Compounds and compositions for treating conditions associated with STING activity

Abstract

The disclosure features chemical entities of formula I (e.g., compounds or pharma- ceutically acceptable salts and / or hydrates and / or cocrystals and / or combination drugs) that inhibit (e.g., antagonize) STING (Stimulator of Interferon Gene). The chemical entities are useful, for example, for treating conditions, diseases, or disorders (e.g., cancer) in which increased (e.g., enhanced) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder in a subject (e.g., a human). The disclosure also features compositions containing the chemical entities, as well as methods of using and making the chemical entities.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 231,672, filed August 10, 2021, U.S. Provisional Patent Application No. 63 / 298,889, filed January 12, 2022, and U.S. Provisional Patent Application No. 63 / 369,343, filed July 25, 2022, each of which is incorporated by reference in its entirety.

[0002] Technical Field The present disclosure features chemical entities (compounds or pharmaceutically acceptable salts and / or hydrates and / or cocrystals and / or drug combinations of the compounds) that inhibit (e.g., antagonize) STING (Stimulator of Interferon Gene). The chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., hyper) 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 chemical entities, as well as methods of using and making the chemical entities. [Background technology]

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

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

[0005] Hyperactivation of STING is associated with a subset of monogenic autoinflammatory conditions, 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 gene responsible for STING). Furthermore, STING is implicated in the pathogenesis of Aicardi-Goutières syndrome (AGS) and inherited forms of lupus. In contrast to SAVI, dysregulation of nucleic acid metabolism underlies the continuous innate immune activation in AGS. Apart from these inherited disorders, emerging evidence points to a more universal pathogenetic role of STING in a wide range of inflammation-related disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and cancer. Therefore, small molecule-based pharmacological interventions in the STING signaling pathway hold significant potential for the treatment of a wide range of diseases. Summary of the Invention

[0006] overview The present disclosure features chemical entities (compounds or pharmaceutically acceptable salts and / or hydrates and / or cocrystals and / or drug combinations of the compounds) that inhibit (e.g., antagonize) STING (Stimulator of Interferon Gene). The chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., hyper) 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 chemical entities, as well as methods of using and making the chemical entities.

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

[0008] In one aspect, the compound of formula (I): TIFF2024532798000001.tif38128, or a pharmaceutically acceptable salt thereof, wherein Q 1 , L A , Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 and ring W can be as defined anywhere herein.

[0009] In one aspect, pharmaceutical compositions are featured that include a chemical entity described herein (e.g., a compound described generically 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 for inhibiting (e.g., antagonizing) STING activity, comprising contacting STING with a chemical entity described herein (e.g., a compound generically or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing same). The method includes an in vitro method, e.g., an in vitro method in which a sample containing one or more cells (e.g., innate immune cells, e.g., mast cells, macrophages, dendritic cells (DCs), and natural killer cells) containing STING is contacted with the chemical entity. The method can further include an in vivo method, e.g., an in vivo method in which the chemical entity is administered to a subject (e.g., a human) having a disease in which increased (e.g., hyperactive) 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 ameliorated by antagonizing STING, e.g., a condition, disease, or disorder in which increased (e.g., hyper) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). The method includes administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generically or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing 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 generically or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing same).

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

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

[0015] In a further aspect, a method of treating a disease in which increased (e.g., enhanced) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the disease is featured. The method includes administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generically or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing same).

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

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

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

[0019] In another aspect, there is provided a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in treating a condition, disease, or disorder associated with increased (e.g., hyperactivity) of 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 described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in treating a cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma.

[0022] In another aspect, there is provided a compound 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 described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in treating type I interferonopathies selected from STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), genetic forms of lupus, and inflammation-related disorders, such as systemic lupus erythematosus and rheumatoid arthritis.

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

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

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

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

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

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

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

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

[0032] In another aspect, there is provided a use of a compound 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 cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma.

[0033] In another aspect, there is provided the use of a compound 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 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-Goutières syndrome (AGS), genetic forms of lupus, and inflammation-related disorders, such as systemic lupus erythematosus and rheumatoid arthritis.

[0035] Embodiments can include one or more of the following features.

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

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

[0038] The chemical entity can be administered in combination with one or more additional cancer therapies (e.g., surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof, e.g., chemotherapy 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), and / or cyclophosphamide (e.g., cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin). taxol, paclitaxel, and / or docetaxel), topoisomerases (e.g., type I topoisomerases and / or type 2 topoisomerases, e.g., camptothecins such as irinotecan and / or topotecan, amsacrine, etoposide, etoposide phosphate, and / or teniposide), cytotoxic antibiotics (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and / or mitomycin), hormones (e.g., luteinizing hormone-releasing hormone agonists, e.g., leuprolidine, goserelin, triptorelin, histrelin, , bicalutamide, flutamide, and / or nilutamide), antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, goli anti-angiogenic agents, cytokines, thrombolytic agents,and an immune checkpoint inhibitor that targets an immune checkpoint receptor, the immune checkpoint receptor being selected from CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), 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, HV EM-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 Selected from the group consisting of 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).

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

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

[0041] The chemical entity may be administered intratumorally.

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

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

[0044] Additional definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the scientific terms 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 throughout this specification and attachments 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 component means having no lasting adverse effects on the general health of the subject being treated.

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

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

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

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

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

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

[0053] The terms "treat," "treating," and "treatment" in the context of treatment of a disease or disorder are meant to include alleviating or preventing the disorder, disease, or condition, or one or more of the symptoms associated with said disorder, disease, or condition, or 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) inhibiting tumor growth to any extent, including (i) slowing and (ii) complete cessation of growth; (2) reducing the number of tumor cells; (3) maintaining tumor size; (4) reducing tumor size; (5) inhibiting tumor cell infiltration into peripheral organs, including (i) reducing, (ii) slowing, or (iii) completely preventing it; (6) inhibiting metastasis, including (i) reducing, (ii) slowing, or (iii) completely preventing it; (7) enhancing an anti-tumor immune response, which may result in (i) maintaining tumor size, (ii) reducing tumor size, (iii) slowing tumor growth; (iv) reducing, slowing, or preventing infiltration; and / or (8) reducing to any extent the severity or number of one or more symptoms associated with the disorder.

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

[0055] The term "alkyl" refers to a saturated acyclic hydrocarbon group, which may be straight or branched, containing the specified number of carbon atoms. For example, C 1~10 indicates that the group may have 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, and n-hexyl. The term "saturated," as used in this context, means that only single bonds exist 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 (eg, -CH2-).

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

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

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

[0062] The term "cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon group, e.g., having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons, 3 to 10 ring carbons, or 3 to 6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, etc. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are joined by only one carbon). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, etc. The term "saturated" as used in this context means that only single bonds exist between the constituent carbon atoms.

[0063] 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, and the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As a partially unsaturated cyclic hydrocarbon group, the cycloalkenyl group may have any degree of unsaturation, provided that one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group as a whole is not fully saturated. Cycloalkenyls may contain multiple fused and / or bridged and / or spirocyclic rings.

[0064] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, or alternatively 5, 6, 9, 10, or 14 ring atoms, and 6, 10, or 14 pi electrons shared in a cyclic array, wherein at least one ring in the system is aromatic and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (although the ring need not contain a heteroatom, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, and pyrazolo[3,4-b]pyridinyl. and the like. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, 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 (e.g., a 5- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring system) having 3 to 16 ring atoms (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms of O, N, or S, respectively, in the monocyclic, bicyclic, or tricyclic ring systems), having 1 to 3 heteroatoms selected from O, N, or S in the monocyclic, 1 to 6 heteroatoms in the bicyclic, or 1 to 9 heteroatoms selected from O, N, or S in the tricyclic or polycyclic systems, and 0, 1, 2, or 3 atoms in each ring may be optionally substituted. 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, and the like. Heterocyclyl also includes spirocyclic rings (eg, spirocyclic bicycles in which the two rings are joined by only one carbon).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-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. The term "saturated" as used in this context means that only single bonds exist between the constituent ring atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0066] The term "heterocycloalkenyl," as used herein, refers to a partially unsaturated cyclic ring system (e.g., a 5- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring system) having 3 to 16 ring atoms (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms of O, N, or S, respectively, in the monocyclic, bicyclic, or tricyclic ring systems), having 1 to 3 heteroatoms selected from O, N, or S in the monocyclic, bicyclic, or tricyclic systems, respectively, in which 0, 1, 2, or 3 atoms in each ring are optionally substituted. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl. As a partially unsaturated cyclic group, a heterocycloalkenyl group can have any degree of unsaturation, provided that one or more double bonds are present in the ring, no ring in 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 spirocyclic rings.

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

[0068] When a ring is described herein as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributable to the ring itself; for example, 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, etc.

[0069] For the avoidance of doubt, unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), such rings and cyclic groups are not limited to those that have fused rings, e.g., those where the fusion points are (i) located on adjacent ring atoms (e.g., [xx0] ring systems where 0 represents no atom bridge) TIFF2024532798000002.tif13128), (ii) Located on a Single Ring Atom (Spiro-Fused Ring Systems) TIFF2024532798000003.tif19128, or (iii) Located on an array of contiguous ring atoms (bridged ring systems with a bridge length >0) TIFF2024532798000004.tif14128 is understood to encompass the file.

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

[0071] Additionally, the compounds disclosed generically or specifically herein are intended to include all tautomeric forms. Thus, by way of example, the moieties: The compound containing TIFF2024532798000005.tif14128 is the moiety: TIFF2024532798000006.tif17128. Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxyl encompass pyridone or pyrimidone tautomers.

[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 entities (compounds or pharmaceutically acceptable salts and / or hydrates and / or cocrystals and / or drug combinations of said compounds) that inhibit (e.g., antagonize) STING (Stimulator of Interferon Gene). The chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., hyper) 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 chemical entities, as well as methods of using and making the chemical entities.

[0075] Compounds of Formula I In one aspect, the present disclosure provides a compound of formula (I): TIFF2024532798000007.tif37128, or a pharmaceutically acceptable salt thereof or a tautomer thereof, During the ceremony: L A But-(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 -*, where * is Q 1 indicates the point of attachment to a1, a2, a3, a4, and a5 are each independently 0 or 1; provided that a1+a2+a3+a4+a5≧1; and 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 O-O, N-O, N-N, O-S, S-S or N-S(O) bond; and 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 C 3~10 Cycloalkylene or C 3~10 Cycloalkenylene is Y 1 , Y 2 , and Y 3 is not directly linked to a six-membered ring containing 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 heterocyclylene or heterocycloalkenylene, optionally substituted by Y 1 , Y 2 , and Y 3 is not directly linked to a six-membered ring containing independently selected from the group consisting of: Q 1 Ga-R g and; Y 1 , Y 2 , and Y 3 But, CR1 , C(=O), N, and NR 2 each independently selected from the group consisting of: X 1 But O, S, N, NR 2 , and C.R. 1 selected from the group consisting of: X 2 But O, S, N, NR 4 , and C.R. 5 selected from the group consisting of: each TIFF2024532798000008.tif2128 are independently single or double bonds, 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 But H;R d ; and R g selected from the group consisting of: W is, H, Each of them has 1 to 6 R a2 optionally substituted with C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 Alkynyl, Each of which is oxo and R c and a monocyclic C 3~8 Cycloalkyl or C 3~8 cycloalkenyl, and Monocyclic heterocyclyl or heterocycloalkenyl of 3 to 8 ring atoms, 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 and R c monocyclic heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of selected from the group consisting of provided that when W is heterocyclyl or heterocycloalkenyl, it is C(=O)NR via a ring carbon atom. 6 attached to the group; R a and R a2 Each occurrence of -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 H;NR'R'', -OH, halo, C 1~4 Alkoxy, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 independently selected from the group consisting of alkoxy; R g Each occurrence of Each of which is oxo and R c C3~12 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 and R c 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 heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl independently selected from the group consisting of: L g Each occurrence of -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; and Each occurrence of R' and R'' is H; -OH; and C 1~4 alkyl.

[0076] In another aspect, the present disclosure provides a compound of formula (I): TIFF2024532798000009.tif37128, or a pharmaceutically acceptable salt thereof or a tautomer thereof; During the ceremony: L A But-(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 -*, where * is Q 1 indicates the point of attachment to a1, a2, a3, a4, and a5 are each independently 0 or 1; provided that a1+a2+a3+a4+a5≧1; and 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 O-O, N-O, N-N, O-S, S-S or N-S(O) bond; and 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 C 3~10 Cycloalkylene or C 3~10 Cycloalkenylene is Y 1 , Y 2 , and Y 3is not directly linked to a six-membered ring containing 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 heterocyclylene or heterocycloalkenylene, optionally substituted by Y 1 , Y 2 , and Y 3 is not directly linked to a six-membered ring containing independently selected from the group consisting of: Q 1 Ga-R g and; Y 1 , Y 2 , and Y 3 But, CR 1 , C(=O), N, and NR 2 each independently selected from the group consisting of: X 1 But O, S, N, NR 2 , and C.R. 1 selected from the group consisting of: X 2 But O, S, N, NR 4 , and C.R. 5 selected from the group consisting of: each TIFF2024532798000010.tif2128 are independently single or double bonds, provided 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 is Y 1 , Y 2, and Y 3 cannot contain a cyclic group directly attached to a six-membered ring containing R 1 and R 5 Each occurrence of H;R c ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 2 and R 4 Each occurrence of H;R d ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 6 But H;R d ; and R g selected from the group consisting of: W is, H, Each of them has 1 to 6 R a2 optionally substituted with C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 In alkynyl, one or more of the optionally substituted methylene groups may be replaced by one or more heteroatoms selected from O or S, and when W is alkenyl or alkynyl, the heteroatoms are sp 2 or not directly linked to an sp carbon, C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 Alkynyl, Each of which is oxo and R c and a monocyclic C 3~8 Cycloalkyl or C 3~8 cycloalkenyl; and Monocyclic heterocyclyl or heterocycloalkenyl of 3 to 8 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(Rd ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c monocyclic heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of selected from the group consisting of provided that when W is heterocyclyl or heterocycloalkenyl, it is C(=O)NR via a ring carbon atom. 6 attached to the group; R a and R a2 Each occurrence of -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 1~4alkyl); -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 H;NR'R'', -OH, halo, C 1~4 Alkoxy, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 independently selected from the group consisting of alkoxy; R g Each occurrence of Each of which is oxo and R c 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) 0~2and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c 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 heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl independently selected from the group consisting of: L g Each occurrence of -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; and Each occurrence of R' and R'' is H; -OH; and C 1~4 alkyl.

[0077] In another aspect, the present disclosure provides a compound of formula (I): TIFF2024532798000011.tif37128, or a pharmaceutically acceptable salt thereof or a tautomer thereof, During the ceremony: L A But-(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5) a5 -*, where * is Q 1 indicates the point of attachment to a1, a2, a3, a4, and a5 are each independently 0 or 1; provided that a1+a2+a3+a4+a5≧1; and 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 O-O, N-O, N-N, O-S, S-S or N-S(O) bond; and 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 C 3~10 Cycloalkylene or C 3~10 Cycloalkenylene is Y 1 , Y 2 , and Y 3 is not directly linked to a six-membered ring containing 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) 0~2and the heterocyclylene or heterocycloalkenylene is selected from the group consisting of 1 to 3 R c heterocyclylene or heterocycloalkenylene, optionally substituted by Y 1 , Y 2 , and Y 3 is not directly linked to a six-membered ring containing independently selected from the group consisting of: Q 1 Ga-R g and; Y 1 , Y 2 , and Y 3 But, CR 1 , C(=O), N, and NR 2 each independently selected from the group consisting of: X 1 But O, S, N, NR 2 , and C.R. 1 selected from the group consisting of: X 2 But O, S, N, NR 4 , and C.R. 5 selected from the group consisting of: each TIFF2024532798000012.tif2128 are independently single or double bonds, provided 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 is Y 1 , Y 2 , and Y 3 cannot contain a cyclic group directly attached to a six-membered ring containing R 1 and R 5 Each occurrence of H;R c ;R g; and -(L g ) bg -R g independently selected from the group consisting of: R 2 and R 4 Each occurrence of H;R d ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 6 But H;R d ; and R g selected from the group consisting of: W is, H, Each of them has 1 to 6 R a2 optionally substituted with C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 In alkynyl, one or more of the optionally substituted methylene groups may be replaced by one or more heteroatoms selected from O or S, and when W is alkenyl or alkynyl, the heteroatoms are sp 2 or not directly linked to an sp carbon, C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 Alkynyl, Each of which is oxo and R c and a monocyclic C 3~8 Cycloalkyl or C 3~8 cycloalkenyl, and Monocyclic heterocyclyl or heterocycloalkenyl of 3 to 8 ring atoms, 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 and R cmonocyclic heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of selected from the group consisting of provided that when W is heterocyclyl or heterocycloalkenyl, it is C(=O)NR via a ring carbon atom. 6 attached to the group; R a and R a2 Each occurrence of -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 dEach 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 H;NR'R'', -OH, halo, C 1~4 Alkoxy, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 independently selected from the group consisting of alkoxy; R g Each occurrence of Each of them is oxo, R c , and R h C 3~12 Cycloalkyl or C 3~12 cycloalkenyl, Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 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 oxo, R c , and R hheterocyclyl 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 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 substituted with 1 to 4 R i heterocyclyl or heterocycloalkenyl, optionally substituted by Heteroaryls 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 1 to 4 R i heteroaryl, optionally substituted with 1 to 4 R i C optionally substituted with 6~10Aryl independently selected from the group consisting of: R i Each occurrence of C 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 independently selected from the group consisting of haloalkoxy; and halo; L g Each occurrence of -O-, -NH-, -NR d , -S(O) 0~2 , C(O), and 1 to 3 R a C optionally substituted with 1~3 independently selected from the group consisting of alkylene; each occurrence of bg is independently 1, 2, or 3; and Each occurrence of R' and R'' is H; -OH; and C 1~4 alkyl.

[0078] In yet another aspect, the present disclosure provides a compound of formula (I): TIFF2024532798000013.tif37128, or a pharmaceutically acceptable salt thereof or a tautomer thereof; During the ceremony: L A But-(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 -*, where * is Q 1 indicates the point of attachment to a1, a2, a3, a4, and a5 are each independently 0 or 1; provided that a1+a2+a3+a4+a5≧1; and L 1 , L 3 , and L 5are -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 O-O, N-O, N-N, O-S, S-S or N-S(O) bond; and 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 C 3~10 Cycloalkylene or C 3~10 Cycloalkenylene is Y 1 , Y 2 , and Y 3 is not directly linked to a six-membered ring containing 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 heterocyclylene or heterocycloalkenylene, optionally substituted by Y 1 , Y 2 , and Y 3 is not directly linked to a six-membered ring containing independently selected from the group consisting of: Q 1 Ga-R g and; Y 1 , Y 2 , and Y 3 But, CR 1 , C(=O), N, and NR 2 each independently selected from the group consisting of: X 1 But O, S, N, NR 2 , and C.R. 1 selected from the group consisting of: X 2 But O, S, N, NR 4 , and C.R. 5 selected from the group consisting of: each TIFF2024532798000014.tif2128 are independently single or double bonds, provided 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 is Y 1 , Y 2 , and Y 3 cannot contain a cyclic group directly attached to a six-membered ring containing R 1 and R 5 Each occurrence of H;R c ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 2 and R 4 Each occurrence of H;R d ;R g ; and -(L g ) bg -R g independently selected from the group consisting of: R 6 But H;R d ; and R g selected from the group consisting of: W is, H, Each of them has 1 to 6 R a2 optionally substituted with C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 In alkynyl, one or more of the optionally substituted methylene groups may be replaced by one or more heteroatoms selected from O or S, and when W is alkenyl or alkynyl, the heteroatoms are sp 2 or not directly linked to an sp carbon, C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 Alkynyl, Each of which is oxo and R c and a monocyclic C 3~8 Cycloalkyl or C 3~8 cycloalkenyl, and Monocyclic heterocyclyl or heterocycloalkenyl of 3 to 8 ring atoms, 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 and R c monocyclic heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of selected from the group consisting of provided that when W is heterocyclyl or heterocycloalkenyl, it is C(=O)NR via a ring carbon atom. 6 attached to the group; R a and R a2 Each occurrence of -OH; -halo; -NR e Rf ;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'';-NR'C(=O)(C 1~4 independently selected from the group consisting of -SF5, -(alkyl), 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 H;NR'R'', -OH, halo, C 1~4 Alkoxy, and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~6 Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CONR'R'';-S(O) 1~2 NR'R'';-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 independently selected from the group consisting of alkoxy; R g Each occurrence of Each of them is oxo, R c , and R h C 3~12 Cycloalkyl or C 3~12 cycloalkenyl, Heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, 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 oxo, R c , and R h 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 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 substituted with 1 to 4 R i heterocyclyl or heterocycloalkenyl, optionally substituted by Heteroaryls 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 1 to 4 R i 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 -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; and Each occurrence of R' and R'' is H; -OH; and C 1~4 alkyl.

[0079] Variable symbol L A (-(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 -*, where * is Q 1 (indicating the attachment point to In some embodiments, L A is a divalent moiety having 1 to 6 (e.g., 2 to 6 (e.g., 2, 3, or 4)) linear array of substituted or unsubstituted carbon and / or heteroatoms. 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, e.g., one cyclic moiety (e.g., C, e.g., C cycloalkylene), and an acyclic moiety (e.g., O).

[0080] In some embodiments, with the proviso that when a3 is 0; and a4 is 1, L 4 Each of them has 1 to 6 R b Optionally substituted with linear C 1~6 Alkylene, linear C 2~6Alkenylene, or linear C 2~6 Other than alkynylene.

[0081] In some embodiments, a2 is 1. In some embodiments, a2 is 0.

[0082] In certain embodiments (when 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.

[0083] In some of the foregoing embodiments, L 2 is 1 to 6 R b Optionally substituted linear C 1~6 It is alkylene.

[0084] In some of the foregoing embodiments, L 2 is 1 to 3 R b Optionally substituted linear C 1~3 It is alkylene.

[0085] In certain embodiments, L 2 -CH2-, -CHR b - and -C(R b )2-. For example, L 2 can be -CH2-.

[0086] In certain embodiments, (L 2 However, 1 to 6 R b Optionally substituted linear C 1~6 alkylene), L 2 is 1 to 3 R b Optionally substituted linear C 2~3 It is alkylene.

[0087] In some of these embodiments, L 2 is 1 to 3 R bIn some of the above embodiments, L is a straight chain C alkylene optionally substituted with 2 is -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is -(L 3 ) a3 - indicates the point of attachment to the -. For example, L 2 can be -CH2CH2-.

[0088] In certain embodiments, L 2 is 1 to 3 R b For example, L 2 teeth, TIFF2024532798000015.tif14128, wherein the asterisk represents -(L 3 ) a3 - indicates the point of attachment to

[0089] In certain embodiments (when a2 is 1), L 2 is 1 to 6 R b Optionally substituted linear C 2~6 In some of these embodiments, L is alkenylene. 2 is 1 to 3 R b Optionally substituted linear C 2~4 Alkenylene. For example, L 2 teeth, TIFF2024532798000016.tif10128, wherein the asterisk is -(L 3 ) a3 - indicates the point of attachment to

[0090] In certain embodiments (when 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 heterocyclylene or heterocycloalkenylene optionally substituted by is selected from the group consisting of:

[0091] In some of these embodiments, L 2 teeth, 1 to 3 R c optionally substituted with C 3~8 cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is 1 to 3 R c heterocyclylene optionally substituted by is selected from the group consisting of:

[0092] In some of the foregoing embodiments, L 2 is 1 to 2 R c may be substituted with TIFF2024532798000017.tif17128, where n1 and n2 are independently 0, 1, or 2; Q 2 CH, CR c , or N; and an asterisk is -(L 3 ) a3 - indicates the point of attachment to

[0093] In some of these aspects, Q 2 is CH.

[0094] In certain embodiments, (L 2 is defined as TIFF2024532798000018.tif17128), n1 and n2 are 0 each.

[0095] As a non-limiting example, (L 2 is defined as TIFF2024532798000019.tif17128), L 2 teeth, TIFF2024532798000020.tif9128, where the asterisk is -(L 3 ) a3 -or-(L 1 ) a1 , for example -(L 1 ) a1 where a1 is 1. For example, L 2 teeth, TIFF2024532798000021.tif9128, where the asterisk is -(L 1 ) a1 In some of these embodiments, -(L 1 ) a1 is O. In some of the aforementioned embodiments, each of a3, a4, and a5 is 0.

[0096] In some embodiments, a1 is 1. In some embodiments, a1 is 0.

[0097] In certain embodiments (when a1 is 1), L 1 -O-, -N(H)-, -N(R d In some of these embodiments, L is selected from the group consisting of - 1 is -O-.

[0098] In some embodiments, a3 is 1. In some embodiments, a3 is 0.

[0099] In certain embodiments (when a3 is 1), L 3 -O-, -N(H)-, -N(R d In some of these embodiments, L is selected from the group consisting of -3 is —O—. In certain other embodiments, L 3 is -N(H)- or -N(R d )- (e.g., -N(H)-).

[0100] In some embodiments, a4 is 1. In some embodiments, a4 is 0.

[0101] In certain embodiments (when a4 is 1), L 4 is 1 to 3 R b Optionally substituted linear C 1~3 In some of these embodiments, L is alkylene. 4 is -CH2-.

[0102] In certain embodiments (when a4 is 1), L 4 teeth, 1 to 3 R c optionally substituted with C 3~8 cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is 1 to 3 R c heterocyclylene optionally substituted by is selected from the group consisting of:

[0103] In some of these embodiments, L 4 is 1 to 2 R c may be substituted with TIFF2024532798000022.tif17128, where n3 and n4 are independently 0, 1, or 2; Q 3 CH, CR c , or N; and an asterisk is -(L 5 ) a5 - indicates the point of attachment to

[0104] In certain embodiments, (L 4 but, TIFF2024532798000023.tif17128), n3 and n4 are each 1. In certain embodiments (L 4 but, TIFF2024532798000024.tif17128), Q 3 is N.

[0105] As a non-limiting example of the foregoing embodiment, L 4 teeth, TIFF2024532798000025.tif10128, where the asterisk is -(L 5 ) a5 - indicates the point of attachment to

[0106] In some embodiments, a5 is 0.

[0107] -(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 - Non-limiting combinations of * In some embodiments, -(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 -* has a length of 1 to 8 atoms (as used herein and for counting purposes only, moieties such as CH, C(O), CF, etc. count as 1 atom whether present in an acyclic or cyclic moiety), e.g., 1 to 6 atoms, or 1 to 5 atoms, or 1 to 4 atoms, or 1 to 3 atoms, or 2 to 6 atoms, or 2 to 4 atoms.

[0108] 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, for example, L 2 When is a cyclic group (eg, cycloalkylene), a1 is 1.

[0109] In certain embodiments, one of a2 and a4 is 1, and the other of a2 and a4 is 0 or 1.

[0110] In some of the aforementioned aspects, one of a1, a3, and a5 is 1, and the other two of a1, a3, and a5 are 0; and One of a2 and a4 is 1, and the other of a2 and a4 is 0 or 1.

[0111] In certain embodiments, 1≦a1+a2+a3+a4+a5≦4. In some of these embodiments, 1≦a1+a2+a3+a4+a5≦3.

[0112] In certain embodiments, a1 and a2 are each 1.

[0113] [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 with linear C 1~3 Alkylene; 1 to 3 R c optionally substituted with C 3~8 cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is 1 to 3 R cheterocyclylene optionally substituted by is selected from the group consisting of:

[0114] [AA2] In certain embodiments, a1 and a2 are each 1; L 1 is -O-; and L 2 is 1 to 3 R b Optionally substituted linear C 1~3 It is alkylene.

[0115] [AA3] In certain embodiments, a1 and a2 are each 1; L 1 is -O-; and L 2 -CH2-, -CHR b - and -C(R b )2-.

[0116] [AA4] In certain embodiments, a1 and a2 are each 1; L 1 is -O-; and L 2 is 1 to 3 R b Optionally substituted linear C 2~3 It is alkylene.

[0117] In certain embodiments of [AA4], L 2 is 1 to 3 R b A non-limiting example of the foregoing embodiment is a straight chain C2 alkylene optionally substituted with 2 is -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is -(L 3 ) a3 - indicates the point of attachment to the -. For example, L 2 can be -CH2CH2-.

[0118] [AA5] In certain embodiments, a1 and a2 are each 1; L 1 is -O-; L 2 teeth, 1 to 3 R c optionally substituted with C 3~8 cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is 1 to 3 R c heterocyclylene optionally substituted by is selected from the group consisting of:

[0119] In certain embodiments of [AA5], L 2 is 1 to 2 R c may be substituted with TIFF2024532798000026.tif17128, where n1 and n2 are independently 0, 1, or 2; Q 2 CH, CR c , or N; and an asterisk is -(L 3 ) a3 - indicates the point of attachment to

[0120] In some of these embodiments, n1 and n2 are independently 0 or 1, optionally 0; and Q 2 is CH. For example, n1 and n2 can both be 0; and Q 2 can be CH, e.g., L 2 can be an optionally substituted cyclobutane-diyl, for example, an optionally substituted cyclobutane-1,3-diyl.

[0121] In certain embodiments, when a1 and a2 are each 1, a3, a4, and a5 are each 0.

[0122] 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.

[0123] In certain embodiments, when a1 and a2 are each 1, a3 and a5 are 0; and a4 is 1.

[0124] 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.

[0125] In certain embodiments (when a1 and a2 are each 1, a3 and a5 are 0; and a4 is 1), L 4 teeth, 1 to 3 R c optionally substituted with C 3~8 cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is 1 to 3 R c heterocyclylene optionally substituted by is selected from the group consisting of:

[0126] In some of these embodiments, L 4 is 1 to 2 R c may be substituted with TIFF2024532798000027.tif17128, where n3 and n4 are independently 0, 1, or 2; Q 3 CH, CR c , or N; and an asterisk is -(L 5 ) a5 In some of the above embodiments, n3 and n4 are independently 0 or 1; and Q 3 is N.

[0127] In certain embodiments, a1 is 0; and a2 is 1.

[0128] [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.

[0129] In certain embodiments of [BB1], L 2 is 1 to 3 R b Optionally substituted linear C 1~3 In some of the above embodiments, L is alkylene. 2 -CH2-, -CHR b - and -C(R b )2-. For example, L 2 can be -CH2-.

[0130] In certain embodiments of [BB1], L 2 is 1 to 3 R b Optionally substituted linear C 2~3 In some of the above embodiments, L is alkylene. 2 is 1 to 3 R b Non-limiting examples include linear C alkylene optionally substituted with L 2 is -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is -(L 3 ) a3 - indicates the point of attachment to the -. For example, L2 can be -CH2CH2-.

[0131] In certain embodiments of [BB1], L 2 is 1 to 3 R b In some of these embodiments, L is a straight chain C alkylene optionally substituted with 2 teeth, TIFF2024532798000028.tif14128, where the asterisk is -(L 3 ) a3 - indicates the point of attachment to

[0132] In certain embodiments (when a1 is 0; and a2 is 1), a3 is 0; and a4 is 0.

[0133] In certain embodiments of [BB1], a3 is 0; and a4 is 0.

[0134] In certain embodiments (when a1 is 0; and a2 is 1), a3 is 1. In certain embodiments of [BB1], a3 is 1.

[0135] In certain embodiments (where a1 is 0; and a2 is 1) or in certain embodiments of [BB1], a3 is 1; and L 3 -O-, -N(H)-, and -N(R d In some of these embodiments, a3 is 1; and L 3 In certain other embodiments, a3 is 1; and L 3 is -N(H)- or -N(R d )-, optionally -N(H)-.

[0136] In certain embodiments (where a1 is 0; and a2 is 1) or in certain embodiments of [BB1], a4 is 1; and L 4 is 1 to 3 R b Optionally substituted linear C 1~3 In some of these embodiments, a4 is 1; and L is alkylene. 4is -CH2-.

[0137] In certain embodiments (when a1 is 0; and a2 is 1) or in certain embodiments of [BB1], a4 is 0.

[0138] [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.

[0139] In certain embodiments of [CC1], L 2 teeth, TIFF2024532798000029.tif9128, wherein the asterisk is -(L 3 ) a3 - indicates the point of attachment to

[0140] In particular embodiments of [CC1], a3 is 0; and a4 is 0.

[0141] For the avoidance of doubt, if any one or more of a1, a2, a3, a4, and a5 is 0, this means that the corresponding variable (L 1 -L 5 ) is L A For example, if a3, a4, and a5 are each 0, this means that the A Formula-L 1 -L 2 - means to have.

[0142] In certain embodiments, L A Ha-L 1 -L 2 -It is.

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

[0144] In certain embodiments, L A Ha-L2 -L 3 -L 4 -It is.

[0145] In certain embodiments, L A can be -CH2CH2-O-*, where * is Q 1 indicates the attachment point to

[0146] In certain embodiments, L A can be -O-CH2CH2-*, where * is Q 1 indicates the attachment point to

[0147] In certain embodiments, L A can be -CH2-O-CH2-.

[0148] In certain embodiments, L A teeth, TIFF2024532798000030.tif8128 (e.g., TIFF2024532798000031.tif9128), where * is Q 1 indicates the attachment point to

[0149] Variable symbol 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 heteroaryl, optionally substituted with 1 to 4 R c C optionally substituted with 6~10 Aryl is selected from the group consisting of:

[0150] In some of these aspects, Q 1 teeth, Heteroaryl of 5-6 ring atoms, 1-4 of which are N, N(H), N(Rd ), O, and S(O) 0~2 and the heteroaryl is one to three R c heteroaryl, optionally substituted with 1 to 3 R c phenyl optionally substituted with is selected from the group consisting of:

[0151] In some of the aforementioned aspects, Q 1 teeth, Heteroaryl having 6 ring atoms, 1 to 2 of which are ring nitrogen atoms, and the heteroaryl is c heteroaryl, optionally substituted with 1 to 3 R c phenyl optionally substituted with is selected from the group consisting of:

[0152] In certain embodiments, Q 1 is 1 to 3 R c In some of these embodiments, Q is phenyl optionally substituted with 1 teeth, TIFF2024532798000032.tif17128.

[0153] 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 c In some of these embodiments, Q is heteroaryl, optionally substituted with 1 is 1 to 3 R c In some of the above embodiments, Q is pyridyl optionally substituted with 1 teeth, TIFF2024532798000033.tif16128.

[0154] In certain embodiments, Q 1is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c and heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0155] In some of these aspects, 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 heterocyclyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0156] In some of the aforementioned aspects, 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 heteroatoms independently selected from the group consisting of: d ) and the heterocyclyl is selected from oxo and R c and heterocyclyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0157] As a non-limiting example of the foregoing embodiment, Q 1 teeth, TIFF2024532798000034.tif17128, wherein m1 and m2 are each independently 0, 1, or 2; and Q 1 is 1 to 2 R c For example, Q 1 teeth, TIFF2024532798000035.tif10128. 1 teeth, It could be TIFF2024532798000036.tif9128.

[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 some of the aforementioned aspects, Q 1 Each R in d C optionally substituted with 1 to 3 independently selected halo 1~6 It is alkyl.

[0160] In some of the aforementioned aspects, 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, 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.

[0162] In certain embodiments, Q 1 Each R in c is halo; cyano; C 1~4Alkoxy;C 1~4 haloalkoxy; and C optionally substituted with 1 to 6 independently selected halo 1~6 alkyl.

[0163] In some of the aforementioned aspects, Q 1 Each R in c C optionally substituted with halo, and 1 to 6 independently selected halo 1~3 alkyl.

[0164] 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.

[0165] In certain embodiments, Q 1 Each R in c is an independently selected halo (e.g., —F or —Cl).

[0166] Variable symbol Y 1 , Y 2 , Y 3 , X 1 , and X 2 In some embodiments, Y 1 is CR 1 is.

[0167] In some embodiments, Y 2 is CR 1 is.

[0168] In some embodiments, Y 3 is CR 1 is.

[0169] In certain embodiments, R 1 Each occurrence of is independently H or R c In some of these embodiments, R 1 Each occurrence of is H.

[0170] In certain other embodiments, R 1 1-2 occurrences of R c and R 1 Each remaining occurrence of is H. For example, R 1 one occurrence of may be halo (e.g., —F or —Cl); and R 1 Each remaining occurrence of can be H.

[0171] In certain embodiments, Y 1 , Y 2 , and Y 3 are independently selected CRs 1 is.

[0172] In certain embodiments, Y 1 , Y 2 , and Y 3 are CH respectively.

[0173] In certain embodiments, Y 1 , Y 2 , and Y 3 One of them is CR c , optionally C-halo; and the remaining two Y 1 , Y 2 , and Y 3 Each of these is CH.

[0174] In some embodiments, X 1 is NR 2 In some of these embodiments, X 1 is NH.

[0175] In some embodiments, X 2 is CR 5 In some of these embodiments, X 2 is CH.

[0176] In certain embodiments, X 1 is NR 2 and X 2 is CR 5 In some of the foregoing embodiments, X 1is NH; and X 2 is CH.

[0177] In certain embodiments, Y 1 , Y 2 , and Y 3 are independently selected CRs 1 and X 1 is NR 2 and X 2 is CR 5 In some of the above embodiments, Y 1 , Y 2 , and Y 3 are CH and X respectively. 1 is NH; and X 2 is CH.

[0178] Variable symbol R 6 and W In some embodiments, R 6 is H.

[0179] In some embodiments, W is selected from 1 to 6 R a2 optionally substituted with C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 It is alkenyl.

[0180] In some of these embodiments, W is 1 to 6 R a2 C optionally substituted with 1~10 In some of the above embodiments, W is selected from 1 to 6 R a2 C optionally substituted with 1~6 It is alkyl.

[0181] In certain embodiments, W is selected from 1 to 6 R a2 C optionally substituted with 1~4 It is alkyl.

[0182] In some of the foregoing embodiments, W is an unsubstituted C 1~4As a non-limiting example of the foregoing embodiment, W can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, and isobutyl. For example, W can be methyl or ethyl.

[0183] In some embodiments, W is selected from 1 to 6 R a2 optionally substituted with C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 Alkenyl in which one or more of the optionally substituted methylene groups therein are replaced by one or more heteroatoms selected from O or S, and when W is alkenyl or alkynyl, the heteroatoms are sp 2 or not directly linked to an sp carbon, C 1~10 Alkyl, C 2~10 Alkenyl, or C 2~10 It is alkenyl.

[0184] In certain embodiments, W is selected from 1 to 6 R a2 C optionally substituted with 1~4 alkyl, wherein one or more of the optionally substituted methylene groups therein are replaced by one or more heteroatoms selected from O or S, and when W is alkenyl or alkynyl, the heteroatoms are sp 2 or not directly linked to an sp carbon, C 1~4 It is alkyl.

[0185] In certain embodiments, W is selected from one R a2 C optionally substituted with 1~4 alkyl in which one or more of the internal methylene groups is replaced by O, C 1~4 It is alkyl.

[0186] In certain embodiments, W is —CH 2 —O—(CH 2 ) 2 —OCH 3 .

[0187] In certain embodiments, W is selected from 1 to 6 R a2is replaced by C 1~4 It is alkyl.

[0188] In some of these embodiments, each R a2 -OH; -halo; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl); and cyano. For example, each R a2 is halo;-OH;C 1~4 Alkoxy; and C 1~4 haloalkoxy may be independently selected from the group consisting of:

[0189] In certain embodiments, W is halo; —OH; C 1~4 Alkoxy; and C 1~4 C substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~4 As a non-limiting example, W is: It could be TIFF2024532798000037.tif10128.

[0190] As another non-limiting example of the above embodiment, W is It could be TIFF2024532798000038.tif7128.

[0191] In some embodiments, W is Each of which is oxo and R c and a monocyclic C 3~8 Cycloalkyl or C 3~8 cycloalkenyl; and Monocyclic heterocyclyl or heterocycloalkenyl of 3 to 8 ring atoms, in which 1 to 3 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 and R c monocyclic heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0192] In some of the foregoing embodiments, W is selected from the group consisting of oxo and R c and a monocyclic C 3~8 Cycloalkyl or C 3~8 It is a cycloalkenyl.

[0193] In some of these embodiments, W is selected from the group consisting of oxo and R c and a monocyclic C 3~8 It is cycloalkyl.

[0194] In certain embodiments, W is an unsubstituted C 3~8 As a non-limiting example of the foregoing embodiment, W can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. For example, W can be cyclobutyl.

[0195] In some embodiments, W is H.

[0196] Non-limiting combinations In certain embodiments, the compound is a compound of formula (Ia): TIFF2024532798000039.tif36128, or a pharmaceutically acceptable salt thereof; During the ceremony: L 1 -O-, -N(H)-, and -N(R d )-selected from the group consisting of; L 2 teeth, 1 to 3 R b Optionally substituted with linear C 1~3Alkylene; 1 to 3 R c optionally substituted with C 3~8 cycloalkylene; and Heterocyclylene having 4 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclylene is 1 to 3 R c heterocyclylene optionally substituted by is selected from the group consisting of:

[0197] In certain embodiments of Formula (Ia), L 1 is -O-.

[0198] In certain embodiments of Formula (Ia), L 2 is 1 to 3 R b Optionally substituted linear C 1~3 It is alkylene.

[0199] In certain embodiments of Formula (Ia), L 2 -CH2-, -CHR b - and -C(R b )2-, optionally wherein L 2 is -CH2-.

[0200] In certain embodiments of Formula (Ia), L 2 is 1 to 3 R b In some of these embodiments, L is a straight chain C alkylene optionally substituted with 2 is -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is -Q 1 indicates the point of attachment to the 2 can be -CH2CH2-.

[0201] In certain embodiments of Formula (Ia), L 2 is 1 to 3 Rb It is a straight chain C3 alkylene optionally substituted with

[0202] In certain embodiments of Formula (Ia), L 2 is 1 to 2 R c optionally substituted with, TIFF2024532798000040.tif17128, where n1 and n2 are independently 0, 1, or 2; Q 2 CH, CR c , or N; and an asterisk is Q 1 indicates the attachment point to

[0203] In some of these embodiments, n1 and n2 are independently 0 or 1, optionally 0; and Q 2 is CH. For example, n1 and n2 can both be 0; and Q 2 can be CH, e.g., L 2 can be an optionally substituted cyclobutane-diyl, for example, an optionally substituted cyclobutane-1,3-diyl.

[0204] In certain embodiments of Formula (Ia), L 1 is -O-; and L 2 is 1 to 2 R c may be substituted with TIFF2024532798000041.tif17128, where n1 and n2 are independently 0 or 1, optionally 0; and Q 2 is CH. For example, n1 and n2 can both be 0; and Q 2 can be CH, e.g., L 2 may be an optionally substituted cyclobutane-diyl, such as an optionally substituted 1,3-cyclobutane-1,3-diyl, such as an unsubstituted cyclobutane-diyl, such as an unsubstituted cyclobutane-1,3-diyl.

[0205] In certain embodiments of Formula (Ia), L 1 is -O-; and L 2 is 1 to 3 Rb Optionally substituted linear C 2~3 It is alkylene.

[0206] In some of the foregoing embodiments of Formula (Ia), L 2 is 1 to 3 R b is a straight-chain C2 alkylene optionally substituted with

[0207] In some of the foregoing embodiments, L 2 is -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is -Q 1 indicates the point of attachment to the 2 can be -CH2CH2-.

[0208] In certain embodiments of Formula (Ia), L 1 is -O-; and L 2 -CH2-, -CHR b - and -C(R b For example, L 2 can be -CH2-.

[0209] In certain embodiments, the compound is a compound of formula (Ib): TIFF2024532798000042.tif36128, or a pharmaceutically acceptable salt thereof; During the ceremony: 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.

[0210] In certain embodiments of Formula (Ib), L 2 is 1 to 3 R b Optionally substituted linear C 2~3 It is alkylene.

[0211] In certain embodiments of Formula (Ib), L2 is 1 to 3 R b In some of these embodiments, L is a straight chain C alkylene optionally substituted with 2 is -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is -Q 1 indicates the point of attachment to the 2 can be -CH2CH2-.

[0212] In certain embodiments of Formula (Ib), L 2 is 1 to 3 R b In some of these embodiments, L is a straight chain C alkylene optionally substituted with 2 teeth, TIFF2024532798000043.tif14128, where the asterisk is -Q 1 indicates the point of attachment to the 2 teeth, It could be TIFF2024532798000044.tif6128.

[0213] In certain embodiments of Formula (Ib), L 2 is 1 to 3 R b Optionally substituted linear C 2~4 It is alkenylene.

[0214] In some of these embodiments, L 2 teeth, TIFF2024532798000045.tif9128, where the asterisk is -Q 1 indicates the attachment point to

[0215] In certain embodiments, the compound is a compound of formula (Ic): TIFF2024532798000046.tif36128, or a pharmaceutically acceptable salt thereof; During the ceremony: L 2 and L 4 is 1 to 6 Rb an independently selected linear C 1~3 alkylene; and L 3 -O-, -N(H)-, and -N(R d )-.

[0216] In certain embodiments of Formula (Ic), L 2 and L 4 -CH2-, -CHR b - and -C(R b In some of these embodiments, L 2 and L 4 are -CH2-, respectively.

[0217] In certain embodiments of Formula (Ic), L 3 is -O-.

[0218] In certain embodiments of Formula (Ic), L 3 is -N(H)- or -N(R d )-. For example, L 3 can be -N(H)-.

[0219] In certain embodiments, the compound is a compound of formula (Id): TIFF2024532798000047.tif36128, or a pharmaceutically acceptable salt thereof; During the ceremony: L 2 is 1 to 6 R b Optionally substituted linear C 1~3 alkylene; and L 3 -O-, -N(H)-, and -N(R d )-.

[0220] In certain embodiments of Formula (Id), L 2 -CH2-, -CHR b - and -C(R b )2.

[0221] In certain embodiments of Formula (Id), L 2 is 1 to 3 R b In some of these embodiments, L is a straight chain C alkylene optionally substituted with 2 is -CH2CH2-, -CH2CH(R b )-*, and -CH2C(R b )2-*, where the asterisk is -L 3 indicates the point of attachment to the 2 can be -CH2CH2-.

[0222] In certain embodiments of Formula (Id), L 3 is -O-.

[0223] In certain embodiments of Formula (Id), L 3 is -N(H)- or -N(R d )-. For example, L 3 can be -N(H)-.

[0224] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, Heteroaryl of 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 one to three R c heteroaryl, optionally substituted with 1 to 3 R c phenyl optionally substituted with is selected from the group consisting of:

[0225] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, Heteroaryl having 6 ring atoms, 1 to 2 of which are ring nitrogen atoms, and the heteroaryl is cheteroaryl, optionally substituted with 1 to 3 R c phenyl optionally substituted with is selected from the group consisting of:

[0226] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 is 1 to 3 R c and n is 1 or 2, each of which is optionally substituted with phenyl or pyridyl.

[0227] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, The file is TIFF2024532798000048.tif16134.

[0228] 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 Here, Q 1 Each R in c C optionally substituted with halo, and 1 to 6 independently selected halo 1~3 alkyl.

[0229] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, TIFF2024532798000049.tif16135; and Q 1 Each R in c are independently selected from the group consisting of -F, -Cl, and -CF3.

[0230] 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 heterocyclyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0231] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, TIFF2024532798000050.tif17128, where m1 and m2 are each independently 0, 1, or 2.

[0232] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, The file is TIFF2024532798000051.tif9128.

[0233] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, TIFF2024532798000052.tif17128; and 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 Here, Q 1 R present in d is C substituted with 1 to 3 -F 2~3 It is alkyl.

[0234] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), Q 1 teeth, TIFF2024532798000053.tif9128; and Q 1 R present in d is -C(O)O(C 1~4alkyl); and 1 to 3 independently selected R a C optionally substituted with 1~6 alkyl; or Here, Q 1 R present in d is C substituted with 1 to 3 -F 2~3 It is alkyl.

[0235] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), each R 1 is H.

[0236] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), R 1 One occurrence of R c and each remaining R 1 is H.

[0237] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), R 2 is H; and R 5 is H.

[0238] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is selected from 1 to 6 R a2 C optionally substituted with 1~6 It is alkyl.

[0239] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is selected from 1 to 6 R a2 C optionally substituted with 1~6 alkyl, wherein one or more of the optionally substituted methylene groups therein are replaced by one or more heteroatoms selected from O or S, and when W is alkenyl or alkynyl, the heteroatoms are sp 2 or not directly linked to an sp carbon, C 1~6 It is alkyl.

[0240] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is an unsubstituted C 1~4 For example, W can be methyl or ethyl.

[0241] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is selected from 1 to 6 R a2 is replaced by C 1~4 It is alkyl.

[0242] In some of these embodiments, W is halo; —OH; C 1~4 Alkoxy; and C 1~4 C substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~4 It is alkyl.

[0243] As a non-limiting example of the foregoing embodiment, W is It could be TIFF2024532798000054.tif10128.

[0244] As another non-limiting example of the above embodiment, W is It could be TIFF2024532798000055.tif7128.

[0245] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is Each of which is oxo and R c and a monocyclic C 3~8 Cycloalkyl or C 3~8 cycloalkenyl; and Monocyclic heterocyclyl or heterocycloalkenyl of 3 to 8 ring atoms, 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 and R cmonocyclic heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of is selected from the group consisting of:

[0246] In certain embodiments of formula (Ia), (Ib), (Ic) or (Id), W is selected from oxo and R c and a monocyclic C 3~8 In some of these embodiments, W is an unsubstituted C 3~8 For example, W can be cyclobutyl.

[0247] 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.

[0248] [Table C1] TIFF2024532798000057.tif218130TIFF2024532798000058.tif222130TIFF2024532798000059.tif221130TIFF2024532798000060.tif224130TIFF2024532798000061.tif222130TIFF2024532798000062.tif209130TIFF2024532798000063.tif202130TIFF2024532798000064.tif220130TIFF2024532798000065.tif212130TIFF2024532798000066.tif220130TIFF2024532798000067.tif220130TIFF2024532798000068.tif219130TIFF2024532798000069.tif215130TIFF2024532798000070.tif210130TIFF2024532798000071.tif219130TIFF2024532798000072.tif216130TIFF2024532798000073.tif209130TIFF2024532798000074.tif209130TIFF2024532798000075.tif200130TIFF2024532798000076.tif219130TIFF2024532798000077.tif222130TIFF2024532798000078.tif222130TIFF2024532798000079.tif204130TIFF2024532798000080.tif223130TIFF2024532798000081.tif212130TIFF2024532798000082.tif225130TIFF2024532798000083.tif214130TIFF2024532798000084.tif198130TIFF2024532798000085.tif220130TIFF2024532798000086.tif212130TIFF2024532798000087.tif218130TIFF2024532798000088.tif216130TIFF2024532798000089.tif228130TIFF2024532798000090.tif212130TIFF2024532798000091.tif222130TIFF2024532798000092.tif222130TIFF2024532798000093.tif214130TIFF2024532798000094.tif232130TIFF2024532798000095.tif212130TIFF2024532798000096.tif204130TIFF2024532798000097.tif224130TIFF2024532798000098.tif216130TIFF2024532798000099.tif206130TIFF2024532798000100.tif205130TIFF2024532798000101.tif202130TIFF2024532798000102.tif223130TIFF2024532798000103.tif206130TIFF2024532798000104.tif236130TIFF2024532798000105.tif212130TIFF2024532798000106.tif225130TIFF2024532798000107.tif200130TIFF2024532798000108.tif200130TIFF2024532798000109.tif223130TIFF2024532798000110.tif200130TIFF2024532798000111.tif211130TIFF2024532798000112.tif214130TIFF2024532798000113.tif203130TIFF2024532798000114.tif214130TIFF2024532798000115.tif219130TIFF2024532798000116.tif214130TIFF2024532798000117.tif205130TIFF2024532798000118.tif222131TIFF2024532798000119.tif218131TIFF2024532798000120.tif211131TIFF2024532798000121.tif225131TIFF2024532798000122.tif202131TIFF2024532798000123.tif216131TIFF2024532798000124.tif189131TIFF2024532798000125.tif203131TIFF2024532798000126.tif228131TIFF2024532798000127.tif217131TIFF2024532798000128.tif220131TIFF2024532798000129.tif218131TIFF2024532798000130.tif227131TIFF2024532798000131.tif205131TIFF2024532798000132.tif200131TIFF2024532798000133.tif217131TIFF2024532798000134.tif205131TIFF2024532798000135.tif221131TIFF2024532798000136.tif225131TIFF2024532798000137.tif222131TIFF2024532798000138.tif222131TIFF2024532798000139.tif204131TIFF2024532798000140.tif204131TIFF2024532798000141.tif229131TIFF2024532798000142.tif183131TIFF2024532798000143.tif224131TIFF2024532798000144.tif227131TIFF2024532798000145.tif204131TIFF2024532798000146.tif219131TIFF2024532798000147.tif209131TIFF2024532798000148.tif221131TIFF2024532798000149.tif220131TIFF2024532798000150.tif216131TIFF2024532798000151.tif212131TIFF2024532798000152.tif228131TIFF2024532798000153.tif194131TIFF2024532798000154.tif212131TIFF2024532798000155.tif221131TIFF2024532798000156.tif217131TIFF2024532798000157.tif219131T IFF2024532798000158.tif201131TIFF2024532798000159.tif237131TIFF2024532 798000160.tif207131TIFF2024532798000161.tif205131TIFF2024532798000162. tif208131TIFF2024532798000163.tif207131TIFF2024532798000164.tif112131.

[0249] 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 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.

[0250] In some embodiments, chemical entities can be administered in combination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, surfactants used in pharmaceutical dosage forms such as self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, Tween, poloxamer or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, wax, polyethylene-polyoxypropylene block polymers, and wool fat. Chemically modified derivatives, such as cyclodextrins, including α-, β-, and γ-cyclodextrin, or hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilized derivatives, can also be used to enhance delivery of the compounds described herein. Dosage forms or compositions may be prepared containing 0.005% to 100% of the chemical entities 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 the chemical entities provided herein. Actual methods for preparing such dosage forms are 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).

[0251] Route of Administration and Composition Components In some aspects, the chemical entities described herein or pharmaceutical compositions thereof can be administered to a subject in need thereof by any approved route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, intrasinusial, intratracheal, enteral, epidural, interstitial, intraabdominal, intraarterial, intrabronchial, intrasynovial, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinusoidal, intraspinal, intrasynovial, intratesticular, intrathecal, intraductal, intratumor, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the preferred route of administration is parenteral (eg, intratumoral).

[0252] Composition can be formulated for parenteral administration, for example, can be formulated for injection via intravenous, intramuscular, subcutaneous or even intraperitoneal route.Typically, such composition can be prepared as an injectable solution, either as a liquid solution or suspension, and can also be prepared in a solid form suitable for preparing solution or suspension by adding liquid before injection, and preparation can also be emulsified.The preparation of such preparations is known to those skilled in the art in light of the present disclosure.

[0253] Suitable pharmaceutical forms for injectable use include sterile aqueous solutions or dispersions, formulations containing sesame oil, peanut oil, or aqueous propylene glycol, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.In all cases, the form must be sterile and fluid to the extent that it can be easily injected.It must also be stable under the conditions of production and storage, and must be protected against the contaminating action of microorganisms such as bacteria and fungi.

[0254] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of injectable compositions can be achieved by using agents delaying absorption, for example, aluminum monostearate and gelatin in the compositions.

[0255] Sterile injectable solution can be prepared by incorporating the active compound in the required amount in suitable solvent with various other components as listed above as required, and then sterile filtering.Generally, dispersion is prepared by incorporating various sterilized active ingredients into sterile medium that contains basic dispersion medium and other components as listed above.For the sterile powder that is used to prepare sterile injectable solution, the preferred method of preparation is vacuum drying and freeze-drying technology, which can produce the powder of active ingredient and any additional desired components from the solution that has been previously sterile filtered.

[0256] Intratumoral injection is discussed, for example, in Lammers, et al., "Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems," Neoplasia. 2006, 10, 788-795.

[0257] Pharmaceutically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerin 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, parabens in aerosols, phenoxyethanol, methyl p-hydroxybenzoate, The additives and preservatives may include, but are not limited to, any one or more of sodium, propyl sodium p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, edetate sodium, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0258] 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 thus melts in the rectum to release the active compound. In other embodiments, compositions for rectal administration are in the form of enemas.

[0259] In other embodiments, the compounds described herein or pharmaceutical compositions thereof are suitable for local delivery to the digestive or GI tract via oral administration (e.g., solid or liquid dosage forms).

[0260] The solid dosage form for oral administration includes capsules, tablets, pills, powders and granules.In such solid dosage form, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) wetting agents, such as glycerol, d) disintegrants, 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) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, dosage forms may also contain buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols.

[0261] In one embodiment, the composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain, together with the chemical entities provided herein, a diluent such as lactose, sucrose, or 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, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated, such as capsules (or tablets in capsules) with granules of each drug, bilayer tablets, bicompartment gelcaps, etc. Enteric-coated or delayed-release oral dosage forms are also contemplated.

[0262] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives specifically useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0263] In certain embodiments, the excipients are sterile and generally free of undesirable substances. 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.

[0264] In certain embodiments, the solid oral dosage form can further comprise one or more components that provide the composition with a chemical and / or structural predisposition for delivery of the chemical entity to the stomach or lower GI, for example, the ascending colon and / or the transverse colon and / or the distal colon and / or the small intestine.Exemplary formulation techniques are described, for example, in Filipski, KJ, et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

[0265] Examples include upper GI targeting technologies such as the Accordion Pill (Intec Pharma), floating capsules, and materials that can adhere to mucosal walls.

[0266] Other examples include lower GI targeting technology. Several enteric / pH-responsive coatings and excipients can be used to target various regions in the intestinal tract. These materials are typically polymers designed to dissolve or erode in 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 juice or limit exposure when the active ingredient may be irritating to the upper GI (e.g., hydroxypropylmethylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer), and Marcoat). Other technologies include dosage forms that respond to local flora in the GI tract, pressure-controlled colonic delivery capsules, and Pulsincap.

[0267] The ophthalmic composition may include, but is not limited to, any one or more of the following: viscogen (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.)).

[0268] External compositions can include ointments and creams. Ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. Creams containing selected active agents are typically viscous liquids or semi-solid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "internal" phase, generally contains petrolatum and a fatty alcohol, such as cetyl or stearyl alcohol, while the aqueous phase usually, but 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 should be inert, stable, non-irritating, and non-sensitizing.

[0269] In any of the foregoing embodiments, the pharmaceutical compositions described herein can comprise one or more of: 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.

[0270] Dosage Dosage may vary depending on the patient's needs, the severity of the condition being treated, and the specific compound being used. Determining the appropriate dosage for a specific situation can be determined by those skilled in the medical field. The total daily dosage may be divided or administered in portions throughout the day or by means of continuous delivery.

[0271] 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).

[0272] Regimen The dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or off-daily (e.g., every other day, every second day, every third day, once a week, twice a week, once every two weeks, once a month).

[0273] In some embodiments, the duration of administration of the compounds described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, the period 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 a period of time, followed by separate periods of time. In another embodiment, a therapeutic compound is administered for a first period of time, and for a second period of time after the first period during which administration is discontinued during the second period, followed by a third period of time during which administration of the therapeutic compound is initiated, and then a fourth period of time after the third period during which administration is discontinued. In one aspect of this embodiment, the period of administration of a therapeutic compound, followed by a period during which administration is discontinued, is repeated for a determined or undetermined period of time. In further embodiments, the duration of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, the period of time for which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0274] Treatment methods In some aspects, methods are provided for treating a subject having a condition, disease, or disorder (e.g., immune disorder, cancer) in which increased (e.g., enhanced) STING activity (e.g., STING signaling, etc.) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder.

[0275] 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 or renal cancer, clear cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung cancer including adenocarcinoma of the lung and squamous carcinoma of the lung, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), cervical cancer, ovarian cancer, prostate cancer, prostate neoplasms, liver cancer, bladder cancer, cancer of the peritoneum, hepatocellular carcinoma, gastric or esophageal cancer including gastrointestinal cancer. Hematological malignancies including tomach cancer, gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, thecoma, allenoblastoma, hepatoma, non-Hodgkin's lymphoma (NHL), multiple myeloma, myelodysplastic disorders, myeloproliferative disorders, chronic myeloid leukemia, and acute hematological malignancies, endometrial or uterine cancer, endometriosis, endometrial stromal sarcoma, fibrosarcoma, choriocarcinoma, salivary gland cancer, vulvar cancer, thyroid cancer Cancers include esophageal cancer, liver cancer, anal cancer, penile cancer, nasopharyngeal cancer, laryngeal cancer, Kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin cancer, schwannoma, oligodendroglioma, neuroblastoma, neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, Ewing's sarcoma, peripheral primitive neuroectodermal tumor, urinary tract cancer, thyroid carcinoma, Wilms' tumor, as well as abnormal blood vessel proliferation associated with phacomatosis, edema (e.g., associated with brain tumors), and Meigs' syndrome. In some cases, the cancer is melanoma.

[0276] In some embodiments, the condition, disease, or disorder is a neurological disorder, which includes disorders involving the central nervous system (brain, brainstem, and cerebellum), the peripheral nervous system (including the 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 epileptic aphasia, acute powder-borne encephalomyelitis, adrenoleukodystrophy, age-related macular degeneration, dysgenesis of the corpus callosum, agnosia, Aicardi syndrome, Alexander disease, Alpers disease, alternating hemiplegia, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis, anencephaly, Angelman syndrome, hemangiomatosis, anoxia, aphasia, apraxia, arachnoid cyst, arachnoiditis, Anronl-Chiari malformation, arteriovenous malformation, Asperger's syndrome, ataxia telegiectasia, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Batten disease, Behcet's disease, Bell's palsy, benign essential blepharospasm, benign focal glaucoma, and glaucoma. focal), muscle atrophy, benign intracranial hypertension, Binswanger's disease, blepharospasm, Bloch-Sulzberger syndrome, brachial plexus injury, brain abscess, brain injury, brain tumor (including glioblastoma multiforme), spinal cord tumor, Brown-Séquard syndrome, Canavan disease, carpal tunnel syndrome, causal pain, central pain syndrome, central pontine myelinolysis, head injury, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, Charcot-Marie-Tooth disease, chemotherapy-induced neuropathy and neuropathic pain, Chiari malformation, chorea, chronic inflammatory demyelinating polyneuropathy, chronic pain, chronic regional pain syndrome, Coffin-Lowry syndrome, coma including persistent vegetative state, congenital facial diplegia, corticobasal ganglia degeneration Neuropathy, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion disease, cytomegalovirus infection, dancing eyes-dancing feet syndrome, Dandy-Walker syndrome, Dawson's disease, Domorsia syndrome, Dejerine-Klumke palsy, dementia, dermatomyositis, diabetic neuropathy, diffuse sclerosis, autonomic dysfunction, dysgraphia, dyslexia, dystonia, early infantile epileptic encephalopathy, empty sella syndrome, encephalitis, encephalitis, cerebral trigeminal angiomatosis, epilepsy, Erb's palsy, essential tremor, Fabry's disease, Fahr's syndrome, syncope, familial spastic paralysis, febrile seizures,Fisher syndrome, Friedreich's ataxia, frontotemporal dementia and other "tauopathies", Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, Guillain-Barré syndrome, HTLV-1-associated myelopathy, Hallervorden-Spatz disease, head injury, headache, hemifacial spasm, hereditary spastic paraplegia, polyneuropathy-type hereditary ataxia, herpes zoster oticus, herpes zoster oticus Herpes, Hirayama syndrome, HIV-associated dementia and neuropathy (also a neurological manifestation of AIDS), holoprosencephaly, Huntington's disease and other polyglutamine repeat diseases, hydrocephalus, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum's disease, infantile spasms, inflammatory myopathy, intracranial cysts, intracranial hypertension, Joubert's disease syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbone syndrome, Klippel-Feil syndrome, Krabbe disease, Kugelberg-Welander disease, Kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, Lateral bulbar (Wallenberg) syndrome, Learning disabilities, Leigh disease, Lennox-Gustaut syndrome, Lesch-Nyhan syndrome, Leukodystrophy, Dementia with Lewy bodies, Lissencephaly, Locked-in syndrome, Lou Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis), Lumbar discopathy, Lyme disease - neurological sequelae, Machado-Joseph disease, Macrencephaly, Megalencephaly, Melkersson-Rosenthal syndrome, Meniere's disease disease), meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, migraine, Miller-Fisher syndrome, ministroke, mitochondrial myopathy, Moebius syndrome, single limb muscular atrophy, motor neuron disease, Moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis and other demyelinating disorders, multiple system atrophy with orthostatic hypotension, p muscular dystrophy, myasthenia gravis, myelinoclastic diffuse sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy,Congenital myotonia, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, neurological symptoms of AIDS, neurological sequelae of lupus, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorders, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occult neuralgia, occult spinal dysraphism sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus, optic neuritis, orthostatic hypotension, overuse syndrome, paresthesia, Parkinson's disease, congenital paramyotonia, paraneoplastic disorders disease, seizures, Paley-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralysis, peripheral neuropathy, painful neuropathy and neuropathic pain, persistent vegetative state, pervasive developmental disorder, photophobia, sneeze reflex, phytanic acid storage disease, Pick's disease, pinched nerve nerve), pituitary tumor, polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia, post-infectious encephalomyelitis, orthostatic hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion disease, progressive hemiface atrophy, progressive multifocal leukoencephalopathy, progressive sclerosing poliodystrophy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay-Hunt syndrome (types I and II), Rasmussen encephalitis, reflex sympathetic dystrophy syndrome, Refsum's disease, repetitive movement disorder, repetitive stress injury, restless legs syndrome, retrovirus-associated myelopathy, Rett's syndrome, Reye's syndrome, chorea, Sandhoff's disease, Schilder's disease, schizencephaly, septo-optic dysplasia, shaken baby syndrome, shingles, Shy-Drager syndrome, Sjögren'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 spinal cord syndrome, Thomsen's disease, thoracic outlet syndrome, trigeminal neuralgia, Todd's palsy, Tourette's syndrome, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraplegia, tuberous sclerosis, vascular dementia (multi-infarct dementia), vasculitis including temporal arteritis, von Hippel-Lindau disease,These include Wallenberg syndrome, Werdnig-Hoffmann disease, West syndrome, whiplash injury, Williams syndrome, Wildon's disease, amyotrophic lateral sclerosis, and Zellweger syndrome.

[0277] In some embodiments, the condition, disease, or disorder is a STING-associated condition, for example, type I interferonopathy (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. In certain embodiments, the condition, disease, or disorder is an autoimmune disease (e.g., cytosolic DNA-induced autoinflammatory disease). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions associated with polygenic susceptibility. In certain embodiments, the condition is inflammatory bowel disease. In certain embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated with one or more alloimmune diseases (e.g., graft-versus-host disease, e.g., acute graft-versus-host disease and chronic graft-versus-host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is an alloimmune disease (e.g., graft-versus-host disease, e.g., acute graft-versus-host disease and chronic graft-versus-host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis, or intestinal mucositis).

[0278] In some embodiments, modulation of the immune system by STING provides treatment for diseases, including diseases caused by foreign agents. Exemplary infections caused by foreign agents 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 infection is a parasitic infection (e.g., an infection caused by a unicellular or multicellular parasite, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondiz). In yet another embodiment, the infectious disease is a viral infection (e.g., AIDS, avian influenza, chickenpox, cold sores, the common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, lower or upper respiratory tract infections (e.g., respiratory syncytial virus), Ebola, Zika, and infections caused by viruses associated with SARS-COV-2 (COVID19)).

[0279] In some embodiments, the condition, disease, or disorder is hepatitis B (see, e.g., WO 2015 / 061294).

[0280] In some embodiments, the condition, disease, or disorder is selected from cardiovascular diseases (including, for example, myocardial infarction).

[0281] In some embodiments, the condition, disease, or disorder is age-related macular degeneration.

[0282] In some aspects, the condition, disease, or disorder is mucositis, also known as stomatitis, which can occur as a result of damage caused by chemotherapy or radiation therapy, either alone or in combination, as well as exposure to radiation outside the context of radiation therapy.

[0283] In some aspects, the condition, disease, or disorder is uveitis, which is an inflammation of the uvea (e.g., anterior uveitis, e.g., iridocyclitis or iritis, intermediate uveitis (also known as pars planitis), posterior uveitis, or chorioretinitis, e.g., panuveitis).

[0284] In some embodiments, the condition, disease, or disorder is selected from the group consisting of cancer, a neurological disorder, an autoimmune disease, hepatitis B, uveitis, cardiovascular disease, age-related macular degeneration, and mucositis.

[0285] In some embodiments, the condition, disease or disorder is selected from the group consisting of familial lupus pernio, RVCL (autosomal dominant retinal vasculopathy with cerebral leukodystrophy), lupus nephritis (LN), Sjogren's syndrome (SS), pulmonary inflammation, acute pulmonary inflammation, idiopathic pulmonary fibrosis, hepatic and renal fibrosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, endomyocardial fibrosis, acute and chronic kidney injury, APOL1-associated podocytopathy, acute pancreatitis, chronic obstructive pulmonary disease (COPD), senescence, and aging.

[0286] Further examples include the indications discussed below herein and contemplated combination therapy regimens.

[0287] Combination therapy The present disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[0288] In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of the compounds described herein.

[0289] In certain embodiments, the methods described herein can further comprise administering one or more additional cancer therapies.

[0290] The one or more additional cancer therapies can include, but are not limited to, surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, Hepatitis B vaccine, Oncophage, Provenge), and gene therapy, as well as combinations thereof. Immunotherapies include, but are not limited to, adoptive cell therapy, stem cell and / or dendritic cell derivation, blood transfusion, lavage, and / or other treatments, including, but not limited to, tumor freezing.

[0291] In some embodiments, the one or more additional cancer therapies is chemotherapy, which can include administering one or more additional chemotherapeutic agents.

[0292] 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 targets an immune checkpoint receptor, such as CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T-cell immunoglobulin and mucin 3 (TIM3 or HAVCR2). ), galectin 9-TIM3, phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-C D160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NK The antigens selected from the group consisting of G2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1). See, for example, Postow, MJ Clin. Oncol. 2015, 33, 1.

[0293] In certain of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of urelumab, PF-05082566, MEDI6469, TRX518, valilumab, CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-L1), avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertib, urocuplumab, BKT140, bavituximab, CC-90002, bevacizumab, and MNRP1685A, and MGA271.

[0294] In certain embodiments, the additional chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because of their ability to alkylate many nucleophilic functional groups under conditions present in cells, including, but not limited to, cancer cells. In further embodiments, alkylating agents include, but are not limited to, cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin. In one embodiment, alkylating agents can function by forming covalent bonds with amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules, thereby impairing cellular function, or they can act by modifying cellular DNA. In further embodiments, the alkylating agent is synthetic, semi-synthetic, or a derivative.

[0295] In certain embodiments, the additional chemotherapeutic agent is an antimetabolite. Antimetabolites masquerade as purines or pyrimidines, the building blocks of DNA, and generally prevent these substances from being incorporated into DNA during the "S" phase (of the cell cycle), halting normal development and division. Antimetabolites can also affect RNA synthesis. In one embodiment, antimetabolites include, but are not limited to, azathioprine and / or mercaptopurine. In further embodiments, the antimetabolite is synthetic, semi-synthetic, or a derivative.

[0296] In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and / or terpenoid. These alkaloids are derived from plants and generally block cell division by preventing microtubule function. In one embodiment, the plant alkaloid and / or terpenoid is a vinca alkaloid, podophyllotoxin, and / or taxane. Vinca alkaloids generally bind to specific sites on tubulin and inhibit the assembly of tubulin into microtubules, generally during the M phase of the cell cycle. In one embodiment, the vinca alkaloid is derived from, but is not limited to, Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). In one embodiment, the vinca alkaloid includes, but is not limited to, vincristine, vinblastine, vinorelbine, and / or vindesine. In one embodiment, the taxanes include, but are not limited to, taxol, paclitaxel, and / or docetaxel. In a further embodiment, the plant alkaloids or terpenoids are synthetic, semi-synthetic, or derivatives. In a further embodiment, the podophyllotoxins are, but are not limited to, etoposide and / or teniposide. In one embodiment, the taxanes are, but are not limited to, docetaxel and / or ortataxel. In one embodiment, the cancer therapeutic agent is a topoisomerase. Topoisomerases are essential enzymes that maintain DNA topology. Inhibition of type I or type II topoisomerases interferes with both DNA transcription and replication by disrupting proper DNA supercoiling. In a further embodiment, the topoisomerase is, but is not limited to, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, the type I topoisomerase inhibitor is, but is not limited to, camptothecin, hi 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 the American mayapple (Podophyllum peltatum).

[0297] In certain embodiments, the additional chemotherapeutic agent is a stilbenoid. In further embodiments, stilbenoids include, but are not limited to, resveratrol, piceatannol, pinosylvin, pterostilbene, α-viniferin, ampelopsin A, ampelopsin E, diptoindonesin C, diptoindonesin F, epsilon-vinferin, flexuosol A, gnetin H, hemsleyanol D, hopeaphenol, trans-diptoindonesin B, astringin, piceid, and diptoindonesin A. In further embodiments, the stilbenoid is synthetic, semi-synthetic, or a derivative.

[0298] 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 aspect, the cytotoxic antibiotic is synthetic, semi-synthetic, or a derivative.

[0299] In certain embodiments, the additional chemotherapeutic agent is endostatin, angiogenin, angiostatin, chemokine, angioarrestin, angiostatin (plasminogen fragment), basement membrane collagen-derived antiangiogenic factor (tumstatin, canstatin, or arrestin), antiangiogenic antithrombin III, signal transduction inhibitor, cartilage-derived inhibitor (CDI), CD59 complement fragment, fibronectin fragment, gro-β, heparinase, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon α / β / γ, interferon-inducible protein (I P-10), interleukin-12, kringle 5 (plasminogen fragment), metalloproteinase inhibitor (TIMP), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4), prolactin 16 kD fragment, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth factor-β (TGF-β), vasculostatin, and vasostatin (calreticulin fragment).

[0300] 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-proly-1-L-proline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'-deoxy-8'-norvin-caleukoblastine, docetaxel, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine Selected from dolastatins, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

[0301] In certain embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide, and doxorubicin. Additional agents include inhibitors of mTOR (mammalian target of rapamycin), including, but not limited to, rapamycin, everolimus, temsirolimus, and deforolimus.

[0302] In still other embodiments, the additional chemotherapeutic agent can be selected from those described in detail in US Pat. No. 7,927,613, which is incorporated herein by reference in its entirety.

[0303] 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), inherited forms of lupus, and inflammation-related disorders such as systemic lupus erythematosus and rheumatoid arthritis.

[0304] Non-limiting examples of additional therapeutic agents and / or regimens for treating rheumatoid arthritis include nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), disease-modifying antirheumatic drugs (DMARDs, e.g., methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), leflunomide (Arava®), hydroxychloroquine (Plaquenil), PF-06650833, iguratimod, tofacitinib (Xeljanz®), ABBV-599, evobrutinib, and sulfasalazine (Azulfidine®), and biologics (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®)).

[0305] 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, filogotinib, GS-9876, rapamycin, and PF-06650833), and biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, obinutuzumab, bovalizumab, lulizumab, izumab), atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edoratide, IFN-α-kinoid, 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., iveldomide, voclosporin, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycobacterial agents (e.g., fluticasone, fluoxetine ... 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, immunomodulatory agents (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), GS-9876, filgotinib, and thalidomide (Thalomid®). Agents and regimens for treating drug-induced and / or neonatal lupus can also be administered.

[0306] 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).

[0307] Non-limiting examples of additional therapeutic agents and / or regimens for treating Aicardi-Goutières syndrome (AGS) include physical therapy, treatment for respiratory complications, anticonvulsant therapy for seizures, tube feeding, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine (e.g., Emtriva®), tenofovir (e.g., Viread®), emtricitabine / tenofovir (e.g., Truvada®), zidovudine, lamivudine, and abacavir), and JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[0308] Non-limiting examples of additional therapeutic agents and / or regimens for treating IBD include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34-selected peripheral blood stem cell transplantation, azathioprine, bertilimumab, BI 655066, BMS-936557, certolizumab pegol (Cimzia®), cobitolimod, corticosteroids (e.g., prednisone, methylprednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbial transplant, filgotinib, fingolimod, filategrast (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, HMPL-004 (Andrographis paniculata paniculata extract), IMU-838, infliximab, interleukin-2 (IL-2), Janus kinase (JAK) inhibitors, laquinimod, masitinib (AB1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mirikizumab (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peficitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab (MK 3222), TJ301, TNF-Kinoid®, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, vatelizumab, VB-201, vedolizumab, and vidofludimus.

[0309] Non-limiting examples of additional therapeutic agents and / or regimens for treating irritable bowel syndrome include alosetron, bile acid sequestrants, sequesterants (e.g., cholestyramine, colestipol, colesevelam), chloride channel activators (e.g., lubiprostone), coated peppermint oil capsules, desipramine, dicyclomine, ebastine, eluxadoline, farnesoid X receptor agonists (e.g., obeticholic acid), fecal microbiota transplantation, fluoxetine, gabapentin, guanylate cyclase-C agonists (e.g., linaclotide, plecanatide), ibodutant, imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, ondansetron, opioids, paroxetine, pinaverium, polyethylene glycol, pregabalin, probiotics, ramosetron, rifaximin, and tenapanor.

[0310] Non-limiting examples of additional therapeutic agents and / or regimens for treating scleroderma include nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), immunomodulators (e.g., azathioprine, methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®). ), Gengraf®), antithymocyte globulin, mycophenolate mofetil, intravenous immunoglobulin, rituximab, sirolimus, and alefacept), calcium channel blockers (e.g., nifedipine), alpha-blockers, serotonin receptor antagonists, angiotensin II receptor inhibitors, statins, topical nitrates, iloprost, phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan, tetracycline antibiotics, endothelin receptor antagonists, prostanoids, and tyrosine kinase inhibitors (e.g., imatinib, nilotinib, and dasatinib).

[0311] 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 transplant, filgotinib, guselkumab, infliximab, IL-2, JAK inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, natalizumab, ozanimod, RHB-104, rifaximin, risankizumab, SHP647, sulfasalazine, thalidomide, upadacitinib, V565, and vedolizumab.

[0312] 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), budesonide), methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, fecal microbial transplant, filgotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mirikizumab (LY3074828), RPC1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tofacitinib, ustekinumab, UTTR1147A, and vedolizumab.

[0313] 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.

[0314] 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.

[0315] 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.

[0316] Non-limiting examples of additional therapeutic agents and / or regimens for treating colitis induced by treatment with adoptive cell therapy include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), diphenoxylate / atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0317] 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.

[0318] Non-limiting examples of additional therapeutic agents and / or regimens for treating radiation enteritis include teduglutide, amifostine, angiotensin-converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril), probiotics, selenium supplementation, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin), sucralfate, and vitamin E.

[0319] Non-limiting examples of additional therapeutic agents and / or regimens for treating collagenous colitis include 6-mercaptopurine, azathioprine, bismuth subsalicate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0320] Non-limiting examples of additional therapeutic agents and / or regimens for treating lyphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), loperamide, mesalamine, methotrexate, and sulfasalazine.

[0321] Non-limiting examples of additional therapeutic agents and / or regimens for treating microscopic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), fecal microbial transplant, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[0322] Non-limiting examples of additional therapeutic agents and / or regimens for treating alloimmune diseases include intrauterine platelet transfusions, intravenous immunoglobulin, maternal steroids, abatacept, alemtuzumab, alpha 1-antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisolone, prednisone), cyclosporine, dacilzumab, defibrotide (d efribrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, nemolizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0323] Non-limiting examples of additional therapeutic agents and / or regimens for treating multiple sclerosis (MS) include alemtuzumab (Lemtrada®), ALKS 8700, amiloride, ATX-MS-1467, azathioprine, baclofen (Lioresal®), beta interferons (e.g., IFN-β-1a, IFN-β-1b), cladribine, corticosteroids (e.g., methylprednisolone), daclizumab, dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), fluoxetine, and fluoxetine. These include cetin, glatiramer acetate (Copaxone®), hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVax™, ocrelizumab, ofatumumab, pioglitazone, and RPC1063.

[0324] Non-limiting examples of additional therapeutic agents and / or regimens for treating graft-versus-host disease include abatacept, alemtuzumab, alpha 1-antitrypsin, AMG592, antithymocyte globulin, baricitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisolone, prednisone), cyclosporine, daclizumab, defibrotide, These include denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, nemolizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0325] Non-limiting examples of additional therapeutic agents and / or regimens for treating acute graft-versus-host disease include alemtuzumab, alpha-1 antitrypsin, antithymocyte globulin, basiliximab, brentuximab, corticosteroids (e.g., methylprednisolone, prednisone), cyclosporine, daclizumab, defibrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate mofetil, natalizumab, nemolizumab, pentostatin, photopheresis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.

[0326] Non-limiting examples of additional therapeutic agents and / or regimens for treating chronic graft-versus-host disease include abatacept, alemtuzumab, AMG592, antithymocyte globulin, basiliximab, bortezomib, corticosteroids (e.g., methylprednisolone, prednisone), cyclosporine, daclizumab, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0327] Non-limiting examples of additional therapeutic agents and / or regimens for treating celiac disease include AMG 714, AMY01, Aspergillus niger prolyl endoprotease, BL-7010, CALY-002, GBR 830, Hu-Mik-Beta-1, IMGX003, KumaMax, larazotide acetate, Nexvan2®, pancrelipase, TIMP-GLIA, vedolizumab, and ZED1227.

[0328] Non-limiting examples of additional therapeutic agents and / or regimens for treating psoriasis include topical corticosteroids, topical crisaborole / AN2728, topical SNA-120, topical SAN021, topical tapinarof, topical tocafinib, topical IDP-118, topical M518101, topical calcipotriene and betamethasone dipropionate (e.g., MC2-01 cream and Taclonex®), topical P-3073, topical LEO 90100 (Enstilar®), topical betamethasone dipropionate, topical ... dipropriate) (Sernivo®), halobetasol propionate (Ultravate®), vitamin D analogs (e.g., calcipotriene (Dovonex®) and calcitriol (Vectical®)), anthralin (e.g., Dritho-scalp® and Dritho-creme®), topical retinoids (e.g., tazarotene (e.g., Tazorac® and Avage®)), calcineurin inhibitors (e.g., tacrolimus (Prograf®) and pimecrolimus (Elidel®)), salicylic acid, coal tar, moisturizers, phototherapy (e.g., sun exposure, UVB phototherapy, narrowband UVB phototherapy, Goeckerman therapy, solar radiation therapy, Treatment options include steroids, antihistamines, anti-inflammatory drugs (anticoagulants, anti-inflammatory drugs ...Etanercept (Enbrel®), etanercept-szzs (Elrezi®), infliximab (Remicade®), adalimumab (Humira®), adalimumab-adbm (Cyltezo®), ustekinumab (Stelara®), golimumab (Simponi®), apremilast (Otezla®), secukinumab (Cosentyx®), certolixumab pegol, secukinumab, tildrakizumab-asmn, infliximab-dyyb, abatacept, ixekizumab (Taltz®), ABP 710, BCD-057, BI695501, bimekizumab (UCB4940), CHS-1420, GP2017, guselkumab (CNTO 1959), HD203, M923, MSB11022, mirikizumab (LY3074828), PF-06410293, PF-06438179, risankizumab (BI655066), SB2, SB4, SB5, siliq (brodalumab), namilumab (MT203, tildrakizumab (MK-3222), and ixekizumab (Taltz®)), thioguanine, and hydroxyurea (e.g., Droxia® and Hydrea®).

[0329] Non-limiting examples of additional therapeutic agents and / or regimens for treating cutaneous T-cell lymphoma include phototherapy (e.g., sunlight exposure, UVB phototherapy, narrowband UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photopheresis, radiation therapy (e.g., spot radiation and 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).

[0330] Non-limiting examples of additional therapeutic agents and / or regimens for treating uveitis include corticosteroids (e.g., intravitreal triamcinolone acetonide injectable suspension), antibiotics, antivirals (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Gengraf®), chlorambucil, azathioprine, methotrexate, and mycophenolate mofetil), biologics (e.g., infliximab (Remicade®), adalimumab (Humira®), etanercept (Enbrel®), golimumab (S imponi®), certolizumab (Cimzia®), rituximab (Rituxan®), abatacept (Orencia®), basiliximab (Simulect®), anakinra (Kineret®), canakinumab (Ilaris®), gevokixumab (XOMA052), tocilizumab (Actem®), ra®), alemtuzumab (Campath®), efalizumab (Raptiva®), LFG316, sirolimus (Santen®), abatacept, sarilumab (Kevzara®), and daclizumab (Zenapax®), cytotoxic drugs, surgical implants (e.g., fluocinolone inserts), and vitrectomy.

[0331] Non-limiting examples of additional therapeutic agents and / or regimens for treating mucositis include AG013, SGX942 (dusquetide), amifostine (Ethyol®), cryotherapy, cepacol lozenges, capsaicin lozenges, mucoadhesives (e.g., MuGard®), oral diphenhydramine (e.g., Benadry® elixir), oral bioadherents (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita (Maetolipids), and others. recutita) mouthwash, table grape plant exosomes, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periodogard®)), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol), corticosteroids (e.g., prednisone), painkillers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor, Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble β-1,3 / 1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, granules containing vaccinium myrtillus extract, macleaya cordata alkaloids, and echinacea angustifolia angustifolia extract (e.g., SAMITAL®), and a gastrointestinal cocktail (acid reducers, such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungals (e.g., nystatin), and pain relievers (e.g., hurricane liquid)). For example, non-limiting examples of treatments for oral mucositis include AG013, amifostine (Ethyol®), cryotherapy, Cepacor lozenges, mucoadhesives (e.g., MuGard®), oral diphenhydramine (e.g., Benadry® elixir), oral bioadhesives (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, chamomilla recutita mouthwash, table grape plant exosomes, antiseptic mouthwashes (e.g., chlorhexidine gluconate (e.g., Peridex® or Periodogard®)), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol), corticosteroids (e.g., prednisone), painkillers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor, Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble β-1,3 / 1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, and gastrointestinal cocktails (acid reducers, e.g., aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungals (e.g., nystatin), and analgesics (e.g., hurricane liquid)). As another example, a non-limiting example of a treatment for esophageal mucositis includes xylocaine (e.g., gel viscous xylocaine 2%). As another example, a treatment for, modifying, or treating the signs and symptoms of intestinal mucositis includes a gastrointestinal cocktail (acid reducers, e.g., aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungals (e.g., nystatin), and pain relievers (e.g., hurricane liquid)).

[0332] In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering the chemical entity (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month).

[0333] In other embodiments, the second therapeutic agent or regimen is administered to the subject at approximately the same time as the chemical entity is contacted or administered.For example, the second therapeutic agent or regimen and the chemical entity are simultaneously provided to the subject in the same dosage form.In another example, the second therapeutic agent or regimen and the chemical entity are simultaneously provided to the subject in separate dosage forms.

[0334] In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the chemical entity (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month).

[0335] 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., via biopsy, endoscopy, or other conventional methods known in the art). In certain embodiments, STING protein can serve as a biomarker for certain types of cancer, such as colon cancer and prostate cancer. In other embodiments, identifying the subject can include assaying the patient's tumor microenvironment, e.g., a patient with one or more cold tumors, for the absence of T cells and / or the presence of exhausted T cells. Such patients can include patients who are resistant to treatment with checkpoint inhibitors. In certain embodiments, such patients can be treated with a chemical entity herein, e.g., to recruit T cells to the tumor, and in some cases, can be further treated with one or more checkpoint inhibitors, e.g., once T cells are exhausted.

[0336] 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 cold tumors, e.g., tumors lacking T cells or exhausted T cells).

[0337] compound preparation As can be appreciated by those skilled in the art, methods for synthesizing the compounds of the formulas herein are clear to those skilled in the art.Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art, and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.The starting materials used in preparing the compounds of the present invention are known, can be made by known methods, or are commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein can be interchanged with alternative equivalents recognized in the art. For example, in many reactions, triethylamine can be interchanged with other bases, such as non-nucleophilic bases (e.g., diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

[0338] Those skilled in the art will recognize the various analytical methods that can be used to characterize the compounds described herein, including, for example, 1 These include H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The above list is a subset of the characterization methods available to those skilled in the art and is not intended to be limiting.

[0339] To further illustrate the foregoing, the following non-limiting, exemplary synthetic schemes are included. Variations of these examples that are within the scope of the claims are within the purview of one of ordinary skill in the art and are considered to fall within the scope of the invention as described and claimed in this application. The reader will recognize that one of ordinary skill in the art, armed with this disclosure and the skill in the art, will be able to make and use the invention without the need for exhaustive examples. [Example]

[0340] Chemical abbreviations Ac = acetyl ADDP = 1,1'-(azodicarbonyl)-dipiperidine ACN = acetonitrile BocO = di-tert-butylpyrocarbonate Bu = butyl BOP = benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate Bn = benzyl Bz = benzoyl CataCxium A = bis(adamant-1-yl)(butyl)phosphine CMPB = (cyanomethylene)tri-n-butylphosphorane DAST = diethylaminosulfur trifluoride DBAD = di-tert-butyl azodiformate DCE = dichloroethane DCM = dichloromethane DEAD = diethyl azodiformate DIBAL-H = diisobutylaluminum hydride 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 = diphenyl azidophosphate Dppf = bis(diphenylphosphino)ferrocene DtBPF = 1,1'-bis[bis(1,1-dimethylethyl)phosphino]ferrocene Grubbs 1 = Grubbs 1st generation catalyst FA = formic acid HATU = 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HMDS = 1,1,1,3,3,3-hexamethyldisilazane H2O = Water HPLC = high-performance liquid chromatography IBX = 2-iodoxybenzoic acid LAH = lithium aluminum hydride LC-MS = liquid chromatography-mass spectrometry Me = methyl NMI = 1-methylimidazole NMR = nuclear magnetic resonance POT = tris(2-methylphenyl)phosphine Pr = propyl Py = pyridine RT = retention time TBDPS = t-butyl-diphenylsilyl TBS = tert-butyldimethylsilyl TBUP = tri-n-butylphosphine TCFH = N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate TEA = trimethylamine Tf = trifluoromethanesulfonyl TFA = trifluoroacetic acid TfO = trifluoromethanesulfonic anhydride THF = tetrahydrofuran TMS = trimethylsilyl Tol = methylbenzene T3P = 2,4,6-tripropyl-2,4,6-trioxo-1,3,5,2,4,6-trioxatriphosphorinane Ts = Tosyl t-AmOH = 2-methylbutan-2-ol XPhos = (2-(2,4,6-triisopropylphenethyl)phenyl)dicyclohexylphosphine Na2SO4 = sodium sulfate Speedvac = Savant SC250EXP Speedvac Concentrator DMSO = dimethyl sulfoxide Cs2CO3 = Cesium carbonate TCFH = N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate N- HPLC-1 = high performance liquid chromatography

[0341] material and method For Schemes 1-51 and Examples 1-195, the LC-MS method and preparative HPLC method are one of the following methods:

[0342] LCMS Method A: Kinetex EVO C18 100A, 30*3mm, injection 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB ~ 95% / 2.00min, hold at 95% MPB for 0.30min, 95% MPB ~ 10% / 0.10min.

[0343] LCMS Method B: Xselect CSH C18, 50*3mm, injection 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: 5% MPB to 100% for 2.00 min, hold at 100% MPB for 0.70 min, 100% MPB to 5% for 0.05 min, then equilibrate to 5% MPB for 0.15 min.

[0344] LCMS Method C: XBridge Shield RP18, 50*4.6mm, injection 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 0.04% NH3·H2O and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% / 2.00min, hold at 95% MPB for 0.79min, 95% MPB to 10% / 0.06min, then equilibrate to 10% MPB for 0.15min.

[0345] LCMS Method D: Kinetex 2.6 μm EVO, 50*3 mm, injection 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% / 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 10% / 0.05 min, then equilibrate to 10% MPB for 0.25 min.

[0346] LCMS Method E: HALOC18, 30*3mm, injection 0.5μL, flow rate 1.5mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 0.05% TFA and mobile phase B (MPB): acetonitrile / 0.05% TFA. Elution: 5% MPB to 100% MPB for 1.20min, hold at 100% MPB for 0.60min, 100% MPB to 5% MPB for 0.02min, then equilibrate to 5% MPB for 0.18min.

[0347] LCMS Method F: Shim-pack Scepter C18-120, 33*3mm, injection 0.5μL, flow rate 1.5mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 50% MPB to 95% / 2.00min, hold at 95% MPB for 0.60min, 95% MPB to 10% / 0.05min, then equilibrate to 10% MPB for 0.25min.

[0348] LCMS Method G: Poroshell HPH C18, 50 * 3 mm, injection 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 + 5 mM NH4OH and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% / 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 5% / 0.05 min, then equilibrate to 5% MPB for 0.25 min.

[0349] Method A Equipment: Agilent LCMS system, DAD and ELSD detectors Ion mode: Positive Column: Waters X-Bridge C18, 50*2.1 mm*5 μm or equivalent Mobile phase: A: H2O (0.04% TFA); B: CH3CN (0.02% TFA) Gradient: 4.5 min gradient method, actual method varies depending 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

[0350] Method B Equipment: Agilent LCMS system, DAD and ELSD detectors Ion mode: Positive Column: Waters X-Bridge ShieldRP18, 50*2.1 mm*5 μm or equivalent Mobile phase: A: H2O (0.05% NH3·H2O) or 10 mM ammonium bicarbonate; B: CH3CN Gradient: 4.5 min gradient; actual method will vary depending on the clogP of the compound Flow rate: 0.6 mL / min or 0.8 mL / min Column temperature: 40℃ UV: 220 nm

[0351] 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 / HO = 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 & 254 nm Slope: Actual method depends on the clogP of the compound Detector: MS Trigger or UV

[0352] 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.

[0353] For Schemes 52-75 and Examples 196-289, LC-MS, NMR, and preparative HPLC are performed using one of the following methods.

[0354] LCMS Method A: Kinetex EVO C18 100A, 30*3mm, injection 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB ~ 95% / 2.00min, hold at 95% MPB for 0.30min, 95% MPB ~ 10% / 0.10min.

[0355] LCMS Method B: Xselect CSH C18, 50*3mm, injection 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: 5% MPB to 100% for 2.00 min, hold at 100% MPB for 0.70 min, 100% MPB to 5% for 0.05 min, then equilibrate to 5% MPB for 0.15 min.

[0356] LCMS Method C: XBridge Shield RP18, 50*4.6mm, injection 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 0.04% NH3·H2O and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% / 2.00min, hold at 95% MPB for 0.79min, 95% MPB to 10% / 0.06min, then equilibrate to 10% MPB for 0.15min.

[0357] LCMS Method D: Kinetex 2.6 μm EVO, 50*3 mm, injection 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% / 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 10% / 0.05 min, then equilibrate to 10% MPB for 0.25 min.

[0358] LCMS Method E: HALOC18, 30*3mm, injection 0.5μL, flow rate 1.5mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 0.05% TFA and mobile phase B (MPB): acetonitrile / 0.05% TFA. Elution: 5% MPB to 100% MPB for 1.20min, hold at 100% MPB for 0.60min, 100% MPB to 5% MPB for 0.02min, then equilibrate to 5% MPB for 0.18min.

[0359] LCMS Method F: Shim-pack Scepter C18-120, 33*3mm, injection 0.5μL, flow rate 1.5mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 50% MPB to 95% / 2.00min, hold at 95% MPB for 0.60min, 95% MPB to 10% / 0.05min, then equilibrate to 10% MPB for 0.25min.

[0360] Method A Equipment: Agilent LCMS system, DAD and ELSD detectors Ion mode: Positive Column: Waters X-Bridge C18, 50*2.1 mm*5 μm or equivalent Mobile phase: A: H2O (0.04% TFA); B: CH3CN (0.02% TFA) Gradient: 4.5 min gradient method, actual method varies depending 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

[0361] Method B Equipment: Agilent LCMS system, DAD and ELSD detectors Ion mode: Positive Column: Waters X-Bridge ShieldRP18, 50*2.1 mm*5 μm or equivalent Mobile phase: A: H2O (0.05% NH3·H2O) or 10 mM ammonium bicarbonate; B: CH3CN Gradient: 4.5 min gradient; actual method will vary depending on the clogP of the compound Flow rate: 0.6 mL / min or 0.8 mL / min Column temperature: 40℃ UV: 220 nm

[0362] Preparative HPLC-1 conditions-1 device: 1. GILSON 281 and Shimadzu LCMS 2010A 2. GILSON 215 and Shimadzu LC-20AP 3. GILSON 215 Mobile phase: A: NH4OH / HO = 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 & 254 nm Slope: Actual method depends on the clogP of the compound Detector: MS Trigger or UV

[0363] 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.

[0364] Preparation Examples Schemes for the preparation of key intermediates: The following schemes illustrate the preparation of key intermediates.

[0365] Scheme 1: Synthesis of Intermediate 1 and Intermediate 2 (N-(5-bromo-1H-indol-3-yl)acetamide and tert-butyl 3-acetamido-5-bromo-1H-indole-1-carboxylate) TIFF2024532798000165.tif85152

[0366] Step 1: 5-Bromo-1H-indole-3-carbonyl azide 5-Bromo-1H-indole-3-carboxylic acid (30.0 g, 124.9 mmol, 1.0 equiv) was dissolved in THF (150 mL), followed by the addition of TEA (26.1 mL, 187.4 mmol, 1.5 equiv) and DPPA (37.8 g, 137.4 mmol, 1.1 equiv). The reaction mixture was stirred at ambient temperature for 12 hours, then quenched by the addition of water and stirred for an additional 10 minutes. The precipitated solid was collected by filtration and dried to give 5-bromo-1H-indole-3-carbonyl azide (33.6 g) as an off-white solid. LCMS Method B: [MH] - = 263.

[0367] Step 2: tert-butyl (5-bromo-1H-indol-3-yl)carbamate 5-Bromo-1H-indole-3-carbonyl azide (33.6 g, 126.7 mmol, 1.0 equiv) was dissolved in t-BuOH (300 mL). The reaction mixture was heated at 80° C. for 12 hours, 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 (1:10) to give tert-butyl (5-bromo-1H-indol-3-yl)carbamate (22.1 g) as a pale white solid. LCMS Method A: [M+H] + =311.

[0368] Step 3: 5-Bromo-1H-indol-3-amine hydrochloride tert-Butyl (5-bromo-1H-indol-3-yl)carbamate (20.0 g, 64.2 mmol, 1.0 equiv.) was dissolved in HCl / 1,4-dioxane (4 M, 150 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo to give 5-bromo-1H-indol-3-amine hydrochloride (18.7 g) as a brown solid. LCMS Method A: [M+H] + = 211.

[0369] Step 4: N-(5-bromo-1H-indol-3-yl)acetamide 5-Bromo-1H-indol-3-amine (18.7 g, 88.6 mmol, 1.0 equiv) and TEA (37.1 mL, 265.8 mmol, 3.0 equiv) were dissolved in DCM (200 mL), and the solution was cooled to 0 °C. AcCl (6.9 mL, 97.4 mmol, 1.1 equiv) was then added dropwise, maintaining the solution at 0 °C. The reaction mixture was stirred at ambient temperature for 3 h and then quenched by the addition of water. The resulting solution was extracted with DCM, 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 (1:3) to give N-(5-bromo-1H-indol-3-yl)acetamide (15.0 g) as a brown solid. LCMS Method A: [M+H] + = 253.

[0370] Step 5: tert-butyl 5-bromo-3-acetamidoindole-1-carboxylate N-(5-bromo-1H-indol-3-yl)acetamide (1.0 g, 4.0 mmol, 1.0 equiv.) was dissolved in THF (30 mL), followed by the addition of TEA (1.1 mL, 7.9 mmol, 2 equiv.), BocO (862.3 mg, 4.0 mmol, 1.0 equiv.), and DMAP (48.3 mg, 0.4 mmol, 0.1 equiv.). The reaction mixture was stirred at ambient temperature for 50 minutes 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 (1:5) to afford tert-butyl 5-bromo-3-acetamidoindole-1-carboxylate (800.0 mg) as a pale yellow solid. LCMS Method C: [M+H] + = 353.

[0371] Using the same methods as described for Intermediates 1 and 2, the intermediates in the table below were prepared.

[0372] TIFF2024532798000166.tif136139

[0373] Scheme 2: Synthesis of intermediate 7 (N-(5-hydroxy-1H-indol-3-yl)acetamide) TIFF2024532798000167.tif77130

[0374] Step 1: N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)acetamide N-(5-Bromo-1H-indol-3-yl)acetamide (10.0 g, 39.5 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (100 mL), followed by the addition of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (20.1 g, 79.0 mmol, 2.0 equiv.), KOAc (7.7 g, 79.0 mmol, 2.0 equiv.), and Pd(dppf)Cl.CHCl (2.8 g, 3.9 mmol, 0.1 equiv.) under a nitrogen atmosphere. The reaction mixture was heated at 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 NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol (20:1) to give N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)acetamide (9.1 g) as a brown solid. LCMS Method A: [M+H] + = 301.

[0375] Step 2: N-(5-hydroxy-1H-indol-3-yl)acetamide N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)acetamide (6.5 g, 21.6 mmol, 1.0 equiv) was dissolved in THF (50 mL) and water (50 mL), then NaOH (1.7 g, 42.5 mmol, 2.0 equiv) was added. This was followed by the dropwise addition of HO (30% wt. in water, 28.0 mL, 420.0 mmol, 20.0 equiv) at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h and then quenched by the addition of saturated aqueous NHCl. The resulting solution was extracted with ethyl acetate, washed with brine, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol (10:1) to give N-(5-hydroxy-1H-indol-3-yl)acetamide (2.5 g) as a grey solid. LCMS Method A: [M+H] + = 191.

[0376] Using the same method as described for Intermediate 7, the intermediates in the table below were prepared.

[0377] TIFF2024532798000168.tif79169

[0378] Scheme 3: Synthesis of intermediate 10 (tert-butyl 3-acetamido-5-hydroxy-1H-indole-1-carboxylate) TIFF2024532798000169.tif78128

[0379] Step 1: tert-Butyl 3-acetamido-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]acetamide (1.0 g, 3.3 mmol, 1.0 equiv.) and BocO (872.5 mg, 4.0 mmol, 1.2 equiv.) were dissolved in THF, followed by the addition of TEA (0.9 mL, 6.7 mmol, 2.0 equiv.) and DMAP (40.7 mg, 0.3 mmol, 0.1 equiv.). The reaction mixture was stirred at ambient temperature overnight 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 (1:7) to give tert-butyl 3-acetamido-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate (907.5 mg) as a yellow solid. LCMS Method B: [M+H] + = 401.

[0380] Step 2: tert-Butyl 3-acetamido-5-hydroxyindole-1-carboxylate tert-Butyl 3-acetamido-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate (1.0 g, 2.5 mmol, 1.0 equiv.) was dissolved in THF (10 mL), followed by the addition of aqueous NaOH (2% wt., 10 mL, 5.0 mmol, 2.0 equiv.) and HO (30% wt., 2.6 mL, 25.0 mmol, 10.0 equiv.). The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was adjusted to pH 6 with saturated aqueous NHHCO, then extracted with ethyl acetate, and the combined organic layers were concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol (20:1) to give tert-butyl 3-acetamido-5-hydroxyindole-1-carboxylate (690.0 mg) as a grey solid. LCMS Method B: [M+H] + = 291.

[0381] Scheme 4: Synthesis of intermediate 11 (tert-butyl 3-acetamido-5-(2-hydroxyethyl)-1H-indole-1-carboxylate) TIFF2024532798000170.tif75141

[0382] Step 1: tert-Butyl 3-acetamido-5-ethenylindole-1-carboxylate tert-Butyl 5-bromo-3-acetamidoindole-1-carboxylate (660.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (4 mL) and water (1 mL), followed by the addition of 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (575.6 mg, 3.7 mmol, 2.0 equiv.), CsCO (1.2 g, 3.7 mmol, 2.0 equiv.), and Pd(dppf)Cl (273.4 mg, 0.4 mmol, 0.2 equiv.) under a nitrogen atmosphere. The reaction mixture was heated at 85 °C for 4 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 (1:4) to give tert-butyl 3-acetamido-5-ethenylindole-1-carboxylate (400.0 mg%) as a pale yellow solid. LCMS Method C: [M+H] + = 301.

[0383] Step 2: tert-butyl 3-acetamido-5-(2-hydroxyethyl)-1H-indole-1-carboxylate tert-Butyl 3-acetamido-5-ethenylindole-1-carboxylate (500.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in THF (20 mL), followed by the dropwise addition of BH-THF (1 M, 2.5 mL, 2.5 mmol, 1.5 equiv.). The reaction mixture was stirred at ambient temperature for 40 minutes. Aqueous NaOH (1 M, 3.3 mL, 3.3 mmol, 2.0 equiv.) was then added, and the reaction mixture was cooled to 0 °C. Following this, HO (30% wt. in water, 1.3 mL, 3.3 mmol, 2.0 equiv.) was added dropwise, maintaining the reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for an additional 30 minutes and then quenched by the addition of saturated aqueous NH Cl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na SO , and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol (12:1) to give tert-butyl 3-acetamido-5-(2-hydroxyethyl)indole-1-carboxylate (300.0 mg) as a pale yellow solid. LCMS Method A: [M+H] + = 319.

[0384] Using the same method as described for Intermediate 11, the intermediates in the table below were prepared.

[0385] TIFF2024532798000171.tif44148

[0386] Scheme 5: Synthesis of intermediate 13 (tert-butyl 3-acetamido-5-(hydroxymethyl)-1H-indole-1-carboxylate) TIFF2024532798000172.tif38134

[0387] tert-Butyl 5-bromo-3-acetamidoindole-1-carboxylate (500.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (5 mL), followed by the addition of (tributylstannyl)methanol (909.1 mg, 2.8 mmol, 2.0 equiv.) and Pd(PPh3)4 (327.2 mg, 0.3 mmol, 0.2 equiv.) under a nitrogen atmosphere. The reaction mixture was heated at 85 °C for 4 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 3-acetamido-5-(hydroxymethyl)indole-1-carboxylate (262.5 mg) as a pale yellow solid. LCMS Method C: [M+H] + = 305.

[0388] Using the same method as described for Intermediate 13, the intermediates in the table below were prepared.

[0389] TIFF2024532798000173.tif47170

[0390] Scheme 6: Synthesis of intermediate 15 (tert-butyl 3-acetamido-5-(2-oxoethyl)-1H-indole-1-carboxylate) TIFF2024532798000174.tif32128

[0391] tert-Butyl 3-acetamido-5-(2-hydroxyethyl)indole-1-carboxylate (320.0 mg, 1.0 mmol, 1.0 equiv) was dissolved in DCM (25 mL), followed by the addition of IBX (562.9 mg, 2.0 mmol, 2.0 equiv). The reaction mixture was heated at 50° C. for 3 hours, cooled to ambient temperature, and the solid was removed by filtration. The filtrate was concentrated in vacuo to give tert-butyl 3-acetamido-5-(2-oxoethyl)indole-1-carboxylate (311.2 mg) as a pale yellow solid. LCMS Method A: [M+H] + = 317.

[0392] Using the same method as described for Intermediate 15, the intermediates in the table below were prepared.

[0393] TIFF2024532798000175.tif45170

[0394] Scheme 7: Synthesis of intermediate 17 (tert-butyl 3-acetamido-5-formyl-1H-indole-1-carboxylate) TIFF2024532798000176.tif42132

[0395] tert-Butyl 3-acetamido-5-ethenylindole-1-carboxylate (400.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in THF (15 mL) and water (15 mL), followed by the addition of KOsO·2HO (98.1 mg, 0.3 mmol, 0.2 equiv.) and NaIO (1.1 g, 5.3 mmol, 4.0 equiv.). The reaction mixture was stirred at ambient temperature for 2 hours and then diluted with water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give tert-butyl 3-acetamido-5-formylindole-1-carboxylate (350.0 mg) as a dark yellow solid. LCMS Method B: [M+H] + = 303.

[0396] Scheme 8: Synthesis of intermediate 18 (2-fluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethan-1-ol) TIFF2024532798000177.tif73161

[0397] Step 1: Benzyl 4-(2-ethoxy-1-fluoro-2-oxoethylidene)piperidine-1-carboxylate Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (1.6 g, 6.4 mmol, 1.5 equiv) was dissolved in THF (20 mL) and cooled to 0 °C, then NaH (60% wt., 342.9 mg, 8.6 mmol, 2.0 equiv) was added while maintaining the reaction mixture at 0 °C. The reaction mixture was stirred at ambient temperature for 30 minutes. Following this, benzyl 4-oxopiperidine-1-carboxylate (1.0 g, 4.3 mmol, 1.0 equiv) was 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 (1:1) to give benzyl 4-(2-ethoxy-1-fluoro-2-oxoethylidene)piperidine-1-carboxylate (1.2 g) as a colorless oil. LCMS Method A: [M+H] + = 322.

[0398] Step 2: ethyl 2-fluoro-2-(piperidin-4-yl)acetate Benzyl 4-(2-ethoxy-1-fluoro-2-oxoethylidene)piperidine-1-carboxylate (1.2 g, 3.7 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL), then Pd / C (120.0 mg, 10% wt.) was added under a nitrogen atmosphere. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature for 2 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 ethyl acetate / petroleum ether (1:1) to give ethyl 2-fluoro-2-(piperidin-4-yl)acetate (650.0 mg) as a colorless oil. LCMS Method A: [M+H] + = 190.

[0399] Step 3: ethyl 2-fluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)acetate Ethyl 2-fluoro-2-(piperidin-4-yl)acetate (1.0 g, 5.3 mmol, 1.0 equiv.) and TEA (1.5 mL, 10.6 mmol, 2.0 equiv.) were dissolved in ACN (20 mL), and then 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.8 g, 7.9 mmol, 1.5 equiv.) was added. 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 (1:1) to give ethyl 2-fluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)acetate (820.0 mg) as a colorless oil. LCMS Method A: [M+H] + = 272.

[0400] Step 4: 2-fluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethan-1-ol Ethyl 2-fluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)acetate (400.0 mg, 1.5 mmol, 1.0 equiv) was dissolved in THF (15 mL) and cooled to 0 °C, then LiAlH (111.9 mg, 2.9 mmol, 2.0 equiv) was added, maintaining the solution at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h and then quenched by the addition of NaSO·10H O. 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 (1:2) to give 2-fluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethan-1-ol (310.0 mg) as a colorless oil. LCMS Method A: [M+H] + = 230.

[0401] Scheme 9: Synthesis of intermediate 19 (2-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)ethan-1-ol) TIFF2024532798000178.tif29144

[0402] 1-Fluoro-4-(trifluoromethyl)benzene (500.0 mg, 3.0 mmol, 1.0 equiv) was dissolved in DMF (10 mL), followed by the addition of KCO (842.1 mg, 6.0 mmol, 2.0 equiv) and 4-piperidineethanol (393.6 mg, 3.0 mmol, 1.0 equiv). The reaction mixture was heated at 120 °C overnight, then cooled to ambient temperature and quenched by the addition of aqueous HCl (2N). 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 2-[1-[4-(trifluoromethyl)phenyl]piperidin-4-yl]ethanol (280.0 mg) as a pale yellow solid. LCMS Method A: [M+H] + = 274.

[0403] Using the same method as described for Intermediate 19, the intermediates in the table below were prepared.

[0404] TIFF2024532798000179.tif137165

[0405] Scheme 10: Synthesis of intermediate 23 (2-methyl-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)propan-1-ol) TIFF2024532798000180.tif21154

[0406] Step 1: Ethyl 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propanoate Ethyl 2-methyl-2-(piperidin-4-yl)propanoate (500.0 mg, 2.5 mmol, 1.0 equiv.) and TEA (0.5 mL, 3.8 mmol, 1.5 equiv.) were dissolved in ACN (25 mL), followed by the addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (873.5 mg, 3.8 mmol, 1.5 equiv.). The reaction mixture was heated at 65° C. for 6 hours, 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 afford ethyl 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propanoate (205.5 mg) as a yellow oil. LCMS Method C: [M+H] + = 282.

[0407] Step 2: 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propan-1-ol Ethyl 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propanoate (200.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in THF (100 mL) and cooled to 0 °C. LiAlH (40.5 mg, 1.1 mmol, 1.5 equiv.) was then added. The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. 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 (1:5) to give 2-methyl-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]propan-1-ol (21.3 mg) as a yellow oil. LCMS Method C: [M+H] + = 240.

[0408] Scheme 11: Synthesis of intermediate 24 (2-((1R,5S,6s)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl)ethan-1-ol) TIFF2024532798000181.tif81150

[0409] Step 1: (1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde Oxalyl chloride (1.0 mL, 12.3 mmol, 2.5 equiv) was dissolved in DCM (30 mL) and cooled to −78° C., then DMSO (1.7 mL, 24.6 mmol, 5.0 equiv) was added dropwise. The reaction mixture was stirred at −78° C. for 1 hour under a nitrogen atmosphere. Following this, a solution of [(1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl]methanol (1.0 g, 4.9 mmol, 1.0 equiv) in DCM (20 mL) was added dropwise, maintaining the solution at −78° C. The reaction mixture was stirred at −78° C. for an additional 2 hours, then TEA (6.9 mL, 49.2 mmol, 10.0 equiv) was added dropwise, and the resulting solution was stirred at ambient temperature for an additional 4 hours. The reaction was quenched by the addition of water, extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give (1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde (980.0 mg) as a pale yellow liquid. LCMS Method A: [M+H] + = 202.

[0410] Step 2: (1R,5S,6S)-3-benzyl-6-ethenyl-3-azabicyclo[3.1.0]hexane Methyltriphenylphosphonium bromide (2.0 g, 5.7 mmol, 1.5 equiv) was dissolved in THF (20 mL) and cooled to −50° C., then n-BuLi (3 M in THF, 1.9 mL, 5.7 mmol, 1.5 equiv) was added dropwise under a nitrogen atmosphere while maintaining the solution at −50° C. After 30 min at −50° C., a solution of (1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde (760.0 mg, 3.8 mmol, 1.0 equiv) in THF (5 mL) was added dropwise. The resulting mixture was stirred at ambient temperature for an additional 4 h and then quenched by the addition of saturated aqueous NH4Cl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to give (1R,5S,6S)-3-benzyl-6-ethenyl-3-azabicyclo[3.1.0]hexane (480.0 mg) as a pale yellow oil. LCMS Method A: [M+H] + = 200.

[0411] Step 3: 2-[(1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl]ethanol (1R,5S,6S)-3-Benzyl-6-ethenyl-3-azabicyclo[3.1.0]hexane (480.0 mg, 2.4 mmol, 1.0 equiv) was dissolved in THF (20 mL), followed by the dropwise addition of BH-SMe (0.80 mL, 2.4 mmol, 1.0 equiv). The reaction mixture was stirred at 65 °C for 1 h and then cooled to 0 °C. A solution of NaOH (578.0 mg, 14.4 mmol, 6.0 equiv) in HO (2 mL) was then added, followed by the dropwise addition of HO (30% aqueous solution, 1.5 mL, 14.4 mmol, 6.0 equiv). The resulting mixture was heated at 50 °C overnight, then cooled to ambient temperature and quenched by the addition of saturated aqueous NHCl. 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 2-[(1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl]ethanol (510.0 mg) as a pale yellow oil. LCMS Method A: [M+H] + = 218.

[0412] Step 4: 2-[(1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-yl]ethanol 2-[(1R,5S,6S)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl]ethanol (450.0 mg, 2.1 mmol, 1.0 equiv) was dissolved in MeOH (20 mL), and then Pd / C (10% wt., 44.1 mg) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at 45° C. for 6 h. The solids were removed by filtration, and the filtrate was concentrated in vacuo to give 2-[(1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-yl]ethanol (250.0 mg) as a pale yellow oil. LCMS Method A: [M+H] + = 128.

[0413] Step 5: 2-[(1R,5S,6S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]ethanol 2-[(1R,5S,6S)-3-Azabicyclo[3.1.0]hexan-6-yl]ethanol (250.0 mg, 2.0 mmol, 1.0 equiv) was dissolved in ACN (5 mL) and cooled to 0 °C, followed by the addition of KCO (543.3 mg, 3.9 mmol, 2.0 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (684.3 mg, 2.9 mmol, 1.5 equiv). The reaction mixture was heated at 80 °C for 50 min, 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 2-[(1R,5S,6S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]ethanol (260.0 mg) as a pale yellow oil. LCMS Method A: [M+H] + = 210.

[0414] Scheme 12: Synthesis of intermediates 25 / 26 (cis-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol and trans-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol) TIFF2024532798000182.tif63151

[0415] Step 1: 3-[4-(trifluoromethyl)phenyl]cyclobutan-1-one DMA (1.3 mL, 13.9 mmol, 1.2 equiv) was dissolved in DCE (30 mL) and cooled to 5 °C, then TfO (2.7 mL, 16.3 mmol, 1.4 equiv) was added dropwise while maintaining the solution at 5 °C. The reaction mixture was stirred at 5 °C for 30 min. Following this, a solution of 1-ethenyl-4-(trifluoromethyl)benzene (840.0 mg, 4.9 mmol, 1.0 equiv) and 2,4,6-collidine (2.0 g, 16.3 mmol, 1.4 equiv) in DCE (10 mL) was added dropwise at 5 °C. The resulting mixture was heated at 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. TIFF2024532798000183.tif19153

[0416] 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., then NaBH (106.0 mg, 2.8 mmol, 2.0 equiv) was added while maintaining the solution at −10° C. The reaction mixture was stirred at −10° C. under a nitrogen atmosphere for 50 minutes 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 pale yellow oil. LCMS Method A: [M+H] + = 217.

[0417] 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 hours 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. LCMS Method A: [M+H] + = 366.

[0418] 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 K2CO3 (227.0 mg, 1.6 mmol, 2.0 equiv.). The reaction mixture was heated at 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 Na2SO4, and concentrated in vacuo to give trans-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol (155.2 mg) as a pale yellow oil. LCMS Method A: [M+H] + = 217.

[0419] Scheme 12A: Synthesis of intermediate 25 (cis-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol) TIFF2024532798000184.tif25144

[0420] Step 1: 3-[4-(trifluoromethyl)phenyl]cyclobutan-1-one DMA (12.1 g, 138.9 mmol, 1.2 equiv.) was dissolved in DCE (400 mL) and cooled to 0 °C. TfO (46.0 g, 163.0 mmol, 1.4 equiv.) was then added dropwise over 30 min at 0–5 °C. The resulting mixture was stirred at 5 °C for 1 h, and then 2,4,6-collidine (19.7 g, 162.5 mmol, 1.4 equiv.) and 1-ethenyl-4-(trifluoromethyl)benzene (20.0 g, 116.2 mmol, 1.0 equiv.) were added at 5 °C. The resulting solution was heated at 80 °C for 48 h, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with 300 mL of water, extracted with ethyl acetate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (3:7) to give 3-(4-(trifluoromethyl)phenyl)cyclobutan-1-one (8.0 g) as a yellow oil. TIFF2024532798000185.tif12128

[0421] Step 2: cis-3-[4-(trifluoromethyl)phenyl]cyclobutan-1-ol 3-(4-(trifluoromethyl)phenyl)cyclobutan-1-one (7.9 g, 36.9 mmol, 1.0 equiv) was dissolved in MeOH (50 mL) and cooled to 0 °C, then NaBH (2.1 g, 55.3 mmol, 1.5 equiv) was added portionwise while maintaining the reaction mixture at 0 °C. The resulting mixture was stirred at 0 °C for 1 h and then quenched by the addition of ice water. The resulting solution was extracted with ethyl acetate, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with DCM / MeOH (99:1) to give cis-3-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol (60.5 g) as a yellow oil. TIFF2024532798000186.tif19153

[0422] Scheme 13: Synthesis of intermediate 27 (2-(6-(trifluoromethyl)pyridin-3-yl)ethyl 4-methylbenzenesulfonate) TIFF2024532798000187.tif19146

[0423] Step 1: 2-[6-(trifluoromethyl)pyridin-3-yl]ethanol [6-(Trifluoromethyl)pyridin-3-yl]acetic acid (500.0 mg, 2.4 mmol, 1.0 equiv) was dissolved in THF (30 mL) and cooled to 0 °C. BH THF (1 M, 4.9 mL, 4.9 mmol, 1.5 equiv) was then added, maintaining the solution at 0 °C. The reaction mixture was stirred overnight at 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 2-[6-(trifluoromethyl)pyridin-3-yl]ethanol (330.0 mg) as a yellow oil. LCMS Method A: [M+H] + = 192.

[0424] Step 2: 2-[6-(trifluoromethyl)pyridin-3-yl]ethyl 4-methylbenzenesulfonate 2-[6-(trifluoromethyl)pyridin-3-yl]ethanol (300.0 mg, 1.6 mmol, 1.0 equiv) and TEA (1.1 mL, 7.8 mmol, 5.0 equiv) were dissolved in DCM (3 mL), followed by the addition of TsCl (897.6 mg, 4.7 mmol, 3.0 equiv). The reaction mixture was stirred at ambient temperature for 16 hours and then quenched by the addition of water. The resulting solution was extracted with DCM, 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 (1:1) to afford 2-[6-(trifluoromethyl)pyridin-3-yl]ethyl 4-methylbenzenesulfonate (500.0 mg) as a yellow solid. LCMS Method A: [M+H] + = 346.

[0425] Scheme 14: Synthesis of intermediate 28 (3-(4,4-difluoropiperidin-1-yl)-2,2-difluoropropyl 4-methylbenzenesulfonate) TIFF2024532798000188.tif78153

[0426] Step 1: 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropan-1-ol 2,2-Difluoropropane-1,3-diol (2.0 g, 17.8 mmol, 1.0 equiv) was dissolved in THF (20.0 mL) and cooled to 0 °C, then NaH (60% wt., 1.0 g, 26.7 mmol, 1.5 equiv) was added while maintaining the solution at 0 °C. After 2 h at 0 °C, TBDPSCl (9.8 g, 35.6 mmol, 2.0 equiv) was added. The resulting mixture was stirred at ambient temperature for an additional 2 h 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 resulting mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropan-1-ol (5.1 g) as a yellow oil. LCMS Method C: [M+H] + = 351.

[0427] Step 2: 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropyl trifluoromethanesulfonate 3-[(tert-Butyldiphenylsilyl)oxy]-2,2-difluoropropan-1-ol (4.9 g, 14.0 mmol, 1.0 equiv.) was dissolved in DCE (20 mL) and cooled to -70 °C. DIEA (9.7 mL, 55.9 mmol, 4.0 equiv.) and trifluoromethanesulfonic anhydride (4.7 mL, 27.9 mmol, 2.0 equiv.) were then added dropwise at -70 °C under a nitrogen atmosphere. The reaction mixture was stirred at -20 °C for 2 h and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:2) to give 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropyl trifluoromethanesulfonate (5.2 g) as a yellow oil. LCMS Method A: [M+H] + = 483.

[0428] Step 3: 1-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropyl]-4,4-difluoropiperidine 3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropyl trifluoromethanesulfonate (5.0 g, 10.3 mmol, 1.0 equiv.) was dissolved in DMF (20 mL), followed by the addition of 4,4-difluoropiperidine (1.5 g, 12.4 mmol, 1.2 equiv.) and DIEA (3.5 mL, 20.7 mmol, 2.0 equiv.). The reaction mixture was heated at 50 °C, 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 1-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropyl]-4,4-difluoropiperidine (3.8 g) as a yellow oil. LCMS method A: [M+H] + = 454.

[0429] Step 4: 3-(4,4-difluoropiperidin-1-yl)-2,2-difluoropropan-1-ol 1-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-difluoropropyl]-4,4-difluoropiperidine (3.6 g, 7.9 mmol, 1.0 equiv.) was dissolved in DCM (10 mL), followed by the addition of HF·Py (70% wt., 1.1 mL, 31.7 mmol, 4.0 equiv.). The reaction mixture was stirred at ambient temperature for 12 h 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 3-(4,4-difluoropiperidin-1-yl)-2,2-difluoropropan-1-ol (1.0 g) as a yellow oil. LCMS Method A: [M+H] + = 216.

[0430] Step 5: 3-(4,4-difluoropiperidin-1-yl)-2,2-difluoropropyl 4-methylbenzenesulfonate 3-(4,4-Difluoropiperidin-1-yl)-2,2-difluoropropan-1-ol (220.0 mg, 1.0 mmol, 1.0 equiv) and TEA (0.3 mL, 2.0 mmol, 2.0 equiv) were dissolved in DCM (10 mL), and then TsCl (389.8 mg, 2.0 mmol, 2.0 equiv) was added. The reaction mixture was stirred at ambient temperature for 12 hours and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 3-(4,4-difluoropiperidin-1-yl)-2,2-difluoropropyl 4-methylbenzenesulfonate (320.0 mg) as a white solid. LCMS Method A: [M+H] + = 370.

[0431] Scheme 15: Synthesis of intermediate 29 (5-(4-(trifluoromethyl)phenoxy)-1H-indol-3-amine hydrochloride) TIFF2024532798000189.tif81156

[0432] Step 1: 2-methyl-1-nitro-4-(4-(trifluoromethyl)phenoxy)benzene 4-Fluoro-2-methyl-1-nitrobenzene (19.0 g, 122.5 mmol, 1.0 equiv.) was dissolved in DMF (100 mL), followed by the addition of KCO (50.8 g, 367.4 mmol, 3.0 equiv.) and 4-(trifluoromethyl)phenol (23.8 g, 146.9 mmol, 1.2 equiv.). The reaction mixture was heated at 80 °C for 2 h, then cooled to ambient 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 flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:9) to give 2-methyl-1-nitro-4-(4-(trifluoromethyl)phenoxy)benzene (30.0 g) as a yellow solid.

[0433] Step 2: (E)-N,N-dimethyl-2-(2-nitro-5-(4-(trifluoromethyl)phenoxy)phenyl)ethen-1-amine 2-Methyl-1-nitro-4-(4-(trifluoromethyl)phenoxy)benzene (20.0 g, 67.3, 1.0 equiv) was dissolved in DMF (100 mL), then DMF-DMA (10.7 mL, 80.7 mmol, 1.2 equiv) was added. The reaction mixture was heated at 140° 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 (E)-N,N-dimethyl-2-(2-nitro-5-(4-(trifluoromethyl)phenoxy)phenyl)ethen-1-amine (24.0 g) as a red solid. LCMS Method A: [M+H] + = 353.

[0434] Step 3: 5-(4-(trifluoromethyl)phenoxy)-1H-indole (E)-N,N-Dimethyl-2-(2-nitro-5-(4-(trifluoromethyl)phenoxy)phenyl)ethen-1-amine (24.0 g, 68.1 mmol, 1.0 equiv) was dissolved in ethyl acetate (250 mL), then Pd / C (10% wt., 2.5 g) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature for 36 h. 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 (1:6) to give 5-(4-(trifluoromethyl)phenoxy)-1H-indole (11.5 g) as a green solid. LCMS Method A: [M+H] + = 278.

[0435] Step 4: 3-nitro-5-(4-(trifluoromethyl)phenoxy)-1H-indole A mixture of AgNO3 (3.6 g, 21.6 mmol, 1.2 equiv) and ACN (50 mL) was cooled to 0 °C, then benzoyl chloride (2.5 mL, 21.6 mmol, 1.2 equiv) was added dropwise, maintaining the solution at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes, then a solution of 5-(4-(trifluoromethyl)phenoxy)-1H-indole (5.0 g, 18.0 mmol, 1.0 equiv) in ACN (5 mL) was added dropwise. The resulting solution 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 Na2SO4, 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 3-nitro-5-(4-(trifluoromethyl)phenoxy)-1H-indole (3.1 g) as a black solid. LCMS Method B: [MH] - = 321.

[0436] Step 5: tert-Butyl (5-(4-(trifluoromethyl)phenoxy)-1H-indol-3-yl)carbamate 3-Nitro-5-(4-(trifluoromethyl)phenoxy)-1H-indole (3.1 g, 9.7 mmol, 1.0 equiv.) was dissolved in MeOH (50 mL), then (Boc)2O (4.2 g, 19.4 mmol, 2.0 equiv.) and Pd / C (10% wt., 0.4 g) were added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature for 10 h. 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-(4-(trifluoromethyl)phenoxy)-1H-indol-3-yl)carbamate (1.3 g) as a brown solid. LCMS Method A: [M+H] + = 393.

[0437] Step 6: 5-(4-(trifluoromethyl)phenoxy)-1H-indol-3-amine hydrochloride tert-Butyl (5-(4-(trifluoromethyl)phenoxy)-1H-indol-3-yl)carbamate (1.3 g, 3.3 mmol, 1.0 equiv.) was dissolved in HCl / 1,4-dioxane (4N, 15 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo to give 5-(4-(trifluoromethyl)phenoxy)-1H-indol-3-amine hydrochloride (910.0 mg) as a green solid. LCMS Method A: [M+H] + = 293.

[0438] Using the same method as described for intermediate 29, the intermediates in the table below were prepared.

[0439] TIFF2024532798000190.tif76170

[0440] Scheme 16: Synthesis of intermediate 32 (5-(2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethoxy)-1H-indol-3-amine hydrochloride) TIFF2024532798000191.tif67163

[0441] 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. This was followed by the dropwise addition of a solution of ADDP (609.8 mg, 2.4 mmol, 2.0 equiv.) in DCM (5 mL), maintaining the solution at 0 °C. 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 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.

[0442] 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.

[0443] Using the same method as described for intermediate 32, the intermediates in the table below were prepared.

[0444] TIFF2024532798000192.tif41164

[0445] Scheme 17: Synthesis of intermediate 34 ((E)-4,4,5,5-tetramethyl-2-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-1,3,2-dioxaborolane) TIFF2024532798000193.tif321371-Allyl-4-(trifluoromethyl)benzene (1.0 g, 5.4 mmol, 1.0 equiv.) was dissolved in DCM (10 mL), followed by the addition of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.7 g, 10.7 mmol, 2.0 equiv.) and Grubbs I (224.8 mg, 0.3 mmol, 0.05 equiv.) under a nitrogen atmosphere. The reaction mixture was heated at 50 °C for 16 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 (1:4) to give (E)-4,4,5,5-tetramethyl-2-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)-1,3,2-dioxaborolane (640 mg) as a brown liquid. LCMS Method A: [M+H] + = 313.

[0446] Scheme 18: Synthesis of intermediate 35 (1-(2-methylallyl)-4-(trifluoromethyl)benzene) TIFF2024532798000194.tif22128 Bromo[4-(trifluoromethyl)phenyl]magnesium (8 mL, 0.5 mol / L, 4.0 mmol, 1.0 equiv) was dissolved in THF (30 mL) and cooled to 0 °C. 3-Chloro-2-methylpropene (0.4 g, 4.0 mmol, 1.0 equiv) was then added while maintaining the solution at 0 °C. The reaction mixture was stirred at 0 °C for 4 h 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. The residue was purified by flash column chromatography on silica gel eluting with petroleum ether (100%) to give 1-(2-methylprop-2-en-1-yl)-4-(trifluoromethyl)benzene (410.0 mg) as a pale yellow solid. TIFF2024532798000195.tif20153

[0447] Scheme 19: Synthesis of intermediate 36 (1-(2-methylallyl)-4-(trifluoromethyl)benzene) TIFF2024532798000196.tif24157

[0448] Step 1: 1-[4-(trifluoromethyl)phenyl]prop-2-en-1-ol 4-(Trifluoromethyl)benzaldehyde (2.0 g, 11.5 mmol, 1.0 equiv.) was dissolved in THF (30 mL) and cooled to 0 °C, then bromo(ethenyl)magnesium (1 M in THF, 13.8 mL, 13.8 mmol, 1.2 equiv.) was added dropwise under a nitrogen atmosphere while maintaining the solution at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h 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. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:2) to give 1-[4-(trifluoromethyl)phenyl]prop-2-en-1-ol (1.0 g) as a pale yellow solid. LCMS Method A: [M+H] += 203.

[0449] Step 2: 1-(1-methoxyprop-2-en-1-yl)-4-(trifluoromethyl)benzene 1-[4-(trifluoromethyl)phenyl]prop-2-en-1-ol (1.0 g, 4.9 mmol, 1.0 equiv) was dissolved in THF (30 mL) and cooled to 0 °C, followed by the addition of NaH (60% wt., 0.4 g, 9.9 mmol, 2.0 equiv). This was followed by the dropwise addition of CHI (0.6 mL, 9.9 mmol, 2.0 equiv) while maintaining the internal reaction temperature at 0 °C. The reaction mixture was warmed to ambient temperature for 2 h 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 1-(1-methoxyprop-2-en-1-yl)-4-(trifluoromethyl)benzene (0.9 g) as a pale yellow solid. TIFF2024532798000197.tif19153LCMS Method A: [M+H] + =217.

[0450] Scheme 20: Synthesis of intermediate 37 (N-(5-bromo-1H-indol-3-yl)cyclopropanecarboxamide) TIFF2024532798000198.tif49132

[0451] Step 1: 5-Bromo-1H-indole-3-carbonyl azide 5-Bromo-1H-indole-3-carboxylic acid (30.0 g, 124.9 mmol, 1.0 equiv) was dissolved in THF (150 mL), followed by the addition of TEA (26.1 mL, 187.4 mmol, 1.5 equiv) and DPPA (37.8 g, 137.4 mmol, 1.1 equiv). The reaction mixture was stirred at ambient temperature for 12 hours, then quenched by the addition of water and stirred for an additional 10 minutes. The precipitated solid was collected by filtration and dried to give 5-bromo-1H-indole-3-carbonyl azide (33.6 g) as an off-white solid. LCMS Method B: [MH]- = 263.

[0452] Step 2: tert-butyl (5-bromo-1H-indol-3-yl)carbamate 5-Bromo-1H-indole-3-carbonyl azide (33.6 g, 126.7 mmol, 1.0 equiv) was dissolved in t-BuOH (300 mL). The reaction mixture was heated at 80° C. for 12 hours, 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 (1:10) to give tert-butyl (5-bromo-1H-indol-3-yl)carbamate (22.1 g) as a pale white solid. LCMS Method A: [M+H] + =311.

[0453] Step 3: 5-Bromo-1H-indol-3-amine hydrochloride tert-Butyl (5-bromo-1H-indol-3-yl)carbamate (20.0 g, 64.2 mmol, 1.0 equiv.) was dissolved in HCl / 1,4-dioxane (4 M, 150 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo to give 5-bromo-1H-indol-3-amine hydrochloride (18.7 g) as a brown solid. LCMS Method A: [M+H] + = 211.

[0454] Step 4: N-(5-bromo-1H-indol-3-yl)cyclopropanecarboxamide Cyclopropanecarboxylic acid (172.0 mg, 2.0 mmol, 1.0 equiv) was dissolved in DCM (20 mL), followed by the addition of DIEA (1.0 mL, 6.0 mmol, 3.0 equiv), HATU (1.1 g, 3.0 mmol, 1.5 equiv), and 5-bromo-1H-indol-3-amine hydrochloride (500.0 mg, 2.0 mmol, 1.0 equiv). The reaction mixture was stirred at ambient temperature for 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 (1:1) to give N-(5-bromo-1H-indol-3-yl)cyclopropanecarboxamide (510.0 mg) as a white solid. LCMS Method A: [M+H] + = 279.

[0455] Using the same method as described for intermediate 37, the intermediates in the table below were prepared.

[0456] TIFF2024532798000199.tif102128

[0457] Scheme 21: Synthesis of intermediate 41 (N-(5-bromo-7-fluoro-1H-indol-3-yl)acetamide) TIFF2024532798000200.tif57137

[0458] Step 1: 5-Bromo-7-fluoro-3-nitro-1H-indole 5-Bromo-7-fluoro-1H-indole (8.5 g, 39.7 mmol, 1.0 equiv.) was dissolved in ACN (150 mL) and cooled to 0 °C, then AgNO (10.1 g, 59.6 mmol, 1.5 equiv.) was added. The resulting mixture was stirred for 15 minutes, then benzoyl chloride (8.4 g, 59.6 mmol, 1.5 equiv.) was added batchwise while maintaining the reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours 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. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 5-bromo-7-fluoro-3-nitro-1H-indole (7.4 g) as a black solid. LCMS Method A: [M+H] + = 259.

[0459] Step 2: tert-butyl (5-bromo-7-fluoro-1H-indol-3-yl)carbamate 5-Bromo-7-fluoro-3-nitro-1H-indole (3.0 g, 11.6 mmol, 1.0 equiv) was dissolved in MeOH (50 mL), followed by the addition of (Boc)O (3.0 g, 13.8 mmol, 1.2 equiv). This was followed by the addition of SnCl (6.6 g, 34.7 mmol, 3.0 equiv) and NaBH (1.3 g, 34.7 mmol, 3.0 equiv) in portions, while maintaining the reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for 4 h 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. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:9) to give tert-butyl (5-bromo-7-fluoro-1H-indol-3-yl)carbamate (1.3 g) as a yellow solid. LCMS Method A: [M+H] + = 329.

[0460] Step 3: 5-Bromo-7-fluoro-1H-indol-3-amine hydrochloride tert-Butyl (5-bromo-7-fluoro-1H-indol-3-yl)carbamate (1.3 g, 3.9 mmol, 1.0 equiv.) was dissolved in HCl / 1,4-dioxane (4N, 15 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo to give 5-bromo-7-fluoro-1H-indol-3-amine hydrochloride (980.0 mg) as a gray solid. LCMS Method A: [M+H] + = 229.

[0461] Step 4: N-(5-bromo-7-fluoro-1H-indol-3-yl)acetamide 5-Bromo-7-fluoro-1H-indol-3-amine (980.0 mg, 4.3 mmol, 1.0 equiv) and TEA (2.3 mL, 17.1 mmol, 4.0 equiv) were dissolved in DCM (10 mL), followed by the addition of acetyl chloride (0.4 mL, 5.1 mmol, 1.2 equiv). The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of water. The resulting solution was extracted with dichloromethane, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol (20:1) to give N-(5-bromo-7-fluoro-1H-indol-3-yl)acetamide (800.0 mg) as a brown solid. LCMS Method A: [M+H] + = 271.

[0462] Using the same method as described for intermediate 41, the intermediates in the table below were prepared.

[0463] TIFF2024532798000201.tif99128

[0464] Scheme 22: Synthesis of intermediate 45 (N-(7-fluoro-5-hydroxy-1H-indol-3-yl)acetamide) TIFF2024532798000202.tif70158

[0465] Step 1: N-(7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)acetamide N-(5-Bromo-7-fluoro-1H-indol-3-yl)acetamide (1.0 g, 3.8 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (100 mL), followed by the addition of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.5 g, 5.8 mmol, 1.5 equiv.), CsCO (2.5 g, 7.7 mmol, 2.0 equiv.), and Pd(dppf)Cl·CHCl (0.3 g, 0.4 mmol, 0.1 equiv.) under a nitrogen atmosphere. The reaction mixture was heated at 100 °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. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:2) to give N-(7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)acetamide (880 mg) as a brown solid. LCMS Method A: [M+H] + = 319.

[0466] Step 2: N-(7-fluoro-5-hydroxy-1H-indol-3-yl)acetamide N-(7-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)acetamide (830.0 mg, 2.6 mmol, 1.0 equiv) was dissolved in THF (10 mL) and cooled to 0 °C, then a solution of NaOH in water (2% wt. / wt., 11 mL, 5.5 mmol, 2.0 equiv) was added. This was followed by the dropwise addition of HO (30% wt. / wt. in water, 2 mL, 19.2 mmol, 7.5 equiv) at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h and then quenched by the addition of saturated aqueous NHCl. The resulting solution was extracted with ethyl acetate, washed with brine, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol (10:1) to give N-(7-fluoro-5-hydroxy-1H-indol-3-yl)acetamide (174.0 mg) as a black solid. LCMS Method A: [M+H] + = 209.

[0467] Scheme 23: Synthesis of intermediate 46 (N-(5-hydroxy-7-methyl-1H-indol-3-yl)acetamide) TIFF2024532798000203.tif57168

[0468] Step 1: N-[7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]acetamide N-(5-Bromo-7-methyl-1H-indol-3-yl)acetamide (150.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (100 mL), followed by the addition of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (213.9 mg, 0.8 mmol, 1.5 equiv.), KOAc (110.2 mg, 1.1 mmol, 2.0 equiv.), and Pd(dppf)Cl.CHCl (41.1 mg, 0.06 mmol, 0.1 equiv.) under a nitrogen atmosphere. The reaction mixture was heated at 85 °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 NaSO, 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 N-[7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]acetamide (100.0 mg) as a pale yellow solid. LCMS Method B: [M+H] + = 315.

[0469] Step 2: tert-butyl 3-acetamido-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate N-[7-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]acetamide (50.0 mg, 0.2 mmol, 1.0 equiv.) and BocO (41.7 mg, 0.2 mmol, 1.2 equiv.) were dissolved in THF (5 mL), followed by the addition of TEA (0.1 mL, 0.3 mmol, 2.0 equiv.) and DMAP (4.0 mg, 0.03 mmol, 0.2 equiv.). The reaction mixture was stirred at ambient temperature overnight 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 (1:7) to give tert-butyl 3-acetamido-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate (45.8 mg) as a pale yellow solid. LCMS Method B: [M+H] + = 415.

[0470] Step 3: tert-Butyl 3-acetamido-5-hydroxy-7-methylindole-1-carboxylate tert-Butyl 3-acetamido-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-1-carboxylate (200.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in THF (10 mL) and cooled to 0 °C, followed by the addition of aqueous NaOH (2% wt. / wt., 2 mL, 1.0 mmol, 1.0 equiv.). This was followed by the dropwise addition of HO (30% wt. / wt. in water, 0.5 mL, 5.0 mmol, 10.0 equiv.) at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h and then quenched by the addition of saturated aqueous NHCl. The resulting solution was extracted with ethyl acetate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol (20:1) to give tert-butyl 3-acetamido-5-hydroxy-7-methylindole-1-carboxylate (60.0 mg) as a pale yellow solid. LCMS Method B: [M+H] + = 305.

[0471] Using the same method as described for Intermediate 46, the intermediates in the table below were prepared.

[0472] TIFF2024532798000204.tif48156

[0473] Scheme 24: Synthesis of intermediate 48 (N-(5-(2-hydroxyethyl)-1H-indol-3-yl)acetamide) TIFF2024532798000205.tif27159

[0474] Step 1: N-(5-vinyl-1H-indol-3-yl)acetamide N-(5-Bromo-1H-indol-3-yl)acetamide (3.0 g, 11.9 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (30 mL) and water (3 mL). Pd(dppf)Cl CHCl (1.9 g, 2.3 mmol, 0.2 equiv.), CsCO (7.7 g, 23.7 mmol, 2.0 equiv.), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.2 g, 14.2 mmol, 1.2 equiv.) were then added under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 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 (1:1) to give N-(5-vinyl-1H-indol-3-yl)acetamide (1.5 g) as a brown solid. LCMS Method C: [M+H] + = 201.

[0475] Step 2: N-(5-(2-hydroxyethyl)-1H-indol-3-yl)acetamide N-(5-vinyl-1H-indol-3-yl)acetamide (1.0 g, 5.0 mmol, 1.0 equiv) was dissolved in THF (30 mL) and cooled to 0 °C, followed by the dropwise addition of BH-THF (1 M, 20 mL, 20.0 mmol, 4.0 equiv). After 2 h at ambient temperature, aqueous NaOH (1 M, 10 mL, 10.0 mmol, 2.0 equiv) was added. This was followed by the addition of HO (30% wt. / wt. in water, 1.3 mL, 38.2 mmol, 7.6 equiv), while maintaining the reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for an additional 30 min and then quenched by the addition of saturated aqueous NH Cl. The resulting solution was adjusted to pH 6–7 with aqueous HCl (6 M), extracted with ethyl acetate, washed with brine, dried over anhydrous Na SO , and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (3:2) to give N-(5-(2-hydroxyethyl)-1H-indol-3-yl)acetamide (294.0 mg) as a light brown solid. LCMS Method A: [M+H] + = 219.

[0476] Using the same method as described for intermediate 48, the intermediates in the table below were prepared.

[0477] TIFF2024532798000206.tif47163TIFF2024532798000207.tif209163

[0478] Scheme 25: Synthesis of intermediate 56 (tert-butyl 5-(hydroxymethyl)-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate) TIFF2024532798000208.tif65154

[0479] 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-oxoacetic 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.

[0480] 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.

[0481] 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 at 100° C. for 6 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 (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.

[0482] Using the same method as described for intermediate 56, the intermediates in the table below were prepared.

[0483] TIFF2024532798000209.tif41157

[0484] Scheme 26: Synthesis of intermediate 58 (N-(5-(2-hydroxyethyl)-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide) TIFF2024532798000210.tif86158

[0485] Step 1: 5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridine 2-Chloro-4-methyl-5-nitropyridine (10 g, 57.9 mmol, 1.0 equiv.) was dissolved in THF (50 mL) and cooled to -60 °C, then bromo(ethenyl)magnesium (1 M in THF, 173.8 mL, 173.8 mmol, 3.0 equiv.) was added dropwise under a nitrogen atmosphere while maintaining the solution at -60 °C. The reaction mixture was stirred overnight at ambient temperature and then quenched by the addition of saturated aqueous NH4Cl at 0 °C. The reaction mixture 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 (1:5) to give 5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridine (1.6 g) as a pale yellow solid. LCMS Method A: [M+H] + = 167.

[0486] Step 2: 5-chloro-7-methyl-3-nitro-1H-pyrrolo[3,2-b]pyridine 5-Chloro-7-methyl-1H-pyrrolo[3,2-b]pyridine (1.0 g, 6.0 mmol, 1.0 equiv) was dissolved in HSO (15 mL) and cooled to 0 °C, then KNO (900.0 mg, 9.0 mmol, 1.5 equiv) was added portionwise while maintaining the solution at 0 °C. The reaction mixture was stirred at ambient temperature for 40 min, then cooled to 0 °C and quenched by the addition of ice water. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried under vacuum to give 5-chloro-7-methyl-3-nitro-1H-pyrrolo[3,2-b]pyridine (890.0 mg) as a pale yellow solid. LCMS Method A: [M+H] + = 212.

[0487] Step 3: 5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-amine 5-Chloro-7-methyl-3-nitro-1H-pyrrolo[3,2-b]pyridine (800.0 mg, 3.8 mmol, 1.0 equiv) was dissolved in MeOH (20 mL), and then Pt / C (147.5 mg, 0.8 mmol, 0.2 equiv) was added. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature overnight. The solids were removed by filtration, and the filtrate was concentrated in vacuo. This gave 5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-amine (550.0 mg) as a yellow solid. LCMS Method A: [M+H] + = 182.

[0488] Step 4: N-{5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}acetamide 5-Chloro-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-amine (550.0 mg, 3.0 mmol, 1.0 equiv) and TEA (0.8 mL, 6.1 mmol, 2.0 equiv) were dissolved in THF (20 mL) and cooled to 0 °C, then acetyl chloride (0.3 mL, 3.6 mmol, 1.2 equiv) was added while maintaining the solution at 0 °C. The reaction mixture was stirred at ambient temperature for 4 h and then quenched by the addition of MeOH. The resulting solution was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give N-{5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}acetamide (600.0 mg) as a yellow solid. LCMS Method A: [M+H] + = 224.

[0489] Step 5: N-{5-[(E)-2-ethoxyethenyl]-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}acetamide N-{5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}acetamide (300.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (3 mL) and water (0.5 mL), followed by the addition of 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (398.5 mg, 2.0 mmol, 1.5 equiv.), CsCO (874.1 mg, 2.7 mmol, 2.0 equiv.), and Pd(dppf)Cl (196.3 mg, 0.3 mmol, 0.2 equiv.) under a nitrogen atmosphere. The reaction mixture was heated 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 (1:2) to give N-{5-[(E)-2-ethoxyethenyl]-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}acetamide (200.0 mg) as a yellow solid. LCMS Method A: [M+H] + = 260.

[0490] Step 6: N-[7-methyl-5-(2-oxoethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl]acetamide N-{5-[(E)-2-ethoxyethenyl]-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}acetamide (200.0 mg, 0.8 mmol, 1.0 equiv) was dissolved in DCM (10 mL) and TFA (1 mL). The reaction mixture was stirred at 60° C. for 2 hours, then cooled to ambient temperature and concentrated in vacuo to give N-[7-methyl-5-(2-oxoethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl]acetamide (175.0 mg) as a brown solid, which was used directly in the next step without further purification. LCMS Method A: [M+H] + = 232.

[0491] Step 7: N-[5-(2-hydroxyethyl)-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl]acetamide N-[7-methyl-5-(2-oxoethyl)-1H-pyrrolo[3,2-b]pyridin-3-yl]acetamide (175.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and cooled to 0 °C, followed by the addition of NaBH (114.5 mg, 3.0 mmol, 3.8 equiv.). The reaction mixture was stirred at ambient temperature for 1 h and then concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 5% to 100% gradient / 10 min; detector, UV 254 nm. This afforded N-[5-(2-hydroxyethyl)-7-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl]acetamide (85.0 mg) as a pale yellow solid. LCMS Method A: [M+H] + = 234.

[0492] Scheme 27: Synthesis of intermediate 59 (tert-butyl (5-(2-hydroxypropyl)-1H-indol-3-yl)carbamate) TIFF2024532798000211.tif69154

[0493] Step 1: 5-Bromoindole-1,3-dicarboxylate 1-tert-butyl 3-methyl Methyl 5-bromo-1H-indole-3-carboxylate (5.0 g, 19.6 mmol, 1.0 equiv.) was dissolved in DCM (100 mL), followed by the addition of BocO (8.6 g, 39.3 mmol, 2.0 equiv.) and DMAP (480.8 mg, 3.9 mmol, 0.2 equiv.). The reaction mixture was stirred at ambient temperature for 3 h and then quenched by the addition of water. The resulting solution was extracted with DCM, 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 (1:5) to give 1-tert-butyl 3-methyl 5-bromoindole-1,3-dicarboxylate (6.5 g) as a white solid. LCMS Method A: [M+H] + = 354.

[0494] Step 2: 1-tert-butyl 3-methyl 5-(2-oxopropyl)indole-1,3-dicarboxylate 1-tert-Butyl 3-methyl 5-bromoindole-1,3-dicarboxylate (3.0 g, 8.4 mmol, 1.0 equiv.) and 1-propen-2-ol acetate (1.7 g, 16.9 mmol, 2.0 equiv.) were dissolved in toluene (60 mL), followed by the addition of BuSnOMe (3.2 g, 10.1 mmol, 1.2 equiv.), PdCl (0.3 g, 1.6 mmol, 0.2 equiv.), and POT (0.6 g, 2.1 mmol, 0.2 equiv.) under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 3 h, 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 (1:5) to give 1-tert-butyl 3-methyl 5-(2-oxopropyl)indole-1,3-dicarboxylate (2.5 g) as a white solid. LCMS Method A: [M+H] + = 332.

[0495] Step 3: 5-(2-oxopropyl)-1H-indole-3-carboxylic acid 1-tert-Butyl 3-methyl 5-(2-oxopropyl)indole-1,3-dicarboxylate (2.5 g, 7.5 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL) and water (4 mL), followed by the addition of KOH (0.8 g, 15.0 mmol, 2.0 equiv.). The reaction mixture was heated at 80° C. overnight, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and adjusted to pH 2 with aqueous HCl (2 N). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give 5-(2-oxopropyl)-1H-indole-3-carboxylic acid (1.5 g) as a white solid. LCMS Method B: [MH] - = 216.

[0496] Step 4: 5-(2-oxopropyl)-1H-indole-3-carbonyl azide 5-(2-Oxopropyl)-1H-indole-3-carboxylic acid (1.5 g, 6.9 mmol, 1.0 equiv.) was dissolved in THF (20 mL), followed by the addition of TEA (2.9 mL, 20.7 mmol, 3.0 equiv.) and DPPA (2.8 g, 10.3 mmol, 1.5 equiv.). The reaction mixture was stirred at ambient temperature overnight and then concentrated in vacuo to give 5-(2-oxopropyl)-1H-indole-3-carbonyl azide (1.1 g) as a white solid, which was used directly in the next step without further purification. LCMS Method A: [M+H] + = 243.

[0497] Step 5: tert-butyl N-[5-(2-oxopropyl)-1H-indol-3-yl]carbamate 5-(2-Oxopropyl)-1H-indole-3-carbonyl azide (1.0 g, 4.1 mmol, 1.0 equiv.) was dissolved in 2-methyl-2-propanol (30 mL). The reaction mixture was heated at 90° C. overnight, then cooled to ambient temperature and concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18; mobile phase, ACN in water (0.5% NH4HCO3), 0% ACN to 100% gradient in 15 min; detector, UV 254 nm. This afforded tert-butyl N-[5-(2-oxopropyl)-1H-indol-3-yl]carbamate (600.0 mg) as a white solid. LCMS Method A: [M+H] + = 289.

[0498] Step 6: tert-butyl N-[5-(2-hydroxypropyl)-1H-indol-3-yl]carbamate tert-Butyl N-[5-(2-oxopropyl)-1H-indol-3-yl]carbamate (550.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in MeOH (15 mL), followed by the addition of NaBH (144.3 mg, 3.8 mmol, 2.0 equiv.). The reaction mixture was stirred at ambient temperature for 4 hours and then concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give tert-butyl N-[5-(2-hydroxypropyl)-1H-indol-3-yl]carbamate (550.0 mg) as a white solid. LCMS Method A: [M+H] + = 291.

[0499] Scheme 28: Synthesis of intermediate 60 (1-[4-(trifluoromethyl)phenyl]azetidin-3-ol) TIFF2024532798000212.tif24128 1-Iodo-4-(trifluoromethyl)benzene (1.0 g, 3.7 mmol, 1.0 equiv.) and azetidin-3-ol (0.5 g, 7.4 mmol, 2.0 equiv.) were dissolved in DMSO (5 mL), followed by the addition of L-proline (0.4 g, 3.7 mmol, 1.0 equiv.), KCO (1.0 g, 7.4 mmol, 2.0 equiv.), and CuI (0.4 g, 1.8 mmol, 0.5 equiv.) under a nitrogen atmosphere. The reaction mixture was stirred at 90 °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 (1:1) to give 1-[4-(trifluoromethyl)phenyl]azetidin-3-ol (600.0 mg) as an off-white solid. LCMS Method B: [M+H] + = 218.

[0500] Scheme 29: Synthesis of intermediate 61 (2-(6-(trifluoromethyl)pyridin-3-yl)ethan-1-ol) TIFF2024532798000213.tif20128 [6-(trifluoromethyl)pyridin-3-yl]acetic acid (4.8 g, 23.2 mmol, 1.0 equiv.) was dissolved in THF (100 mL) and cooled to 0 °C, then BH3-THF (1 M, 69.5 mL, 69.5 mmol, 3.0 equiv.) was added dropwise, maintaining the solution at 0 °C. The reaction mixture was stirred at ambient temperature for 1 h and then quenched by the addition of ice 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 dichloromethane / methanol (95:5) to give 2-[6-(trifluoromethyl)pyridin-3-yl]ethanol (4.3 g) as a yellow oil. LCMS Method A: [M+H] + = 192.

[0501] Using the same method as described for Intermediate 61, the intermediates in the table below were prepared.

[0502] TIFF2024532798000214.tif41152

[0503] Scheme 30: Synthesis of intermediate 63 (2-(2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl)ethan-1-ol) TIFF2024532798000215.tif69153

[0504] Step 1: tert-Butyl 6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate Triethyl phosphonoacetate (1.3 g, 5.7 mmol, 1.2 equiv.) was dissolved in THF (50 mL), cooled to 0 °C, and then NaH (60% wt. in mineral oil, 0.3 g, 7.1 mmol, 1.5 equiv.) was added. After 30 min at 0 °C, tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.0 g, 4.7 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at ambient temperature for an additional 2 h 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 tert-butyl 6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate (1.3 g) as a yellow oil. LCMS Method A: [M+H] + = 282.

[0505] Step 2: 2-{2-azaspiro[3.3]heptan-6-ylidene}ethyl acetate TFA salt tert-Butyl 6-(2-ethoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate (1.3 g, 4.6 mmol, 1.0 equiv.) was dissolved in DCM (40 mL) and TFA (2 mL). The reaction mixture was stirred at ambient temperature for 40 minutes and then concentrated in vacuo to give ethyl 2-{2-azaspiro[3.3]heptan-6-ylidene}acetate TFA salt (1.0 g) as a yellow oil. LCMS Method A: [M+H] + = 182.

[0506] Step 3: Ethyl 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-ylidene]acetate 2-{2-azaspiro[3.3]heptan-6-ylidene}ethyl acetate TFA salt (1.0 g, 5.5 mmol, 1.0 equiv.) was dissolved in ACN (40 mL), followed by the addition of KCO (1.5 g, 11.0 mmol, 2.0 equiv.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.4 g, 6.1 mmol, 1.1 equiv.). The reaction mixture was heated at 80° C. for 2 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 NaSO, and concentrated in vacuo to give 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-ylidene]ethyl acetate (1.4 g) as a pale yellow oil. LCMS Method A: [M+H] + = 264.

[0507] Step 4: Ethyl 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]acetate Ethyl 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-ylidene]acetate (1.2 g, 4.6 mmol, 1.0 equiv.) was dissolved in MeOH (40 mL), and then Pd / C (120.0 mg, 10% wt.) was added under a nitrogen atmosphere. The reaction mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature for 2 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 ethyl acetate / petroleum ether (1:3) to afford ethyl 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]acetate (260.0 mg) as a pale yellow oil. LCMS Method A: [M+H] + = 266.

[0508] Step 5: 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]ethanol Ethyl 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]acetate (260.0 mg, 1.0 mmol, 1.0 equiv) was dissolved in THF (15 mL) and cooled to 0 °C, then LiAlH (74.4 mg, 2.0 mmol, 2.0 equiv) was added. The reaction mixture was stirred at ambient temperature for 60 minutes, then cooled to 0 °C and 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 2-[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl]ethanol (210.0 mg) as a pale yellow oil. LCMS Method A: [M+H] + = 224.

[0509] Using the same method as described for intermediate 63, the intermediates in the table below were prepared.

[0510] TIFF2024532798000216.tif42150

[0511] Scheme 31: Synthesis of intermediate 65 ((1-(4-(trifluoromethyl)phenyl)cyclopropyl)methanol) TIFF2024532798000217.tif21128 1-[4-(Trifluoromethyl)phenyl]cyclopropane-1-carboxylic acid (200.0 mg, 0.8 mmol, 1.0 equiv.) was dissolved in THF (5 mL) and cooled to 0 °C, then BH3-THF (1 M, 4.3 mL, 4.3 mmol, 5.0 equiv.) was added dropwise, maintaining the solution at 0 °C. The reaction mixture was stirred at ambient temperature for 1 h and then concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give [1-[4-(trifluoromethyl)phenyl]cyclopropyl]methanol (150.0 mg) as a yellow oil. LCMS Method A: [M+H] + = 217.

[0512] Scheme 32: Synthesis of intermediate 66 (1-(4-(trifluoromethyl)phenyl)propan-2-ol) TIFF2024532798000218.tif21128 1-[4-(trifluoromethyl)phenyl]propan-2-one (1.0 g, 4.9 mmol, 1.0 equiv.) was dissolved in MeOH (30 mL), followed by the addition of NaBH (0.2 g, 5.8 mmol, 1.2 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 NaSO, and concentrated in vacuo to give 1-[4-(trifluoromethyl)phenyl]propan-2-ol (0.9 g) as a pale yellow oil.

[0513] Scheme 33: Synthesis of intermediate 67 (2-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)ethan-1-ol) TIFF2024532798000219.tif18128 2-(Piperidin-3-yl)ethanol hydrochloride (2.0 g, 12.1 mmol, 1.0 equiv.) was dissolved in DMF (30 mL), followed by the addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (5.6 g, 24.2 mmol, 2.0 equiv.) and K2CO3 (3.3 g, 24.2 mmol, 2.0 equiv.). The reaction mixture was heated at 80 °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 Na2SO4, and concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18; mobile phase, MeOH in water, 10% to 50% gradient / 10 min; detector, UV 254 nm. This gave 2-[1-(2,2,2-trifluoroethyl)piperidin-3-yl]ethanol (1.4 g) as a yellow oil. LCMS Method A: [M+H] + = 212.

[0514] Scheme 34: Synthesis of intermediate 68 (4,4-difluoro-1-(2-hydroxyethyl)cyclohexan-1-ol) TIFF2024532798000220.tif23145

[0515] Step 1: Ethyl 2-(4,4-difluoro-1-hydroxycyclohexyl)acetate Zinc powder (2.4 g, 37.3 mmol, 5.0 equiv) was suspended in THF (25 mL) and cooled to 0 °C, then I (1.9 g, 7.5 mmol, 1.0 equiv) was added. After 10 min at 0 °C, 4,4-difluorocyclohexan-1-one (1.0 g, 7.5 mmol, 1.0 equiv) and ethyl 2-bromoacetate (1.5 g, 8.9 mmol, 1.2 equiv) were added dropwise while maintaining the reaction mixture at 0 °C. The reaction mixture was heated at 65 °C for 2 h, then cooled to ambient temperature and quenched by the addition of saturated aqueous NaHCO solution. The mixture 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 ethyl 2-(4,4-difluoro-1-hydroxycyclohexyl)acetate (380.0 mg) as a colorless oil. LCMS Method A: [M+H] + = 223.

[0516] Step 2: 4,4-Difluoro-1-(2-hydroxyethyl)cyclohexan-1-ol Ethyl 2-(4,4-difluoro-1-hydroxycyclohexyl)acetate (380.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in THF (10 mL) and cooled to 0 °C, then LiAlH (97.4 mg, 2.6 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at ambient temperature for 2 h and then quenched by the addition of solid NaSO-10·H0. The solid was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol (10:1) to give 4,4-difluoro-1-(2-hydroxyethyl)cyclohexan-1-ol (120.0 mg) as a colorless oil. LCMS Method A: [M+H] + = 181.

[0517] Scheme 35: Synthesis of intermediate 69 (2-(3-phenylbicyclo[1.1.1]pentan-1-yl)ethan-1-ol) TIFF2024532798000221.tif52145

[0518] Step 1: 3-Phenylbicyclo[1.1.1]pentane-1-carbonyl chloride 3-Phenylbicyclo[1.1.1]pentane-1-carboxylic acid (500.0 mg, 2.7 mmol, 1.0 equiv) was dissolved in DCM (20 mL) and cooled to 0 °C, then (COCl) (0.35 mL, 4.0 mmol, 1.5 equiv) was added dropwise while maintaining the solution at 0 °C. This was followed by the addition of DMF (0.03 mL, 0.3 mmol, 0.1 equiv). The reaction mixture was stirred at ambient temperature for 2.5 h and then concentrated in vacuo to give 3-phenylbicyclo[1.1.1]pentane-1-carbonyl chloride (620 mg) as a yellow solid.

[0519] Step 2: 2-Diazo-1-{3-phenylbicyclo[1.1.1]pentan-1-yl}ethanone 3-Phenylbicyclo[1.1.1]pentane-1-carbonyl chloride (600.0 mg, 2.9 mmol, 1.0 equiv) was dissolved in DCM (10 mL) and ACN (10 mL) and cooled to 0 °C. TEA (1.2 mL, 8.7 mmol, 3.0 equiv) and TMSCHN (1.3 mg, 11.6 mmol, 4.0 equiv) were then added. The reaction mixture was stirred at ambient temperature for 4 h and then quenched by the addition of saturated aqueous citric acid. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give 2-diazo-1-{3-phenylbicyclo[1.1.1]pentan-1-yl}ethanone (610.0 mg) as a pale yellow solid.

[0520] Step 3: {3-phenylbicyclo[1.1.1]pentan-1-yl}acetic acid 2-Diazo-1-{3-phenylbicyclo[1.1.1]pentan-1-yl}ethanone (600.0 mg, 2.8 mmol, 1.0 equiv.) was dissolved in THF (15 mL) and HO (5 mL), followed by the addition of TEA (1.6 mL, 11.3 mmol, 4.0 equiv.) and PhCO2Ag (129.5 mg, 0.6 mmol, 0.2 equiv.). The reaction mixture was heated at 70 °C for 2 h. The solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 100% gradient in 20 min; detector, UV 254 nm. This afforded {3-phenylbicyclo[1.1.1]pentan-1-yl}acetic acid (330.0 mg) as a yellow solid. LCMS method B: [MH] - = 201.

[0521] Step 4: 2-{3-phenylbicyclo[1.1.1]pentan-1-yl}ethanol {3-Phenylbicyclo[1.1.1]pentan-1-yl}acetic acid (300.0 mg, 1.5 mmol, 1.0 equiv.) was dissolved in THF (10 mL) and cooled to 0 °C, followed by the dropwise addition of BH3.THF (1 M, 1.5 mL, 1.5 mmol, 3.0 equiv.). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was diluted with water, extracted with ethyl acetate, and concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 100% gradient / 20 min; detector, UV 254 nm. This afforded 2-{3-phenylbicyclo[1.1.1]pentan-1-yl}ethanol (130.0 mg) as a pale yellow solid. LCMS Method A: [M+H] + = 189.

[0522] Scheme 36: Synthesis of intermediate 70 (2-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol) TIFF2024532798000222.tif23128 2-Chloro-5-(trifluoromethyl)pyridine (1.0 g, 5.5 mmol, 1.0 equiv.) was dissolved in ACN (10 mL), followed by the addition of 2-(piperidin-4-yl)ethan-1-ol (850 mg, 6.6 mmol, 1.2 equiv.) and K2CO3 (1.5 g, 11.0 mmol, 2.0 equiv.). The reaction mixture was heated at 70 °C for 2 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was then 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 dichloromethane / MeOH (10:1) to give 2-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)ethan-1-ol (980 mg) as a white solid. LCMS Method A: [M+H] + = 275.

[0523] Scheme 37: Synthesis of intermediate 71 (2-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)ethan-1-ol) TIFF2024532798000223.tif51157

[0524] Step 1: 5-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine 5-Bromo-2,3-difluoropyridine (4.0 g, 20.6 mmol, 1.0 equiv.) and 4,4-difluoropiperidine (2.7 g, 22.7 mmol, 1.1 equiv.) were dissolved in DMF (20 mL), followed by the addition of K2CO3 (5.7 g, 41.2 mmol, 2.0 equiv.). The reaction mixture was heated at 80 °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 sodium sulfate, 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 5-bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (4.5 g) as a yellow solid. LCMS Method A: [M+H] + = 295.

[0525] Step 2: 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-vinylpyridine 5-Bromo-2-(4,4-difluoropiperidin-1-yl)-3-fluoropyridine (3.0 g, 10.2 mmol, 1.0 equiv.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.9 g, 12.2 mmol, 1.2 equiv.) were dissolved in 1,4-dioxane (30 mL), and then Pd(dppf)Cl·CHCl (0.4 g, 0.5 mmol, 0.05 equiv.) and CsCO (6.6 g, 20.3 mmol, 2.0 equiv.) were added under a nitrogen atmosphere. The reaction mixture was heated at 80 °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 sodium sulfate, 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 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-5-vinylpyridine (1.1 g) as a yellow oil. LCMS Method A: [M+H] + = 243.

[0526] Step 3: 2-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)ethan-1-ol 2-(4,4-Difluoropiperidin-1-yl)-3-fluoro-5-vinylpyridine (1.0 g, 4.1 mmol, 1.0 equiv) was dissolved in THF and cooled to 0 °C, then BH-THF (1 M, 16.5 mL, 16.5 mmol, 4.0 equiv) was added dropwise while maintaining the solution at 0 °C. The reaction mixture was stirred at ambient temperature for 1 hour. Aqueous NaOH (1 M, 2.9 mL, 2.9 mmol, 0.7 equiv) was then added, and the reaction mixture was cooled to 0 °C. Following this, HO (30% wt. / wt. in water, 4.8 mL, 7.2 mmol, 1.8 equiv) was added dropwise while maintaining the reaction mixture at 0 °C. The reaction mixture was stirred at ambient temperature for an additional 1 hour, then quenched by the addition of saturated aqueous NHCl. 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 dichloromethane / MeOH (10:1) to give 2-(6-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl)ethan-1-ol (880.0 mg) as a white solid. LCMS Method A: [M+H] + = 261.

[0527] Using the same method as described for Intermediate 71, the intermediates in the table below were prepared.

[0528] TIFF2024532798000224.tif42158

[0529] Scheme 38: Synthesis of intermediate 73 (4-(3,3-difluorocyclobutyl)phenol) TIFF2024532798000225.tif47145

[0530] Step 1: 1-Bromo-4-(3,3-difluorocyclobutyl)benzene 3-(4-Bromophenyl)cyclobutan-1-one (1.0 g, 4.4 mmol, 1.0 equiv) was dissolved in DCM (20 mL) and cooled to 0 °C, then DAST (2.2 g, 13.3 mmol, 3.0 equiv) was added dropwise while maintaining the solution at 0 °C. The reaction mixture was stirred at 40 °C for 4 h, then cooled to 0 °C 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 (1:5) to give 1-bromo-4-(3,3-difluorocyclobutyl)benzene (870.0 mg) as a colorless oil. TIFF2024532798000226.tif20153

[0531] Step 2: 2-(4-(3,3-difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1-Bromo-4-(3,3-difluorocyclobutyl)benzene (800.0 mg, 3.2 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (150 mL), followed by the addition of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.2 g, 4.9 mmol, 1.5 equiv.), Pd(dppf)Cl2 (236.9 mg, 0.3 mmol, 0.1 equiv.), and KOAc (635.5 mg, 6.5 mmol, 2.0 equiv.) under a nitrogen atmosphere. The reaction mixture was heated at 90 °C for 4 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 2-(4-(3,3-difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (805.0 mg) as a colorless oil. LCMS Method A: [M+H] + = 295.

[0532] Step 3: 4-(3,3-difluorocyclobutyl)phenol 2-(4-(3,3-Difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (800.0 mg, 2.7 mmol, 1.0 equiv) was dissolved in THF (20 mL) and cooled to 0 °C, followed by the dropwise addition of aqueous NaOH (2% wt. / wt., 10 mL, 5.0 mmol, 2.0 equiv) and HO (30% wt. / wt., 1.0 mL, 8.8 mmol, 3.0 equiv). The reaction mixture was stirred at ambient temperature for an additional 2 h and then quenched by the addition of saturated aqueous NHCl. The mixture was extracted with ethyl acetate 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 4-(3,3-difluorocyclobutyl)phenol (320.0 mg) as a colorless oil. LCMS method B: [MH] - = 183.

[0533] Scheme 39: Synthesis of intermediate 74 (4-(tetrahydro-2H-pyran-4-yl)phenol) TIFF2024532798000227.tif27138

[0534] Step 1: 4-[4-(benzyloxy)phenyl]-3,6-dihydro-2H-pyran 1-(Benzyloxy)-4-bromobenzene (1.0 g, 3.8 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (10 mL), followed by the addition of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 5.7 mmol, 1.5 equiv.), CsCO (2.5 g, 7.6 mmol, 2.0 equiv.), and Pd(dppf)ClCHCl (309.0 mg, 0.4 mmol, 0.1 equiv.) under a nitrogen atmosphere. The reaction mixture was heated at 90 °C for 6 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 (1:8) to give 4-[4-(benzyloxy)phenyl]-3,6-dihydro-2H-pyran (712.0 mg) as a yellow solid. LCMS Method A: [M+H] + = 267.

[0535] Step 2: 4-(oxan-4-yl)phenol 4-[4-(benzyloxy)phenyl]-3,6-dihydro-2H-pyran (500.0 mg, 1.9 mmol, 1.0 equiv) was dissolved in EtOH (10 mL), then Pd / C (10% wt., 50.0 mg) was added under a nitrogen atmosphere. The mixture was sparged with nitrogen, placed under an atmosphere of hydrogen gas (balloon), and then stirred at ambient temperature for 5 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 ethyl acetate / petroleum ether (1:5) to give 4-(oxan-4-yl)phenol (150.0 mg) as a pale yellow solid. LCMS Method B: [MH] - = 177.

[0536] Using the same method as described for Intermediate 74, the intermediates in the table below were prepared.

[0537] TIFF2024532798000228.tif95147

[0538] Scheme 40: Synthesis of intermediate 77 (2-(4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenol) TIFF2024532798000229.tif23143

[0539] Step 1: 4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-ol 1-(2,2,2-trifluoroethyl)piperidin-4-one (1.0 g, 5.5 mmol, 1.0 equiv) was dissolved in EtO (40 mL) and cooled to -55 °C, then MeMgBr (1 M in THF, 11.0 mL, 11.0 mmol, 2.0 equiv) was added dropwise while maintaining the solution at -5 °C. The reaction mixture was stirred at ambient temperature for 4 h and then quenched by the addition of saturated aqueous NH Cl at 0 °C. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na SO , and concentrated in vacuo to give 4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-ol (1.0 g) as a pale yellow oil. LCMS Method A: [M+H] + = 198.

[0540] Step 2: 2-[4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenol 4-Methyl-1-(2,2,2-trifluoroethyl)piperidin-4-ol (600.0 mg, 3.0 mmol, 1.0 equiv.) was dissolved in CFSOH (5 mL), followed by the addition of phenol (859.0 mg, 9.1 mmol, 3.0 equiv.). The reaction mixture was stirred overnight at ambient temperature 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. The residue was purified by reverse flash chromatography using the following conditions: column, silica gel; mobile phase, ACN in water, 10% to 100% gradient / 15 min; detector, UV 254 nm. This afforded 2-[4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenol (170.0 mg) as a pale yellow oil. LCMS Method A: [M+H]+ = 274.

[0541] Scheme 41: Synthesis of intermediate 78 (4-(4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenol) TIFF2024532798000230.tif54146

[0542] Step 1: 4-Methylidenepiperidine TFA salt tert-Butyl 4-methylidenepiperidine-1-carboxylate (2.0 g, 10.1 mmol, 1.0 equiv.) was dissolved in DCM (40 mL) and then TFA (3.1 mL, 40.6 mmol, 4.0 equiv.) was added. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated in vacuo to give 4-methylidenepiperidine TFA as a yellow solid, which was used directly in the next step without further purification. LCMS Method A: [M+H] + = 98.

[0543] Step 2: 2,2,2-trifluoro-1-(4-methylenepiperidin-1-yl)ethan-1-one 4-Methylidenepiperidine (1.0 g, 10.3 mmol, 1.0 equiv) and TEA (2.9 mL, 20.6 mmol, 2.0 equiv) were dissolved in ACN (10 mL), followed by the dropwise addition of TFAA (2.9 mL, 20.6 mmol, 2.0 equiv). The reaction mixture was heated at 80° C. for 2 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 NaSO, and concentrated in vacuo to give 2,2,2-trifluoro-1-(4-methylidenepiperidin-1-yl)ethanone (710.0 mg) as a colorless oil. LCMS Method A: [M+H] + = 194.

[0544] Step 3: 2,2,2-trifluoro-1-[4-(4-hydroxyphenyl)-4-methylpiperidin-1-yl]ethanone 2,2,2-Trifluoro-1-(4-methylidenepiperidin-1-yl)ethanone (700.0 mg, 3.6 mmol, 1.0 equiv.) was dissolved in CFSOH (10 mL), followed by the addition of phenol (1.0 g, 10.9 mmol, 3.0 equiv.). The reaction mixture was stirred at ambient temperature overnight and then quenched by the addition of ice water. The resulting solution was adjusted to pH 6 with aqueous NaOH (20% wt. / wt), extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, 5% to 100% gradient / 25 min; detector, UV 254 nm. This gave 2,2,2-trifluoro-1-[4-(4-hydroxyphenyl)-4-methylpiperidin-1-yl]ethanone (180.0 mg) as a yellow oil. LCMS Method B: [MH] - = 286.

[0545] Step 4: 4-[4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenol 2,2,2-Trifluoro-1-[4-(4-hydroxyphenyl)-4-methylpiperidin-1-yl]ethanone (180.0 mg, 0.6 mmol, 1.0 equiv) was dissolved in THF (15 mL) and cooled to 0 °C, followed by the dropwise addition of BH THF (1 M, 2.5 mL, 2.5 mmol, 4.0 equiv). The reaction mixture was heated at 70 °C for 1 h, then cooled to 0 °C and quenched by the addition of MeOH. The resulting solution was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:8) to give 4-[4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]phenol (150.0 mg) as a pale yellow oil. LCMS Method B: [MH] - = 272.

[0546] Scheme 42: Synthesis of intermediate 79 (2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-ol) TIFF2024532798000231.tif22128

[0547] 4-(Trifluoromethyl)-1H-pyrazole (500.0 mg, 3.7 mmol, 1.0 equiv.) and 2-bromoethanol (918.3 mg, 7.3 mmol, 2.0 equiv.) were dissolved in DMF (5 mL), followed by the addition of CsCO (2.4 g, 7.3 mmol, 2.0 equiv.). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mM NHHCO), 10% ACN to 50% gradient / 10 min; detector, UV 254 nm. This afforded 2-[4-(trifluoromethyl)pyrazol-1-yl]ethanol (310.0 mg) as a pale yellow oil. LCMS Method A: [M+H] + = 181.

[0548] Scheme 43: Synthesis of intermediate 80 (2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-ol) TIFF2024532798000232.tif22148

[0549] Step 1: Ethyl 2-[3-(trifluoromethyl)pyrazol-1-yl]acetate 3-(Trifluoromethyl)-1H-pyrazole (2.0 g, 14.7 mmol, 1.0 equiv.) was dissolved in ACN (20 mL), followed by the addition of KCO (4.1 g, 29.4 mmol, 2.0 equiv.) and ethyl bromoacetate (2.5 g, 14.7 mmol, 1.0 equiv.). The reaction mixture was heated at 60° 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 NaSO, 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 ethyl 2-[3-(trifluoromethyl)pyrazol-1-yl]acetate (1.8 g) as a yellow solid. LCMS Method A: [M+H] + = 223.

[0550] Step 2: 2-[3-(trifluoromethyl)pyrazol-1-yl]ethanol Ethyl 2-[3-(trifluoromethyl)pyrazol-1-yl]acetate (800.0 mg, 3.6 mmol, 1.0 equiv.) was dissolved in THF (10 mL) and cooled to 0° C., then LiAlH (164.0 mg, 4.3 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at 0° C. for 2 h and then quenched by the addition of saturated aqueous sodium hyposulfite solution. The solids were removed by filtration, and the filtrate was concentrated in vacuo to give 2-[3-(trifluoromethyl)pyrazol-1-yl]ethanol (560.0 mg) as a yellow oil, which was used directly in the next step without further purification. LCMS Method A: [M+H] + = 181.

[0551] Scheme 44: Synthesis of intermediate 81 (tert-butyl 3-acetamido-5-(2-aminoethyl)-1H-indole-1-carboxylate) TIFF2024532798000233.tif66148

[0552] Step 1: tert-butyl 5-(hydroxymethyl)-3-(2-(methylamino)-2-oxoacetamido)-1H-indole-1-carboxylate tert-Butyl 3-acetamido-5-(2-hydroxyethyl)indole-1-carboxylate (300.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in THF (3 mL), followed by the addition of phthalimide (277.3 mg, 1.9 mmol, 2.0 equiv.) and PPh3 (494.3 mg, 1.9 mmol, 2.0 equiv.). The reaction mixture was cooled to 0 °C, and then DIAD (381.1 mg, 1.9 mmol, 2.0 equiv.) was added dropwise, maintaining the solution at 0 °C. The reaction mixture was stirred at ambient temperature for 6 hours 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 (1:1) to give tert-butyl 5-[2-(1,3-dioxoisoindol-2-yl)ethyl]-3-acetamidoindole-1-carboxylate (340.0 mg) as a brown solid. LCMS Method A: [M+H] + = 448.

[0553] Step 2: tert-butyl 5-(2-aminoethyl)-3-acetamidoindole-1-carboxylate tert-Butyl 5-[2-(1,3-dioxoisoindol-2-yl)ethyl]-3-acetamidoindole-1-carboxylate (310.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in EtOH (3.5 mL), followed by the addition of hydrazine (44.4 mg, 1.4 mmol, 2.0 equiv.). The reaction mixture was stirred at ambient temperature for 5 hours 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 to give crude tert-butyl 5-(2-aminoethyl)-3-acetamidoindole-1-carboxylate (280.0 mg) as a brown solid. LCMS Method A: [M+H] + = 318.

[0554] Using the same method as described for Intermediate 81, the intermediates in the table below were prepared.

[0555] TIFF2024532798000234.tif49153

[0556] Scheme 45: Synthesis of intermediate 83 (tributyl({[4-(trifluoromethyl)phenyl]methoxy}methyl)stannane) TIFF2024532798000235.tif17128

[0557] [4-(Trifluoromethyl)phenyl]methanol (5.0 g, 28.4 mmol, 1.0 equiv.) was dissolved in THF (50 mL) and cooled to 0° C., followed by the addition of NaH (60% wt., 1.4 g, 34.1 mmol, 1.2 equiv.). After 30 min at 0° C., tributyl(iodomethyl)stannane (13.4 g, 31.2 mmol, 1.1 equiv.) was added. The reaction mixture was stirred at ambient temperature for an additional 4 h, then cooled to 0° C. and quenched by the addition of MeOH. The resulting solution was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / petroleum ether (5:1) to give tributyl({[4-(trifluoromethyl)phenyl]methoxy}methyl)stannane (9.5 g) as a colorless oil. LCMS Method A: [M+H] + = 481.

[0558] Scheme 46: Synthesis of intermediate 85 (5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-amine TFA salt) TIFF2024532798000236.tif80144

[0559] 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.

[0560] 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.

[0561] 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 the dropwise addition of HO (30% wt / wt / , 3.0 g, 26.2 mmol, 2.0 equiv) while maintaining the reaction mixture at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h 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.

[0562] 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., then TBUP (1.7 g, 8.6 mmol, 3.0 equiv.) was added at 0° C. under a nitrogen atmosphere. This was followed by the dropwise addition of ADDP (2.2 g, 8.6 mmol, 3.0 equiv.) while maintaining the solution at 0° C. The reaction mixture was heated at 50° C. for 2 hours, 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, 45% phase B to 70% gradient in 20 min; detector, UV 254 nm, to give 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.

[0563] 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 resulting 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.

[0564] Using the same method as described for Intermediate 85, the intermediates in the table below were prepared.

[0565] TIFF2024532798000237.tif214170

[0566] Scheme 47: Synthesis of intermediate 92 (5-(2-(4-(trifluoromethyl)phenoxy)ethyl)-1H-indol-3-amine TFA salt) TIFF2024532798000238.tif47146

[0567] Steps 1-2: tert-butyl (5-(2-hydroxyethyl)-1H-indol-3-yl)carbamate The title compound was prepared using the same method as described for Intermediate 48 (Steps 1-2). LCMS Method A: [M+H] + = 277.

[0568] 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 at 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.

[0569] 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.

[0570] Using the same method as described for Intermediate 92, the intermediates in the table below were prepared.

[0571] TIFF2024532798000239.tif98170

[0572] Scheme 48: Synthesis of intermediate 96 (7-methyl-5-(4-(trifluoromethyl)phenethoxy)-1H-pyrrolo[3,2-b]pyridin-3-amine TFA salt) TIFF2024532798000240.tif82150

[0573] Step 1: 4-Methyl-5-nitro-2-{2-[4-(trifluoromethyl)phenyl]ethoxy}pyridine 2-[4-(trifluoromethyl)phenyl]ethanol (5.0 g, 26.3 mmol, 1.0 equiv.) was dissolved in THF (30 mL) and cooled to 0° C., then 4-methyl-5-nitropyridin-2-ol (4.1 g, 26.3 mmol, 1.0 equiv.) and DIAD (10.6 g, 52.6 mmol, 2.0 equiv.) were added. The reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 6 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 4-methyl-5-nitro-2-{2-[4-(trifluoromethyl)phenyl]ethoxy}pyridine (6.2 g) as a pale yellow solid. LCMS Method A: [M+H] + = 327.

[0574] Step 2: 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine 4-Methyl-5-nitro-2-{2-[4-(trifluoromethyl)phenyl]ethoxy}pyridine (1.0 g, 3.15 mmol, 1.0 equiv.) was dissolved in THF (20 mL) and cooled to −60° C., then bromo(ethenyl)magnesium (1 M in THF, 70.0 mL, 70.0 mmol, 22 equiv.) was added dropwise under a nitrogen atmosphere, maintaining the solution at −60° C. The reaction mixture was stirred at ambient temperature for 8 h and then quenched by the addition of saturated aqueous NH4Cl. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:2) to give 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine (380.0 mg) as a yellow solid. LCMS Method A: [M+H] + = 321.

[0575] Step 3: 2,2,2-trichloro-1-(7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone 7-Methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine (500.0 mg, 1.6 mmol, 1 equiv.) and pyridine (246.9 mg, 3.1 mmol, 2.0 equiv.) were dissolved in CHCl3 (20 mL), followed by the dropwise addition of trichloroacetyl chloride (851.4 mg, 4.7 mmol, 3.0 equiv.). The reaction mixture was heated at 65 °C for 2 days and then concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 5% to 100% gradient in 10 min; detector, UV 254 nm. This gave 2,2,2-trichloro-1-(7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone (130.0 mg) as a yellow solid. LCMS Method A: [M+H] + = 465.

[0576] Step 4: 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid 2,2,2-Trichloro-1-(7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone (220.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in THF (15 mL) and water (3 mL), and then NaOH (37.8 mg, 0.9 mmol, 2.0 equiv.) was added. The reaction mixture was heated at 65° C. for 1 hour, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and then adjusted to pH 5 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 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (150.0 mg) as a yellow solid. LCMS Method B: [MH] - = 363.

[0577] Step 5: 7-Methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine-3-carbonyl azide 7-Methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (150.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in THF (15 mL), followed by the addition of TEA (0.1 mL, 0.8 mmol, 2.0 equiv.) and DPPA (226.6 mg, 0.8 mmol, 2.0 equiv.). The reaction mixture was stirred at ambient temperature for 6 hours 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 to give 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine-3-carbonyl azide (150.0 mg) as a yellow solid. LCMS Method A: [M+H] += 390.

[0578] Step 6: tert-butyl N-(7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate 7-Methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridine-3-carbonyl azide (150.0 mg, 0.4 mmol, 1.0 equiv.) was dissolved in toluene (3 mL), followed by the addition of t-BuOH (142.8 mg, 1.9 mmol, 5 equiv.). The reaction mixture was heated at 100 °C overnight, 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, ACN in water, 5% to 100% gradient / 10 min; detector, UV 254 nm. This gave tert-butyl N-(7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (50.0 mg) as a yellow solid. LCMS Method A: [M+H] + = 436.

[0579] Step 7: 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-amine TFA salt tert-Butyl N-(7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate (50.0 mg, 0.1 mmol, 1.0 equiv.) was dissolved in DCM (2 mL) and TFA (0.5 mL). The reaction mixture was stirred at ambient temperature for 50 minutes and then concentrated in vacuo to give crude 7-methyl-5-{2-[4-(trifluoromethyl)phenyl]ethoxy}-1H-pyrrolo[3,2-b]pyridin-3-amine TFA salt (35.0 mg) as a pale yellow solid. LCMS Method A: [M+H] + = 336.

[0580] Using the same method as described for Intermediate 96, the intermediates in the table below were prepared.

[0581] TIFF2024532798000241.tif41144

[0582] Scheme 49: Synthesis of intermediate 98 (5-(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)propyl)-1H-indol-3-amine TFA salt) TIFF2024532798000242.tif43150

[0583] Step 1: 1-(prop-2-en-1-yl)-4-(trifluoromethyl)pyrazole 4-(Trifluoromethyl)-1H-pyrazole (500.0 mg, 3.6 mmol, 1.0 equiv.) and K2CO3 (1.0 g, 7.3 mmol, 2.0 equiv.) were dissolved in ACN (10 mL), and then allyl bromide (666.7 mg, 5.5 mmol, 1.5 equiv.) was added. The reaction mixture was heated at 100 °C for 2 h and then cooled to ambient temperature. The solid was removed by filtration, and the filtrate was used directly in the next step without further manipulation. LCMS Method A: [M+H] + = 165.

[0584] Step 2: tert-butyl N-{5-[(1E)-3-[4-(trifluoromethyl)pyrazol-1-yl]prop-1-en-1-yl]-1H-indol-3-yl}carbamate To the above solution of 1-(prop-2-en-1-yl)-4-(trifluoromethyl)pyrazole in ACN (10 mL) was added tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate (1.3 g, 4.2 mmol, 1.5 equiv.), TEA (0.8 mL, 5.6 mmol, 2.0 equiv.), POT (172.8 mg, 0.5 mmol, 0.2 equiv.), and Pd(OAc) (127.4 mg, 0.5 mmol, 0.2 equiv.) under a nitrogen atmosphere. The reaction mixture was heated at 100° C. for 5 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 tert-butyl N-{5-[(1E)-3-[4-(trifluoromethyl)pyrazol-1-yl]prop-1-en-1-yl]-1H-indol-3-yl}carbamate (370.0 mg) as a brown oil. LCMS Method A: [M+H] + = 407.

[0585] Step 3: tert-butyl N-(5-{3-[4-(trifluoromethyl)pyrazol-1-yl]propyl}-1H-indol-3-yl)carbamate tert-Butyl N-{5-[(1E)-3-[4-(trifluoromethyl)...

Claims

1. Compounds of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof or a tautomer thereof, During the ceremony: L A But-(L 1 ) a1 -(L 2 ) a2 -(L 3 ) a3 -(L 4 ) a4 -(L 5 ) a5 -*, where * is Q 1 indicates the point of attachment to a1, a2, a3, a4, and a5 are each independently 0 or 1; However, a1+a2+a3+a4+a5≧1; and 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 The combinations are OO bond, NO bond, NN bond, OS bond, SS bond, NS(O) 0 No bond can be formed; and 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 C 3～10 Cycloalkylene or C 3～10 Cycloalkenylene is Y 1 , Y 2 , and Y 3 is not directly linked to a six-membered ring containing 3～10 Cycloalkylene or C 3～10 cycloalkenylene, and heterocyclylene or heterocycloalkenylene, each having 4 to 10 ring atoms, 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 the heterocyclylene or heterocycloalkenylene may be substituted by Y 1 , Y 2 , and Y 3 heterocyclylene or heterocycloalkenylene, which is not directly linked to a 6-membered ring containing are independently selected from the group consisting of: Q 1 Ga-R g and Y 1 , Y 2 , and Y 3 But, CR 1 , C(=O), N, and NR 2 are each independently selected from the group consisting of: X 1 But O, S, N, NR 2 , and C.R. 1 selected from the group consisting of: X 2 But O, S, N, NR 4 , and C.R. 5 selected from the group consisting of: each 【Chemistry 2】 are independently a single bond or a double bond, provided that X 1 and X 2 is a heteroaryl, and Y 1 , Y 2 , and Y 3 is an aryl or heteroaryl; Furthermore, however, L A is Y 1 , Y 2 , and Y 3 cannot contain a cyclic group directly attached to a six-membered ring containing R 1 and R 5 Each occurrence of H;R c ;R g ; and -(L g ) bg -R g 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, ・H、 ・Each of them has 1 to 6 R a2 optionally substituted with C 1～10 Alkyl, C 2～10 Alkenyl, or C 2～10 In alkynyl, one or more of the optionally substituted methylene groups may be replaced by one or more heteroatoms selected from O or S, and when W is alkenyl or alkynyl, the heteroatoms are sp 2 Not directly linked to a carbon or sp carbon, C 1～10 Alkyl, C 2～10 Alkenyl, or C 2～10 Alkynyl, - 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 Cycloalkyl or C 3～8 cycloalkenyl, and Monocyclic heterocyclyl or heterocycloalkenyl of 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 heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c a monocyclic heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: selected from the group consisting of provided that when W is heterocyclyl or heterocycloalkenyl, it is C(=O)NR via a ring carbon atom. 6 is bonded to a group; R a and R a2 Each occurrence of is -OH; -halo; -NR e R f ;C 1～4 Alkoxy; C 1～4 Haloalkoxy; -C(=O)O(C 1～4 alkyl); -C(=O)(C 1～4 alkyl); -C(=O)OH; -CONR'R''; -S(O) 1～2 NR'R'';-S(O) 1～2 (C 1～4 alkyl); and cyano; R b and R c each occurrence of is selected from halo; cyano; 1 to 6 independently selected R a C 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''; -NR'C(=O)(C 1～4 alkyl) and -SF 5 are independently selected from the group consisting of: 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 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, 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 oxo, R c , and R h heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl of 5 to 12 ring atoms, 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 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, 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 substituted with 1 to 4 R i 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 one to four R i 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 -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; and Each occurrence of R' and R'' is H; -OH; and C 1～4 independently selected from the group consisting of alkyl, The compound, or a pharmaceutically acceptable salt thereof, or a tautomer thereof.

2. The compound of claim 1, wherein a2 is 1.

3. L 2 However, 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 is alkynylene, Optionally, where L 2 However, 1 to 6 R b Optionally substituted linear C 1～6 alkylene; Optionally, where L 2 But 1 to 3 R b Optionally substituted linear C 1～3 is alkylene, 2. The compound of claim 1.

4. L 2 but, ・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 heterocyclylene or heterocycloalkenylene, optionally substituted by 2. The compound of claim 1, selected from the group consisting of:

5. The compound of claim 1, wherein a1 is 1.

6. L 1 However, -O-, -N(H)-, -N(R d )-, and -S-; Optionally, where L 1 is -O-, 2. The compound of claim 1.

7. The compound of claim 1, wherein a1 is 0.

8. 2. The compound of claim 1, wherein a3 is 1.

9. L 3 However, -O-, -N(H)-, -N(R d )-, and -S-; Optionally, where L 3 is -O-, 2. The compound of claim 1.

10. 2. The compound of claim 1, wherein a3 is 0.

11. The compound of claim 1, wherein a4 is 1.

12. a1 and a2 are each 1; Optionally, where a1 and a2 are each 1; L 1 is -O-, -N(H)-, or -N(R d )- and L 2 but, ・1 to 3 R b Optionally substituted with linear C 1～3 alkylene, ・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 substituted with one to three ring heteroatoms each independently selected from the group consisting of c heterocyclylene, optionally substituted by selected from the group consisting of: Optionally, where a1 and a2 are each 1; L 1 is -O-, and L 2 But 1 to 3 R b Optionally substituted linear C 1～3 alkylene; Optionally, where a1 and a2 are each 1; L 1 is -O-; and L 2 But 1 to 3 R c C optionally substituted with 3～8 cycloalkylene, optionally where L 2 But one or two R c may be substituted with 【Chemistry 3】 where n1 and n2 are independently 0, 1, or 2; Q 2 CH, CR c , or N; and an asterisk is -(L 3 ) a3 - indicates the point of attachment to optionally wherein n1 and n2 are independently 0 or 1, optionally 0; and Q 2 is CH; optionally wherein n1 and n2 are 0 and Q 2 is CH; optionally, where L 2 is 1 to 2 R c cyclobutane-diyl optionally substituted with 2 is 1 to 2 R c cyclobutane-1,3-diyl optionally substituted by 2 is unsubstituted cyclobutane-diyl; optionally wherein L 2 is unsubstituted cyclobutane-1,3-diyl; 2. The compound of claim 1.

13. a3, a4, and a5 are each 0, and optionally, where L A But -O-CH 2 CH 2 -*,or 【Chemistry 4】 (for example, 【Chemistry 5】 ), where * is Q 1 13. The compound of claim 12, showing the point of attachment to:

14. a1 is 0; a2 is 1; and optionally, where L 2 However, 1 to 6 R b Optionally substituted linear C 1～6 is alkylene, Optionally, where L 2 But 1 to 3 R b Optionally substituted linear C 1～3 is alkylene, 2. The compound of claim 1.

15. a3 is 1; optionally, where L 3 -O-, -N(H)-, and -N(R d )-, optionally wherein L 3 15. The compound of claim 14, wherein is -O-.

16. 15. The compound of claim 14, wherein a4 is 0; and a5 is 0.

17. Q 1 but, Heteroaryl of 5 to 6 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0～2 and the heteroaryl is one to three R c heteroaryl, optionally substituted with ・1 to 3 R c phenyl optionally substituted with 2. The compound of claim 1, selected from the group consisting of:

18. Q 1 is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0～2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c heterocyclyl or heterocycloalkenyl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Optionally, here, Q 1 but, 【Chemistry 6】 wherein m1 and m2 are each independently 0, 1, or 2; and Q 1 1 or 2 R c and Optionally, here, 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 independently selected from the group consisting of alkyl, 2. The compound of claim 1.

19. Y 1 is CR 1 and Y 2 is CR 1 and / or Y 3 is CR 1 2. The compound of claim 1, wherein:

20. Y 1 , Y 2 , and Y 3 10. The compound of claim 1, wherein each is CH.

21. X 1 NR 2 and X 2 is CR 5 and optionally where X 1 is NH; and X 2 2. The compound of claim 1, wherein is CH.

22. R 6 2. The compound of claim 1, wherein

23. W is, (i) Each of them has 1 to 6 R a2 optionally substituted with C 1～10 Alkyl, C 2～10 Alkenyl, or C 2～10 In alkynyl, one or more of the optionally substituted methylene groups may be replaced by one or more heteroatoms selected from O or S, and when W is alkenyl or alkynyl, the heteroatoms are sp 2 Not directly linked to a carbon or sp carbon, C 1～10 Alkyl, C 2～10 Alkenyl, or C 2～10 alkenyl, Optionally, 1 to 6 R a2 C optionally substituted with 1～10 alkyl; optionally, 1 to 6 R a2 C optionally substituted with 1～4 Alkyl, 2. The compound of claim 1, wherein:

24. W is, (i) 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 Cycloalkyl or C 3～8 cycloalkenyl, Optionally, oxo and R c a monocyclic C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3～8 cycloalkyl, 2. The compound of claim 1, wherein:

25. A compound selected from the following, or a pharmaceutically acceptable salt thereof: 【Chemistry 7】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

26. The compound described in claim 25, wherein the compound is the following compound: 【Chemistry 8】

27. ​​The compound described in claim 25, wherein the compound is the following compound: 【Chemistry 9】

28. The compound described in claim 25, wherein the compound is the following compound: 【Chemistry 10】

29. The compound described in claim 25, wherein the compound is the following compound: 【Chemistry 11】

30. The compound described in claim 25, wherein the compound is the following compound: 【Chemistry 12】

31. The compound described in claim 25, wherein the compound is the following compound: 【Chemistry 13】

32. The compound described in claim 25, wherein the compound is the following compound: 【Chemistry 14】

33. The compound described in claim 25, wherein the compound is the following compound: 【Chemistry 15】

34. The compound described in claim 25, wherein the compound is the following compound: 【Chemistry 16】

35. The compound described in claim 25, wherein the compound is the following compound: 【Chemistry 17】

36. The compound described in claim 25, wherein the compound is the following compound: 【Chemistry 18】

37. 37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

38. 38. The pharmaceutical composition of claim 37 for use in a method for inhibiting STING activity.

39. 38. The pharmaceutical composition of claim 37 for use in a method of inducing an immune response in a subject in need thereof.

40. 38. The pharmaceutical composition of claim 37 for use in a method for treating a STING-associated disease, disorder, or condition.

41. A combination comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt or tautomer thereof and one or more therapeutically active agents.

42. 38. The pharmaceutical composition of claim 37, for use in the treatment of a disease, condition or disorder modulated by STING inhibition.

43. The pharmaceutical composition of claim 42, wherein the disease, condition, or disorder is type I interferonism, Aicardi-Goutieres syndrome (AGS), systemic lupus erythematosus, an inflammatory-related disorder, or rheumatoid arthritis.

44. The pharmaceutical composition described in claim 43, wherein the disease, condition or disorder is systemic lupus erythematosus.

45. The pharmaceutical composition of claim 42, wherein the disease, condition, or disorder is Parkinson's disease.

46. The pharmaceutical composition described in claim 42, wherein the disease, condition or disorder is amyotrophic lateral sclerosis.

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