. In certain embodiments, L B is 1 to 6 R a1 Branched chain C optionally substituted with 2~6 alkylene, for example, —CH(Me)—, —C(Me)—, or —C(Me)—CH—. In certain embodiments, L AE is 1 to 6 R a1 Optionally substituted linear C 2~6 Alkylene, for example CH2CH2 or CH2CH2CH2.

[0359] In certain embodiments, L AE is 1 to 6 R a1 C optionally substituted with 2~6 In certain of these embodiments, L AE is 1 to 6 R a1 C optionally substituted with 2~4 alkenyl. In certain embodiments, NR 6 C(=O) group and (L A ) a1 The group is L AE Two sp 2 A non-limiting example is L AE can be CH=CH or C(Me)=CH*, and the asterisk indicates (L AF ) aa4 Represents a point of attachment to

[0360] In some embodiments, L AE teeth, Each of which is oxo and R c a monocyclic C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~8Cycloalkylene or C 3~8 cycloalkenylene; and Monocyclic heterocyclylene or heterocycloalkenylene having 3 to 8 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is selected from the group consisting of oxo and R c and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C(═O)NR 6 the monocyclic heterocyclylene or heterocycloalkenylene bonded to a group is selected from the group consisting of:

[0361] In certain embodiments, L AE is oxo and R c a monocyclic C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~8 cycloalkylene, for example, L AE is 1 to 4 R c C optionally substituted with 4~8 cycloalkylene, for example, L AE is cyclobutylene.

[0362] In certain embodiments, L AE is a monocyclic heterocyclylene of 4 to 8 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene is selected from the group consisting of oxo and R c and the heterocyclylene may be substituted with 1 to 4 substituents independently selected from the group consisting of: B are each optionally substituted with oxo, and 1 to 2 R c pyrrolidinylene or morpholinylene, which may be further substituted by, for example, L AE teeth, TIFF2025503675000165.tif26170, where bb is (L AF ) aa4 It is the connection point to

[0363] Variable L AF and aa4 In some embodiments, aa4 is 0.

[0364] In some embodiments, aa4 is 1.

[0365] In some embodiments, L AF is —O—, —S(O)—, C(═O), or CH. In certain embodiments, L AF is —O—. In certain embodiments, L AF is -S(O)-. In certain embodiments, L AF is C(=O). In certain embodiments, L A is CH2.

[0366] In some embodiments, aa4 is 1; L AF is —O—, —S(O)—, C(═O), or CH. In certain of these embodiments, L AF is —O—. In certain embodiments, L AF is -S(O)-. In certain embodiments, L AF is C(=O). In certain embodiments, L AF is CH2.

[0367] In some embodiments, aa4 is 2 or 3. In certain of these embodiments, L AF Each occurrence of is independently C(=O), S(O)2, NH, N(C 1~3 alkyl), -O- or CH2, provided that (L AF ) aa4 does not contain an OO or NO bond.

[0368] Variable ring C4 In some embodiments, ring C4 is Heteroaryl of 5 to 12 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is R c , R h and -(L g ) bg -R h the 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:

[0369] In certain of these embodiments, ring C4 is Heteroaryl of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R cC the heteroaryl, optionally substituted with 1 to 4 R cC and each R cC are independently selected R c C 6~10 Aryl is selected from the group consisting of:

[0370] In certain embodiments, ring C4 is Heteroaryl with 5-6 ring atoms, 1-4 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R cCthe heteroaryl, optionally substituted with 1 to 4 R cC and each R cC are independently selected R c C6 aryl is selected from the group consisting of:

[0371] In certain embodiments, ring C4 is TIFF2025503675000166.tif32170, where nc is 0 or 1, for example 0; cC are independently selected R c is.

[0372] In certain embodiments, ring C4 is TIFF2025503675000167.tif32170; or ring C4 is TIFF2025503675000168.tif32170, where nc is 0 or 1, for example 0; cC are independently selected R c is.

[0373] In some embodiments, ring C4 is unsubstituted phenyl or pyridyl.

[0374] In some embodiments, ring C4 is Heteroaryl with 5-6 ring atoms, 1-4 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of one R hC Or -(L g ) bg -R hC (For example, R hC or -CH2R hC ) and one or two R cC the heteroaryl, optionally further substituted with One R hC Or -(L g )bg -R hC (For example, R hC or -CH2R hC ) and one or two R cC C aryl, optionally further substituted with cC are independently selected R c and each R hC are independently selected R h The C6 aryl is selected from the group consisting of:

[0375] In certain of these embodiments, ring C4 is TIFF2025503675000169.tif33170, where nc is 0 or 1, for example 0; cC are independently selected R c and each R hC are independently selected R h is.

[0376] In certain embodiments, ring C4 is TIFF2025503675000170.tif32170; or ring C4 is TIFF2025503675000171.tif32170, where nc is 0 or 1; cC are independently selected R c and each R hC are independently selected R h is.

[0377] In certain embodiments, R hC teeth, 1 to 4 R i C optionally substituted with 3~8 cycloalkyl, and Heterocyclyl 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 is selected from the group consisting of 1 to 4 R ithe heterocyclyl optionally substituted by is selected from the group consisting of:

[0378] In certain embodiments, R hC teeth, TIFF2025503675000172.tif26170, where X C is N or CH, for example, TIFF2025503675000173.tif26170, and each R i are independently selected halo, e.g., —F.

[0379] In some embodiments, ring C4 is oxo and R cC C 3~8 cycloalkyl; and Heterocyclyl of 3 to 8 ring atoms, wherein 1 to 3 of the ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is selected from the group consisting of oxo and R cC and each R cC are independently selected R c The heterocyclyl is selected from the group consisting of:

[0380] In certain embodiments, ring C4 is selected from 1 to 4 R cC C optionally substituted with 3~8 Cycloalkyl, e.g., 1 to 2 R cC and optionally substituted C3, C4, C5 or C6 cycloalkyl, for example, unsubstituted C3, C4, C5 or C6 cycloalkyl.

[0381] In certain embodiments, R cC Each occurrence of is halo; cyano; C 1~4alkyl, e.g., methyl; C substituted with 1 to 6 independently selected halo, e.g., —CF 1~4 Alkyl; C 1~4 Alkoxy, such as methoxy, ethoxy or isopropoxy; and C 1~4 haloalkoxy, for example, —OCF 3 or —OCHF 2 .

[0382] Non-limiting combinations In certain embodiments, the compound has formula (Ia): TIFF2025503675000174.tif32170 or a pharmaceutically acceptable salt thereof, wherein L 1 represents -O-, -N(H)- and -N(R d )-selected from the group consisting of; L 2 teeth, 1 to 3 R b Optionally substituted linear C 1~3 Alkylene; 1 to 3 R c C optionally substituted with 3~8 cycloalkylene; and Heterocyclylenes having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene is a ring heteroatom independently selected from the group consisting of 1 to 3 R c the heterocyclylene optionally substituted by is selected from the group consisting of:

[0383] In certain embodiments of Formula (Ia), L 1 is -O-.

[0384] In certain embodiments of Formula (Ia), L 2 is 1 to 3 R b Optionally substituted linear C 1~3 It is alkylene.

[0385] In certain embodiments of Formula (Ia), L 2 -CH2-, -CHR b - and -C(R b )2-, and optionally, L 2 is -CH2-.

[0386] In certain embodiments of Formula (Ia), L 2 is 1 to 3 R b In certain of these embodiments, L 2 is -CH2CH2-, -CH2CH(R b )-* and -CH2C(R b )2-*, where the asterisk represents -Q 1 represents the point of attachment to the 2 can be -CH2CH2-.

[0387] In certain embodiments of Formula (Ia), L 2 is 1 to 3 R b It is a straight chain C3 alkylene optionally substituted with

[0388] In certain embodiments of Formula (Ia), L 2 is 1 to 2 R c optionally substituted with, TIFF2025503675000175.tif20170, and n1 and n2 are independently 0, 1, or 2; Q 2 , CH, CR c or N; an asterisk indicates Q 1 Represents a point of attachment to

[0389] In certain of these embodiments, n1 and n2 are independently 0 or 1, optionally 0; Q 2 For example, n1 and n2 can both be 0; Q 2 can be CH, for example, L 2 can be an optionally substituted cyclobutane-diyl, such as an optionally substituted cyclobutane-1,3-diyl.

[0390] In certain embodiments of Formula (Ia), L 1 is -O-;L 2 is 1 to 2 R c may be substituted with TIFF2025503675000176.tif20170, where n1 and n2 are independently 0 or 1, optionally 0; Q 2 For example, n1 and n2 can both be 0; Q 2 can be CH, for example, L 2 may be an optionally substituted cyclobutane-diyl, such as optionally substituted 1,3-cyclobutane-1,3-diyl, such as unsubstituted cyclobutane-diyl, such as unsubstituted cyclobutane-1,3-diyl.

[0391] In certain embodiments of Formula (Ia), L 1 is -O-;L 2 is 1 to 3 R b Optionally substituted linear C 2~3 It is alkylene.

[0392] In certain of the foregoing embodiments of Formula (Ia), L 2 is 1 to 3 R b is a straight-chain C2 alkylene optionally substituted with

[0393] In certain of the foregoing embodiments, L 2 is -CH2CH2-, -CH2CH(R b )-* and -CH2C(R b )2-*, where the asterisk represents -Q 1 represents the point of attachment to the 2 can be -CH2CH2-.

[0394] In certain embodiments of Formula (Ia), L 1 is -O-;L 2 -CH2-, -CHR b - and -C(R b For example, L2 can be -CH2-.

[0395] In certain embodiments, the compound has formula (Ib): TIFF2025503675000177.tif39170 or a pharmaceutically acceptable salt thereof, wherein L 2 Each of them has 1 to 6 R b Optionally substituted with linear C 1~6 Alkylene or linear C 2~6 It is alkenylene.

[0396] In certain embodiments of Formula (Ib), L 2 is 1 to 3 R b Optionally substituted linear C 2~3 It is alkylene.

[0397] In certain embodiments of Formula (Ib), L 2 is 1 to 3 R b In certain of these embodiments, L 2 is -CH2CH2-, -CH2CH(R b )-* and -CH2C(R b )2-*, where the asterisk represents -Q 1 represents the point of attachment to the 2 can be -CH2CH2-.

[0398] In certain embodiments of Formula (Ib), L 2 is 1 to 3 R b In certain of these embodiments, L 2 teeth, TIFF2025503675000178.tif20170, and the asterisk represents -Q 1 represents the point of attachment to the 2 teeth, It could be TIFF2025503675000179.tif13170.

[0399] In certain embodiments of Formula (Ib), L 2 is 1 to 3 R b Optionally substituted linear C 2~4 It is alkenylene.

[0400] In certain of these embodiments, L 2 teeth, TIFF2025503675000180.tif20170, and the asterisk represents -Q 1 Represents a point of attachment to

[0401] In certain embodiments, the compound has formula (Ic): TIFF2025503675000181.tif39170 or a pharmaceutically acceptable salt thereof, wherein L 2 and L 4 is 1 to 6 R b an independently selected linear C 1~3 is alkylene; L 3 represents -O-, -N(H)- and -N(R d )-.

[0402] In certain embodiments of Formula (Ic), L 2 and L 4 -CH2-, -CHR b - and -C(R b In certain of these embodiments, L 2 and L 4 are -CH2-, respectively.

[0403] In certain embodiments of Formula (Ic), L 3 is -O-.

[0404] In certain embodiments of Formula (Ic), L 3 is -N(H)- or -N(R d )-. For example, L 3 can be —N(H)—.

[0405] In certain embodiments, the compound has formula (Id): TIFF2025503675000182.tif39170 or a pharmaceutically acceptable salt thereof, wherein L 2 is 1 to 6 R b Optionally substituted linear C 1~3 is alkylene; L 3 represents -O-, -N(H)- and -N(R d )-.

[0406] In certain embodiments of Formula (Id), L 2 -CH2-, -CHR b - and -C(R b )2.

[0407] In certain embodiments of Formula (Id), L 2 is 1 to 3 R b In certain of these embodiments, L 2 is -CH2CH2-, -CH2CH(R b )-* and -CH2C(R b )2-*, where the asterisk represents -L 3 represents the point of attachment to the 2 can be -CH2CH2-.

[0408] In certain embodiments of Formula (Id), L 3 is -O-.

[0409] In certain embodiments of Formula (Id), L 3 is -N(H)- or -N(R d )-. For example, L 3 can be —N(H)—.

[0410] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), Q 1 teeth, Heteroaryl with 5-6 ring atoms, 1-4 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 3 R c’ the heteroaryl, optionally substituted with 1 to 3 R c’ phenyl optionally substituted with is selected from the group consisting of:

[0411] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), Q 1 teeth, A heteroaryl having six ring atoms, one to two of which are ring nitrogen atoms, and the heteroaryl is c’ the heteroaryl, optionally substituted with 1 to 3 R c’ phenyl optionally substituted with is selected from the group consisting of:

[0412] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), Q 1 is 1 to 3 R c’ and phenyl or pyridyl, each of which may be substituted by

[0413] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), Q 1 teeth, The file is TIFF2025503675000183.tif19170.

[0414] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), Q 1 is 1 to 3 R c’ phenyl or pyridyl, each of which may be substituted by Q 1 Each R in cC optionally substituted with halo and 1 to 6 independently selected halo 1~3 alkyl.

[0415] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), Q 1 teeth, TIFF2025503675000184.tif20170;Q 1 Each R in c are independently selected from the group consisting of -F, -Cl, and -CF3.

[0416] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), Q 1 is a heterocyclyl of 4 to 10 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclyl is selected from the group consisting of oxo and R c’ and the heterocyclyl may be substituted with 1 to 4 substituents independently selected from the group consisting of:

[0417] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), Q 1 teeth, TIFF2025503675000185.tif20170, and m1 and m2 are each independently 0, 1, or 2.

[0418] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), Q 1 teeth, The file is TIFF2025503675000186.tif20170.

[0419] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), Q 1 teeth, TIFF2025503675000187.tif20170; Q1 R present in d is -C(O)O(C 1~4 alkyl); and 1 to 3 independently selected R a C optionally substituted with 1~6 alkyl; or Q 1 R present in d is C substituted with 1 to 3 -F 2~3 It is alkyl.

[0420] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), Q 1 teeth, TIFF2025503675000188.tif20170; Q 1 R present in d is -C(O)O(C 1~4 alkyl); and 1 to 3 independently selected R a C optionally substituted with 1~6 alkyl; or Q 1 R present in d is C substituted with 1 to 3 -F 2~3 It is alkyl.

[0421] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), R c’ is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 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 selected from the group consisting of 1 to 4 independently selected R c and heterocyclyl or heterocycloalkenyl as defined above, optionally substituted by:

[0422] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), R c’ is 1 to 4 R c C optionally substituted with6~10 It is aryl.

[0423] In certain embodiments of Formula (Ia), (Ib), (Ic), or (Id), each R 1 is H.

[0424] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), R 1 One occurrence of R c and the remaining R 1 is H.

[0425] In certain embodiments of formula (Ia), (Ib), (Ic), or (Id), R 2 is H;R 5 is H.

[0426] In certain embodiments of Formula (Ia), (Ib), (Ic), or (Id), W has Formula (A-1), as defined in [1] herein and in (i) of the claims, and elsewhere herein.

[0427] In certain embodiments of Formula (Ia), (Ib), (Ic), or (Id), W has Formula (A-2), as defined herein as [2] and in the claims as (ii), and elsewhere herein.

[0428] In certain embodiments of Formula (Ia), (Ib), (Ic), or (Id), W is a heteroaryl of five ring atoms, as defined herein under [3] and in the claims under (iii), and elsewhere herein, wherein one to four ring atoms are selected from N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R c provided that said heteroaryl is substituted via a ring carbon atom with C(=O)NR 6 is said heteroaryl bonded to a group.

[0429] In certain embodiments of Formula (Ia), (Ib), (Ic), or (Id), W has Formula (A-3), as defined herein as [4] and in the claims as (iv), and elsewhere herein.

[0430] In certain embodiments of Formula (Ia), (Ib), (Ic), or (Id), W has Formula (A-3-1), as defined herein as [4] and in the claims as (iv), and elsewhere herein.

[0431] In certain embodiments of Formula (Ia), (Ib), (Ic), or (Id), W is a bicyclic or polycyclic ring as defined herein in [5] and in the claims in (v), and elsewhere herein.

[0432] In certain embodiments of Formula (Ia), (Ib), (Ic), or (Id), W has Formula (A-4), as defined herein as [6] and in the claims as (vi), and elsewhere herein.

[0433] 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 pharmaceutically acceptable salt thereof.

[0434] [Table C1] TIFF2025503675000190.tif227170TIFF2025503675000191.tif224170TIFF2025503675000192.tif209170TIFF202 5503675000193.tif227170TIFF2025503675000194.tif230170TIFF2025503675000195.tif200170TIFF20255036750 00196.tif209170TIFF2025503675000197.tif217170TIFF2025503675000198.tif227170TIFF2025503675000199.t if218170TIFF2025503675000200.tif227170TIFF2025503675000201.tif230170TIFF2025503675000202.tif233170 TIFF2025503675000203.tif195170TIFF2025503675000204.tif221170TIFF2025503675000205.tif199166TIFF202 5503675000206.tif232170TIFF2025503675000207.tif201170TIFF2025503675000208.tif205170TIFF20255036750 00209.tif202170TIFF2025503675000210.tif220170TIFF2025503675000211.tif209170TIFF2025503675000212.t if210170TIFF2025503675000213.tif210170TIFF2025503675000214.tif208170TIFF2025503675000215.tif136170

[0435] Pharmaceutical Compositions and Administration overview In some embodiments, a chemical entity (e.g., a compound that inhibits (e.g., antagonizes) STING, or a pharmaceutically acceptable salt, and / or hydrate, and / or cocrystal, and / or combination with a drug thereof) is administered as a pharmaceutical composition comprising the chemical entity, one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0436] In some embodiments, the chemical substance can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in formulation administration such as Tween, poloxamer or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, salts or electrolytes such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers and wool fat. Chemically modified or otherwise solubilized derivatives of cyclodextrins, such as α-, β-, and γ-cyclodextrin, or hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, may also be used to enhance delivery of the compounds described herein. Dosage forms or compositions may be prepared containing 0.005% to 100% of chemicals as described herein, with the remainder consisting of non-toxic excipients. Contemplated compositions may contain 0.001% to 100%, in one embodiment 0.1 to 95%, in another embodiment 75 to 85%, and in a further embodiment 20 to 80%, of chemicals provided herein. Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art, and are described, for example, in Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0437] Route of Administration and Composition Components In some embodiments, the chemical entities described herein or pharmaceutical compositions thereof can be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, oral, cutaneous, intracervical, intrasinus, intratracheal, intraintestinal, epidural, intrainterstitial, intraperitoneal, intraarterial, intrabronchial, intracapsular, intracerebral, intracapsular, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intrathecal, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal, nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0438] The composition can be formulated for parenteral administration, for example, it can be formulated for injection by intravenous, intramuscular, subcutaneous or intraperitoneal route.Generally, such compositions can be prepared as injections, either as liquid solutions or suspensions, or as solid forms suitable for adding liquid to prepare solutions or suspensions before injection, and these preparations can also be emulsified.The preparation of such formulations will be known to those skilled in the art in light of the present disclosure.

[0439] Pharmaceutical forms suitable for use in injections include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.In all cases, the form must be sterile and fluid enough to allow easy injection.It must be stable under the conditions of manufacture and storage, and must be protected against the contaminating action of microorganisms such as bacteria and fungi.

[0440] 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, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained by using a coating material, for example, lecithin, to maintain the required particle size in the case of dispersion, and by using surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of injectable compositions can be brought about by using agents that delay absorption in the composition, for example, aluminum monostearate and gelatin.

[0441] Sterile injectable solution can be prepared by adding the active compound of the required amount to a suitable solvent, and then sterilizing by filtration, together with various other components as listed above, if necessary.Generally, dispersion is prepared by adding various sterilized active ingredients to a sterile vehicle that contains a basic dispersion medium and other desired components from the components listed above.For the sterile powder used to prepare sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying, which can obtain the powder of active ingredient and any other desired components from the solution that has been previously sterilized and filtered.

[0442] Intratumoral injection is described, for example, in Lammers et al., "Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems," Neoplasia. 2006, 10, 788-795.

[0443] Pharmaceutically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, aerosols, and palm oils in phenoxyethanol. These ingredients may include one or more of: lavene, methyl p-hydroxybenzoate sodium salt, propyl p-hydroxybenzoate sodium salt, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxymetabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamin A and vitamin E, and potassium acetate.

[0444] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum to release the active compound. In other embodiments, compositions for rectal administration are in the form of enemas.

[0445] In other embodiments, the compounds described herein or pharmaceutical compositions thereof are suitable for local delivery to the digestive or GI tract by oral administration (eg, in solid or liquid dosage form).

[0446] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0447] In one embodiment, the composition is in the form of a unit dosage form such as a pill or tablet. Accordingly, the composition may contain, together with the chemical compounds provided herein, a diluent such as lactose, sucrose, or dibasic dicalcium phosphate, a lubricant such as magnesium stearate, and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, or a cellulose derivative. In another solid dosage form, a powder, quince, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (e.g., a gelatin or cellulose-based capsule). Unit dosage forms in which one or more chemical compounds provided herein or additional active agents are physically separated are also contemplated, such as capsules (or tablets within capsules) containing granules of each agent, bilayer tablets, bicompartment gelcaps, and the like. Enteric-coated or delayed-release oral dosage forms are also contemplated.

[0448] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives, which are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0449] In certain embodiments, the excipients are sterile and generally free of undesirable material. These compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not required for excipients in various oral dosage forms, such as tablets and capsules. USP / NF standards are usually sufficient.

[0450] In certain embodiments, the solid oral dosage form may further comprise one or more ingredients that chemically and / or structurally pretreat the composition so that the chemical is delivered to the stomach or lower GI (e.g., the ascending colon and / or the transverse colon and / or the distal colon and / or the small intestine). Exemplary formulation techniques are described, for example, in Filipski, KJ, et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

[0451] Examples include upper GI targeting approaches such as the Accordion Pill (Intec Pharma), floating capsules and materials capable of adhering to the mucosal wall.

[0452] Other examples include lower GI targeting approaches. Several enteric / pH-responsive coatings and excipients are available to target various regions of 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 if the active ingredient may irritate the upper GI tract (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer), and Marcoat). Other approaches include dosage forms that respond to the local microflora in the GI tract, enteric pressure-disintegrating colon delivery capsules, and Pulsincap.

[0453] 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 copolymer), 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.)).

[0454] Topical compositions can include ointments and creams. Ointments are generally semi-solid preparations based on petrolatum or other petroleum derivatives. Creams containing selected active agents are generally viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil. Cream bases are generally water-washable and contain an oil phase, an emulsified phase, and an aqueous phase. The oil phase, sometimes called the "internal" phase, is generally composed of petrolatum and a fatty alcohol (e.g., cetyl or stearyl alcohol), while the aqueous phase usually, though not necessarily, exceeds the oil phase in volume and generally contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases must be inert, stable, non-irritating, and non-sensitizing.

[0455] In any of the foregoing embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0456] Dosage The dosage may vary depending on the patient's requirements, the severity of the condition being treated, and the specific compound being used. The appropriate dosage for a particular situation can be determined by those skilled in the medical field. The total daily dosage can be divided and administered in portions throughout the day or by means of continuous delivery.

[0457] 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).

[0458] Regimen The aforementioned dosages can be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, once a week, twice every few weeks, once every two weeks, once a month).

[0459] In some embodiments, the administration period of the compounds described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In further embodiments, the period of time during which administration is 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. In one embodiment, a therapeutic compound is administered to an individual for one period of time, followed by another period of time. In another embodiment, a therapeutic compound is administered for a first period of time and a second period of time following the first period, administration is discontinued during the second period of time, followed by administration of the therapeutic compound for a third period of time, followed by administration being discontinued for a fourth period of time following the third period of time. In one aspect of this embodiment, the period of administration of a therapeutic compound followed by a period of time during which administration is discontinued is repeated for a set or indefinite period of time. In further embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In further embodiments, the period during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more.

[0460] Treatment method In some embodiments, methods are provided for treating a subject having a condition, disease, or disorder in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathology, and / or symptoms, and / or progression of the condition, disease, or disorder (e.g., immune disorder, cancer).

[0461] 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 cancers include breast cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer or renal carcinoma, lung cancer including clear cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), cervical cancer, ovarian cancer, prostate cancer, prostate tumors, liver cancer, bladder cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer or stomach cancer, including gastrointestinal cancer. cancer), gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, theca cell tumor, androgenic tumor, hepatocellular carcinoma, hematologic malignancies including non-Hodgkin's lymphoma (NHL), multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, chronic myeloid leukemia and acute hematologic malignancies, endometrial or uterine cancer, endometriosis, endometrial stromal sarcoma, fibrosarcoma, choriocarcinoma, salivary gland cancer, vulvar cancer, thyroid cancer, esophageal cancer, liver cancer Cancers include anal cancer, penile cancer, nasopharyngeal cancer, laryngeal cancer, Kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin cancer, schwannoma, oligodendroglioma, neuroblastoma, neuroectodermal tumor, rhabdomyosarcoma, osteosarcoma, leiomyosarcoma, Ewing's sarcoma, peripheral primitive neuroectodermal tumor, urinary tract cancer, thyroid cancer, Wilms' tumor, and abnormal blood vessel proliferation associated with nevus syndrome, edema (e.g., associated with brain tumors), and Meigs' syndrome. In some cases, the cancer is melanoma.

[0462] In some embodiments, the condition, disease, or disorder is a neurological disorder, including disorders involving the central nervous system (brain, brainstem, and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (portions of which are located in both the central and peripheral nervous systems). Non-limiting examples of neurological disorders include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers disease; alternating hemiplegia; Alzheimer's disease; vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cyst; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger's syndrome; ataxia-telangiectasia; attention deficit hyperactivity disorder; autism; and autonomic nervous system disorders. Neurologic dysfunction; back pain; Batten disease; Behçet's disease; Bell's palsy; benign idiopathic blepharospasm; benign focal muscular atrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch-Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumor (including glioblastoma multiforme); spinal cord tumor; Brown-Séquard syndrome; Canavan disease; carpal tunnel syndrome; burning pain; central pain syndrome; central pontine myelinolysis; craniopathy; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; transformation 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 paraplegia; Corticobasal degeneration; Cranial arteritis; Craniosynostosis; Creutzfeldt-Jakob disease; Cumulative trauma disease; Cushing's syndrome; Giant cell inclusion disease; Cytomegalovirus infection; Dancing eyes, dancing feet syndrome; Dandy-Walker syndrome; Dawson's disease; Domorsia Syndrome; Dejerine-Klumpke palsy; Dementia; Dermatomyositis; Diabetic neuropathy; Diffuse sclerosis; Autonomic neuropathy; Dysgraphia; Dyslexia; Dystonia; Early infantile epileptic encephalopathy; Empty Sella syndrome; Encephalitis; Encephalopathy; Trigeminal angiomatosis; Epilepsy; Erb's palsy; Essential tremor; Fabry disease; Fahr's syndrome; Syncope; Familial spastic paraparesis; Febrile convulsions; Fisher syndrome; Friedreich's ataxia; Frontotemporal dementia and other "tauopathies"; Gaucher 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 trauma; Headache; Hemifacial spasm; Hereditary spastic paraplegia; Hereditary polyneuropathic ataxia; Herpes zoster oticus; Herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (also a neurological manifestation of AIDS); Holoprosencephaly; Huntington's disease and other polyglutamine repeat diseases; Hydranencephaly; Hydrocephalus; Hypercorticosteroidism; Hypoxia; Immune-mediated encephalomyelitis; Inclusion body myositis; Incontinentia pigmenti; Childhood phytanic acid storage disease; Childhood Refsum disease; Infantile spasms; Inflammation Myopathies; Intracranial cysts; Intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease, Kinsborn syndrome; Klippel-Feil syndrome; Krabbe disease; Kugelberg-Welander disease; Kuru disease; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; Lateral myelodystrophies (Wallenberg syndrome); Learning disabilities; Leigh disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; Leukodystrophy; Lewy body dementia; Lissencephaly; Locked-in syndrome; Lou Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis) ); Lumbar disc disorders; Lyme disease - neurological sequelae; Macado-Joseph disease; Myelopathy; Megalencephaly; Melkersson-Rosenthal syndrome; Meniere's disease; Meningitis; Menkes disease; Metachromatic leukodystrophy; Microcephaly; Migraine; Miller-Fisher syndrome; Minor stroke; Mitochondrial myopathy; Moebius syndrome; Single limb muscular atrophy; Motor neuron disease; Moyamoya disease; Mucopolysaccharidoses; Multi-infarct dementia; Multiple focal motor peripheral neuropathy; Multiple sclerosis and other demyelinating disorders; Multiple system atrophy with orthostatic hypotension; Muscular dystrophy; Myasthenia gravis; Myelin-destructive diffuse sclerosis; Infantile myoclonic encephalopathy; myoclonus; myopathy; congenital myotonia; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus-myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease; congenital paramyotonia; paraneoplastic disorders; seizuresParry-Romberg syndrome; Pelizaeus-Merzbach disease; Periodic paralysis; Peripheral neuropathy; Painful neuropathy and neuropathic pain; Persistent vegetative state; Pervasive developmental disorder; Photo-sneeze reflex; Phytanic acid storage disease; Pick's disease; Compressed 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 facial hemifacial atrophy; Progressive multifocal Focal leukoencephalopathy; Progressive sclerosing poliodystrophy; Progressive supranuclear palsy; Pseudotumor cerebri; Ramsay-Hunt syndrome (types I and II); Rasmussen's encephalitis; Reflex sympathetic dystrophy syndrome; Refsum's disease; Repetitive movement disorder; Repetitive stress injury; Restless legs syndrome; Retroviral-associated myelopathy; Rett's syndrome; Reye's syndrome; Chorea; Sandhoff's disease; Schilder's disease; Schizencephaly; Septo-optic dysplasia; Shaken baby syndrome; Pediculosis Eruption; 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 chorea; Syncope; Syringomyelia; Tardive dyskinesia; Tay-Sachs disease; Temporal arteritis; Tethered cord syndrome; Thomsen's disease; Thoracic outlet syndrome; Painful tics; Todd's palsy; Tumors Rett syndrome, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraparesis, tuberous sclerosis, vascular dementia (multi-infarct dementia), vasculitis including temporal arteritis, von Hippel-Lindau disease, Wallenberg syndrome, Werdnig-Hoffmann disease, West syndrome, whiplash injury, Williams syndrome, Wilson's disease, amyotrophic lateral sclerosis, and Zellweger syndrome.

[0463] In some embodiments, the condition, disease, or disorder is a STING-associated condition, e.g., type I interferonopathy (e.g., infantile-onset STING-associated vasculitis (SAVI)), Aicardi-Goutières syndrome (AGS), hereditary forms of lupus, and inflammatory disorders such as systemic lupus erythematosus and rheumatoid arthritis. In certain embodiments, the condition, disease, or disorder is an autoimmune disease (e.g., an autoinflammatory disease induced by cytosolic DNA). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (IBD), including the polygenic susceptibility chronic inflammatory conditions Crohn's disease (CD) and ulcerative colitis (UC). In certain embodiments, the condition is inflammatory bowel disease. In certain embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by adoptive cell therapy treatment, colitis associated with one or more alloimmune diseases (such as 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 alloimmune disease (such as acute graft-versus-host disease and chronic graft-versus-host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral, esophageal, or intestinal mucositis).

[0464] In some embodiments, STING-mediated immune system modulation is provided to treat diseases, including diseases caused by foreign pathogens. Exemplary infections caused by foreign pathogens that can be treated and / or prevented by the methods of the present invention include bacterial (e.g., gram-positive or gram-negative) infections, fungal infections, parasitic infections, and viral infections. In one embodiment of the present invention, the infection is a bacterial infection (e.g., an infection caused 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 infectious disease 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 infectious disease is a viral infection (e.g., an infection caused by a virus associated with AIDS, avian influenza, chickenpox, herpes, the common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and lower or upper respiratory tract infections (e.g., respiratory syncytial virus)).

[0465] In some embodiments, the condition, disease, or disorder is hepatitis B (see, e.g., WO 2015 / 061294).

[0466] In some embodiments, the condition, disease, or disorder is selected from cardiovascular diseases (including, for example, myocardial infarction).

[0467] In some embodiments, the condition, disease or disorder is age-related macular degeneration.

[0468] In some embodiments, the condition, disease, or disorder is mucositis, also known as stomatitis, which may occur as a result of damage caused by chemotherapy or radiation therapy, alone or in combination, and exposure to radiation other than that associated with radiation therapy.

[0469] In some embodiments, the condition, disease, or disorder is uveitis, which is an inflammation of the uvea (e.g., anterior uveitis, e.g., iridocyclitis or iritis; intermediate uveitis (also known as pars planitis); posterior uveitis; or chorioretinitis, e.g., panuveitis).

[0470] In some embodiments, the condition, disease or disorder is selected from the group consisting of cancer, neurological disorders, autoimmune diseases, hepatitis B, uveitis, cardiovascular diseases, age-related macular degeneration and mucositis.

[0471] Further examples include the indications discussed herein and below in contemplated combination therapy regimens.

[0472] Combination therapy The present disclosure contemplates both monotherapy and combination therapy regimens.

[0473] In some embodiments, the methods described herein may further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of the compounds described herein.

[0474] In certain embodiments, the methods described herein can further comprise administering one or more additional cancer therapies.

[0475] The one or more additional cancer therapies can include, but are not limited to, surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, Hepatitis B vaccine, Oncophage, Provenge), and gene therapy, and combinations thereof. Immunotherapy includes, but is not limited to, adoptive cell therapy, stem cell and / or dendritic cell derivation, blood transfusion, lavage, and / or other treatments, such as, but not limited to, tumor freezing.

[0476] In some embodiments, the one or more additional cancer therapies is chemotherapy and can include administering one or more additional chemotherapeutic agents.

[0477] In certain embodiments, the additional chemotherapeutic agent is an immunomodulatory moiety, e.g., an immune checkpoint inhibitor. In certain of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T-cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM3, and ribozyme inhibitors. 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-BTL A-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244 , CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73, 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.

[0478] In certain of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of urelumab, PF-05082566, MEDI6469, TRX518, varlilumab, CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-L1), avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertib, urocuplumab, BKT140, bavituximab, CC-90002, bevacizumab, and MNRP1685A and MGA271.

[0479] In certain embodiments, the additional chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because of their ability to alkylate many nucleophilic functional groups under conditions present in cells, including, but not limited to, cancer cells. In further embodiments, alkylating agents include, but are not limited to, cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin. In one embodiment, alkylating agents may function by forming covalent bonds with amino, carboxyl, sulfhydryl, and phosphate groups of biologically important molecules, thereby impairing cellular function or by modifying cellular DNA. In further embodiments, the alkylating agent is synthetic, semi-synthetic, or a derivative.

[0480] In certain embodiments, the additional chemotherapeutic agent is an antimetabolite. Antimetabolites behave as purines or pyrimidines, which are 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 may also affect RNA synthesis. In one embodiment, antimetabolites include, but are not limited to, azathioprine and / or mercaptopurine. In further embodiments, the antimetabolite is synthetic, semi-synthetic, or a derivative.

[0481] In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and / or a plant terpenoid. These alkaloids are derived from plants and generally block cell division by inhibiting microtubule function. In one embodiment, the plant alkaloid and / or plant terpenoid is a vinca alkaloid, podophyllotoxin, and / or taxane. Vinca alkaloids generally bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules, usually during the M phase of the cell cycle. In one embodiment, the vinca alkaloid is derived from, but 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 taxane includes, but is not limited to, taxol, paclitaxel, and / or docetaxel. In a further embodiment, the plant alkaloid or plant terpenoid is synthetic, semi-synthetic, or a derivative. In a further embodiment, the podophyllotoxin is, but is not limited to, etoposide and / or teniposide. In one embodiment, the taxane is, but is 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 disrupts both DNA transcription and replication by disrupting proper DNA supercoiling. In a further embodiment, the topoisomerase is, but is not limited to, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, the type I topoisomerase inhibitor is, but is not limited to, camptothecin. In another embodiment, the camptothecin is, but is not limited to, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67), and / or ST 1481.In one embodiment, the type II topoisomerase inhibitor is, but is not limited to, epipodophyllotoxin. In a further embodiment, the epipodophyllotoxin is, but is not limited to, amsacrine, etoposide, 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 roots of American mayapple (Podophyllum peltatum).

[0482] In certain embodiments, the additional chemotherapeutic agent is a stilbenoid, including, but not limited to, resveratrol, piceatannol, pinosylvin, pterostilbene, α-viniferin, ampelopsin A, ampelopsin E, diptoindonesin C, diptoindonesin F, ε-viniferin, flexosol A, gnetin H, hemsleyanol D, hopeaphenol, trans-diptoindonesin B, astringin, piceid, and diptoindonesin A. In further embodiments, the stilbenoid is synthetic, semi-synthetic, or a derivative.

[0483] In certain embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. In one embodiment, the cytotoxic antibiotic is, but is not limited to, actinomycin, an anthracenedione, an anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and / or clofazimine. In one embodiment, the actinomycin is, but is not limited to, actinomycin D, bacitracin, colistin (polymyxin E), and / or polymyxin B. In another embodiment, the anthracenedione is, but is not limited to, mitoxantrone and / or pixantrone. In a further embodiment, the anthracycline is, but is not limited to, bleomycin, doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin, and / or valrubicin. In a further embodiment, the cytotoxic antibiotic is synthetic, semi-synthetic, or derivative.

[0484] In certain embodiments, the additional chemotherapeutic agent is endostatin, angiogenin, angiostatin, chemokine, angioarrestin, angiostatin (plasminogen fragment), basement membrane collagen-derived anti-angiogenic factor (tumstatin, canstatin, or arrestin), anti-angiogenic 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 (IP -10), interleukin-12, kringle 5 (plasminogen fragment), metalloproteinase inhibitor (TIMP), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor 4 (PF4), prolactin 16kD fragment, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth factor-β (TGF-β), vasculostatin, vasostatin (calreticulin fragment), etc.

[0485] In certain embodiments, the additional chemotherapeutic agent is 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-prolyl-1-L-proline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, docetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine, dolastatin, doxorubicin (adipromycin) riamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea taxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobuline isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, estramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

[0486] In certain embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide, and doxorubicin. Additional agents include mTOR (mammalian target of rapamycin) inhibitors, including but not limited to rapamycin, everolimus, temsirolimus, and deforolimus.

[0487] In still other embodiments, the additional chemotherapeutic agents may include those described in US Pat. No. 7,927,613, which is incorporated herein by reference in its entirety.

[0488] In some embodiments, the additional therapeutic agent and / or regimen can be used to treat other STING-associated conditions, such as type I interferonopathies (e.g., infantile-onset STING-associated vasculitis (SAVI)), Aicardi-Goutières syndrome (AGS), hereditary forms of lupus, and inflammation-related disorders such as systemic lupus erythematosus and rheumatoid arthritis.

[0489] 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, evoflunomide, fluticasone ... These include brutinib and sulfasalazine (Azulfidine®) and biologics (e.g., 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®)).

[0490] 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®) and mycophenolate mofetil) baricitinib, iguratimod, filgotinib, GS-9876, rapamycin and PF-06650833) and biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, obinutuzumab, bovalizumab, lulis Mabs, atacicept, PF-06823859 and lupzole, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edoratide, IFN-α-kinoids, OMS721, RC18, RSLV-132, celalizumab, XmAb5871 and ustekinumab (Stelara®).For example, non-limiting treatments for systemic lupus erythematosus include nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarials (e.g., hydroxychloroquine (Plaquenil)), corticosteroids (e.g., prednisone), and immunomodulatory agents (e.g., iveldimide, voclosporin, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenone. and PF-06650833) and biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, bovalilizumab, lurizumab, atacicept, PF-06823859, lupzole, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edoratide, IFN-α-kinoid, RC18, RSLV-132, celalizumab, 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®). Medications and regimens for treating drug-induced lupus and / or neonatal lupus may also be administered.

[0491] 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).

[0492] Non-limiting examples of additional therapeutic agents and / or regimens for treating Aicardi-Goutières syndrome (AGS) include physical therapy, treatment of respiratory complications, anticonvulsant therapy for seizures, tube feeding, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine (e.g., Emtriva®), tenofovir (e.g., Viread®), emtricitabine / tenofovir (e.g., Truvada®), zidovudine, lamivudine, and abacavir), and JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[0493] Non-limiting examples of additional therapeutic agents and / or regimens for treating IBD include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34-selected peripheral blood stem cell transplantation, azathioprine, bertilimumab, BI 655066, BMS-936557, certolizumab pegol (Cimzia®), cobitolimod, corticosteroids (e.g., prednisone, methylprednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbiota transplant, filgotinib, fingolimod, filategrast (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, HMPL-004 (Andrographis paniculata paniculata extract), IMU-838, infliximab, interleukin-2 (IL-2), Janus kinase (JAK) inhibitors, laquinimod, masitinib (AB1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mirikizumab (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peficitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab (MK 3222), TJ301, TNF-Kinoid®, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, batelizumab, VB-201, vedolizumab, and bidofludimus.

[0494] Non-limiting examples of additional therapeutic agents and / or regimens for treating irritable bowel syndrome include alosetron, bile acid sequestrants (e.g., cholestyramine, colestipol, colesevelam), chloride channel activators (e.g., lubiprostone), coated peppermint oil capsules, desipramine, dicyclomine, ebastine, eluxadoline, farnesoid X receptor agonists (e.g., obeticholic acid), fecal These include microbiota transplant, fluoxetine, gabapentin, guanylate cyclase-C agonists (e.g., linaclotide, plecanatide), ivodutant, imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, ondansetron, opioids, paroxetine, pinaverium, polyethylene glycol, pregabalin, probiotics, ramosetron, rifaximin, and tenapanol.

[0495] Non-limiting examples of additional therapeutic agents and / or regimens for treating scleroderma include nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), immunomodulators (e.g., azathioprine, methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®). ), Gengraf®), antithymocyte globulin, mycophenolate mofetil, intravenous immunoglobulin, rituximab, sirolimus, and alefecept), calcium channel blockers (e.g., nifedipine), alpha-blockers, serotonin receptor antagonists, angiotensin II receptor inhibitors, statins, topical nitrates, iloprost, phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan, tetracycline antibiotics, endothelin receptor antagonists, prostanoids, and tyrosine kinase inhibitors (e.g., imatinib, nilotinib, and dasatinib).

[0496] Non-limiting examples of additional therapeutic agents and / or regimens for treating Crohn's disease (CD) include adalimumab, autologous CD34-selected peripheral blood stem cell transplantation, 6-mercaptopurine, azathioprine, certolizumab pegol (Cimzia®), corticosteroids (e.g., prednisone), etrolizumab, E6011, fecal microbiota transplantation, 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.

[0497] 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, methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, fecal microbiota 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.

[0498] 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.

[0499] 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.

[0500] 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.

[0501] Non-limiting examples of additional therapeutic agents and / or regimens for treating colitis induced by adoptive cell therapy treatment include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0502] 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.

[0503] Non-limiting examples of additional therapeutic agents and / or regimens for treating radiation enterocolitis include teduglutide, amifostine, angiotensin-converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril), probiotics, selenium administration, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin), sucralfate, and vitamin E.

[0504] Non-limiting examples of additional therapeutic agents and / or regimens for treating collagenous colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0505] Non-limiting examples of additional therapeutic agents and / or regimens for treating lymphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), loperamide, mesalamine, methotrexate, and sulfasalazine.

[0506] Non-limiting examples of additional therapeutic agents and / or regimens for treating microscopic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), fecal microbiota transplant, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0507] Non-limiting examples of additional therapeutic agents and / or regimens for treating alloimmune disorders include intrauterine platelet transfusions, intravenous immunoglobulin, maternal steroids, abatacept, alemtuzumab, alpha 1-antitrypsin, AMG592, antithymocyte globulin, baricitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dapagliflozin ... These include crizumab, defibrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neiflizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0508] 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 xetine, glatiramer acetate (Copaxone®), hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVax™, ocrelizumab, ofatumumab, pioglitazone, and RPC1063.

[0509] 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., methylprednisone, prednisone), cyclosporine, daclizumab, defibrotide, dendritic cell carcinoma, thiazolinone ... These include leukindiftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neiflizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0510] Non-limiting examples of additional therapeutic agents and / or regimens for treating acute graft-versus-host disease include alemtuzumab, alpha-1-antitrypsin, antithymocyte globulin, basiliximab, brentuximab, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, daclizumab, defibrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate mofetil, natalizumab, neiflizumab, pentostatin, photopheresis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.

[0511] Non-limiting examples of additional therapeutic agents and / or regimens for treating chronic graft-versus-host disease include abatacept, alemtuzumab, AMG592, antithymocyte globulin, basiliximab, bortezomib, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, daclizumab, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0512] Non-limiting examples of additional therapeutic agents and / or regimens for treating celiac disease include AMG 714, AMY01, Aspergillus niger prolyl endoprotease, BL-7010, CALY-002, GBR 830, Hu-Mik-β-1, IMGX003, KumaMax, larazotide acetate, Nexvan2®, pancrelipase, TIMP-GLIA, vedolizumab, and ZED1227.

[0513] Non-limiting examples of additional therapeutic agents and / or regimens for treating psoriasis include topical corticosteroids, topical crisaborole / AN2728, topical SNA-120, topical SAN021, topical tapinarof, topical tocafinib, topical IDP-118, topical M518101, topical calcipotriene and betamethasone dipropionate (e.g., MC2-01 Cream and Taclonex®), topical P-3073, topical LEO90100 (Enstilar®), topical betamethasone dipropionate (Sernivo®), halobetasol propionate (Ultravate®), vitamin D analogs (e.g., calcipotriene (Dovonex®) and calcitriol (Vectical®)), anthralin (e.g., Dritho-scalp® and Dritho-creme®), topical retinoids (e.g., tazarotene (e.g., Tazorac® and Avage®)), ), calcineurin inhibitors (e.g., tacrolimus (Prograf®) and pimecrolimus (Elidel®)), salicylic acid, coal tar, moisturizers, phototherapy (e.g., sun exposure, UVB phototherapy, narrowband UVB phototherapy, Goeckerman therapy, psoralen long-wave ultraviolet A (PUVA) treatment, and excimer laser), retinoids (e.g., acitretin (Soriatane®)), methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheu matrex®), Apo805K1, baricitinib, FP187, KD025, Prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (serlopitant), upadacitinib (ABT-494), apremilast, tofacitinib, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biologics (e.g., etanercept (Enbrel®), etanercept-szzs (Elr ezi®), infliximab (Remicade®), adalimumab (Humira®), adalimumab-adbm (Cyltezo®), ustekinumab (Stelara®), golimumab (Simponi®), apremilast (Otezla®), secukinumab (Cosentyx®), certolizumab pegol, secukinumab, tildrakizumab-asmn, infliximab-dyyb, abatacept, ixekizumab (Taltz®), ABP710, 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®).

[0514] Non-limiting examples of additional therapeutic agents and / or regimens for treating cutaneous T-cell lymphoma include phototherapy (e.g., sun exposure, UVB phototherapy, narrowband UVB phototherapy, Goeckerman therapy, psoralen long-wave ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photopheresis, radiation therapy (e.g., spot irradiation and whole-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).

[0515] 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 (Simponi®), certolizumab (Cimzia®), rituximab (Rituxan®), abatacept (Orencia®), basiliximab (Simulect®), anakinra (Kineret®), canakinumab (Ilaris®), gevokizumab (XOMA052), tocilizumab (Actemra®), alemtuzumab (Campath®), efalizumab (Raptiva®), LFG316, sirolimus (Santen®), abatacept, sarilumab (Kevzara®), and daclizumab (Zenapax®), cytotoxic drugs, surgical implants (e.g., fluocinolone inserts), and vitrectomy.

[0516] Non-limiting examples of additional therapeutic agents and / or regimens for treating mucositis include AG013, SGX942 (dasketide), amifostine (Ethyol®), cryotherapy, cepacol troches, capsaicin troches, mucoadhesives (e.g., MuGard®), oral diphenhydramine (e.g., Benadry® elixir), oral bioadhesives (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita (chamomilla recutita mouthwash, table grape plant exosomes, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periodogard®)), topical sedatives (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%) and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen), phen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine, lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble β-1,3 / 1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, vaccinium myrtillus (vaccinium myrtillus extract, macleaya cordata alkaloids and echinacea angustifolia extract (e.g., SAMITAL®), and GI cocktails (gastric acid suppressants such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungals (e.g., nystatin), and analgesics (e.g., hurricane liquid)).For example, non-limiting examples of treatments for oral mucositis include AG013, amifostine (Ethyol®), cryotherapy, Cepacol troches, mucoadhesives (e.g., MuGard®), oral diphenhydramine (e.g., Benadry® elixir), oral bioadhesives (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), Caphosol, chamomilla recutita (chamomilla recutita) mouthwash, table grape plant exosomes, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periodogard®), topical sedatives (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%) and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC 4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine, lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble β-1,3 / 1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, and GI cocktail (gastric acid suppressants such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungals (e.g., nystatin), and analgesics (e.g., hurricane As another example, non-limiting examples of treatments for esophageal mucositis include xylocaine (e.g., gel viscous xylocaine 2%). As another example, treatments for intestinal mucositis, treatments to alleviate intestinal mucositis, and treatments for the signs and symptoms of intestinal mucositis include GI cocktails (gastric acid suppressants such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungals (e.g., nystatin), and pain relievers (e.g., hurricane liquid)).

[0517] In certain embodiments, the subject is administered a second therapeutic agent or treatment regimen prior to contacting or administering the chemical compound (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).

[0518] In other embodiments, the subject is administered a second therapeutic agent or regimen at approximately the same time as contacting or administering the chemical entity. For example, the second therapeutic agent or regimen and the chemical entity are administered to the subject simultaneously in the same dosage form. For another example, the second therapeutic agent or regimen and the chemical entity are administered to the subject simultaneously in separate dosage forms.

[0519] In still other embodiments, a second therapeutic agent or treatment regimen is administered to the subject after contact with or administration of the chemical compound (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).

[0520] Patient selection In some embodiments, the methods described herein further include identifying a subject (e.g., a patient) in need of such treatment (e.g., by biopsy, endoscopy, or other conventional methods known in the art). In certain embodiments, STING protein can serve as a biomarker for certain types of cancer, e.g., colon cancer and prostate cancer. In other embodiments, identifying the subject can include assaying for the absence of T cells and / or the presence of exhausted T cells in the patient's tumor microenvironment (e.g., the patient has one or more non-inflammatory tumors). Such patients can also include patients who are resistant to treatment with checkpoint inhibitors. In certain embodiments, such patients can be treated with chemical entities described herein, e.g., to recruit T cells to the tumor, and optionally, can be further treated with one or more checkpoint inhibitors, e.g., once T cells have become exhausted.

[0521] In some embodiments, the chemical entities, methods, and compositions described herein can be administered to certain treatment-resistant patient populations (e.g., patients resistant to checkpoint inhibitors; e.g., patients with one or more non-inflammatory tumors, e.g., tumors lacking T cells or exhausted T cells).

[0522] Preparation of compounds As those skilled in the art will recognize, methods for synthesizing the compounds of the formulae herein will be readily apparent to those skilled in the art. Synthetic chemical transformations and protecting group techniques (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); T.W. Greene and R.G.M. 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, can be prepared by known methods, or are commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein may be interchangeable with alternative, art-recognized equivalents. For example, in many reactions, triethylamine may be interchangeable with other bases, such as non-nucleophilic bases (e.g., diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

[0523] Those skilled in the art will understand, for example, 1One will recognize the various analytical methods that can be used to characterize the compounds described herein, including H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of the characterization methods available to one of skill in the art and is not intended to be limiting.

[0524] To further illustrate the foregoing, the following non-limiting exemplary synthetic schemes are included. Variations of these examples within the scope of the claims are within the purview of one of ordinary skill in the art and are considered to be within the scope of the invention as described and claimed herein. The reader will recognize that engineers and those skilled in the art armed with this disclosure will be able to prepare and use the invention without the need for exhaustive examples. [Example]

[0525] The compounds described herein can be prepared using conventional synthetic methods known to those skilled in the art.

[0526] The following abbreviations have the indicated meanings: Ac = acetyl ADDP = 1,1'-(azodicarbonyl)-dipiperidine ACN = acetonitrile Boc2O = di-tert-butylpyrocarbonate Bu = butyl Bz = benzoyl CataCxium A = Bis(adamant-1-yl)(butyl)phosphine CMPB = (cyanomethylene)tri-n-butylphosphorane DAST = diethylaminosulfur trifluoride DCE = dichloroethane DCM = dichloromethane DIAD = diisopropyl azodicarboxylate DIEA = N,N-diisopropylethylamine DMA = dimethylacetamide DMAP = 4-dimethylaminopyridine DMF = N,N-dimethylformamide DMF-DMA = N,N-dimethylformamide dimethyl acetal DMSO = dimethyl sulfoxide DPPA = diphenylphosphoryl azide Dppf = bis(diphenylphosphino)ferrocene DtBPF = 1,1'-bis[bis(1,1-dimethylethyl)phosphino]ferrocene HATU = 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HMDS = 1,1,1,3,3,3-hexamethyldisilazane HPLC = High-Performance Liquid Chromatography LAH = lithium aluminum hydride LC-MS = Liquid Chromatography Mass Spectrometry Me = methyl NMI = 1-methylimidazole NMR=nuclear magnetic resonance POT = tris(2-methylphenyl)phosphine Py = pyridine RT=retention time TBS = tert-butyldimethylsilyl TBUP = tri-n-butylphosphine TCFH = N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate TEA = trimethylamine TFA = trifluoroacetic acid TFAA = trifluoromethanesulfonic anhydride THF = tetrahydrofuran TMS = trimethylsilyl T3P = 2,4,6-tripropyl-2,4,6-trioxo-1,3,5,2,4,6-trioxatriphosphorinane

[0527] Example Materials and Methods LC-MS for Schemes 1-7 and Examples 1-11 were recorded using one of the following methods.

[0528] LCMS Method A: Kinetex EVO C18 100A, 30*3mm, injection volume 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% at 2.00min, hold at 95% MPB for 0.30min, and 95% MPB to 10% at 0.10min.

[0529] LCMS Method B: Xselect CSH C18, 50*3mm, injection volume 1.0 μL, flow rate 1.2 mL / min, scan range 90-900 amu, UV detection 254 nm. Mobile phase A (MPA): water / 0.1% FA and mobile phase B (MPB): acetonitrile / 0.1% FA. Elution was from 5% MPB to 100% in 2.00 min, held at 100% MPB for 0.70 min, then equilibrated to 5% MPB in 0.05 min.

[0530] LCMS Method C: XBridge Shield RP18, 50*4.6mm, injection volume 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 0.04% NH₃·H₂O and mobile phase B (MPB): acetonitrile. Elution was from 10% MPB to 95% at 2.00min, held at 95% MPB for 0.79min, then equilibrated to 10% MPB at 0.06min.

[0531] LCMS Method D: Kinetex 2.6 μm EVO, 50*3 mm, injection volume 0.5 μL, flow rate 1.2 mL / min, scan range 30-2000 amu, UV detection 254 nm. Mobile phase A (MPA): water / 5 mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% in 2.00 min, held at 95% MPB for 0.70 min, 95% MPB to 10% in 0.05 min, then equilibrated to 10% MPB for 0.25 min.

[0532] LCMS Method E: HALOC18, 30*3mm, injection volume 0.5 μL, flow rate 1.5 mL / min, scan range 30-2000 amu, UV detection 254 nm. Mobile phase A (MPA): water / 0.05% TFA and mobile phase B (MPB): acetonitrile / 0.05% TFA. Elution was from 5% MPB to 100% in 1.20 min, held at 100% MPB for 0.60 min, then equilibrated to 5% MPB in 0.02 min.

[0533] LCMS Method F: Shim-pack Scepter C18-120, 33*3mm, injection volume 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 was from 50% MPB to 95% in 2.00 min, held at 95% MPB for 0.60 min, then equilibrated to 10% MPB in 0.05 min.

[0534] LCMS Method G: Poroshell HPH C18, 50*3mm, injection volume 0.5μL, flow rate 1.2mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 + 5mM NH4OH and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% in 2.00 min, held at 95% MPB for 0.70 min, 95% MPB to 5% in 0.05 min, then equilibrated to 5% MPB for 0.25 min.

[0535] 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.

[0536] LC-MS for Schemes 8-16 and Examples 10-26 were recorded using one of the following methods.

[0537] LCMS Method A: Kinetex EVO C18 100A, 30*3mm, injection volume 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% at 2.00min, hold at 95% MPB for 0.30min, and 95% MPB to 10% at 0.10min.

[0538] LCMS Method B: Xselect CSH C18, 50*3mm, injection volume 1.0 μL, flow rate 1.2 mL / min, scan range 90-900 amu, UV detection 254 nm. Mobile phase A (MPA): water / 0.1% FA and mobile phase B (MPB): acetonitrile / 0.1% FA. Elution was from 5% MPB to 100% in 2.00 min, held at 100% MPB for 0.70 min, then equilibrated to 5% MPB in 0.05 min.

[0539] LCMS Method C: Kinetex 2.6 μm EVO, 50*3 mm, injection volume 0.5 μL, flow rate 1.2 mL / min, scan range 30-2000 amu, UV detection 254 nm. Mobile phase A (MPA): water / 5 mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution was from 10% MPB to 95% in 2.00 min, held at 95% MPB for 0.70 min, then equilibrated to 10% MPB in 0.05 min.

[0540] LCMS Method D: HALOC18, 30*3mm, injection volume 0.5 μL, flow rate 1.5 mL / min, scan range 30-2000 amu, UV detection 254 nm. Mobile phase A (MPA): water / 0.05% TFA, mobile phase B (MPB): acetonitrile / 0.05% TFA. Elution was from 5% MPB to 100% in 1.20 min, held at 100% MPB for 0.60 min, then equilibrated to 5% MPB in 0.02 min.

[0541] LCMS Method E: Shim-pack Scepter C18-120, 33*3mm, injection volume 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 was from 50% MPB to 95% in 2.00 min, held at 95% MPB for 0.60 min, then equilibrated to 10% MPB in 0.05 min.

[0542] LCMS Method F: Luna Omega PS C18, 33*3mm, injection volume 0.5μL, flow rate 1.5mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 0.1% FA and mobile phase B (MPB): acetonitrile / 0.1% FA. Elution was from 5% MPB to 100% in 1.20 min, held at 100% MPB for 0.60 min, then equilibrated to 5% MPB in 0.02 min.

[0543] 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.

[0544] The chemical abbreviations, LCMS and HPLC conditions for Examples 27 to 51 are listed below.

[0545] Chemical abbreviations ACN = acetonitrile DCM = dichloromethane DMF = dimethylformamide HATU = 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) TEA = triethylamine TFA = trifluoroacetic acid H2O = Water FA = formic acid HPLC = High-Performance Liquid Chromatography LCMS = Liquid Chromatography Mass Spectrometry NMR=nuclear magnetic resonance Speedvac=Savant SC250EXP SpeedVac Concentrator DMSO = dimethyl sulfoxide

[0546] LCMS analysis conditions Method A Equipment: Agilent LCMS system equipped with DAD and ELSD detectors Ion mode: Positive Column: Waters X-Bridge C18, 50*2.1mm*5μm or equivalent Mobile phase: A: H2O (0.04%TFA); B: CH3CN (0.02%TFA) Gradient: 4.5 min gradient method, actual method depends on the clogP of the compound. Flow rate: 0.6 mL / min or 0.8 mL / min Column temperature: 40°C or 50°C UV: 220 nm

[0547] Method B Equipment: Agilent LCMS system equipped with DAD and ELSD detectors Ion mode: Positive Column: Waters X-Bridge ShieldRP18, 50*2.1mm*5μm or equivalent Mobile phase: A: H2O (0.05% NH3·H2O) or 10 mM ammonium bicarbonate; B: CH3CN Gradient: 4.5 min gradient method; actual method depends on the clogP of the compound. Flow rate: 0.6 mL / min or 0.8 mL / min Column temperature: 40℃ UV: 220 nm

[0548] Preparative HPLC conditions device: 1. GILSON 281 and Shimadzu LCMS 2010A 2. GILSON 215 and Shimadzu LC-20AP 3. GILSON 215 Mobile phase: A: NH4OH / H2O = 0.05% v / v; B: ACN A: FA / HO = 0.225% v / v; B: ACN column Xtimate C18 150*25mm*5μm Flow rate: 25 mL / min or 30 mL / min Monitor wavelength: 220 and 254 nm Slope: Actual method depends on the clogP of the compound Detector: MS trigger or UV

[0549] Preparation Examples Scheme for preparing key intermediates: The following schemes show the preparation of key intermediates.

[0550] Scheme 1: Synthesis of Intermediate 1: (5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethoxy)-1H-indol-3-amine hydrochloride) TIFF2025503675000216.tif58170 Step 1: tert-Butyl N-(5-[2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethoxy]-1H-indol-3-yl)carbamate tert-Butyl N-(5-hydroxy-1H-indol-3-yl)carbamate (300.0 mg, 1.2 mmol, 1.0 equiv) was dissolved in DCM (20 mL) and cooled to 0 °C. 2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethanol (306.3 mg, 1.5 mmol, 1.2 equiv) and P(n-Bu) (733.4 mg, 3.6 mmol, 3.0 equiv) were then added under a nitrogen atmosphere. A solution of ADDP (609.8 mg, 2.4 mmol, 2.0 equiv) in DCM (5 mL) was then added dropwise, and the solution was maintained at 0 °C. The reaction mixture was stirred at ambient temperature for 4 h and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to give tert-butyl N-(5-[2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethoxy]-1H-indol-3-yl)carbamate (285.0 mg) as a pale yellow solid. LCMS Method C: [M+H] + =442.

[0551] Step 2: 5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethoxy)-1H-indol-3-amine hydrochloride tert-Butyl N-(5-[2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethoxy]-1H-indol-3-yl)carbamate (1.0 g, 2.3 mmol, 1.0 equiv) was dissolved in HCl / 1,4-dioxane (4N, 10 mL). The reaction mixture was stirred at ambient temperature for 40 minutes and then concentrated in vacuo to give 5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethoxy)-1H-indol-3-amine hydrochloride (910.0 mg) as a yellow solid. LCMS Method A: [M+H] + =342.

[0552] The intermediates in the table below were prepared using the same method as described for Intermediate 1. TIFF2025503675000217.tif56170

[0553] Scheme 2: Synthesis of intermediate 3 (tert-butyl 5-(hydroxymethyl)-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate) TIFF2025503675000218.tif102170 Step 1: N1-(5-bromo-1H-indol-3-yl)-N2-methyloxalamide 5-Bromo-1H-indol-3-amine (1.7 g, 8.0 mmol, 1.0 equiv.) was dissolved in THF (20 mL), followed by the addition of TEA (3.3 mL, 24.1 mmol, 3.0 equiv.), 2-(methylamino)-2-glyoxylic acid (830.2 mg, 8.0 mmol, 1.0 equiv.), and T3P (50 wt.%, 3.84 g, 12.0 mmol, 1.5 equiv.). The reaction mixture was stirred at ambient temperature for 30 minutes 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 in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give N1-(5-bromo-1H-indol-3-yl)-N2-methyloxalamide (1.2 g) as a brown solid. LCMS method A: [M+H] + =296.

[0554] Step 2: tert-butyl 5-bromo-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate N1-(5-Bromo-1H-indol-3-yl)-N2-methyloxalamide (1.2 g, 4.0 mmol, 1.0 equiv.) was dissolved in DCM (12 mL), followed by the addition of DMAP (50.0 mg, 0.4 mmol, 0.1 equiv.) and (Boc)2O (1.0 g, 4.8 mmol, 1.2 equiv.). The reaction mixture was stirred at ambient temperature for 1 hour 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 in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:2) to give tert-butyl 5-bromo-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate (950.0 mg) as a white solid. LCMS Method A: [M+H] + =396

[0555] Step 3: tert-butyl 5-(hydroxymethyl)-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate tert-Butyl 5-bromo-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate (900.0 mg, 2.2 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (10 mL), followed by the addition of (tributylstannyl)methanol (1823.2 mg, 5.6 mmol, 2.5 equiv.), butyldi-1-adamantylphosphine (162.8 mg, 0.4 mmol, 0.20 equiv.), and CataCXium A-Pd-G2 (151.8 mg, 0.2 mmol, 0.1 equiv.) under a nitrogen atmosphere. The reaction mixture was heated to 100°C for 6 h, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (2:1) to give tert-butyl 5-(hydroxymethyl)-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate (750.0 mg) as an off-white solid. LCMS Method C: [M+H] + =348.

[0556] The intermediates in the table below were prepared using the same method as described for Intermediate 3. TIFF2025503675000219.tif46169

[0557] Scheme 4: Synthesis of Intermediate 5: (5-(((4-(trifluoromethyl)benzyl)oxy)methyl)-1H-indol-3-amine) TIFF2025503675000220.tif45170 Step 1: tert-Butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate tert-Butyl N-(5-bromo-1H-indol-3-yl)carbamate (5.0 g, 16.0 mmol, 1.0 equiv.) was dissolved in DCM (30 mL), followed by the addition of BocO (4.2 g, 19.3 mmol, 1.2 equiv.) and DMAP (0.2 g, 1.6 mmol, 0.1 equiv.). The reaction mixture was stirred at ambient temperature for 4 hours and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to give tert-butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate (6.0 g) as a white solid. Method A: [M+H] + =411.

[0558] Step 2: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(((4-(trifluoromethyl)benzyl)oxy)methyl)-1H-indole-1-carboxylate tert-Butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate (4.0 g, 9.7 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (50 mL), followed by the addition of tributyl({[4-(trifluoromethyl)phenyl]methoxy}methyl)stannane (4.6 g, 9.7 mmol, 1.0 equiv.), Pd(PPh3)4 (1.1 g, 1.0 mmol, 0.1 equiv.), and LiCl (0.8 g, 19.4 mmol, 2.0 equiv.) under a nitrogen atmosphere. The reaction mixture was heated to 90 °C overnight and then cooled to ambient temperature. The solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:3) to give tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(((4-(trifluoromethyl)benzyl)oxy)methyl)-1H-indole-1-carboxylate (1.0 g) as an off-white solid. LCMS Method A: [M+H] + =521.

[0559] Step 3: 5-(((4-(trifluoromethyl)benzyl)oxy)methyl)-1H-indol-3-amine tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-(((4-(trifluoromethyl)benzyl)oxy)methyl)-1H-indole-1-carboxylate (500.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in DCM (5 mL), followed by the addition of 2,6-lutidine (308.8 mg, 2.9 mmol, 3.0 equiv.) and TMSOTf (640.4 mg, 2.9 mmol, 3.0 equiv.). The reaction mixture was stirred overnight at ambient temperature and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / MeOH (10:1) to give 5-({[4-(trifluoromethyl)phenyl]methoxy}methyl)-1H-indol-3-amine (100.0 mg) as a brown solid. LCMS Method A: [M+H] + =321.

[0560] Scheme 5: Synthesis of Intermediate 6: (5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt) TIFF2025503675000221.tif83170 Step 1: tert-Butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate tert-Butyl (5-bromo-1H-indol-3-yl)carbamate (5.0 g, 16.1 mmol, 1.0 equiv.) was dissolved in THF (80.0 mL), followed by the addition of (Boc)O (4.2 g, 19.3 mmol, 1.2 equiv.), DMAP (0.2 g, 1.6 mmol, 0.1 equiv.), and TEA (4.6 mL, 32.1 mmol, 2.0 equiv.). The reaction mixture was stirred at ambient temperature for 4 hours and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to give tert-butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate (6.5 g) as a white solid.

[0561] Step 2: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate tert-Butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate (6.0 g, 14.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (100.0 mL), followed by the addition of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.6 g, 21.9 mmol, 1.5 equiv.), Pd(dppf)Cl (1.1 g, 1.5 mmol, 0.1 equiv.), and CsCO (9.5 g, 29.2 mmol, 2.0 equiv.) under a nitrogen atmosphere. The reaction mixture was stirred under nitrogen at 90 °C overnight, then cooled to ambient temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:4) to give tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (6.0 g) as a white solid.

[0562] Step 3: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-hydroxy-1H-indole-1-carboxylate tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (6.0 g, 13.1 mmol, 1.0 equiv.) was dissolved in THF (80.0 mL) and cooled to 0 °C. NaOH (1.6 g, 39.3 mmol, 3.0 equiv.) was then added at 0 °C, followed by dropwise addition of HO (30% w / w, 3.0 g, 26.2 mmol, 2.0 equiv.), and the reaction mixture was maintained at 0 °C. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of brine. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:1) to give tert-butyl 3-((tert-butoxycarbonyl)amino)-5-hydroxy-1H-indole-1-carboxylate (2.2 g) as a grey solid.

[0563] Step 4: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-hydroxy-1H-indole-1-carboxylate (1.0 g, 2.9 mmol, 1.0 equiv.) and cis-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol (1.2 g, 5.7 mmol, 2.0 equiv.) were dissolved in THF (20.0 mL) and cooled to 0° C., and then TBUP (1.7 g, 8.6 mmol, 3.0 equiv.) was added at 0° C. under a nitrogen atmosphere. ADDP (2.2 g, 8.6 mmol, 3.0 equiv.) was then added dropwise, and the solution was maintained at 0° C. The reaction mixture was heated to 50° C. for 2 h, then cooled to ambient temperature and concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase A: 0.05% NH4HCO3 in water; mobile phase B: acetonitrile, gradient from 45% to 70% of phase B in 20 min; detector, UV 254 nm. This gave tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate (1.2 g) as an off-white solid.

[0564] Step 5: 5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate (190.0 mg, 0.3 mmol, 1.0 equiv) was dissolved in DCM (2.0 mL) and then TFA (2.0 mL) was added. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated in vacuo to give 5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-3-amine TFA salt (120.0 mg) as a white solid. LCMS Method A: [M+H] + =347.

[0565] The intermediates in the following table were prepared using the same method as described in Intermediate 6. TIFF2025503675000222.tif62170

[0566] Scheme 6: Synthesis of Intermediate 8: (5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-amine TFA salt) TIFF2025503675000223.tif51170 Step 3: tert-Butyl N-(5-[2-[4-(trifluoromethyl)phenoxy]ethyl]-1H-indol-3-yl)carbamate tert-Butyl N-[5-(2-hydroxyethyl)-1H-indol-3-yl]carbamate (338.0 mg, 1.2 mmol, 1.0 equiv.) and 4-(trifluoromethyl)phenol (198.2 mg, 1.2 mmol, 1.0 equiv.) were dissolved in THF (10 mL), followed by the addition of ADDP (612.4 mg, 2.4 mmol, 2.0 equiv.) and TBUP (494.9 mg, 2.4 mmol, 2.0 equiv.). The reaction mixture was heated to 70°C for 5 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give tert-butyl N-(5-[2-[4-(trifluoromethyl)phenoxy]ethyl]-1H-indol-3-yl)carbamate (260.0 mg) as a brown solid. LCMS Method A: [M+H] + =421.

[0567] Step 4: 5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-amine TFA salt tert-Butyl N-(5-{2-[4-(trifluoromethyl)phenoxy]ethyl}-1H-indol-3-yl)carbamate (260.0 mg, 0.6 mmol, 1.0 equiv) was dissolved in DCM (2 mL) and TFA (2 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then concentrated in vacuo to give 5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-amine TFA salt (350.0 mg) as a yellow solid. LCMS Method A: [M+H] + =321.

[0568] Scheme 7 Synthesis of Intermediate 9: (5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indol-3-amine TFA salt) TIFF2025503675000224.tif102170Step 1: 1-(tert-butyl) 3-methyl 5-bromo-1H-indole-1,3-dicarboxylate Methyl 5-bromo-1H-indole-3-carboxylate (5.0 g, 19.7 mmol, 1.0 equiv.) and DMAP (0.24 g, 1.9 mmol, 0.1 equiv.) were dissolved in DCM (50 mL), followed by the dropwise addition of a solution of (Boc)O (6.4 g, 29.1 mmol, 1.5 equiv.) in DCM (5 mL). The reaction mixture was stirred at ambient temperature for 4 h and then quenched by the addition of water. The resulting solution was extracted with dichloromethane, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:7) to give 1-(tert-butyl)3-methyl 5-bromo-1H-indole-1,3-dicarboxylate (6.2 g) as a white solid. LCMS Method A: [M+H] + =354.

[0569] Step 2: 1-(tert-butyl) 3-methyl 5-vinyl-1H-indole-1,3-dicarboxylate 1-(tert-Butyl) 3-methyl 5-bromo-1H-indole-1,3-dicarboxylate (6.5 g, 18.3 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (60 mL), followed by the addition of tributyl(ethenyl)stannane (13.3 g, 41.8 mmol, 2.3 equiv.), butyldi-1-adamantylphosphine (1.3 g, 3.6 mmol, 0.2 equiv.), and CataCXium A-Pd-G2 (0.1 g, 0.1 mmol, 0.1 equiv.) under a nitrogen atmosphere. The reaction mixture was heated to 100 °C for 4 h, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:9) to give 1-(tert-butyl) 3-methyl 5-vinyl-1H-indole-1,3-dicarboxylate (2.8 g) as a yellow solid. LCMS Method A: [M+H] + =302.

[0570] Step 3: Methyl 5-(3-oxocyclobutyl)-1H-indole-3-carboxylate DMA (1.1 mL, 11.9 mmol, 1.2 equiv) was dissolved in DCE (50 mL) and cooled to 5 °C. TfO (2.0 mL, 11.9 mmol, 1.2 equiv) was then added dropwise, and the solution was maintained at 5 °C. The reaction mixture was stirred at 5 °C for 30 min. A solution of 1-(tert-butyl) 3-methyl 5-vinyl-1H-indole-1,3-dicarboxylate (3.0 g, 9.9 mmol, 1.0 equiv) in DCE (10 mL) was then added dropwise at 5 °C. The resulting mixture was heated to 80 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:2) to give methyl 5-(3-oxocyclobutyl)-1H-indole-3-carboxylate (300.0 mg) as a yellow solid. LCMS Method A: [M+H]+ =244.

[0571] Step 4: Methyl 5-(cis-3-hydroxycyclobutyl)-1H-indole-3-carboxylate Methyl 5-(3-oxocyclobutyl)-1H-indole-3-carboxylate (300.0 mg, 1.2 mmol, 1.0 equiv) was dissolved in MeOH (10 mL) and cooled to 0 °C. NaBH (93.3 mg, 2.5 mmol, 2.0 equiv) was added, and the solution was maintained at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then quenched by adding water. The resulting solution was extracted with EtO, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / MeOH (10:1) to give methyl 5-(cis-3-hydroxycyclobutyl)-1H-indole-3-carboxylate (150.0 mg) as a yellow solid. LCMS Method A: [M+H] + =246.

[0572] Step 5: Methyl 5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indole-3-carboxylate Methyl 5-(cis-3-hydroxycyclobutyl)-1H-indole-3-carboxylate (130.0 mg, 0.5 mmol, 1.0 equiv.) and 4-(trifluoromethyl)phenol (129.7 mg, 0.8 mmol, 1.5 equiv.) were dissolved in THF (5 mL) and cooled to 0 °C, followed by the addition of TBUP (25.7 mg, 0.1 mmol, 0.2 equiv.) and ADDP (273.3 mg, 1.1 mmol, 2.0 equiv.). The reaction mixture was heated to 70 °C for 4 h, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:1) to give methyl 5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indole-3-carboxylate (140.0 mg) as a yellow solid. LCMS Method A: [M+H] + =390.

[0573] Step 6: 5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indole-3-carboxylic acid Methyl 5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indole-3-carboxylate (200.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and aqueous NaOH (2 mL, 2 M, 4.0 mmol, 8.0 equiv.) was added. The reaction mixture was heated to 70° C. for 2 h, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and adjusted to pH 4 with aqueous HCl (4 M). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give 5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indole-3-carboxylic acid (180.0 mg) as a yellow solid. LCMS Method A: [MH] - =374.

[0574] Step 7: 5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indole-3-carbonyl azide 5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indole-3-carboxylic acid (170.0 mg, 0.4 mmol, 1.0 equiv.) and TEA (0.3 mL, 2.3 mmol, 5.2 equiv.) were dissolved in THF (10 mL), followed by the addition of DPPA (186.9 mg, 0.7 mmol, 1.5 equiv.). The reaction mixture was stirred at ambient temperature for 2 h and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to give 5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indole-3-carbonyl azide (150.0 mg) as a yellow solid. LCMS Method A: [M+H] + =401.

[0575] Step 8: tert-butyl (5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indol-3-yl)carbamate 5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indole-3-carbonyl azide (140.0 mg, 0.3 mmol, 1.0 equiv) was dissolved in t-BuOH (5 mL). The reaction mixture was heated to 90° C. for 2 h, then cooled to ambient temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to give tert-butyl (5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indol-3-yl)carbamate (100.0 mg) as a yellow solid. LCMS Method A: [M+H] + =447.

[0576] Step 9: 5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indol-3-amine TFA salt tert-Butyl (5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indol-3-yl)carbamate (90.0 mg, 0.2 mmol, 1.0 equiv) was dissolved in DCM (5 mL) and TFA (1.5 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo to give 5-(trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)-1H-indol-3-amine TFA salt (82.0 mg) as a yellow solid. LCMS Method A: [M+H] + =347.

[0577] Scheme 8: Synthesis of intermediates 11 / 12 (cis-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol and trans-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol) TIFF2025503675000225.tif64170Step 1: 3-[4-(trifluoromethyl)phenyl]cyclobutan-1-one DMA (1.21 g, 13.941 mmol, 1.2 equiv) was dissolved in DCE (30 mL) and cooled to 5 °C. TfO (2.7 mL, 16.3 mmol, 1.4 equiv) was then added dropwise, and the solution was maintained at 5 °C. The reaction mixture was stirred at 5 °C for 30 min. A solution of 1-ethenyl-4-(trifluoromethyl)benzene (840.0 mg, 4.9 mmol, 1.0 equiv) was then added, followed by the dropwise addition of 2,4,6-collidine (2.0 g, 16.3 mmol, 1.4 equiv) in DCE (10 mL) at 5 °C. The resulting mixture was heated to 80 °C overnight, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:7) to give 3-[4-(trifluoromethyl)phenyl]cyclobutan-1-one (450.0 mg) as a pale yellow oil. 1H NMR(400MHz,chloroform-d)δ 7.64(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),3.77(p,J=8.0Hz,1H),3.63-3.50(m,2H),3.34-3.23(m,2H).

[0578] Step 2: cis-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol 3-[4-(trifluoromethyl)phenyl]cyclobutan-1-one (300.0 mg, 1.4 mmol, 1.0 equiv) was dissolved in MeOH (15 mL) and cooled to −10 °C. NaBH (106.0 mg, 2.8 mmol, 2.0 equiv) was then added and the solution was maintained at −10 °C. The reaction mixture was stirred at −10 °C for 50 min under a nitrogen atmosphere and then quenched by the addition of ice water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give cis-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol (260.0 mg) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.58 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.41-4.29 (m, 1H), 3.10-2.99 (m, 1H), 2.88-2.78 (m, 2H), 2.12-2.00 (m, 2H).

[0579] Step 3: trans-3-[4-(trifluoromethyl)phenyl]cyclobutyl 4-nitrobenzoate Cis-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol (130.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in THF (2 mL), followed by the addition of p-nitrobenzoic acid (100.5 mg, 0.6 mmol, 1.0 equiv.), PPh3 (315.4 mg, 1.2 mmol, 2.0 equiv.), and DIAD (243.2 mg, 1.2 mmol, 2.0 equiv.). The reaction mixture was stirred at ambient temperature for 4 h and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:6) to afford trans-3-[4-(trifluoromethyl)phenyl]cyclobutyl 4-nitrobenzoate (160.0 mg) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.38(d,J=8.8Hz,2H),8.26(d,J=8.8Hz,2H),7.71(d,J=8.0Hz,2H),7.58(d,J =8.0Hz,2H),5.41(p,J=6.0Hz,1H),3.88(p,J=9.2Hz,1H),2.80-2.61(m,4H).

[0580] Step 4: trans-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol trans-3-[4-(trifluoromethyl)phenyl]cyclobutyl 4-nitrobenzoate (300.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in MeOH (4 mL) and water (1 mL), followed by the addition of KCO (227.0 mg, 1.6 mmol, 2.0 equiv.). The reaction mixture was heated to 65° C. for 2 h, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give trans-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol (155.2 mg) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δ 7.64(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,2H),5.14(d,J=5.6Hz,1H),4.39-4.2 7(m,1H),3.58(p,J=7.3Hz,1H),2.39-2.31(m,4H),1.36(s,0H),1.23(s,0H).

[0581] Scheme 9: Synthesis of intermediate 13 (2-((3aR,5r,6aS)-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethan-1-ol) TIFF2025503675000226.tif77170 Step 1: tert-Butyl (Z)-5-(2-ethoxy-2-oxoethylidene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 2-(Diethoxyphosphoryl)acetate (28.1 g, 125.2 mmol, 1.2 equiv.) was dissolved in THF (250 mL) and cooled to 0 °C, then sodium hydride (6.9 g, 60 wt %, 103.5 mmol, 1.0 equiv.) was added portionwise under a nitrogen atmosphere. After stirring for 15 min, tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (23.5 g, 104.3 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at room temperature for 2 h and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / petroleum ether (1:1) to give tert-butyl (Z)-5-(2-ethoxy-2-oxoethylidene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (16.4 g) as a colorless oil. LCMS Method A: [M+H] + =296.1.

[0582] Step 2: tert-butyl trans-5-(2-ethoxy-2-oxoethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-Butyl (Z)-5-(2-ethoxy-2-oxoethylidene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (16.3 g, 55.3 mmol, 1.0 equiv.) was dissolved in MeOH (200 mL), and then Pd / C (10 wt %, 2.9 g) was added. The reaction mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature for 4 hours. The solids were removed by filtration, and the filtrate was concentrated in vacuo to give crude tert-butyl trans-5-(2-ethoxy-2-oxoethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (15.5 g) as a colorless oil. LCMS Method A: [M+H] + =298.2.

[0583] Step 3: tert-butyl trans-5-(2-hydroxyethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-Butyl trans-5-(2-ethoxy-2-oxoethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (13.5 g, 45.4 mmol, 1.0 equiv.) was dissolved in THF (140 mL) and cooled to 0 °C, and then LiAlH (1.7 g, 45.4 mmol, 1.0 equiv.) was added portionwise. The reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h and then quenched by adding ice water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give tert-butyl trans-5-(2-hydroxyethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (10.8 g) as a colorless oil. LCMS Method A: [M+H] + =256.2.

[0584] Step 4: 2-(trans-octahydrocyclopenta[c]pyrrol-5-yl)ethan-1-ol hydrochloride tert-Butyl trans-5-(2-hydroxyethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (10.0 g, 39 mmol, 1.0 equiv.) was dissolved in HCl (gas) in 1,4-dioxane (4 M, 50 mL). The reaction mixture was stirred at ambient temperature for 1 h and then concentrated in vacuo to give crude 2-(trans-octahydrocyclopenta[c]pyrrol-5-yl)ethan-1-ol hydrochloride (8.0 g) as a brown solid. LCMS Method A: [M+H] + =156.1.

[0585] Step 5: 2-(trans-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethan-1-ol 2-(trans-octahydrocyclopenta[c]pyrrol-5-yl)ethan-1-ol (7.5 g, 48.1 mmol, 1.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (13.0 g, 57.5 mmol, 1.2 equiv.) were dissolved in ACN (150 mL), followed by the addition of KCO (20.0 g, 144.5 mmol, 3.0 equiv.). The reaction mixture was stirred at 70 °C for 2 h, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (3:1) to give 2-(trans-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethan-1-ol (5.6 g) as a pale yellow oil. LCMS Method A: [M+H] + =238.2.

[0586] Scheme 10: Synthesis of intermediate 14 (5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt) TIFF2025503675000227.tif121170 Step 1: tert-Butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate tert-Butyl (5-bromo-1H-indol-3-yl)carbamate (5.0 g, 16.1 mmol, 1.0 equiv.) was dissolved in THF (80.0 mL), followed by the addition of (Boc)2O (4.2 g, 19.3 mmol, 1.2 equiv.), DMAP (0.2 g, 1.6 mmol, 0.1 equiv.), and TEA (4.6 mL, 32.1 mmol, 2.0 equiv.). The reaction mixture was stirred at ambient temperature for 4 hours and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to give tert-butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate (6.5 g) as a white solid. LCMS Method A: [M+H] + =411.3.

[0587] Step 2: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate tert-Butyl 5-bromo-3-((tert-butoxycarbonyl)amino)-1H-indole-1-carboxylate (6.0 g, 14.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (100.0 mL), followed by the addition of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.6 g, 21.9 mmol, 1.5 equiv.), Pd(dppf)Cl (1.1 g, 1.5 mmol, 0.1 equiv.), and CsCO (9.5 g, 29.2 mmol, 2.0 equiv.) under a nitrogen atmosphere. The reaction mixture was stirred under nitrogen at 90 °C overnight, then cooled to ambient temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:4) to give tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (6.0 g) as a white solid. LCMS Method A: [M+H] + =459.3.

[0588] Step 3: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-hydroxy-1H-indole-1-carboxylate tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (6.0 g, 13.1 mmol, 1.0 equiv.) was dissolved in THF (80.0 mL) and cooled to 0 °C. NaOH (1.6 g, 39.3 mmol, 3.0 equiv.) was then added at 0 °C, followed by dropwise addition of HO (30% w / w, 3.0 g, 26.2 mmol, 2.0 equiv.), and the reaction mixture was maintained at 0 °C. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of brine. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:1) to give tert-butyl 3-((tert-butoxycarbonyl)amino)-5-hydroxy-1H-indole-1-carboxylate (2.2 g) as a grey solid. LCMS Method A: [M+H] + =349.2.

[0589] Step 4: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-hydroxy-1H-indole-1-carboxylate (1.0 g, 2.9 mmol, 1.0 equiv.) and cis-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol (1.2 g, 5.7 mmol, 2.0 equiv.) were dissolved in THF (20.0 mL) and cooled to 0° C., and then TBUP (1.7 g, 8.6 mmol, 3.0 equiv.) was added at 0° C. under a nitrogen atmosphere. ADDP (2.2 g, 8.6 mmol, 3.0 equiv.) was then added dropwise, and the solution was maintained at 0° C. The reaction mixture was heated to 50° C. for 2 h, then cooled to ambient temperature and concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase A: 0.05% NH4HCO3 in water; mobile phase B: acetonitrile, gradient from 45% to 70% of phase B in 20 min; detector, UV 254 nm. This gave tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate (1.2 g) as an off-white solid. LCMS Method A: [M+H] + =547.2.

[0590] Step 5: 5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate (190.0 mg, 0.3 mmol, 1.0 equiv) was dissolved in DCM (2.0 mL) and then TFA (2.0 mL) was added. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated in vacuo to give 5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-3-amine TFA salt (120.0 mg) as a white solid. LCMS Method A: [M+H] + =347.2.

[0591] The intermediates in the following table were prepared using the same method as described for Intermediate 14. TIFF2025503675000228.tif108170

[0592] Scheme 11: Synthesis of intermediate 19 (5-(trans-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indol-3-amine TFA salt) TIFF2025503675000229.tif134170Step 1: 3-(benzyloxy)-1-(6-(trifluoromethyl)pyridin-3-yl)cyclobutan-1-ol 5-Bromo-2-(trifluoromethyl)pyridine (4.0 g, 17.6 mmol, 1.0 equiv.) was dissolved in THF (40 mL) and cooled to −70° C. Then, n-BuLi (2.5 M in hexanes, 8.5 mL, 21.3 mmol, 1.2 equiv.) was added dropwise, and the solution was maintained at −70° C. under a nitrogen atmosphere. After stirring at −70° C. for 30 min, 3-(benzyloxy)cyclobutan-1-one (3.7 g, 21.2 mmol, 1.2 equiv.) was added dropwise. The reaction mixture was stirred at room temperature for an additional 2 h and then quenched by the addition of saturated aqueous NH4Cl. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by reverse flash column chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.5% NH4HCO3) in water, gradient 10% to 100% in 25 min; detector, UV 254 nm. This gave 3-(benzyloxy)-1-(6-(trifluoromethyl)pyridin-3-yl)cyclobutan-1-ol (2.7 g) as a pale yellow solid. LCMS Method A: [M+H] + =324.2.

[0593] Step 2: 5-(3-(benzyloxy)-1-fluorocyclobutyl)-2-(trifluoromethyl)pyridine 3-(Benzyloxy)-1-(6-(trifluoromethyl)pyridin-3-yl)cyclobutan-1-ol (2.7 g, 8.3 mmol, 1.0 equiv.) was dissolved in DCM (10 mL) and cooled to -70 °C. DAST (2.6 g, 16.6 mmol, 2.0 equiv.) was then added dropwise, and the solution was maintained at -70 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h and then quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by reverse flash column chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NHHCO) in water, 10% to 100% gradient in 30 min; detector, UV 254 nm. This gave 5-(3-(benzyloxy)-1-fluorocyclobutyl)-2-(trifluoromethyl)pyridine (2.5 g) as a pale yellow solid. LCMS Method A: [M+H] + =326.0.

[0594] Step 3: 3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutan-1-ol 5-[3-(benzyloxy)-1-fluorocyclobutyl]-2-(trifluoromethyl)pyridine (2.0 g, 6.1 mmol, 1.0 equiv.) was dissolved in MeOH (40 mL) and then HCOOH (282.9 mg, 6.1 mmol, 1.0 equiv.) was added. Then, under a nitrogen atmosphere, Pd / C (10 wt.%, 130.8 mg) was added. The mixture was sparged with nitrogen, placed under a hydrogen gas (balloon) atmosphere, and stirred at 40 °C for 4 h. The solids were removed by filtration, and the filter cake was washed with MeOH. The combined filtrates were concentrated in vacuo. The residue was purified by reverse flash column chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH4HCO3) in water, 10% to 100% gradient over 30 min; detector, UV 254 nm. This gave 3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutan-1-ol (1.0 g) as a pale yellow oil. LCMS Method A: [M+H] + =261.0.

[0595] Steps 4-5: tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indole-1-carboxylate and tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(cis-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indole-1-carboxylate 3-[6-(trifluoromethyl)pyridin-3-yl]cyclobutan-1-ol (1.0 g, 4.6 mmol, 1.0 equiv.) was dissolved in THF (13 mL), followed by the addition of tert-butyl 3-[(tert-butoxycarbonyl)amino]-5-hydroxyindole-1-carboxylate (1.6 g, 4.6 mmol, 1.0 equiv.), TBUP (1.8 g, 9.2 mmol, 2.0 equiv.), and ADDP (2.3 g, 9.2 mmol, 2.0 equiv.) under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 5 h, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH4HCO3) in water, 10% to 100% gradient in 25 min; detector, UV 254 nm, to give tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indole-1-carboxylate (1.0 g) as a pale yellow solid. The mixture was separated by chiral HPLC under the following conditions: Column: JW-CHIRAL-Amylose-SA, 20 x 250 mm, 5 μm; Mobile Phase A: IPA-HPLC, Mobile Phase B: Hex (0.5% 2M NH3-MeOH)-HPLC; Flow Rate: 20 mL / min; Gradient: 90% B to 90% B in 14 min; Wavelength: 220 / 254 nm; RT1: 8.2 min; RT2: 10.22 min. This afforded tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(cis-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indole-1-carboxylate (710.0 mg) as a pale yellow solid. LCMS Method B: [MH] - = 548. Also obtained was tert-butyl 3-((tert-butoxycarbonyl)amino)-5-(trans-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indole-1-carboxylate (170.0 mg) as a pale yellow solid. LCMS Method B: [MH] -=548.1.

[0596] Step 5: 5-(trans-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indol-3-amine TFA salt tert-Butyl 3-[(tert-butoxycarbonyl)amino]-5-[trans-3-[6-(trifluoromethyl)pyridin-3-yl]cyclobutoxy]indole-1-carboxylate (160.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in DCM (2 mL) and then TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to give crude 5-(trans-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indole-3-amine TFA salt (103.0 mg) as a red solid. LCMS Method B: [M+H] + =348.2.

[0597] Scheme 12: Synthesis of intermediate 20 (5-(cis-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indol-3-amine TFA salt) TIFF2025503675000230.tif64170 tert-Butyl 3-[(tert-butoxycarbonyl)amino]-5-[cis-3-[6-(trifluoromethyl)pyridin-3-yl]cyclobutoxy]indole-1-carboxylate (500.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in DCM (3 mL) and then TFA (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to give crude 5-(trans-3-(6-(trifluoromethyl)pyridin-3-yl)cyclobutoxy)-1H-indole-3-amine TFA salt (400.0 mg) as a brown solid. LCMS Method B: [M+H] + =348.2.

[0598] Scheme 13: Synthesis of intermediate 22 (5-phenoxy-1H-indol-3-amine hydrochloride) TIFF2025503675000231.tif102170Step 1: 2-Methyl-1-nitro-4-phenoxybenzene 4-Fluoro-2-methyl-1-nitrobenzene (10.0 g, 64.4 mmol, 1.0 equiv.) was dissolved in DMF (15 mL), followed by the addition of phenol (9.1 g, 96.6 mmol, 1.5 equiv.) and K2CO3 (22.2 g, 161.1 mmol, 2.50 equiv.). The reaction mixture was stirred at 80 °C for 18 h, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with EtOAc / petroleum ether (1:3) to give 2-methyl-1-nitro-4-phenoxybenzene (12.9 g) as a brown solid. GCMS = 229.

[0599] Step 2: (E)-N,N-dimethyl-2-(2-nitro-5-phenoxyphenyl)ethen-1-amine 2-Methyl-1-nitro-4-phenoxybenzene (10.0 g, 43.6 mmol, 1.0 equiv.) was dissolved in DMF (20 mL), and then DMF-DMA (6.2 g, 52.3 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at 140 °C for 10 h, then cooled to room temperature and concentrated in vacuo. The residue was diluted with water, then extracted with EtOAc, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give crude (E)-N,N-dimethyl-2-(2-nitro-5-phenoxyphenyl)ethen-1-amine (15.0 g) as a red solid. LCMS Method A: [M+H] + =285.1.

[0600] Step 3: 5-phenoxy-1H-indole (E)-N,N-Dimethyl-2-(2-nitro-5-phenoxyphenyl)ethen-1-amine (15.0 g, 52.7 mmol, 1.0 equiv.) was dissolved in EtOAc (20 mL), followed by the addition of Pd / C (2.9 g, 27.9 mmol, 0.5 equiv.). The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at room temperature overnight. The solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to give 5-phenoxy-1H-indole (4 g) as a brown solid. LCMS Method A: [M+H] + =210.1.

[0601] Step 4: 3-nitro-5-phenoxy-1H-indole AgNO3 (4.8 g, 28.6 mmol, 1.5 equiv) was dissolved in ACN (8 mL) and cooled to 0 °C, then benzoyl chloride (4.0 g, 28.6 mmol, 1.5 equiv) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. 5-Phenoxy-1H-indole (4.0 g, 19.1 mmol, 1.0 equiv) was added to the above mixture, and the resulting mixture was stirred for an additional 1 h at room temperature. The reaction was quenched by adding ice water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with EtOAc / petroleum ether (1:3) to give 3-nitro-5-phenoxy-1H-indole (2.5 g) as a brown solid. LCMS Method A: [MH] - =253.1.

[0602] Step 5: tert-butyl (5-phenoxy-1H-indol-3-yl)carbamate 3-Nitro-5-phenoxy-1H-indole (3.0 g, 11.8 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL), followed by the addition of (Boc)2O (3.8 g, 17.7 mmol, 1.5 equiv.) and Pd / C (600.0 mg, 5.6 mmol, 0.4 equiv.). The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at room temperature overnight. The solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:4) to give tert-butyl (5-phenoxy-1H-indol-3-yl)carbamate (1.5 g) as a bright pink solid. LCMS Method A: [M+H] + =325.2.

[0603] Step 6: 5-phenoxy-1H-indol-3-amine hydrochloride tert-Butyl (5-phenoxy-1H-indol-3-yl)carbamate (1.5 g, 4.6 mmol, 1.0 equiv.) was dissolved in HCl / 1,4-dioxane (4N, 5 mL). The resulting solution was stirred at room temperature for 30 minutes and concentrated in vacuo to give 5-phenoxy-1H-indol-3-amine hydrochloride (1.0 g) as a brown solid. LCMS Method A: [M+H] + =225.1.

[0604] Scheme 14: Synthesis of intermediate 23 (6-methyl-2-oxaspiro[3.3]heptane-6-carboxylic acid) TIFF2025503675000232.tif26170Step 1: Ethyl 6-methyl-2-oxaspiro[3.3]heptane-6-carboxylate Ethyl 2-oxaspiro[3.3]heptane-6-carboxylate (300.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in THF (10 mL) and cooled to −78 °C. LDA (2 M in THF, 1.3 mL, 2.6 mmol, 1.5 equiv.) was then added dropwise with stirring at −78 °C under a nitrogen atmosphere. The reaction mixture was stirred at −78 °C for 1 h under a nitrogen atmosphere. Methyl iodide (750.5 mg, 5.3 mmol, 3.0 equiv.) was added to the above mixture, and the resulting mixture was stirred at room temperature for an additional 4 h and then quenched by adding saturated aqueous NH4Cl. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. This afforded crude ethyl 6-methyl-2-oxaspiro[3.3]heptane-6-carboxylate (360 mg) as a crude yellow oil.

[0605] Step 2: 6-methyl-2-oxaspiro[3.3]heptane-6-carboxylic acid Ethyl 6-methyl-2-oxaspiro[3.3]heptane-6-carboxylate (360.0 mg, 2.0 mmol, 1.0 equiv) was dissolved in MeOH (5 mL), followed by the addition of a solution of NaOH in water (2 M, 3 mL). The reaction mixture was stirred at 70 °C for 1 h, then cooled to room temperature and concentrated in vacuo. The residue was diluted with water (20 mL) and adjusted to pH 5 with aqueous HCl. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. This afforded 6-methyl-2-oxaspiro[3.3]heptane-6-carboxylic acid (240 mg, 78.6%) as a yellow oil. LCMS Method A: [MH] - =155.1.

[0606] Scheme 15: Synthesis of intermediate 24 (1-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxylic acid) TIFF2025503675000233.tif70170Step 1: Ethyl 1-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylate Ethyl 1H-pyrazole-4-carboxylate (300.0 mg, 2.1 mmol, 1.0 equiv.) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (511.7 mg, 2.1 mmol, 1.0 equiv.) were dissolved in DMF (6 mL), followed by the addition of CsCO (2.1 g, 6.4 mmol, 3.0 equiv.). The reaction mixture was stirred overnight at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated in vacuo. The residue was purified by flash preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, water (NHHCO 3.1 g / 1 L) and ACN, increasing from 0% ACN to 100% ACN within 25 min; detector, UV 254 nm. This afforded ethyl 1-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylate (310 mg) as a white solid. LCMS method A: [M+H] + =299.1.

[0607] Step 2: 1-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylic acid Ethyl 1-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylate (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in MeOH (2 mL) and water (2 mL), followed by the addition of NaOH (53.6 mg, 1.3 mmol, 2.0 equiv.). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated in vacuo. The residue was purified by flash preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, water (10 mM NH4HCO3) and ACN, increasing from 0% ACN to 100% within 25 minutes; detector, UV 254 nm. This afforded 1-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylic acid (130 mg) as a white solid. LCMS Method B: [MH] - =269.1.

[0608] Scheme 16: Synthesis of intermediate 25 (1-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)-1H-1,2,3-triazole-4-carboxylic acid) TIFF2025503675000234.tif108170Step 1: 2-(4,4-Difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine 2-Chloro-3-fluoro-5-nitropyridine (10.0 g, 56.6 mmol, 1.0 equiv.) was dissolved in DMF (150 mL), followed by the addition of CsCO (37.3 g, 114.5 mmol, 2.0 equiv.) and 4,4-difluoropiperidine (9.8 g, 81.0 mmol, 1.4 equiv.). The reaction mixture was heated to 90 °C for 15 h, then cooled to ambient temperature and quenched by the addition of water. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to give 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine (13.3 g) as a yellow solid. LCMS Method D: [M+H] + =262.

[0609] Step 2: 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine 2-(4,4-Difluoropiperidin-1-yl)-3-fluoro-5-nitropyridine (13.2 g, 50.5 mmol, 1.0 equiv) was dissolved in MeOH (100 mL), and then Pd / C (10 wt%, 2.0 g) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature for 15 hours. The solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane / methanol (97:3), to give 6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-amine (11.4 g) as a yellow solid. LCMS Method D: [M+H] + =232.

[0610] Step 3: 5-Azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine 6-(4,4-Difluoropiperidin-1-yl)-5-fluoropyridin-3-amine (400.0 mg, 1.7 mmol, 1.0 equiv) was dissolved in ACN (10 mL) and cooled to 0 °C. t-BuNO (0.3 mL, 2.7 mmol, 1.6 equiv) was then added dropwise, and the solution was maintained at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. TMSN (0.3 mL, 2.5 mmol, 1.5 equiv) was then added dropwise at 0 °C. The resulting mixture was stirred at ambient temperature for an additional 2 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:2) to give 5-azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (380.0 mg) as a yellow oil. LCMS Method A: [M+H] + =258.

[0611] Step 4: Methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate 5-Azido-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (350.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (3.6 mL) and water (0.4 mL), followed by the addition of methyl propiolate (228.8 mg, 2.7 mmol, 2.0 equiv.), sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (53.9 mg, 0.3 mmol, 0.2 equiv.), and CuSO (21.7 mg, 0.1 mmol, 0.1 equiv.). The reaction mixture was stirred overnight at ambient temperature and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:2) to give methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate (150.0 mg) as a yellow solid. LCMS Method A: [M+H] + =341.

[0612] Step 5: 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid Methyl 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylate (300.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in MeOH (3 mL) and water (7 mL), followed by the addition of NaOH (70.3 mg, 1.8 mmol, 2.0 equiv.). The reaction mixture was heated to 80° C. for 2 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and adjusted to pH 6 with 1 M aqueous HCl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give 1-[6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]-1,2,3-triazole-4-carboxylic acid (200.1 mg) as a yellow solid. LCMS Method A: [M+H] + =328.

[0613] Example 1: trans-N-(5-(-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (Compound 135) TIFF2025503675000235.tif321705-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt is dissolved in THF, and then bicyclo[1.1.1]pentane-1-carboxylic acid, HATU, and DIEA are added. The reaction mixture is stirred at ambient temperature for 1 hour and then concentrated under vacuum. The residue is purified by reverse flash chromatography. This gives the product trans-N-(5-(-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)bicyclo[1.1.1]pentane-1-carboxamide).

[0614] The analogs prepared in the table below were prepared using the same method as described in Example 1. TIFF2025503675000236.tif116170TIFF2025503675000237.tif244170TIFF2025503675000238.tif109170

[0615] Example 10: 3-Hydroxy-N-(5-(cis-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (Compound 204) TIFF2025503675000239.tif321705-(cis-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt (385.0 mg, 0.8 mmol, 1.0 equiv.) and 3-hydroxybicyclo[1.1.1]pentane-1-carboxylic acid (110.9 mg, 0.8 mmol, 1.0 equiv.) were dissolved in DCM (5 mL), followed by the addition of HATU (494.0 mg, 1.3 mmol, 1.5 equiv.) and DIEA (335.8 mg, 2.6 mmol, 3.0 equiv.). The reaction mixture was stirred at room temperature for 1 h and then quenched by the addition of water. The resulting solution was extracted with DCM, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD column, 19*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 60% B to 80% B in 5.3 min; Wavelength: 210 / 254 nm; RT1: 5.3 min. This gave 3-hydroxy-N-(5-(cis-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (144.7 mg, 36.6%) as an off-white solid. LCMS Method F: [M+H] + =457.2. 1H NMR(400MHz,DMSO-d6)δ 10.68(s,1H),9.24(s,1H),7.69(d,J=8.0Hz,2H),7.56-7.52(m,3H),7.24-7.19(m,2H),6.76-6.73(m,1H), 6.35(s,1H),4.73-4.69(m,1H),3.33-3.29(m,1H),3.00-2.93(m,2H),2.20-2.18(m,2H),2.16-2.13(m,6H).

[0616] The analogs prepared in Table 2 were prepared using the same method as described in Example 10.

[0617] [Table 2] TIFF2025503675000241.tif231170

[0618] Example 21: N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)benzamide (Compound 218) TIFF2025503675000242.tif391705-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-amine (350 mg, 1.14 mmol, 1.0 equiv) and TEA (462.5 mg, 4.6 mmol, 4.0 equiv) were dissolved in DCM (7 mL), and then benzoyl chloride (160.6 mg, 1.1 mmol, 1.0 equiv) was added at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour and then quenched by adding water. The resulting mixture was extracted with EtOAc, washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / EtOAc = 1:1) to give the crude product, which was further purified by preparative HPLC using the following conditions: Column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 49% B to 68% B in 8 min; Wavelength: 254 nm; RT1: 7.3 min. This gave N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)benzamide (177.0 mg, 37.7%) as a white solid. LCMS Method E: [MH] - =409.1. 1 H NMR(400MHz,DMSO-d6):δ 10.80(s,1H),10.09(s,1H),8.01-7.98(m,2H),7.81-7.77(m,3H),7.73-7.71(m ,2H),7.61-7.52(m,4H),7.29(d,J=8.8Hz,1H),6.89-6.86(m,1H),5.21(s,2H).

[0619] The analogs prepared in the table below were prepared using the same method as described in Example 21. TIFF2025503675000243.tif163170TIFF2025503675000244.tif108170

[0620] Example 27: Synthesis of 1-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 244) TIFF2025503675000245.tif32170 tert-Butyl 3-{[(tert-butoxy)carbonyl]amino}-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-indole-1-carboxylate (83.2 mg, 0.16 mmol, 1.0 equiv) was dissolved in DCM (2 mL) and TFA (500 μL) was added to the mixture. The mixture was heated at 30° C. for 2 h. The reaction mixture was concentrated in a Speedvac to give a residue. This residue and 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (40.64 mg, 0.32 mmol, 2.0 equiv.) were then dissolved in DMF (2 mL), followed by the addition of TEA (116 μL, 0.8 mmol, 5.0 equiv.) and HATU (63.84 mg, 0.168 mmol, 1.05 equiv.). The mixture was heated at 30° C. for 16 h. The crude product was purified by preparative HPLC to give 1-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide (41.72 mg, 0.097 mmol) as a powder. MS-ESI, 430.2 [M+H + ]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.81-10.72(m,1H),10.19(s,1H),8.62(s,1H),7.75-7.70(m,1H),7.71-7.66(m,2H), 7.59(d,2H),7.45(d,1H),7.23(d,1H),6.72(dd,1H),4.22(t,2H),4.13(s,3H),3.17(br t,2H).

[0621] Example 28: Synthesis of 1-methyl-N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 243) TIFF2025503675000246.tif32170 tert-Butyl (5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-yl)carbamate (83.2 mg, 0.16 mmol, 1.0 equiv) was dissolved in DCM (2 mL), and to this mixture was added TFA (500 μL). The mixture was heated at 30° C. for 2 hours. The reaction mixture was concentrated in a Speedvac to give a residue. This residue and 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (40.64 mg, 0.32 mmol, 2.0 equiv) were then dissolved in DMF (2 mL), followed by the addition of TEA (116 μL, 0.8 mmol, 5.0 equiv) and HATU (63.84 mg, 0.168 mmol, 1.05 equiv). The mixture was heated at 30° C. for 16 hours. The crude product was purified by preparative HPLC to give 1-methyl-N-(5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide (17.82 mg, 0.041 mmol) as a powder. MS-ESI, 430.3 [M+H + ].

[0622] Example 29: Synthesis of N-(5-(2-((3aR,5R,6aS)-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethoxy)-1H-indol-3-yl)spiro[2.3]hexane-1-carboxamide (Compound 223) TIFF2025503675000247.tif45170 tert-Butyl 5-{2-[(3aR,5R,6aS)-2-(2,2,2-trifluoroethyl)-octahydrocyclopenta[c]pyrrol-5-yl]ethoxy}-3-{[(tert-butoxy)carbonyl]amino}-1H-indole-1-carboxylate (96.4 mg, 0.17 mmol, 1.0 equiv) was dissolved in DCM (3 mL), and then TFA (1 mL) was added to the solution. The mixture was heated at 30 °C for 2 h. The reaction mixture was concentrated in a Speedvac to give a residue. This residue and spiro[2.3]hexane-1-carboxylic acid (42.84 mg, 0.34 mmol, 2.0 equiv) were then dissolved in DMF (2 mL), followed by the addition of TEA (123 μL, 0.85 mmol, 5.0 equiv) and HATU (68.4 mg, 0.18 mmol, 1.05 equiv). The mixture was heated at 30 °C for 16 h. The reaction mixture was concentrated in a Speedvac to give a residue that was purified by preparative HPLC to give N-(5-(2-((3aR,5R,6aS)-2-(2,2,2-trifluoroethyl)octahydrocyclopenta[c]pyrrol-5-yl)ethoxy)-1H-indol-3-yl)spiro[2.3]hexane-1-carboxamide (34.18 mg, 0.072 mmol) as a powder. MS-ESI, 476.4 [M+H + ]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.52(s,1H),9.81(s,1H),7.63(d,1H),7.32(d,1H),7.18(d,1H),6.71(dd,1H),3.97(t,2H),3.18(q,2H),2.64(br d,2H),2.46(br s,1H),2.42(br d,2H),2.33-2.15(m,2H),2.15-2.01(m,6H),2.00-1.94(m,1H),1.91-1.85(m,2H),1.78(q,2H),1.06(t,1H),1.01-0.92(m,3H).

[0623] Example 30: Synthesis of 1-methyl-N-(5-(cis)-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 241) TIFF2025503675000248.tif32170 tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-((1S,3S)-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate (98.4 mg, 0.18 mmol, 1.0 equiv) was dissolved in DCM (3 mL), and then TFA (1 mL) was added to the solution. The mixture was heated at 30° C. for 2 h. The reaction mixture was concentrated in a Speedvac to give a residue. This residue and 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (45.7 mg, 0.36 mmol, 2.0 equiv.) were then dissolved in DMF (2 mL), followed by the addition of TEA (130 μL, 0.9 mmol, 5.0 equiv.) and HATU (71.8 mg, 0.189 mmol, 1.05 equiv.). The mixture was heated at 30° C. for 16 h. The reaction mixture was concentrated in a Speedvac to give a residue that was purified by preparative HPLC to give 1-methyl-N-(5-((1S,3S)-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide (41.88 mg, 0.092 mmol) as a powder. MS-ESI, 456.3 [M+H + ]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.78(br s,1H),10.23(s,1H),8.63(s,1H),7.74-7.71(m,1H),7.67(d,2H),7.52(d,2H),7.35(d,1H),7.25(d ,1H),6.73(dd,1H),4.72(quin,1H),4.14(s,3H),3.32-3.28(m,1H),3.00(q,2H),2.21-2.07(m,2H).

[0624] Example 31: Synthesis of 1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 240) TIFF2025503675000249.tif32170 tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-((4-(trifluoromethyl)benzyl)oxy)-1H-indole-1-carboxylate (91.08 mg, 0.18 mmol, 1.0 equiv) was dissolved in DCM (3 mL), and then TFA (1 mL) was added to the solution. The mixture was heated at 30 °C for 2 h. The reaction mixture was concentrated in a Speedvac to give a residue. This residue and 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (45.7 mg, 0.36 mmol, 2.0 equiv) were then dissolved in DMF (2 mL), and then TEA (130 μL, 0.9 mmol, 5.0 equiv) and HATU (71.8 mg, 0.189 mmol, 1.05 equiv) were added. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated in a Speedvac to give a residue that was purified by preparative HPLC to give 1-methyl-N-(5-((4-(trifluoromethyl)benzyl)oxy)-1H-indol-3-yl)-1H-1,2,3-triazole-4-carboxamide (41.88 mg, 0.092 mmol) as a powder. MS-ESI, 456.3 [M+H + ]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.86-10.77(m,1H),10.17(s,1H),8.63(s,1H),7.79-7.70(m,5H),7.57(d,1H),7.28(d,1H),6.86(dd,1H),5.22(s,2H),4.14(s,3H).

[0625] Example 32: Synthesis of N-(5-((1R,3R)-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)thiazole-4-carboxamide (Compound 239) TIFF2025503675000250.tif39170 tert-Butyl 3-((tert-butoxycarbonyl)amino)-5-((1R,3R)-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indole-1-carboxylate (98.3 mg, 0.18 mmol, 1.0 equiv) was dissolved in DCM (3 mL), and then TFA (1 mL) was added to the solution. The mixture was heated at 30 °C for 2 h. The reaction mixture was concentrated in a Speedvac to give a residue. This residue and thiazole-4-carboxylic acid (46.44 mg, 0.36 mmol, 2.0 equiv) were then dissolved in DMF (2 mL), and then TEA (130 μL, 0.9 mmol, 5.0 equiv) and HATU (71.8 mg, 0.189 mmol, 1.05 equiv) were added. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated in a Speedvac to give a residue that was purified by preparative HPLC to give N-(5-((1R,3R)-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)thiazole-4-carboxamide (30.8 mg, 0.067 mmol) as a powder. MS-ESI, 458.2 [M+H + ]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.82(d,1H),10.09(s,1H),9.27(d,1H),8.43(d,1H),7.78-7.67(m,3H),7.59(d,2H),7.2 7(d,1H),7.18(d,1H),6.76(dd,1H),4.95(quin,1H),3.85-3.76(m,1H),2.69-2.58(m,4H).

[0626] [Table 1] TIFF2025503675000252.tif200170TIFF2025503675000253.tif213170TIFF2025503675000254.tif136170

[0627] Biological assays STING pathway activity by the compounds described herein was measured using THP1-Dual™ cells (KO-IFNAR2).

[0628] THP1-Dual™ KO-IFNAR2 cells (obtained from Invivogen) were maintained in RPMI, 10% FCS, 5 ml of P / S, 2 mM L-glutamate, 10 mM Hepes, and 1 mM sodium pyruvate. Compounds were spotted onto empty 384-well tissue culture plates (Greiner 781182) using an Echo spotter to final concentrations of 0.0017–100 μM. Cells were plated at 2×10E6 cells / mL in 40 μL per well of TC plates. For STING ligand activation, 2'3'cGAMP (MW 718.38, obtained from Invivogen) was prepared in Optimem medium.

[0629] The following solutions were prepared for each of the 1x384 plates: Solution A: 2 mL of Optimem containing one of the following stimuli: 60 μL of 10 mM 2'3'cGAMP → Stock 150 μM Solution B: 2 mL of Optimem containing 60 μL of Lipofectamine 2000 → Incubate at room temperature for 5 minutes

[0630] 2 mL of solution A and 2 mL of solution B were mixed and incubated at room temperature (RT) for 20 minutes. 20 μL of transfection solution (A+B) was added on top of the plated cells to a final 2'3'cGAMP concentration of 15 μM. The plate was then immediately centrifuged at 340 g for 1 minute and then incubated at 37°C, 5% CO2, and >98% humidity for 24 hours. Luciferase reporter activity was then measured. EC was measured using standard methods known in the art. 50 values ​​were calculated.

[0631] Luciferase reporter assay: 10 μL of supernatant from the assay was transferred to a white 384-well plate with flat bottom and square wells. One QUANTI-Luc™ Plus pouch was dissolved in 25 mL of water. 100 μL of QLC stabilizer was added per 25 mL of QUANTI-Luc™ Plus solution. 50 μL of QUANTI-Luc™ Plus / QLC solution was then added per well. Luminescence was measured using a plate reader (e.g., Spectramax I3X (Molecular Devices GF3637001)).

[0632] Luciferase reporter activity was then measured. EC 50 values ​​were calculated.

[0633] Table BA shows the activity of compounds in the STING reporter assay: <0.008 μM = "++++++"; ≥0.008 and <0.04 μM = "+++++"; ≥0.04 and <0.2 μM = "++++"; ≥0.2 and <1 μM = "+++"; ≥1 and <5 μM = "++"; ≥5 and <100 μM = "+".

[0634] [Table BA] TIFF2025503675000256.tif237170TIFF2025503675000257.tif234170TIFF2025503675 000258.tif235170TIFF2025503675000259.tif232170TIFF2025503675000260.tif99170

[0635] Numbered Sections The compounds, compositions, methods and other subject matter described herein are further described in the numbered sections below.

[0636] 1. Formula (I): TIFF2025503675000261.tif39170 or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein: L A But, -(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 -*, where * is Q 1 represents the attachment point to; a1, a2, a3, a4, and a5 each independently represent 0 or 1; However, a1+a2+a3+a4+a5≧1, L 1 , L 3 and L 5 are -O-, -N(H)-, -N(R d )-, S(O) 0~2 and -C(=O)-; However, if one or both of a2 and a4 are 0, L 1 , L 3 and L 5 cannot form an OO, NO, NN, OS, SS or NS(O) bond, L 2 and L 4 Each of the Each of them has 1 to 6 R b Optionally substituted with linear C 1~6 Alkylene, linear C 2~6 Alkenylene or linear C 2~6 Alkynylene; Each of them has 1 to 3 R c optionally substituted with C 3~10 Cycloalkylene or C 3~10 cycloalkenylene; and Heterocyclylene or heterocycloalkenylene, each having 4 to 10 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is selected from the group consisting of 1 to 3 R c the heterocyclylene or heterocycloalkenylene optionally substituted by independently selected from the group consisting of: Q 1 But -R g and; Y 1 , Y 2 and Y 3 But, CR 1 , C(═O), N and NR 2 each independently selected from the group consisting of: X 1 But O, S, N, NR 2 and CR 1 selected from the group consisting of: X 2 But O, S, N, NR 4 and CR 5 selected from the group consisting of: Each TIFF2025503675000262.tif4170 are independently a single bond or a double bond, with the proviso that X 1 and X 2 is a heteroaryl, and Y 1 , Y 2 and Y 3 is an aryl or heteroaryl; Furthermore, however, L A But, Y 1 , Y 2 and Y 3 cannot contain cyclic groups directly attached to a six-membered ring containing R 1 and R 5 Each occurrence of H;R c ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 2 and R 4 Each occurrence of H;Rd ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 6 But H;R d ; and R g selected from the group consisting of: W is, (i) TIFF2025503675000263.tif32170In the formula, ring B1 is a heteroarylene of 5 ring atoms, and 1 to 4 of the ring atoms are N, NH, N(R d ), heteroatoms independently selected from the group consisting of O and S; the heteroarylene of ring B1 is oxo and R c and optionally substituted with 1 to 2 substituents independently selected from the group consisting of: 6 is attached to a group; Each L AA But one or two R a C optionally substituted with 1~3 Alkylene; -O-; -NH-; -NR d ;-S(O) 0~2 and C(O); aa1 is 0, 1 or 2; Ring C1 is Oxo, R c and (L AA ) aa1 -R g C, each of which 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, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heterocyclylene or heterocycloalkenylene is oxo, R c and (L AA) aa1 -R g the heterocyclylene or heterocycloalkenylene optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroarylene of 5 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and the heteroarylene is R c and (L AA ) aa1 -R g the heteroarylene, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ·R c and (L AA ) aa1 -R g C 6~10 Arylene selected from the group consisting of: R 7 But R g and -(L 7 ) b7 -R g selected from the group consisting of: Each L 7 But one or two R a1 C optionally substituted with 1~3 Alkylene; -O-; -NH-; -NR d ;-S(O) 0~2 and C(O); b7 is 1, 2 or 3; (ii) TIFF2025503675000264.tif32170In the formula, ring B2 is a heteroarylene having five ring atoms, and 1 to 4 of the ring atoms are N, NH, N(R d ), heteroatoms independently selected from the group consisting of O and S, and the heteroarylene of ring B is oxo and R cand optionally substituted with 1 to 2 substituents independently selected from the group consisting of: 6 is attached to a group; Each L AB However, 1 to 4 R a1 C optionally substituted with 1~3 Alkylene; -O-; -NH-; -NR d ;-S(O) 0~2 and C(O); aa2 is 0, 1, 2 or 3; Ring C2 is Oxo and R c C, each of which may be 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, in which 1 to 3 ring atoms are N, N(H), N(R d ), O and S(O) 0~2 and wherein the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c the heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl of 5 to 12 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O and S(O) 0~2 and the heteroaryl is selected from the group consisting of 1 to 4 R c the heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl selected from the group consisting of: (iii) Heteroaryl of 5 ring atoms, wherein 1 to 4 ring atoms are N, N(H), N(R d ), O and S(O) 0~2and the heteroaryl is selected from the group consisting of 1 to 4 R c provided that said heteroaryl is substituted via a ring carbon atom with C(=O)NR 6 the heteroaryl being bound to a group; (iv) TIFF2025503675000265.tif20170, P 1 , P 2 , P 3 , P 4 and P 5 But N, NH, NR d , N.R. 71 , C.H., C.R. c , C.R. 71 and C(═O); R 71 Each occurrence of is independently -(L AC ) aa3 -R 8 and Each L AC However, 1 to 4 R a C optionally substituted with 1~3 Alkylene; -O-; -NR N ;-S(O) 0~2 ;C(O);C(O)O;OC(O);NR N C(O);C(O)NR N ;NR N C(O)NR N ;NR N C...

Claims

[Claim 1] Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein L Ａ But, -(L １ ) ａ１ - (L ２ ) ａ２ - (L ３ ) ａ３ - (L ４ ) ａ４ - (L ５ ) ａ５ -*, where * is Q １ represents a point of attachment to a1, a2, a3, a4, and a5 each independently represent 0 or 1; However, a1+a2+a3+a4+a5≧1, L １ , L ３ and L ５ are each -O-, -N(H)-, -N(R ｄ ) -, S(O) ０～２ and —C(═O)—; However, when one or both of a2 and a4 is 0, L １ , L ３ and L ５ The combination is O-O, N-O, N-N, O-S, S-S or N-S(O) ０ unable to form bonds, Furthermore, however, L Ａ But Y １ , Y ２ and Y ３ cannot contain cyclic groups directly attached to the six-membered ring containing L ２ and L ４ Each of the ・Each of them has 1 to 6 R ｂ a linear C １～６ Alkylene, linear C ２～６ Alkenylene or linear C ２～６ Alkynylene; ・Each of them has 1 to 3 R ｃ optionally substituted with C ３～１０ Cycloalkylene or C ３～１０ Cycloalkenylene, provided that Y １ , Y ２ and Y ３ The C is not directly connected to the 6-membered ring containing ３～１０ Cycloalkylene or C ３～１０ cycloalkenylene; and heterocyclylene or heterocycloalkenylene, each having 4 to 10 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R ｄ ), O and S(O) ０～２ and the heterocyclylene or heterocycloalkenylene is selected from the group consisting of 1 to 3 R ｃ and wherein said heterocyclylene or heterocycloalkenylene is substituted by Y １ , Y ２ and Y ３ the heterocyclylene or heterocycloalkenylene, which is not directly linked to the six-membered ring comprising are independently selected from the group consisting of: Q １ But, -R ｇ and Y １ , Y ２ and Y ３ But, CR １ , C(═O), N and NR ２ are each independently selected from the group consisting of: X １ But O, S, N, NR ２ and CR １ selected from the group consisting of: X ２ But O, S, N, NR ４ and CR 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 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 ｇ and -(L ｇ ) ｂｇ -R ｇ are independently selected from the group consisting of: R ２ and R ４ Each occurrence of H;R ｄ ;R ｇ and -(L ｇ ) ｂｇ -R ｇ are independently selected from the group consisting of: R ６ But H;R ｄ and R ｇ selected from the group consisting of: W is, (i) 【Transformation 3】 wherein ring B1 is a heteroarylene of five ring atoms, and 1 to 4 of the ring atoms are N, NH, N(R ｄ ), heteroatoms independently selected from the group consisting of O and S; and the heteroarylene of ring B1 is oxo and R ｃ and optionally substituted with 1 to 2 substituents independently selected from the group consisting of: ６ is bonded to a group; Each L ＡＡ But one or two R ａ C optionally substituted with １～３ Alkylene; —O—; —NH—; —NR ｄ -S(O) ０～２ and C(O); aa1 is 0, 1 or 2; Ring C1 is ・Oxo, R ｃ and (L ＡＡ ) ａａ１ -R ｇ C, each of which 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 the heterocyclylene or heterocycloalkenylene is oxo, R ｃ and (L ＡＡ ) ａａ１ -R ｇ the 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 (L ＡＡ ) ａａ１ -R ｇ the heteroarylene optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ・R ｃ and (L ＡＡ ) ａａ１ -R ｇ 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: R ７ But, R ｇ and -(L ７ ) ｂ７ -R ｇ selected from the group consisting of: Each L ７ But one or two R ａ１ C optionally substituted with １～３ Alkylene; —O—; —NH—; —NR ｄ -S(O) ０～２ and C(O); b7 is 1, 2 or 3; (ii) 【Chemistry 4】 wherein ring B2 is a heteroarylene of five ring atoms, and 1 to 4 of the ring atoms are N, NH, N(R ｄ ), heteroatoms independently selected from the group consisting of O and S, and the heteroarylene of ring B is selected from oxo and R ｃ and wherein ring B is substituted with one or two substituents independently selected from the group consisting of C(═O)NR ６ is bonded to a group; Each L ＡＢ However, 1 to 4 R ａ１ C optionally substituted with １～３ Alkylene; —O—; —NH—; —NR ｄ -S(O) ０～２ and C(O); aa2 is 0, 1, 2 or 3; Ring C2 is Oxo and R ｃ C, each of which may be substituted with 1 to 4 substituents independently selected from the group consisting of ３～１２ Cycloalkyl or C ３～１２ cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R ｄ ), O and S(O) ０～２ and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R ｃ the heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl of 5 to 12 ring atoms, 1 to 4 of which are N, N(H), N(R ｄ ), O and S(O) ０～２ and the heteroaryl is selected from the group consisting of 1 to 4 R ｃ the heteroaryl, optionally substituted with ・1 to 4 R ｃ C optionally substituted with ６～１０ Aryl selected from the group consisting of: (iii) Heteroaryl of 5 ring atoms, wherein 1 to 4 ring atoms are N, N(H), N(R ｄ ), O and S(O) ０～２ and the heteroaryl is selected from the group consisting of 1 to 4 R ｃ wherein said heteroaryl is optionally substituted through a ring carbon atom with said C(═O)NR ６ the heteroaryl bonded to a group; (iv) 【Transformation 5】 In the formula, P １ , P ２ , P ３ , P ４ and P ５ But N, NH, NR ｄ , N.R. ７１ , C.H., C.R. ｃ , C.R. ７１ and C(═O); R ７１ Each occurrence of independently represents -(L ＡＣ ) ａａ３ -R ８ and Each L ＡＣ However, 1 to 4 R ａ C optionally substituted with １～３ Alkylene; —O—; —NR Ｎ -S(O) ０～２ ;C(O);C(O)O;OC(O);NR Ｎ C(O); C(O)NR Ｎ ;NR Ｎ C(O)NR Ｎ ;NR Ｎ C(O)O; and OC(O)NR Ｎ are independently selected from the group consisting of: aa3 is 0, 1, 2 or 3; R ８ Each occurrence of ｇ , or 1 to 6 R ａ１ C optionally substituted with １～１０ is alkyl; R Ｎ each occurrence of is independently H or R ｄ that is; (v) a bicyclic or polycyclic ring system, ・Oxo, R ｃ and -(L ＡＤ ) ｂＢ -R ｇ a bicyclic or polycyclic C, each optionally substituted with 1 to 4 substituents independently selected from the group consisting of ５～１５ Cycloalkyl or C ５～１５ cycloalkenyl; Bicyclic or polycyclic heterocyclyl or heterocycloalkenyl of 7 to 15 ring atoms, 1 to 4 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, R ｃ and -(L ＡＤ ) ｂＢ -R ｇ the bicyclic or polycyclic heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Bicyclic or polycyclic heteroaryl of 8 to 15 ring atoms, 1 to 6 of which are N, N(H), N(R ｄ ), O and S(O) ０～２ and the heteroaryl is selected from the group consisting of oxo, R ｃ and -(L ＡＤ ) ｂＢ -R ｇ the bicyclic or polycyclic heteroaryl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ・Oxo, R ｃ and -(L ＡＤ ) ｂＢ -R ｇ a bicyclic or polycyclic C optionally substituted with 1 to 4 substituents independently selected from the group consisting of ８～１５ Aryl is selected from the group consisting of provided that the bicyclic or polycyclic heterocycle is connected via a ring carbon atom to the C(=O)NR ６ is bonded to a group; L ＡＤ each occurrence of is -O-, -NH-, -NR ｄ , -S(O) ０～２ , C(O), and 1 to 3 R ａ C optionally substituted with １～３ alkylene; the bicyclic or polycyclic ring system wherein bB is 0, 1, 2 or 3; and (vi) 【Transformation 6】 In the ceremony, L ＡＥ but, ・Each of them has 1 to 6 R ａ optionally substituted with C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Alkynylene; each of which is oxo and R ｃ a monocyclic C optionally substituted with 1 to 4 substituents independently selected from the group consisting of ３～８ Cycloalkylene or C ３～８ cycloalkenylene; and Monocyclic heterocyclylene or heterocycloalkenylene 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 heterocyclylene or heterocycloalkenylene is selected from the group consisting of oxo and R ｃ and wherein said heterocyclylene or heterocycloalkenylene is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ６ the monocyclic heterocyclylene or heterocycloalkenylene bonded to a group selected from the group consisting of: Each L ＡＦ However, 1 to 4 R ａ１ C optionally substituted with １～３ Alkylene; —O—; —NH—; —NR ｄ -S(O) ０～２ and C(O); aa4 is 0, 1, 2 or 3; Ring C4 is R ｇ Something that is selected from the group consisting of: R ａ each occurrence of is -OH; -halo; -NR ｅ R ｆ ; C １～４ Alkoxy; C １～４ Haloalkoxy; —C(═O)O(C １～４ alkyl); -C(=O)(C １～４ alkyl); -C(=O)OH; -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); and cyano; R ｂ and R ｃ each occurrence of is selected from halo; cyano; 1 to 6 independently selected R ａ C optionally substituted with １～１０ Alkyl; C ２～６ Alkenyl; C ２～６ Alkynyl; C １～４ Alkoxy; C １～４ Haloalkoxy; -S(O) １～２ (C １～４ alkyl); -S(O)(=NH)(C １～４ alkyl); -NR ｅ R ｆ ;-OH;-S(O) １～２ NR'R'';-C １～４ Thioalkoxy; -NO ２ -C(=O)(C １～１０ alkyl); -C(=O)O(C １～４ alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF ５ are independently selected from the group consisting of: R ｄ each occurrence of ａ C optionally substituted with １～６ Alkyl; —C(O)(C １～４ alkyl); -C(O)O(C １～４ alkyl); -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); —OH; and C １～４ independently selected from the group consisting of alkoxy; R ｅ and R ｆ Each occurrence of １～４ Alkoxy and C １～４ C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of haloalkoxy １～６ Alkyl; —C(O)(C １～４ alkyl); -C(O)O(C １～４ alkyl); -CONR'R''; -S(O) １～２ NR'R'';-S(O) １～２ (C １～４ alkyl); —OH; and C １～４ independently selected from the group consisting of alkoxy; R ｇ Each occurrence of -Each of them is oxo, R ｃ and R ｈ C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of ３～１２ Cycloalkyl or C ３～１２ cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R ｄ ), O and S(O) ０～２ and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo, R ｃ and R ｈ the heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of: Heteroaryl of 5 to 12 ring atoms, 1 to 4 of which are N, N(H), N(R ｄ ), O and S(O) ０～２ and the heteroaryl is selected from the group consisting of oxo, R ｃ and R ｈ the heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ・Oxo, R ｃ and R ｈ C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of ６～１０ Aryl are independently selected from the group consisting of: R ｈ Each occurrence of ・Each of them has 1 to 4 R ｉ optionally substituted with C ３～１２ Cycloalkyl or C ３～１２ cycloalkenyl; Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R ｄ ), O and S(O) ０～２ and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of 1 to 4 R ｉ the heterocyclyl or heterocycloalkenyl optionally substituted by Heteroaryl of 5 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R ｄ ), O and S(O) ０～２ and the heteroaryl is selected from the group consisting of 1 to 4 R ｉ the heteroaryl, optionally substituted with ・1 to 4 R ｉ C optionally substituted with ６～１０ Aryl are independently selected from the group consisting of: R ｉ Each occurrence of C １～６ Alkyl; C １～４ Haloalkyl; C １～４ Alkoxy; C １～４ Independently selected from the group consisting of haloalkoxy; and halo; L ｇ each occurrence of is -O-, -NH-, -NR ｄ , -S(O) ０～２ , C(O), and 1 to 3 R ａ C optionally substituted with １～３ independently selected from the group consisting of alkylene; each occurrence of bg is independently 1, 2, or 3; Each occurrence of R' and R'' is selected from the group consisting of H; -OH; and C １～４ independently selected from the group consisting of alkyl, The compound or a pharmaceutically acceptable salt thereof or a tautomer thereof.

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