Compounds and compositions for treating conditions associated with STING activity

Abstract

The present disclosure features chemical entities (e.g., 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.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 955,853, filed December 31, 2019, and U.S. Provisional Patent Application No. 63 / 090,547, filed October 12, 2020, each of which is incorporated herein 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 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. [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 pivotal 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 STING's interaction 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. Additionally, STING has been shown to induce activation of NF-κB and MAP kinases. After initiating signaling, STING is rapidly degraded, a step that may 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 continuous innate immune activation in AGS. Apart from these inherited disorders, emerging evidence points to a more general pathogenic 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 prodrugs and / or tautomers 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.

[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, a compound of formula (I): TIFF2023509421000001.tif38128, or a pharmaceutically acceptable salt thereof, wherein Z, Y 1 , Y 2 , Y 3 , X 1 , X 2 , R 6 , W, Q, P 1 , P 2 , P 3 , P 4 , and P 5 may be as defined anywhere herein.

[0009] In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a tautomer thereof, or any combination thereof, is featured. The term "prodrug" is intended to refer to a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound described herein (e.g., a compound of formula (I)). Thus, a "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. In some aspects, a prodrug is inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often have advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are given in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties.

[0010] 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.

[0011] 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.

[0012] 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).

[0013] 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).

[0014] 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).

[0015] 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).

[0016] 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).

[0017] 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.

[0018] 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.

[0019] Another aspect is a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in the treatment of a disease, condition, or disorder modulated by STING inhibition.

[0020] Another aspect is 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.

[0021] Another aspect is a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in the treatment of cancer.

[0022] Another aspect is a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in treating a cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma.

[0023] Another aspect is a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in the treatment of type I interferonopathy.

[0024] Another aspect is 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-Goutieres syndrome (AGS), genetic forms of lupus, and inflammation-related disorders, such as systemic lupus erythematosus and rheumatoid arthritis.

[0025] Another aspect is the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in the manufacture of a medicament for the treatment of a condition, disease, or disorder associated with increased (e.g., enhanced) STING activation.

[0026] Another aspect is the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in the manufacture of a medicament for the treatment of cancer.

[0027] Another aspect is the use of a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in the manufacture of a medicament for 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.

[0028] Another aspect is the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in the manufacture of a medicament for the treatment of type I interferonopathy.

[0029] Another aspect is the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, for use in the manufacture of a medicament for the treatment of type I interferonopathies selected from infantile-onset STING-associated vasculitis (SAVI), Aicardi-Goutieres syndrome (AGS), genetic forms of lupus, and inflammation-related disorders, such as systemic lupus erythematosus and rheumatoid arthritis.

[0030] Another aspect is the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, to treat a disease, condition, or disorder modulated by STING inhibition.

[0031] Another aspect is the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, to treat a condition, disease, or disorder associated with increased (e.g., hyperactivity) of STING activation.

[0032] Another aspect is the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, to treat cancer.

[0033] Another aspect is the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, to treat a cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma.

[0034] Another aspect is the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, to treat type I interferonopathy.

[0035] Another aspect is the use of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, to treat type I interferonopathies selected from infantile-onset STING-associated vasculitis (SAVI), Aicardi-Goutieres syndrome (AGS), genetic forms of lupus, and inflammation-related disorders, such as systemic lupus erythematosus and rheumatoid arthritis.

[0036] Embodiments can include one or more of the following features.

[0037] 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.

[0038] 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.

[0039] 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 the like. Taxol, paclitaxel, and / or docetaxel), topoisomerases (e.g., type I topoisomerases and / or type 2 topoisomerases, e.g., camptothecins such as irinotecan and / or topotecan, amsacrine, etoposide, etoposide phosphate, and / or teniposide), cytotoxic antibiotics (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and / or mitomycin), hormones (e.g., luteinizing hormone-releasing hormone agonists, e.g., leuprolidine, goserelin, triptorelin, histrelin, bica fluthamide, flutamide, and / or nilutamide), antibodies (e.g., abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumab, ranibizumab, rituximab, tocilizumab, tositumomab, and / or trastuzumab), antiangiogenic agents, cytokines, thrombotic agents, growth inhibitors, antihelminthic agents, andThe immune checkpoint inhibitor is selected from immune checkpoint inhibitors that target immune checkpoint receptors, including CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T-cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), and galectin. 9-TIM3, phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members, KIR, ILT and LIR, NKG2D and NKG2 A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

[0040] The subject can have cancer, for example, the subject has undergone and / or is undergoing and / or will undergo one or more cancer therapies.

[0041] 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.

[0042] The chemical entity may be administered intratumorally.

[0043] The method can further include identifying the subject.

[0044] Other aspects include those described in the detailed description and / or claims.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] "API" refers to the active pharmaceutical ingredient.

[0049] 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.

[0050] 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 components 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.

[0051] 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 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.

[0052] The term "pharmaceutical composition" refers to a mixture of compounds 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. Pharmaceutical compositions facilitate the 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.

[0053] 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.

[0054] The terms "treat," "treating," and "treatment" in the context of treating 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.

[0055] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0056] 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.

[0057] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with an independently selected halo.

[0058] The term "alkoxy" refers to an -O-alkyl group (e.g., -OCH3).

[0059] The term "alkylene" refers to a divalent alkyl (eg, -CH2-).

[0060] 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. Alkenyl groups can be unsubstituted or substituted with one or more substituents.

[0061] The term "alkynyl" refers to an acyclic hydrocarbon chain, which may be straight or branched, having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2~6 indicates that the group may have 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can be unsubstituted or substituted with one or more substituents.

[0062] 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.

[0063] 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, where the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, etc. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which 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.

[0064] 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.

[0065] 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, pyrazolo[3,4-b]pyridinyl, pyrazolo[3, [4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, indolinyl, isoindolinyl, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0066] 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 may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]pentanyl, 2-azabicyclo[1.1.1]pentanyl, 3-azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[ 3.2.1]octanyl, 2-oxabicyclo[1.1.0]butanyl, 2-oxabicyclo[2.1.0]pentanyl, 2-oxabicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[4.2.0]octanyl, 2-oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1]octanyl, and the like. Heterocyclyl also includes spirocyclic rings (eg, spirocyclic bicycles in which the two rings are joined by only one carbon).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-oxaspiro[2. 2]pentanyl, 4-oxaspiro[2.5]octanyl, 1-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonanyl, 1,7-dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, 1-oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl, etc. The term "saturated" as used in this context means that only single bonds exist between the constituent ring atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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 having fused rings, e.g., those in which the points of fusion are located on (i) adjacent ring atoms (e.g., [xx0] ring systems where 0 represents no atom bridge). TIFF2023509421000002.tif13128), (ii) located on a single ring atom (spiro-fused ring systems) TIFF2023509421000003.tif17128, or (iii) located on an array of contiguous ring atoms (bridged ring systems with a bridge length >0). TIFF2023509421000004.tif14128 is understood to encompass the file.

[0071] 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.

[0072] 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 TIFF2023509421000005.tif15128 is the moiety: TIFF2023509421000006.tif16128. Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxyl encompass pyridone or pyrimidone tautomers.

[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 prodrugs and / or tautomers 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): TIFF2023509421000007.tif37128 or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, Z, Y1 , Y 2 , and Y 3 Each of the 1 , N, and NR 2 wherein Z, Y are independently selected from the group consisting of 1 , Y 2 , and Y 3 One to three of these are independently selected as N or NR 2 and X 1 are O, S, N, and NR 2 , and C.R. 1 selected from the group consisting of X 2 are O, S, N, and NR 4 , and C.R. 5 selected from the group consisting of each TIFF2023509421000008.tif2128 are independently single or double bonds, provided that X 1 and X 2 A five-membered ring containing Z, Y is heteroaryl. 1 , Y 2 , and Y 3 is a heteroaryl, and P 1 , P 2 , P 3 , P 4 , and P 5 the ring containing is aromatic; W is (i) C(=O), (ii) C(=S), (iii) S(O) 1~2 , (iv) C(=NR d ) or C(=N-CN), (v) C(=NH), (vi) C(=C-NO2), (vii) S(=O)(=N(R d )), and (viii) S(═O)(═NH), Q is NH, N(C 1~6 alkyl), *-NH-(C 1~3 alkylene)-, and *-N(C 1~6 alkyl)-(C 1~3 alkylene)-, wherein C 1~6 Alkyl is one to two independently selected Ra and the asterisk represents the point of attachment to W; P 1 , P 2 , P 3 , P 4 , and P 5 teeth, (AA) or (BB) Defined according to: (AA) P 1 , P 2 , P 3 , P 4 , and P 5 Each of these is N, CH, CR 7 , and C.R. c are independently selected from the group consisting of: 1 , P 2 , P 3 , P 4 , and P 5 One or two of these are independently selected CRs. 7 is; or (BB) P 1 is absent, thereby providing a five-membered ring, P 2 , P 3 , P 4 , and P 5 are O, S, N, NH, and NR d , N.R. 7 , C.H., C.R. 7 , and C.R. c are independently selected from the group consisting of However, P 2 , P 3 , P 4 , and P 5 1 to 3 of these are O, S, N, NH, NR d , or NR 7 and P 2 , P 3 , P 4 , and P 5 One or two of these are independently selected NR 7 Or CR 7 and Each R7 -R 8 and -L 3 -R 9 are independently selected from the group consisting of -R 8 teeth, (a) 1 to 4 independently selected R 7 ', respectively, C 3~12 Cycloalkyl or C 3~12 cycloalkenyl, (b) a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 heterocyclyl or heterocycloalkenyl substituted by '; (c) 1 to 4 independently selected C 1~4 each optionally substituted with alkyl, C 3~6 Cycloalkyl or C 3~6 cycloalkenyl, (d) 1 to 4 independently selected C 1~4 each optionally substituted with alkyl, C 7~12 Cycloalkyl or C 7~12 cycloalkenyl, (e) Heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected C 1~4 heterocyclyl or heterocycloalkenyl optionally substituted by alkyl; (f) Heteroaryl having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heteroaryl, optionally substituted with ', and (g) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl selected from the group consisting of -L 3 -O-, -S-, -NH-, S(O) 1~2 , -CH2-, C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2, and S(O)2NH; -R 9 teeth, (a) 1 to 4 independently selected R 7 ', C 3~12 Cycloalkyl or C 3~12 cycloalkenyl, (b) a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 heterocyclyl or heterocycloalkenyl optionally substituted by '; (c) Heteroaryl having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are independently selected from the group consisting of 1 to 4 independently selected R 7', heteroaryl, optionally substituted with ', and (d) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl selected from the group consisting of R 7 Each occurrence of ' is selected from the group consisting of halo; -CN; -NO; -OH; and 1 to 2 independently selected R a may be substituted with -C 1~4 Alkyl;-C 2~4 Alkenyl;-C 2~4 Alkynyl;-C 1~4 haloalkyl; 1 to 2 independently selected R a may be substituted with -C 1~6 Alkoxy;-C 1~6 Haloalkoxy;S(O) 1~2 (C 1~4 alkyl);-NR'R'';oxo;-S(O) 1~2 (NR'R'');-C 1~4 Thioalkoxy; -C(=O)(C 1~4 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R''); However, R 7 R 8 and R 8 is cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl, and 1 to 4 R 7 ', R 8 is C 1~4 may not be monosubstituted with alkyl, and However, R 8 2 to 4 R 7 ', at least one R 7 ' is C 1~4 The substituent must be other than alkyl; R 1 Each occurrence of is H; halo; cyano; 1-2 R a C optionally substituted with 1~6 Alkyl; C 2~6Alkenyl; C 2~6 Alkynyl; C 1~4 Haloalkyl; -OH, C 1~4 Alkoxy, C 1~4 Haloalkoxy, or -NR e R f optionally substituted with C 1~4 Alkoxy;C 1~4 Haloalkoxy;-L 1 -L 2 -R h ;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);SF5;-NR e R f ;-OH;oxo;-S(O) 1~2 (NR'R'');-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R''); R 2 Each occurrence of (i) H, (ii) 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl, (iii) 1 to 3 independently selected R a may be substituted with -C(O)(C 1~6 alkyl), (iv) 1 to 3 independently selected R a may be substituted with -C(O)O(C 1~4 alkyl), (v)-CON(R')(R''), (vi)-S(O) 1~2 (NR'R''), (vii) 1 to 3 independently selected R a -S(O) optionally substituted with 1~2 (C 1~4 alkyl), (viii) -OH, (ix) C1~4 Alkoxy, and (x)-L 4 -L 5 -R i are independently selected from the group consisting of R 4 is H; and 1 to 3 independently selected R a C optionally substituted with 1~6 is selected from the group consisting of alkyl, R 5 H; halo; -OH; -C 1~4 Alkyl;-C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CON(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano; and 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6 cycloalkenyl; R 6 is H; 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl; -OH; C 1~4 Alkoxy; C(=O)H; C(=O)(C 1~4 alkyl); 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~10 aryl; and heteroaryl having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of 1 to 4 independently selected C 1~4 selected from the group consisting of heteroaryl, optionally substituted with alkyl; Ra Each occurrence of is -OH; -F; -Cl; -Br; -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;-CON(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano; and 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6 cycloalkenyl; R b Each occurrence of a C optionally substituted with 1~10 Alkyl; C 1~4 Haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-C(=O)N(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano; and -L 1 -L 2 -R h are independently selected from the group consisting of 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 1~4alkyl);-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)N(R')(R''); and -L 1 -L 2 -R h are independently selected from the group consisting of R d Ha, Halo, C 1~4 C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkoxy, and OH 1~6 C, each of which may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, halo, and OH; 3~6 Cycloalkyl or C 3~6 Cycloalkenyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CON(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R e and R f Each occurrence of H;C 1~6 Alkyl; C 1~6 Haloalkyl;C 3~6 Cycloalkyl or C 3~6 Cycloalkenyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CON(R')(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 ftogether with the nitrogen atom to which each is attached form a ring of 3 to 8 ring atoms, where the ring is 1~3 (b) N(R d 0 to 3 ring heteroatoms (R e and R f In addition to the nitrogen atom bonded to -L 1 is a bond or C 1~3 alkylene, and -L 2 -O-, -N(H)-, -S(O) 0~2 - or a bond, R h teeth, Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 haloalkoxy, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 3~8 Cycloalkyl or C 3~8 cycloalkenyl, Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O, and S(O) 0~2 wherein the heterocyclyl or heterocycloalkenyl is selected from the group consisting of halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl having 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 6~10 Aryl selected from the group consisting of -L 4 - is a bond, -C(O)-, -C(O)O-, -C(O)NH-, C(O)NR d , S(O) 1~2 , S(O) 1~2 NH, and S(O) 1~2 NR d selected from the group consisting of -L 5 - is bond and C 1~4 alkylene; R i teeth, ·Halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 haloalkoxy, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C3~8 Cycloalkyl or C 3~8 cycloalkenyl, Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of halo; OH; NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl having 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is independently selected from the group consisting of halo; OH; NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; ·Halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 6~10Aryl selected from the group consisting of Each occurrence of R' and R'' is H; -OH; C 1~4 Alkyl; Halo, C 1~4 Alkyl, and C 1~4 C optionally substituted with 1 to 2 substituents selected from the group consisting of haloalkyl 6~10 aryl; and heteroaryl having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is independently selected from the group consisting of halo, —OH, NH, NH(C 1~4 alkyl), N(C 1~4 Alkyl)2, C 1~4 Alkyl, and C 1~4 independently selected from the group consisting of heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; R' and R'' together with the nitrogen atom to which they are attached form a ring of 3 to 8 ring atoms, where the ring is: (a) H and C 1~3 (b) N(H), N(C 1~6 and 0 to 3 ring heteroatoms (in addition to the nitrogen atom bonded to R′ and R″) each independently selected from the group consisting of alkyl, O, and S.

[0076] In one aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: Formula (I): TIFF2023509421000009.tif37128 or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, Z, Y 1 , Y 2 , and Y 3 Each of the 1 , N, and NR 2 wherein Z, Y are independently selected from the group consisting of1 , Y 2 , and Y 3 One to three of these are independently selected as N or NR 2 and X 1 are O, S, N, and NR 2 , and C.R. 1 selected from the group consisting of X 2 are O, S, N, and NR 4 , and C.R. 5 selected from the group consisting of each TIFF2023509421000010.tif2128 are independently single or double bonds, provided that X 1 and X 2 A five-membered ring containing Z, Y is heteroaryl. 1 , Y 2 , and Y 3 is a heteroaryl, and P 1 , P 2 , P 3 , P 4 , and P 5 the ring containing is aromatic; W is (i) C(=O), (ii) C(=S), (iii) S(O) 1~2 , (iv) C(=NR d ) or C(=N-CN), (v) C(=NH), (vi) C(=C-NO2), (vii) S(=O)(=N(R d )), and (viii) S(═O)(═NH), Q is NH, N(C 1~6 alkyl), *-NH-(C 1~3 alkylene)-, and *-N(C 1~6 alkyl)-(C 1~3 alkylene)-, wherein C 1~6 Alkyl is one to two independently selected R a and the asterisk represents the point of attachment to W; P 1 , P 2 , P 3 , P 4 , and P5 teeth, (AA) or (BB) Defined according to: (AA) P 1 , P 2 , P 3 , P 4 , and P 5 Each of these is N, CH, CR 7 , and C.R. c are independently selected from the group consisting of: 1 , P 2 , P 3 , P 4 , and P 5 One or two of these are independently selected CRs. 7 is; or (BB) P 1 is absent, thereby providing a five-membered ring, P 2 , P 3 , P 4 , and P 5 are O, S, N, NH, and NR d , N.R. 7 , C.H., C.R. 7 , and C.R. c are independently selected from the group consisting of However, P 2 , P 3 , P 4 , and P 5 1 to 3 of these are O, S, N, NH, NR d , or NR 7 and P 2 , P 3 , P 4 , and P 5 One or two of these are independently selected NR 7 Or CR 7 and Each R 7 -R 8 and -L 3 -R 9 are independently selected from the group consisting of -R 8 teeth, (a) 1 to 4 independently selected R 7 ', respectively, C 3~12 Cycloalkyl or C 3~12 cycloalkenyl, (b) a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 heterocyclyl or heterocycloalkenyl substituted by '; (c) 1 to 4 independently selected C 1~4 C3 cycloalkyl, C3 cycloalkenyl, C5 cycloalkyl, or C5 cycloalkenyl, each optionally substituted with alkyl; (d) 1 to 4 independently selected C 1~4 each optionally substituted with alkyl, C 7~12 Cycloalkyl or C 7~12 cycloalkenyl, (e) Heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and wherein heterocyclyl is other than tetrahydropyranyl and one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are selected from the group consisting of 1 to 4 independently selected C 1~4 heterocyclyl or heterocycloalkenyl optionally substituted by alkyl; (f) Heteroaryl having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2and one or more ring carbon atoms of the heteroaryl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heteroaryl, optionally substituted with ', and (g) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl selected from the group consisting of -L 3 -O-, -S-, -NH-, S(O) 1~2 , -CH2-, C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2, and S(O)2NH; -R 9 teeth, (a) 1 to 4 independently selected R 7 ', C 3~12 Cycloalkyl or C 3~12 cycloalkenyl, (b) a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 heterocyclyl or heterocycloalkenyl optionally substituted by '; (c) Heteroaryl having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heteroaryl, and (d) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl selected from the group consisting of R 7 Each occurrence of ' is selected from the group consisting of halo; -CN; -NO; -OH; and 1 to 2 independently selected R a may be substituted with -C 1~4 Alkyl;-C 2~4 Alkenyl;-C 2~4 Alkynyl;-C 1~4 haloalkyl; 1 to 2 independently selected R a may be substituted with -C 1~6 Alkoxy;-C 1~6 Haloalkoxy;S(O) 1~2 (C 1~4 alkyl);-NR'R'';oxo;-S(O) 1~2 (NR'R'');-C 1~4 Thioalkoxy; -C(=O)(C 1~4 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R''); However, R 7 R 8 and R 8 is cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl, and 1 to 4 R 7 ', R 8 is C 1~4 may not be monosubstituted with alkyl, and However, R 8 2 to 4 R 7 ', at least one R 7 ' is C 1~4 The substituent must be other than alkyl; R 1 Each occurrence of is H; halo; cyano; 1-2 R a C optionally substituted with 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 Haloalkoxy;-L1 -L 2 -R h ;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);SF5;-NR e R f ;-OH;oxo;-S(O) 1~2 (NR'R'');-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R''); R 2 Each occurrence of (i) H, (ii) 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl, (iii) 1 to 3 independently selected R a may be substituted with -C(O)(C 1~6 alkyl), (iv) 1 to 3 independently selected R a may be substituted with -C(O)O(C 1~4 alkyl), (v)-CON(R')(R''), (vi)-S(O) 1~2 (NR'R''), (vii) 1 to 3 independently selected R a -S(O) optionally substituted with 1~2 (C 1~4 alkyl), (viii) -OH, (ix) C 1~4 Alkoxy, and (x)-L 4 -L 5 -R i are independently selected from the group consisting of R 4 is H; and 1 to 3 independently selected R a C optionally substituted with1~6 is selected from the group consisting of alkyl, R 5 H; halo; -OH; -C 1~4 Alkyl;-C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CON(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano; and 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6 cycloalkenyl; R 6 is H; 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl; -OH; C 1~4 Alkoxy; C(=O)H; C(=O)(C 1~4 alkyl); 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~10 aryl; and heteroaryl having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of 1 to 4 independently selected C 1~4 selected from the group consisting of heteroaryl, optionally substituted with alkyl; R a Each occurrence of is -OH; -F; -Cl; -Br; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4alkyl);-C(=O)OH;-CON(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano; and 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6 cycloalkenyl; R b Each occurrence of a C optionally substituted with 1~10 Alkyl; C 1~4 Haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-C(=O)N(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano; and -L 1 -L 2 -R h are independently selected from the group consisting of 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);-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)N(R')(R''); and -L 1 -L 2 -R h are independently selected from the group consisting of R d Ha, Halo, C 1~4 C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkoxy, and OH 1~6 C, each of which may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, halo, and OH; 3~6 Cycloalkyl or C 3~6 Cycloalkenyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CON(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R e and R f Each occurrence of H;C 1~6 Alkyl; C 1~6 Haloalkyl;C 3~6 Cycloalkyl or C 3~6 Cycloalkenyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CON(R')(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 together with the nitrogen atom to which each is attached form a ring of 3 to 8 ring atoms, where the ring is 1~3 (b) N(R d0 to 3 ring heteroatoms (R e and R f In addition to the nitrogen atom bonded to -L 1 is a bond or C 1~3 alkylene, and -L 2 -O-, -N(H)-, -S(O) 0~2 - or a bond, R h teeth, Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 haloalkoxy, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 3~8 Cycloalkyl or C 3~8 cycloalkenyl, Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O, and S(O) 0~2 wherein the heterocyclyl or heterocycloalkenyl is selected from the group consisting of halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl having 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo; 1 to 2 independently selected R aC optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 6~10 Aryl selected from the group consisting of -L 4 - is a bond, -C(O)-, -C(O)O-, -C(O)NH-, C(O)NR d , S(O) 1~2 , S(O) 1~2 NH, and S(O) 1~2 NR d selected from the group consisting of -L 5 - is bond and C 1~4 alkylene; R i teeth, ·Halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 haloalkoxy, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 3~8 Cycloalkyl or C 3~8 cycloalkenyl, Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of halo; OH; NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl having 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is independently selected from the group consisting of halo; OH; NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; ·Halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 6~10 Aryl and Each occurrence of R' and R'' is H; -OH; C 1~4 Alkyl; Halo, C 1~4 Alkyl, and C 1~4C optionally substituted with 1 to 2 substituents selected from the group consisting of haloalkyl 6~10 aryl; and heteroaryl having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is independently selected from the group consisting of halo, —OH, NH, NH(C 1~4 alkyl), N(C 1~4 Alkyl)2, C 1~4 Alkyl, and C 1~4 independently selected from the group consisting of heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; R' and R'' together with the nitrogen atom to which they are each attached form a ring of 3 to 8 ring atoms, where the ring is: (a) H and C 1~3 (b) N(H), N(C 1~6 and 0 to 3 ring heteroatoms (in addition to the nitrogen atom bonded to R′ and R″) each independently selected from the group consisting of alkyl, O, and S.

[0077] In one aspect, the present disclosure provides a compound of formula (I): TIFF2023509421000011.tif37128 or a pharmaceutically acceptable salt thereof or a tautomer thereof, During the ceremony, Z, Y 1 , Y 2 , and Y 3 Each of the 1 , N, and NR 2 wherein Z, Y are selected from the group consisting of 1 , Y 2 , and Y 3 One to three of these are independently selected as N or NR 2 and X 1 are O, S, N, and NR 2 , and C.R.1 selected from the group consisting of X 2 are O, S, N, and NR 4 , and C.R. 5 selected from the group consisting of each TIFF2023509421000012.tif2128 are independently single or double bonds, provided that X 1 and X 2 A five-membered ring containing Z, Y is heteroaryl. 1 , Y 2 , and Y 3 is a heteroaryl, and P 1 , P 2 , P 3 , P 4 , and P 5 the ring containing is aromatic; W is (i)C(=O), (ii)C(=S), (iii)S(O) 1~2 , (iv) C(=NR d ) or C(=N-CN), (v) C(=NH), (vi) C(=C-NO2), (vii) S(O)N(R d (viii) S(O)NH; Q is NH, N(C 1~6 alkyl), *-NH-(C 1~3 alkylene)-, and *-N(C 1~6 alkyl)-(C 1~3 alkylene)-, wherein C 1~6 Alkyl is one to two independently selected R a and the asterisk represents the point of attachment to W; P 1 , P 2 , P 3 , P 4 , and P 5 teeth,( AA) or( BB) Defined according to: (AA) P 1 , P 2 , P 3, P 4 , and P 5 Each of these is N, CH, CR 7 , and C.R. c are independently selected from the group consisting of: 1 , P 2 , P 3 , P 4 , and P 5 One or two of these are independently selected CRs. 7 is; or (BB) P 1 is absent (thereby providing a five-membered ring), P 2 , P 3 , P 4 , and P 5 are O, S, N, NH, and NR d , N.R. 7 , C.H., C.R. 7 , and C.R. c are independently selected from the group consisting of However, P 2 , P 3 , P 4 , and P 5 One to three of these are O, S, N, NH, and NR d , or NR 7 and P 2 , P 3 , P 4 , and P 5 One or two of these are independently selected NR 7 Or CR 7 and Each R 7 -R 8 and -L 3 -R 9 are independently selected from the group consisting of -R 8 teeth, (a) 1 to 4 independently selected R 7 ', respectively, C 3~12 Cycloalkyl or C 3~12 cycloalkenyl, (b) a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 heterocyclyl or heterocycloalkenyl substituted by '; (c) 1 to 4 independently selected C 1~4 C3 cycloalkyl, C3 cycloalkenyl, C5 cycloalkyl, or C5 cycloalkenyl, each optionally substituted with alkyl; (d) 1 to 4 independently selected C 1~4 each optionally substituted with alkyl, C 7~12 Cycloalkyl or C 7~12 cycloalkenyl, (e) Heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and wherein heterocyclyl is other than tetrahydropyranyl and one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are selected from the group consisting of 1 to 4 independently selected C 1~4 heterocyclyl or heterocycloalkenyl optionally substituted by alkyl; (f) Heteroaryl having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heteroaryl, optionally substituted with ', and (g) 1 to 4 independently selected R 7 ' may be substituted with C6~10 Aryl selected from the group consisting of -L 3 -O-, -S-, -NH-, S(O) 1~2 , -CH2-, C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2, and S(O)2NH; -R 9 teeth, (a) 1 to 4 independently selected R 7 ', C 3~12 Cycloalkyl or C 3~12 cycloalkenyl, (b) a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 heterocyclyl or heterocycloalkenyl optionally substituted by '; (c) Heteroaryl having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heteroaryl, optionally substituted with ', and (d) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl selected from the group consisting of R 7 Each occurrence of ' is selected from the group consisting of halo; -CN; -NO; -OH; and 1 to 2 independently selected R a may be substituted with -C 1~4 Alkyl;-C 2~4 Alkenyl;-C2~4 Alkynyl;-C 1~4 haloalkyl; 1 to 2 independently selected R a may be substituted with -C 1~6 Alkoxy;-C 1~6 Haloalkoxy;S(O) 1~2 (C 1~4 alkyl);-NR'R'';oxo;-S(O) 1~2 (NR'R'');-C 1~4 Thioalkoxy; -C(=O)(C 1~4 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R''); However, R 7 R 8 and R 8 When R is cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl, 7 One or more occurrences of ' are treated as -C 1~4 is other than alkyl; R 1 Each occurrence of is H; halo; cyano; 1-2 R a C optionally substituted with 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 Haloalkoxy;-L 1 -L 2 -R h ;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);SF5;-NR e R f ;-OH;oxo;-S(O) 1~2 (NR'R'');-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R''); R 2 Each occurrence of (i) H, (ii) 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl, (iii) 1 to 3 independently selected R a may be substituted with -C(O)(C 1~6 alkyl), (iv) 1 to 3 independently selected R a may be substituted with -C(O)O(C 1~4 alkyl), (v)-CON(R')(R''), (vi)-S(O) 1~2 (NR'R''), (vii) 1 to 3 independently selected R a -S(O) optionally substituted with 1~2 (C 1~4 alkyl), (viii) -OH, (ix) C 1~4 Alkoxy, and (x)-L 4 -L 5 -R i are independently selected from the group consisting of R 4 is H; and 1 to 3 independently selected R a C optionally substituted with 1~6 is selected from the group consisting of alkyl, R 5 H; halo; -OH; -C 1~4 Alkyl;-C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CON(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4alkyl); cyano; and 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6 cycloalkenyl; R 6 is H; 1 to 3 independently selected R a C optionally substituted with 1~6 Alkyl; -OH; C 1~4 Alkoxy; C(=O)H; C(=O)(C 1~4 alkyl); 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~10 aryl; and heteroaryl having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of 1 to 4 independently selected C 1~4 selected from the group consisting of heteroaryl, optionally substituted with alkyl; R a Each occurrence of is -OH; -F; -Cl; -Br; -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;-CON(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano; and 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6 cycloalkenyl; R b Each occurrence of a C optionally substituted with 1~10 Alkyl; C 1~4Haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-C(=O)N(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano; and -L 1 -L 2 -R h are independently selected from the group consisting of R c each occurrence of is (a) halo, (b) cyano, (c) 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl, (d) C 2~6 Alkenyl, (e) C 2~6 Alkynyl, (g) C 1~4 Alkoxy, (h)C 1~4 Haloalkoxy, (i) -S(O) 1~2 (C 1~4 alkyl), (j)-NR e R f , (k)-OH, (l)-S(O) 1~2 (NR'R''), (m)-C 1~4 Thioalkoxy, (n)-NO2, (o)-C(=O)(C 1~10 alkyl), (p)-C(=O)O(C 1~4 alkyl), (q)-C(=O)OH, (r)-C(=O)N(R')(R''), and (s)-L 1 -L 2 -R h are independently selected from the group consisting of R d C may be substituted with 1 to 3 substituents each independently selected from the group consisting of halo and OH. 1~6 C, each of which may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, halo, and OH; 3~6 Cycloalkyl or C3~6 Cycloalkenyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CON(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy; R e and R f Each occurrence of H;C 1~6 Alkyl; C 1~6 Haloalkyl;C 3~6 Cycloalkyl or C 3~6 Cycloalkenyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 alkyl);-CON(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 alkoxy, or R e and R f together with the nitrogen atom to which each is attached form a ring of 3 to 8 ring atoms, where the ring is 1~3 (b) N(R d 0 to 3 ring heteroatoms (R e and R f In addition to the nitrogen atom bonded to -L 1 is a bond or C 1~3 alkylene, and -L 2 -O-, -N(H)-, -S(O) 0~2 - or a bond, R h teeth, Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 haloalkoxy, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 3~8 Cycloalkyl or C 3~8 cycloalkenyl, Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O, and S(O) 0~2 wherein the heterocyclyl or heterocycloalkenyl is selected from the group consisting of halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl having 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy6~10 Aryl selected from the group consisting of -L 4 - is a bond, -C(O)-, -C(O)O-, -C(O)NH-, C(O)NR d , S(O) 1~2 , S(O) 1~2 NH, and S(O) 1~2 NR d selected from the group consisting of -L 5 - is bond and C 1~4 alkylene; R i teeth, ·Halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 haloalkoxy, each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of C 3~8 Cycloalkyl or C 3~8 cycloalkenyl, Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is independently selected from the group consisting of halo; OH; NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl having 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is independently selected from the group consisting of halo; OH; NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; ·Halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 6~10 Aryl and Each occurrence of R' and R'' is H; -OH; C 1~4 Alkyl; Halo, C 1~4 Alkyl, and C 1~4 C optionally substituted with 1 to 2 substituents selected from the group consisting of haloalkyl 6~10 aryl; and heteroaryl having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is independently selected from the group consisting of halo, —OH, NH, NH(C 1~4 alkyl), N(C 1~4 Alkyl)2, C 1~4 Alkyl, and C 1~4or R′ and R″ together with the nitrogen atom to which they are attached form a ring of 3 to 8 ring atoms, wherein the ring is substituted with one to four substituents independently selected from the group consisting of: (a) H and C 1~3 (b) N(H), N(C 1~6 and 0 to 3 ring heteroatoms (in addition to the nitrogen atom bonded to R′ and R″) each independently selected from the group consisting of alkyl, O, and S.

[0078] Compound disclaimer In some embodiments, the compound of formula (I) It is specified as anything other than TIFF2023509421000013.tif53158.

[0079] In some embodiments, R 8 (e) heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected C 1~4 When it is a heterocyclyl or heterocycloalkenyl optionally substituted with alkyl, the heterocyclyl is other than tetrahydropyranyl (e.g., unsubstituted tetrahydropyranyl), and R 8 (c) 1 to 4 independently selected C 1~4 C, each of which may be substituted with alkyl 3~6 Cycloalkyl or C 3~6 When R is cycloalkenyl, 8 is 1 to 4 independently selected C 1~4It is a C3 cycloalkyl, a C3 cycloalkenyl, a C5 cycloalkyl, or a C5 cycloalkenyl, each of which may be substituted with alkyl.

[0080] In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 is as defined according to (BB), and P 2 and P 5 One of them is S and the other is P 3 and P 4 One of them is CR 7 If R 7 is other than unsubstituted phenyl.

[0081] In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 is as defined according to (BB) and P 2 and P 5 If one of them is S, then R 7 is other than unsubstituted phenyl.

[0082] In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 is as defined according to (AA), and P 3 is CR 7 where R 7 L 3 -R 9 and P 1 , P 2 , P 4 , and P 5 Each of these is CH and CR c R when independently selected from the group consisting of 9 is 1 to 4 C 1~4 Other than C3 cycloalkyl substituted with alkyl.

[0083] In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 is as defined according to (AA), and P 3 is CR 7 where R 7 L 3 -R 9 If R 9 is 1 to 4 C 1~4 Other than C3 cycloalkyl substituted with alkyl.

[0084] In some embodiments, R 7 R 8 If R 8 teeth, (a) 1 to 4 independently selected R 7 ', respectively, C 4~12 Cycloalkyl or C 4~12 cycloalkenyl, (b) a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heterocyclyl or heterocycloalkenyl, substituted by (c) 1 to 4 independently selected C 1~4 C5 cycloalkyl or C5 cycloalkenyl, each optionally substituted with alkyl; (d) 1 to 4 independently selected C 1~4 each optionally substituted with alkyl, C 7~12 Cycloalkyl or C 7~12 cycloalkenyl, (e) Heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and wherein heterocyclyl is other than tetrahydropyranyl and one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected C 1~4 heterocyclyl or heterocycloalkenyl optionally substituted with alkyl; (f) Heteroaryl having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heteroaryl, optionally substituted with ', and (g) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl is selected from the group consisting of:

[0085] In some embodiments, R 7 L 3 -R 9 If R 9 teeth, (a) 1 to 4 independently selected R 7 ', C 3~12 Cycloalkyl or C 3~12 cycloalkenyl, (b) a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7', heterocyclyl or heterocycloalkenyl, optionally substituted by (c) Heteroaryl having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heteroaryl, optionally substituted with (d) 1 to 4 independently selected R 7 C6 aryl substituted with ', and (e) 1 to 4 independently selected R 7 ' may be substituted with C 8~10 Aryl is selected from the group consisting of:

[0086] In some embodiments, the compound of Formula (I) is other than a compound disclosed in International Patent Application No. PCT / US2019 / 040317, filed July 2, 2019 (published as WO 2020 / 010092), which is incorporated herein by reference in its entirety.

[0087] In some embodiments, the compound of Formula (I) is other than a compound disclosed in U.S. Patent Application No. 16 / 460,381, filed July 2, 2019 (published as US 2020 / 0172534), which is incorporated herein by reference in its entirety.

[0088] In certain of these embodiments, the compound of formula (I) is other than a compound selected from the group consisting of: TIFF2023509421000014.tif78153TIFF2023509421000015.tif202153TIFF2023509421000016.tif48153.

[0089] In certain embodiments, the compounds are 2408407-73-6, 2408407-81-6, 2408408-01-3, 2408409-07-2, 2408409-17-4, 2408409-18-5, 2408409-19-6, 2408409-20-9, 2408409-21-0, 2408409-28-7, 2408409-29-8, 24 2408409-49-2, 2408409-51-6, 2408409-67-4, 2408409-68-5, 2408409-70-9, 2408409-71-0, 2408409-81-2, 2408409-82-3, 2408409-86-7, and 2408409-88-9.

[0090] Aspects may include any one or more of the features set forth below and / or in the claims.

[0091] Variable symbol P 1 , P 2 , P 3 , P 4 , and P 5 P 1 、P 2 、P 3 、P 4 , and P 5 is as defined according to (AA) In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 is as defined according to (AA).

[0092] In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 One or more (e.g., one) of P is N. In certain embodiments, P 1 , P 2, P 3 , P 4 , and P 5 is N. In certain embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 Two of them are N.

[0093] In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 One of each is CH, CR 7 , and C.R. c are independently selected from the group consisting of:

[0094] In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 One of them is CR 7 is.

[0095] In some embodiments, P 3 is CR 7 In a particular embodiment (P 1 , P 2 , P 3 , P 4 , and P 5 One of them is CR 7 In the case where 3 is CR 7 is.

[0096] In some embodiments, P 4 is N. In certain embodiments (P 1 , P 2 , P 3 , P 4 , and P 5 One of them is CR 7 and P 3 is CR 7 In the case where 4 is N.

[0097] In some embodiments, P 1 , P 2 , and P 5 Each of the CH and CR c In certain embodiments, P 1 , P 2 , and P 5 0 to 1 of them are CR c and P 1 , P 2 , and P 5 and each of the remaining is CH. As a non-limiting example, P 2 is CR c and P 1 and P 5 is CH. Another non-limiting example is P 1 , P 2 and P 5 Each of these is CH.

[0098] In certain embodiments, P 3 is CR 7 and P 4 is N and P 1 , P 2 , and P 5 Each of the CH and CR c In certain of these embodiments, P 1 , P 2 , and P 5 0 to 1 of them are CR c and P 1 , P 2 , and P 5 and each of the remaining is CH. As a non-limiting example, P 2 is CR c and P 1 and P 5 is CH. Another non-limiting example is P 1 , P 2 and P 5 Each of these is CH.

[0099] In certain embodiments, P 3 is CR 7and P 4 is N and P 1 , P 2 , and P 5 One of them is N and the other is P 1 , P 2 , and P 5 The remaining ones are CH and CR c are independently selected from the group consisting of:

[0100] As a non-limiting example, P 3 is CR 7 and P 4 is N and P 1 is N and P 2 and P 5 Each of the CH and CR c As another non-limiting example, P 3 is CR 7 and P 4 is N and P 5 is N and P 2 and P 1 Each of the CH and CR c are independently selected from the group consisting of:

[0101] In certain other embodiments, P 3 is CR 7 and P 1 , P 2 , P 4 and P 5 Each of the CH and CR c In certain of these embodiments, P 1 , P 2 , P 4 and P 5 0 to 1 of them are CR c and P 1 , P 2 , P 4 and P 5 Each of the remaining is CH.

[0102] In some embodiments, P 1 is N. In certain of these embodiments, P3 is CR 7 and P 2 , P 4 , and P 5 Each of the CH and CR c In certain other embodiments, P 3 is CR 7 and P 2 , P 4 , and P 5 One of them is N and the other is P 2 , P 4 , and P 5 The remaining ones are CH and CR c are independently selected from the group consisting of:

[0103] In certain embodiments, P 3 is CR 7 and P 1 is N and P 2 , P 4 , and P 5 Each of the CH and CR c are independently selected from the group consisting of:

[0104] In some embodiments, P 4 is CR 7 In a particular embodiment (P 4 is CR 7 In the case where 1 , P 2 , P 3 , and P 5 are N, CH, and CR, respectively. c In certain of these embodiments, P 1 , P 2 , P 3 , and P 5 Each of the CH and CR c In certain other embodiments (P 4 is CR 7 In the case where 1 , P 2 , P 3 , and P 5One of them is N and the other is P 1 , P 2 , P 3 , and P 5 The remaining ones are CH and CR c are independently selected from the group consisting of:

[0105] P 1 、P 2 、P 3 、P 4 , and P 5 is as defined according to (BB) In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 is as defined according to (BB).

[0106] In some embodiments, P 2 , P 3 , P 4 , and P 5 One of them is CR 7 or NR 7 For example, P 3 is CR 7 or NR 7 In certain of these embodiments, P 2 , P 3 , P 4 , and P 5 The remaining ones are CH, CR c , S, N, NH, and NR d are independently selected from the group consisting of: 2 , P 3 , P 4 , and P 5 One to three of these are S, N, NH, or NR d is.

[0107] In certain embodiments, P 3 is CR 7 and P 2 , P4 , and P 5 Each of these is CH, CR c , S, N, NH, and NR d are independently selected from the group consisting of: 2 , P 4 , and P 5 One to two (e.g., two) of the d is.

[0108] In certain embodiments, P 3 is CR 7 and P 2 , NH, NR d , or S (e.g., S), and P 5 is N and P 4 is CH or CR c (e.g. CH).

[0109] In certain embodiments, P 3 is CR 7 and P 2 , NH, NR d , or S (e.g., S), and P 5 is CH or CR c and P 4 is N.

[0110] In certain embodiments, P 3 is NR 7 and P 2 is CH or CR c (e.g., CH), and P 4 is N and P 5 is CH or CR c (e.g. CH).

[0111] P 1 、P 2 、P 3 、P 4 , and P 5 Non-limiting combinations of In some embodiments, The TIFF2023509421000017.tif17128 part has the formula: TIFF2023509421000018.tif16128, where Q 1 is N or CH, and Q 2 is N or CH, and n2 is 0, 1, or 2.

[0112] In some embodiments, The TIFF2023509421000019.tif18128 part is the formula: TIFF2023509421000020.tif13128, where n2 is 0, 1, or 2. In certain of these embodiments, The TIFF2023509421000021.tif18128 part is the formula: TIFF2023509421000022.tif13128. In certain other embodiments, The TIFF2023509421000023.tif17128 part is the formula: I have TIFF2023509421000024.tif16128.

[0113] In some embodiments, The TIFF2023509421000025.tif17128 part is the formula: TIFF2023509421000026.tif12128, where n2 is 0, 1, or 2. In certain of these embodiments, The TIFF2023509421000027.tif18128 part is the formula: TIFF2023509421000028.tif12128. In certain other embodiments, The TIFF2023509421000029.tif18128 part is the formula: I have TIFF2023509421000030.tif15128.

[0114] In some embodiments, The TIFF2023509421000031.tif18128 part is the formula: TIFF2023509421000032.tif14128, where n2 is 0, 1, or 2.

[0115] In some embodiments, The TIFF2023509421000033.tif17128 part is the formula: TIFF2023509421000034.tif13128, wherein n2 is 0, 1, or 2. In certain embodiments, The TIFF2023509421000035.tif17128 part is the formula: I have TIFF2023509421000036.tif23128.

[0116] In some embodiments, The TIFF2023509421000037.tif18128 part is the formula: TIFF2023509421000038.tif17128, where Q 1 , Q 2 , and Q 3 are independently N or CH, and n2 is 0, 1, or 2 (e.g., TIFF2023509421000039.tif15128).

[0117] In some embodiments, The TIFF2023509421000040.tif18128 part is the formula: TIFF2023509421000041.tif16128, where Q 4 is N or C.

[0118] In some embodiments, The TIFF2023509421000042.tif18128 part is the formula: I have TIFF2023509421000043.tif13128.

[0119] Variable symbol R7 In some embodiments, R 7 is R 8 In certain embodiments, P 3 is CR 7 and R 7 is R 8 is.

[0120] In a particular aspect (R 7 R 8 In the case where 8 teeth, (a) 1 to 4 independently selected R 7 ', respectively, C 3~12 Cycloalkyl or C 3~12 cycloalkenyl, and (b) a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heterocyclyl or heterocycloalkenyl substituted with is selected from the group consisting of:

[0121] In certain of these embodiments, R 8 is 1 to 4 independently selected R 7 ' respectively replaced by C 3~12 Cycloalkyl or C 3~12 In certain embodiments, R 8 is 1 to 4 independently selected R 7 ' respectively replaced by C 4~10 Cycloalkyl or C 4~10 In certain embodiments, R 8 is 1 to 4 independently selected R 7 ' respectively replaced by C 4~8 Cycloalkyl or C4~8 In certain embodiments, R 8 is 1 to 4 independently selected R 7 C replaced with ' 4~8 cycloalkyl, e.g., R 8 is 2 to 4 independently selected R 7 C replaced with ' 4~8 It is cycloalkyl.

[0122] In certain embodiments, R 8 is 2 to 4 independently selected R 7 ' is cyclohexyl substituted with '.

[0123] As a non-limiting example of said embodiment, R 8 teeth, It can be TIFF2023509421000044.tif25128.

[0124] In certain embodiments, R 8 is 2 to 4 independently selected R 7 ' is a cyclobutyl substituted with '.

[0125] As a non-limiting example of said embodiment, R 8 teeth, It can be TIFF2023509421000045.tif22128.

[0126] In certain embodiments, R 8 is one to three independently selected R 7 C replaced with ' 4~8 cycloalkyl, e.g., R 8 is 1 to 2 (e.g., 1) independently selected R 7 C replaced with ' 4~8 It is cycloalkyl.

[0127] In certain embodiments, R 8 is 1 to 2 (e.g., 1) independently selected R 7A non-limiting example is cyclohexyl substituted with R 8 teeth, It can be TIFF2023509421000046.tif26128.

[0128] In certain embodiments, R 8 is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heterocyclyl or heterocycloalkenyl.

[0129] In certain of these embodiments, R 8 is a heterocyclyl or heterocycloalkenyl of 4 to 10 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heterocyclyl or heterocycloalkenyl.

[0130] In certain embodiments, R 8 is a heterocyclyl or heterocycloalkenyl of 4 to 8 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heterocyclyl or heterocycloalkenyl.

[0131] In certain of these embodiments, R 8 is a heterocyclyl having 4 to 8 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', and heterocyclyl substituted with '.

[0132] In certain embodiments, R 8 is a heterocyclyl having 4 to 6 ring atoms, in which 1 to 2 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring are independently selected from the group consisting of 2 to 4 independently selected R 7 ', and heterocyclyl substituted with '.

[0133] In certain of these embodiments, R 8 is 2 to 4 (e.g., 2) independently selected R 7 and tetrahydropyranyl, each of which is substituted with '.

[0134] In certain embodiments, R 8 is 2 to 4 (e.g., 2) independently selected R 7 ' is selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl, each substituted with '.

[0135] As a non-limiting example of said embodiment, R 8 teeth, TIFF2023509421000047.tif25128.

[0136] In certain embodiments, R 8 is a heterocyclyl having 4 to 6 ring atoms, in which 1 to 2 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 3 (e.g., 1 to 2, e.g., 1) independently selected R 7 ', and heterocyclyl substituted with '.

[0137] In certain of these embodiments, R 8 is 1 to 3 (e.g., 1 to 2, e.g., 1) independently selected R 7 and tetrahydropyranyl, each of which is substituted with '.

[0138] In certain embodiments, R 8 is 1 to 3 (e.g., 1 to 2, e.g., 1) independently selected R 7 ' is selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl, each substituted with '.

[0139] As a non-limiting example, R 8 teeth, It can be TIFF2023509421000048.tif26128.

[0140] In certain embodiments, R 8 is a spirocyclic heterocyclyl having 6 to 12 (e.g., 6 to 10 (e.g., 7 to 10)) ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', and spirocyclic heterocyclyl substituted by '.

[0141] As a non-limiting example of said embodiment, R 8 is 1 to 4 independently selected R 7 2-azaspiro[3.3]heptane, substituted with R 8 teeth It can be TIFF2023509421000049.tif28128.

[0142] As a further non-limiting example, R 8 is 1 to 4 independently selected R 7 ', for example, R 8 teeth It can be TIFF2023509421000050.tif32128.

[0143] In certain embodiments, R 8 teeth, (c) 1 to 4 independently selected C 1~4 C3 cycloalkyl, C3 cycloalkenyl, C5 cycloalkyl, or C5 cycloalkenyl, each optionally substituted with alkyl, and (d) C, each of which is optionally substituted with 1 to 4 independently selected C alkyl. 7~12 Cycloalkyl or C 7~12 cycloalkenyl is selected from the group consisting of:

[0144] In certain embodiments, R 8 teeth, (c) 1 to 4 independently selected C 1~4 C3 cycloalkyl or C5 cycloalkyl, each optionally substituted with alkyl, and (d) 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 7~12 cycloalkyl is selected from the group consisting of:

[0145] In certain embodiments, R 8 is 1 to 4 independently selected C 1~4 C3 cycloalkyl or C5 cycloalkyl, each optionally substituted with alkyl, for example, unsubstituted C3 or C5 cycloalkyl. 8 can be cyclopentyl.

[0146] In certain embodiments, R 8 is 1 to 4 independently selected C 1~4 It is a C3 cycloalkyl or a C5 cycloalkyl, each substituted with alkyl.

[0147] In some embodiments, R 8 is an unsubstituted C 7~12 It is a bicyclic cycloalkyl.

[0148] In certain embodiments, R 8 is an unsubstituted C 7~12 A non-limiting example is R 8 teeth, It could be TIFF2023509421000051.tif22128.

[0149] In some embodiments, R 8 is an unsubstituted C 7~12 A non-limiting example is R 8 teeth, It could be TIFF2023509421000052.tif13128.

[0150] In certain embodiments, R 8 is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2and wherein heterocyclyl is other than tetrahydropyranyl and one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are selected from the group consisting of 1 to 4 independently selected C 1~4 It is heterocyclyl or heterocycloalkenyl, optionally substituted with alkyl.

[0151] In certain embodiments, R 8 is a monocyclic heterocyclyl of 3 to 8 ring atoms, in which 1 to 2 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and wherein heterocyclyl is other than tetrahydropyranyl and one or more ring carbon atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 4 independently selected C 1~4 In certain of these embodiments, R is a monocyclic heterocyclyl optionally substituted with alkyl. 8 is the ring N(R d ) group, and R d Ha, Halo, C 1~4 C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkoxy, and OH 1~6 alkyl. For example, R d is C substituted with 1 to 3 independently selected halo 1~6 It can be alkyl.

[0152] In certain embodiments, R 8 is 1 to 4 independently selected C 1~4 It is selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and azepinyl, each of which may be substituted with alkyl.

[0153] In certain embodiments, R 8 is one to two independently selected C 1~4azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, each of which may be substituted with alkyl. For example, R 8 is morpholinyl.

[0154] Another non-limiting example is R 8 is piperidinyl (e.g. TIFF2023509421000053.tif22128, for example or oxepanyl, and the ring nitrogen atom of piperidinyl is R d may be substituted with.

[0155] In certain embodiments, R 8 is a bicyclic or polycyclic heterocyclyl or heterocycloalkenyl of 7 to 12 ring atoms, in which 1 to 3 ring atoms are heteroatoms, each heteroatom being selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected C 1~4 It is a bicyclic or polycyclic heterocyclyl or heterocycloalkenyl optionally substituted with alkyl.

[0156] In certain embodiments, R 8 is a bicyclic or polycyclic heterocyclyl of 7 to 12 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 4 independently selected C 1~4 A non-limiting example of R is a bicyclic or polycyclic heterocyclyl optionally substituted with alkyl. 8 teeth It could be TIFF2023509421000055.tif21128.

[0157] In certain embodiments, R 8 is a spirocyclic heterocyclyl of 6 to 12 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected C 1~4 In one non-limiting example of this embodiment, R 8 teeth, It could be TIFF2023509421000056.tif21128.

[0158] In certain embodiments, R 8 is a heteroaryl having 5 to 12 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ' is a heteroaryl optionally substituted with '.

[0159] In certain embodiments, R 8 is a heteroaryl having 5-6 ring atoms, in which 1-3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are independently selected from the group consisting of 1 to 2 independently selected R 7 ' is a heteroaryl optionally substituted with '.

[0160] In certain embodiments, R 8 is a bicyclic heteroaryl of 7 to 12 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(Rd ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are independently selected from the group consisting of 1 to 2 independently selected R 7 A non-limiting example of R is a bicyclic heteroaryl, optionally substituted with R'. 8 teeth, It can be TIFF2023509421000057.tif23128.

[0161] In some embodiments, R 7 Ha-L 3 -R 9 is.

[0162] In certain embodiments, -L 3 is —O—, —NH—, or —S—.

[0163] In certain embodiments, -L 3 is -O-.

[0164] In certain embodiments, -L 3 is -NH-.

[0165] In certain embodiments, -L 3 is -S- or S(O) 1~2 is.

[0166] In certain embodiments, -L 3 is selected from the group consisting of C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2, and S(O)2NH.

[0167] In certain embodiments, R 9 teeth, (a) 1 to 4 independently selected R 7 ', C 3~12 Cycloalkyl or C 3~12 cycloalkenyl, and (b) a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 Optionally substituted heterocyclyl or heterocycloalkenyl is selected from the group consisting of:

[0168] In certain embodiments, R 9 is 1 to 4 independently selected R 7 ', each of which may be substituted with C 3~12 Cycloalkyl or C 3~12 It is a cycloalkenyl.

[0169] In certain of these embodiments, R 9 is one to two independently selected R 7 ' may be substituted with C 4~8 In one non-limiting example of this embodiment, R 9 is one to two independently selected R 7 ' is cyclobutyl, cyclopentyl, or cyclohexyl, each of which may be substituted (e.g., unsubstituted) by '.

[0170] In certain embodiments, R 9 is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ' is a heterocyclyl or heterocycloalkenyl optionally substituted by '.

[0171] In certain embodiments, R 9 is a heterocyclyl having 4 to 8 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 2 independently selected R 7 In one non-limiting example of the above embodiment, R 9 is one to two independently selected R 7 ' may be selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and azepinyl, each of which may be optionally substituted (e.g., unsubstituted) by '.

[0172] In certain embodiments, R 7 L 3 -R 9 and L 3 is -O- or -NH-, and R 9 teeth, 1 to 2 independently selected R 7 ' may be substituted with C 4~8 cycloalkyl, and Heterocyclyl having 4 to 8 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 2 independently selected R 7 Optionally substituted heterocyclyl In certain of these embodiments, L 3 is -O-. In certain other embodiments, L 3 is -NH-.

[0173] In certain of these embodiments, R 7 L 3 -R 9and L 3 is -O- or -NH, and R 9 is one to two independently selected R 7 In certain of these embodiments, L is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and oxetanyl, each of which may be substituted (e.g., unsubstituted) with '. 3 is -O-. In certain other embodiments, L 3 is -NH-.

[0174] R 7 L 3 -R 9 If R 7 Non-limiting examples of: TIFF2023509421000058.tif44159 is an example.

[0175] R 7 Further non-limiting examples of: TIFF2023509421000059.tif30140 is an example.

[0176] In certain embodiments, The TIFF2023509421000060.tif17128 part has the formula: TIFF2023509421000061.tif13128, where n2 is 0, 1, or 2, and R 7 is R 8 where R 8 teeth, 1 to 4 independently selected R 7 C replaced with ' 4~8 cycloalkyl, and Heterocyclyl having 4 to 8 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heterocyclyl is selected from the group consisting of:

[0177] In certain of these embodiments, n2 is 0.

[0178] In certain other embodiments, n2 is 1. In certain of these embodiments, R c is R 7 It is in the ortho position relative to

[0179] Certain aspects ( The TIFF2023509421000062.tif17128 part is the formula: TIFF2023509421000063.tif13128) in R 7 is R 8 and R 8 is 2 to 4 independently selected R 7 C replaced with ' 4~8 In one non-limiting example of this embodiment, R 8 is 2 to 4 independently selected R 7 cyclohexyl substituted with ', e.g. It can be TIFF2023509421000064.tif23128.

[0180] Certain aspects ( The TIFF2023509421000065.tif17128 part is the formula: TIFF2023509421000066.tif13128) in R 7 is R 8 and R 8 is a heterocyclyl having 4 to 8 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', and heterocyclyl substituted with '.

[0181] In certain of these embodiments, R 8 is a heterocyclyl having 4 to 6 ring atoms, in which 1 to 2 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring are independently selected from the group consisting of 2 to 4 independently selected R 7 ', and heterocyclyl substituted with '.

[0182] In certain such embodiments, R 8 is 2 to 4 (e.g., 2) independently selected R 7 and tetrahydropyranyl, each of which is substituted with '.

[0183] As a non-limiting example of said embodiment, R 8 is 2 to 4 (e.g., 2) independently selected R 7 azetidinyl, pyrrolidinyl, and piperidinyl, each substituted by ', e.g. TIFF2023509421000067.tif25128.

[0184] In a particular aspect (R 7 R 8 In the case where 7 teeth, TIFF2023509421000068.tif23128, where m1 and m2 are independently 0, 1, or 2, and T 1 is CH or N. For example, m1 can be 1 and m2 can be 1. As another non-limiting example, m1 can be 0 and m2 can be 0. In certain embodiments, each R 7 ' is an independently selected halo, e.g., -F.

[0185] In a particular aspect (R 7 R 8 In the case where 7 teeth TIFF2023509421000069.tif33128, where m3, m4, m5 and m6 are independently 0 or 1, and T 1 is CH or N. For example, m1, m2, m3, and m4 can each be 0. As a non-limiting example, R 7 teeth TIFF2023509421000070.tif28128. As another non-limiting example, R 7 teeth TIFF2023509421000071.tif32128. In certain embodiments, each R 7 ' is an independently selected halo, e.g., -F.

[0186] In certain embodiments, The TIFF2023509421000072.tif17128 part is the formula: TIFF2023509421000073.tif13128, where n2 is 0, 1, or 2, and R 7 Ha-L 3 -R 9 where: L 3 is -NH- or -O-, and R 9 teeth, 1 to 2 independently selected R 7 ' may be substituted with C 4~8 cycloalkyl, and Heterocyclyl having 4 to 8 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 2 independently selected R 7 Optionally substituted heterocyclyl is selected from the group consisting of:

[0187] In certain of these embodiments, R 7 L 3 -R 9 and L 3 is -O- or -NH, and R 9 is one to two independently selected R 7 In certain such embodiments, L is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and oxetanyl, each of which may be substituted (e.g., unsubstituted) with '. 3 is -O-. In certain other embodiments, L 3 is -NH-. Non-limiting examples include R 7 teeth It can be TIFF2023509421000074.tif32128.

[0188] Variable symbol R 7 ' In certain embodiments, R 7 One occurrence of ' means halo, -CN, -NO2, -OH, -C 2~4 Alkenyl, -C 2~4 Alkynyl, -C 1~4 Haloalkyl, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, S(O) 1~2 (C 1~4 alkyl), -NR'R'', oxo, -S(O) 1~2 (NR'R''), -C 1~4 Thioalkoxy, -C(=O)(C 1~4 alkyl), -C(=O)O(C 1~4 alkyl), —C(═O)OH, and —C(═O)N(R′)(R″), and each remaining R 7 'Halo, -CN, -NO2, -OH, -C 1~4 Alkyl, -C 2~4 Alkenyl, -C 2~4 Alkynyl, -C 1~4 Haloalkyl, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, S(O) 1~2(C 1~4 alkyl), -NR'R'', oxo, -S(O) 1~2 (NR'R''), -C 1~4 Thioalkoxy, -C(=O)(C 1~4 alkyl), -C(=O)O(C 1~4 alkyl), —C(═O)OH, and —C(═O)N(R′)(R″).

[0189] In certain embodiments, R 7 If ' is present, then each R 7 'Halo, -CN, -OH, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, S(O) 1~2 (C 1~4 alkyl), -NR'R'', -S(O) 1~2 (NR'R''), -C 1~4 Thioalkoxy, -C(=O)(C 1~4 alkyl), -C(=O)O(C 1~4 alkyl), —C(═O)OH, and —C(═O)N(R′)(R″), with the proviso that R 7 R 8 and R 8 When R is cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl, 7 One or more occurrences of ' -C 1~4 It is other than alkyl.

[0190] In certain embodiments, R 7 If ' is present, then each R 7 ', halo, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, S(O) 1~2 (C 1~4 alkyl), -NR'R'', -S(O) 1~2 (NR'R''), -C 1~4Thioalkoxy, -C(=O)(C 1~4 alkyl), -C(=O)O(C 1~4 alkyl), and —C(═O)N(R′)(R″), where R 7 R 8 and R 8 When R is cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl, 7 One or more occurrences of ' -C 1~4 It is other than alkyl.

[0191] In certain embodiments, R 7 If ' is present, then each R 7 ' are independently halo. A non-limiting example is R 7 If ' is present, then each R 7 ' can be -F.

[0192] In certain embodiments, R c If there is, then each R c is halo; cyano; 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl; C 1~4 Alkoxy;C 1~4 Haloalkoxy;-S(O) 1~2 (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; and -C(=O)N(R')(R'').

[0193] In certain embodiments, R c If there is, then each R c is halo; cyano; C optionally substituted with 1 to 6 independently selected halo 1~10 Alkyl; C 1~4Alkoxy;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl); and -C(=O)(C 1~10 alkyl), e.g., each R c are independently halo (e.g., -F), C 1~4 alkyl (e.g., CH3), or CF3.

[0194] In certain embodiments, R c If there is, then each R c is halo (e.g., —F or —Cl). In certain embodiments, R c If there is, then each R c is CN. In certain embodiments, R c If there is, then each R c is C 1~4 Alkoxy or C 1~4 In certain embodiments, R c If there is, then each R c is C 1~4 It is alkyl (e.g., CH3).

[0195] Variable symbols Q and W In some embodiments, Q is NH. In some embodiments, Q is N(C 1~3 alkyl).

[0196] In some embodiments, Q is —NH—(C 1~3 alkylene)-, where the asterisk represents the point of attachment to W.

[0197] In some embodiments, W is C(=O). In some embodiments, W is S(O). 1~2 (e.g., S(O)2). In some embodiments, W is C(=S). In some embodiments, W is C(=NR d ) (e.g., C(=NH)). In some embodiments, W is C(=C-NO). In some embodiments, W is C(=N-CN).

[0198] In certain embodiments, Q is NH and W is C(=O).

[0199] Variable symbol X 1 , X 2 , Z, Y 1 , Y 2 , and Y 3 In some embodiments, X 1 is NR 2 In certain of these embodiments, X 1 is NH.

[0200] In some embodiments, X 2 is CR 5 In certain of these embodiments, X 2 is CH.

[0201] In some embodiments, X 1 is NR 2 and X 2 is CR 5 In certain of these embodiments, X 1 is NH and X 2 is CH.

[0202] In some embodiments, Z is CR 1 is.

[0203] In certain embodiments, Y 1 , Y 2 , and Y 3 One or two of these are independently N or NR 2 (e.g., N) and Y 1 , Y 2 , and Y 3 Each of the remaining is an independently selected CR 1 is.

[0204] In certain embodiments, Y 1 , Y 2 , and Y 3 One of the is independently N or NR 2 and Y 1 , Y2 , and Y 3 Each of the remaining is an independently selected CR 1 is.

[0205] In certain embodiments, Y 1 , Y 2 , and Y 3 one of is independently N, and Y 1 , Y 2 , and Y 3 Each of the remaining is an independently selected CR 1 is.

[0206] In certain embodiments, The TIFF2023509421000075.tif18128 part is TIFF2023509421000076.tif18128. In certain embodiments, The TIFF2023509421000077.tif18128 part is TIFF2023509421000078.tif13128. In certain embodiments, The TIFF2023509421000079.tif18128 part is TIFF2023509421000080.tif14128. In certain embodiments, The TIFF2023509421000081.tif19128 part is TIFF2023509421000082.tif13128. In certain embodiments, The TIFF2023509421000083.tif18128 part is TIFF2023509421000084.tif22128. In certain embodiments, The TIFF2023509421000085.tif18128 part is TIFF2023509421000086.tif12128. In certain embodiments, The TIFF2023509421000087.tif18128 part is TIFF2023509421000088.tif24128. In certain embodiments, The TIFF2023509421000089.tif18128 part is The file is TIFF2023509421000090.tif12128.

[0207] In some embodiments, Z is N.

[0208] In certain of these embodiments, Y 1 , Y 2 , and Y 3 Each of the 1 is.

[0209] In certain embodiments, The TIFF2023509421000091.tif18128 part is The file is TIFF2023509421000092.tif19128.

[0210] In some embodiments, the compound has the following formula: The compound is selected from compounds in TIFF2023509421000093.tif70145.

[0211] In certain embodiments, the compound has formula (Ia): I have TIFF2023509421000094.tif32128.

[0212] In certain embodiments, the compound has formula (Ia-1): I have TIFF2023509421000095.tif32128.

[0213] In certain embodiments, the compound has formula (Ia-2): I have TIFF2023509421000096.tif31128.

[0214] In certain embodiments, the compound has formula (Ia-3): I have TIFF2023509421000097.tif31128.

[0215] In certain embodiments, the compound has formula (Ib): I have TIFF2023509421000098.tif34128.

[0216] In certain embodiments, the compound has formula (Ib-1): I have TIFF2023509421000099.tif33128.

[0217] In certain embodiments, the compound has formula (Ic): I have TIFF2023509421000100.tif33128.

[0218] In certain embodiments, the compound has formula (Ic-1): I have TIFF2023509421000101.tif32128.

[0219] In certain embodiments, the compound has formula (Id): I have TIFF2023509421000102.tif32128.

[0220] In certain embodiments, the compound has formula (Id-1): I have TIFF2023509421000103.tif32128.

[0221] In certain embodiments, the compound has formula (Id-2): I have TIFF2023509421000104.tif32128.

[0222] In certain embodiments, the compound has formula (Id-3): I have TIFF2023509421000105.tif32128.

[0223] Variable symbol R 1 In some embodiments, R1 Each occurrence of is H; halo; cyano; 1-2 R a C optionally substituted with 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 Haloalkoxy;-L 1 -L 2 -R h ;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);SF5;-S(O) 1~2 (NR'R'');-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R'').

[0224] In some embodiments, R 1 0 to 2 (e.g., 0, 1, or 2) occurrences of are other than H, and R 1 Each of the remaining occurrences of is H.

[0225] In certain embodiments, R 1 Each occurrence of is H.

[0226] In certain other embodiments, R 1 is other than H. In certain of these embodiments, R 1 One occurrence of is other than H.

[0227] In certain embodiments, R 1 One occurrence of is halo; cyano; one or two R a C optionally substituted with 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Haloalkyl;C 1~4 Alkoxy;C1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O) 1~2 (NR'R'');-NO2;-L 1 -L 2 -R h ;-C(=O)(C 1~4 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R'').

[0228] In certain embodiments, R 1 One occurrence of is halo (e.g., F or Cl (e.g., F)). In certain of these embodiments, each remaining R 1 is H. In certain other embodiments, the remaining R 1 One of the R 1 One of the groups is a halo (e.g., F), and the other remaining R 1 Each of these is H.

[0229] In certain embodiments, R 1 One occurrence of is one or two R a C optionally substituted with 1~6 Alkyl (e.g., 1-2 R a C optionally substituted with 1~3 Alkyl (e.g., C 1~3 In certain of these embodiments, each remaining R 1 is H. In certain other embodiments, the remaining R 1 One of the R 1 One of the groups is a halo (e.g., F), and the other remaining R 1 Each of these is H.

[0230] In some embodiments, R 1 One occurrence of C 1~4 Haloalkoxy (e.g., C 2~4 haloalkoxy); and -OH, C 1~4 Alkoxy, C 1~4Haloalkoxy, or -NR e R f optionally substituted with C 1~4 For example, R 1 is C 1~4 Haloalkoxy (e.g., C 2~4 haloalkoxy). Another non-limiting example is R 1 is C 1~4 Alkoxy-substituted C 1~4 Alkoxy (e.g., C 1~4 Alkoxy-substituted C 2~4 As a further non-limiting example, R 1 is C 1~4 It can be an alkoxy.

[0231] In certain embodiments, R 1 One occurrence of -L 1 -L 2 -R h In certain of these embodiments, -L 1 is a bond. In certain embodiments, R 1 Ha-L 1 -L 2 -R h and -L 4 is a bond. In certain embodiments, R 1 Ha-L 1 -L 2 -R h and L 1 is a bond and L 2 is a bond.

[0232] In certain embodiments, R 1 Ha-L 1 -L 2 -R h and -R h teeth, Heteroaryl having 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2and the heteroaryl ring is selected from the group consisting of halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 6~10 Aryl is selected from the group consisting of:

[0233] In certain embodiments, -R h teeth, Heteroaryl (e.g., pyrazolyl) having 5 to 6 ring atoms, in which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 heteroaryl, optionally substituted with 1 to 2 substituents independently selected from the group consisting of haloalkoxy; Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4phenyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of haloalkoxy; is selected from the group consisting of:

[0234] In certain embodiments, R 1 One of them is Heteroaryl (e.g., pyrazolyl) having 5 to 6 ring atoms, in which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 Heteroaryl optionally substituted with 1 to 2 substituents independently selected from the group consisting of haloalkoxy TIFF2023509421000106.tif15128, and Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 phenyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of haloalkoxy; TIFF2023509421000107.tif14128. In certain of these embodiments, each remaining R 1 is H.

[0235] Variable symbol R 2 In some embodiments, R 2 is H.

[0236] In some embodiments, R 2 teeth, (iii) 1 to 3 independently selected R amay be substituted with -C(O)(C 1~6 alkyl), (iv) 1 to 3 independently selected R a may be substituted with -C(O)O(C 1~4 alkyl), (v)-CON(R')(R''), (vi)-S(O) 1~2 (NR'R''), and (vii) 1 to 3 independently selected R a -S(O) optionally substituted with 1~2 (C 1~4 alkyl) is selected from the group consisting of:

[0237] In certain embodiments, R 2 is one to three independently selected R a may be substituted with -C(O)(C 1~6 In certain of these embodiments, R 2 Each R a The substituents are independently -F, -Cl, -OH, or -NR e R f is.

[0238] As a non-limiting example, R 2 is C(=O)Me, TIFF2023509421000108.tif24128.

[0239] In certain embodiments, R 2 is one to three independently selected R a -S(O) optionally substituted with 1~2 (C 1~4 alkyl) (e.g., S(O)Me).

[0240] In some embodiments, R 2 Ha-L 4 -L 5 -R i In certain of these embodiments, -L 4is a bond. In certain embodiments, -L 4 is C(=O). In certain embodiments, R 2 Ha-L 4 -L 5 -R i and -L 4 is S(O). In certain embodiments, R 2 Ha-L 4 -L 5 -R i and -L 5 is a bond. In certain other embodiments, -L 5 is C 1~4 Alkylene (e.g., C 1~2 alkylene).

[0241] In certain embodiments, R 2 Ha-L 4 -L 5 -R i and R i is halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 3~8 cycloalkyl (e.g., R i teeth TIFF2023509421000109.tif20128, where "Boc" stands for tert-butoxycarbonyl).

[0242] In certain embodiments, R 2 Ha-L 4 -L 5 -R i and R i is a heterocyclyl having 3 to 8 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2and heterocyclyl is independently selected from the group consisting of halo; OH; NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 and heterocyclyl (e.g., R i teeth TIFF2023509421000110.tif22128, where "Boc" stands for tert-butoxycarbonyl).

[0243] In certain embodiments, R 2 Ha-L 4 -L 5 -R i and R i is a heteroaryl having 5-6 ring atoms, in which 1-2 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is independently selected from the group consisting of halo; OH; NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 and heteroaryl (e.g., R i Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, Cyano, C 1~4 Alkoxy, and C 1~4 pyridyl, pyrimidyl, or pyrazolyl, optionally substituted with 1 to 2 substituents independently selected from haloalkoxy).

[0244] In certain embodiments, R 2 Ha-L 4 -L 5 -R i and R i is halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 6~10 Aryl (e.g., halo, C 1~4 Alkyl, C 1~4 Haloalkyl, Cyano, C 1~4 Alkoxy, and C 1~4 haloalkoxy).

[0245] In certain embodiments, R 2 Ha-L 4 -L 5 -R i and L 4 is a bond and L 5 is a bond or C 1~4 alkylene, and R i is halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 3~8 Cycloalkyl (e.g., "Boc" represents tert-butoxycarbonyl) TIFF2023509421000111.tif20128).

[0246] In certain embodiments, R 2 Ha-L4 -L 5 -R i and L 4 is a bond and L 5 is a bond or C 1~4 alkylene, and R i is a heterocyclyl having 3 to 8 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and heterocyclyl is independently selected from the group consisting of halo; OH; NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 haloalkoxy, optionally substituted with 1 to 4 substituents independently selected from the group consisting of heterocyclyl (e.g., (e.g., "Boc" represents tert-butoxycarbonyl); TIFF2023509421000112.tif22128).

[0247] In certain embodiments, R 2 Ha-L 4 -L 5 -R i and L 4 is a bond and L 5 is a bond or C 1~4 alkylene, and R i is a heteroaryl having 5-6 ring atoms, in which 1-2 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is independently selected from the group consisting of halo; OH; NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C1~4 Heteroaryl (e.g., halo, C 1~4 Alkyl, C 1~4 Haloalkyl, Cyano, C 1~4 Alkoxy, and C 1~4 pyridyl, pyrimidyl, or pyrazolyl, optionally substituted with 1 to 2 substituents independently selected from haloalkoxy.

[0248] In certain embodiments, R 2 Ha-L 4 -L 5 -R i and L 4 is a bond and L 5 is a bond or C 1~4 alkylene, and R i is halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 6~10 Aryl (e.g., halo, C 1~4 Alkyl, C 1~4 Haloalkyl, Cyano, C 1~4 Alkoxy, and C 1~4 haloalkoxy).

[0249] In certain embodiments, R 2 Ha-L 4 -L 5 -R i and L 4 is C(=O) or S(O)2, and L 5 is a bond or C 1~4 alkylene, and R iis a heteroaryl having 5-6 ring atoms, in which 1-2 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is independently selected from the group consisting of halo; OH; NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 Heteroaryl (e.g., halo, C 1~4 Alkyl, C 1~4 Haloalkyl, Cyano, C 1~4 Alkoxy, and C 1~4 pyridyl, pyrimidyl, or pyrazolyl, optionally substituted with 1 to 2 substituents independently selected from haloalkoxy.

[0250] In certain embodiments, R 2 Ha-L 4 -L 5 -R i and L 4 is C(=O) or S(O)2, and L 5 is a bond or C 1~4 alkylene, and R i is halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 6~10 Aryl (e.g., halo, C 1~4 Alkyl, C 1~4 Haloalkyl, Cyano, C 1~4 Alkoxy, and C 1~4haloalkoxy).

[0251] As a non-limiting example, R 2 teeth, TIFF2023509421000113.tif30128, wherein R j H, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, Cyano, C 1~4 Alkoxy, or C 1~4 It is haloalkoxy.

[0252] Variable symbol R 5 In some embodiments, R 5 is H.

[0253] Variable symbol R 6 In some embodiments, R 6 is H. In some embodiments, R 6 is C 1~3 It is alkyl.

[0254] Non-limiting combinations In some embodiments, the compound has formula (I-1a): TIFF2023509421000114.tif36128 or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , and R 1c Each of R is independently selected 1 and Q 1 is N or CH, and n2 is 0, 1, or 2.

[0255] In some embodiments, the compound has formula (I-1b): TIFF2023509421000115.tif38128 or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , and R 1c are independently selected R 1 and Q 1 is N or CH, and n2 is 0, 1, or 2.

[0256] In certain embodiments of formula (I-1a) or (I-1b), R 8 is 1 to 4 independently selected R 7 ' respectively replaced by C 3~12 Cycloalkyl or C 3~12 It is a cycloalkenyl.

[0257] In certain embodiments of formula (I-1a) or (I-1b), R 8 is 2 to 4 independently selected R 7 C replaced with ' 4~8 In certain of these embodiments, R 8 is 2 to 4 independently selected R 7 A non-limiting example of this embodiment is cyclohexyl substituted with R 8 teeth, The file is TIFF2023509421000116.tif25128.

[0258] In certain embodiments of formula (I-1a) or (I-1b), R 8 is a heterocyclyl or heterocycloalkenyl of 4 to 12 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl or heterocycloalkenyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', heterocyclyl or heterocycloalkenyl.

[0259] In certain of these embodiments, R 8is a heterocyclyl having 4 to 8 ring atoms, in which 1 to 2 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring atoms of the heterocyclyl ring are independently selected from the group consisting of 2 to 4 independently selected R 7 ', and heterocyclyl substituted with '.

[0260] In certain embodiments of formula (I-1a) or (I-1b), R 8 is 2 to 4 (e.g., 2) independently selected R 7 In certain of these embodiments, R is selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, each of which is substituted with '. 8 is 2 to 4 (e.g., 2) independently selected R 7 ' is selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl, each substituted with '.

[0261] As a non-limiting example of said embodiment, R 8 teeth, TIFF2023509421000117.tif25128.

[0262] In certain embodiments of formula (I-1a) or (I-1b), R 8 is a spirocyclic heterocyclyl of 6 to 12 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 4 independently selected R 7 ', and spirocyclic heterocyclyl substituted by '.

[0263] As a non-limiting example of said embodiment, R 8 teeth TIFF2023509421000118.tif32128.

[0264] In certain embodiments of formula (I-1a) or (I-1b), R 8 is a monocyclic heterocyclyl of 3 to 8 ring atoms, in which 1 to 2 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and wherein heterocyclyl is other than tetrahydropyranyl and one or more ring carbon atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 4 independently selected C 1~4 It is a monocyclic heterocyclyl optionally substituted with alkyl.

[0265] In certain embodiments of formula (I-1a) or (I-1b), R 8 is 1 to 4 independently selected C 1~4 is selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and azepinyl, each of which may be substituted with alkyl, e.g., R 8 is morpholinyl.

[0266] In certain embodiments of formula (I-1a) or (I-1b), R 8 teeth, (c) 1 to 4 independently selected C 1~4 C3 cycloalkyl or C5 cycloalkyl, each optionally substituted with alkyl, and (d) 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 7~12 cycloalkyl is selected from the group consisting of:

[0267] As a non-limiting example, R 8 is an unsubstituted C3, C5, or C 7~12 It can be cycloalkyl (eg, cyclopentyl).

[0268] In certain embodiments of formula (I-1a) or (I-1b), R 8 teeth, TIFF2023509421000119.tif34128; During the ceremony, T 1 is N or CH, m1 and m2 are independently 0, 1, or 2; and m3, m4, m5, and m6 are independently 0 or 1.

[0269] In certain of these embodiments, each R 7 ' are independently selected halo (eg, -F).

[0270] Certain embodiments of formula (I-1a) or (I-1b) (R 8 but TIFF2023509421000120.tif34128), R 8 teeth, TIFF2023509421000121.tif32170.

[0271] In some embodiments, the compound has formula (I-2): TIFF2023509421000122.tif35128, During the ceremony, R 1a , R 1b , and R 1c Each of R is independently selected 1 and Q 1 is N or CH, and n2 is 0, 1, or 2.

[0272] In certain embodiments of formula (I-2), L 3 is -O-.

[0273] In certain other embodiments, L 3 is -NH-.

[0274] In certain embodiments of formula (I-2), L 3 is selected from the group consisting of -S-, -S(O)2-, C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2, and S(O)2NH.

[0275] In certain embodiments of formula (I-2), R 9 is 1 to 4 independently selected R 7 ', C 3~12 Cycloalkyl or C 3~12 It is a cycloalkenyl.

[0276] In certain embodiments of formula (I-2), R 9 is one to two independently selected R 7 ' may be substituted with C 4~8 It is cycloalkyl.

[0277] In certain embodiments of formula (I-2), R 9 is one to two independently selected R 7 ' is cyclobutyl, cyclopentyl, or cyclohexyl, each of which may be substituted (e.g., unsubstituted) by '.

[0278] In certain embodiments of formula (I-2), R 9 is a heterocyclyl having 4 to 8 ring atoms, in which 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are independently selected from the group consisting of 1 to 2 independently selected R 7 ' is a heterocyclyl optionally substituted by '.

[0279] In certain embodiments of formula (I-2), R 9 is one to two independently selected R 7and azepinyl, each of which may be optionally substituted (e.g., unsubstituted) by '.

[0280] Non-limiting examples include -L in formula (I-2) 3 -R 9 teeth, TIFF2023509421000123.tif32128.

[0281] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 7 If ' is present, then each R 7 ', halo, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, S(O) 1~2 (C 1~4 alkyl), -NR'R'', -S(O) 1~2 (NR'R''), -C 1~4 Thioalkoxy, -C(=O)(C 1~4 alkyl), -C(=O)O(C 1~4 alkyl), and —C(═O)N(R′)(R″), where R 7 ' is R 8 and R 8 When R is cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl, 7 One or more occurrences of ' -C 1~4 It is other than alkyl.

[0282] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 7 If ' is present, then each R 7 ', halo, -CN, -C 1~4 Haloalkyl, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, S(O)1~2 (C 1~4 alkyl), -NR'R'', -S(O) 1~2 (NR'R''), -C 1~4 Thioalkoxy, -C(=O)(C 1~4 alkyl), -C(=O)O(C 1~4 alkyl), and —C(═O)N(R′)(R″), where R 7 ' is R 8 and R 8 When R is cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl, 7 One or more occurrences of ' -C 1~4 It is other than alkyl.

[0283] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 7 If ' is present, then each R 7 ', halo, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, S(O) 1~2 (C 1~4 alkyl), -NR'R'', -S(O) 1~2 (NR'R''), -C 1~4 Thioalkoxy, -C(=O)(C 1~4 alkyl), -C(=O)O(C 1~4 alkyl), and —C(═O)N(R′)(R″).

[0284] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 7 If ' is present, then each R 7 ' are independently halo. A non-limiting example is R 7 If ' is present, then each R 7 ' can be -F.

[0285] In certain embodiments of formula (I-1a), (I-1b), or (I-2), n2 is 0.

[0286] In certain embodiments of formula (I-1a), (I-1b), or (I-2), n2 is 1.

[0287] In certain of these embodiments, R c If there is R c are (a) halo, (b) cyano, and (c) C 1~10 Alkyl, (g) C 1~4 Alkoxy, (h)C 1~4 Haloalkoxy, (i) -S(O) 1~2 (C 1~4 alkyl); and -C(=O)(C 1~10 alkyl).

[0288] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R c If there is, then each R c is halo (e.g., —F, —Br, or —Cl) or cyano.

[0289] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R c If there is, then each R c is C 1~3 It is alkyl (eg, methyl or ethyl).

[0290] In certain embodiments of formula (I-1a), (I-1b), or (I-2), Q 1 is N.

[0291] In certain embodiments of formula (I-1a), (I-1b), or (I-2), Q 1 is CH.

[0292] In certain embodiments of formula (I-1a), (I-1b), or (I-2), Q is NH.

[0293] In certain embodiments of formula (I-1a), (I-1b), or (I-2), W is C(=O).

[0294] In certain embodiments of formula (I-1a), (I-1b), or (I-2), Q is NH and W is C(=O).

[0295] In certain embodiments of formula (I-1a), (I-1b), or (I-2), W is S(O)2, C(=S), or C(=NR d )

[0296] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 1a , R 1b , and R 1c each one of H; halo; cyano; 1-2 R a C optionally substituted with 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Haloalkyl;C 1~4 C optionally substituted with alkoxy 1~4 Alkoxy;C 1~4 Haloalkoxy;-L 1 -L 2 -R h ;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);SF5;-S(O) 1~2 (NR'R'');-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R'').

[0297] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 1a , R 1b , and R 1ceach one of H; halo; cyano; 1-2 R a C optionally substituted with 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Alkynyl; C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 Haloalkoxy;-L 1 -L 2 -R h ;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);SF5;-S(O) 1~2 (NR'R'');-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl);-C(=O)O(C 1~4 alkyl); -C(=O)OH; and -C(=O)N(R')(R'').

[0298] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 1a is H.

[0299] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 1c is H.

[0300] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 1b is H.

[0301] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 1b is other than H. In certain of these embodiments, R 1b is halo. In one non-limiting example of the embodiment, R 1b can be -F. As another non-limiting example of the above embodiment, R 1b can be -Br or -Cl. In certain embodiments of formula (I-1a), (I-1b) or (I-2), R1b is C 1~3 In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 1b is C 1~4 Alkoxy-substituted C 1~4 Alkoxy (e.g., C 2~4 In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 1b is C 1~4 Haloalkoxy (e.g., C 2~4 haloalkoxy).

[0302] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 1b L 1 -L 2 -R h In certain of these embodiments, -L 1 is a bond. In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 1b L 1 -L 2 -R h and -L 2 is a bond.

[0303] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 1b L 1 -L 2 -R h and -R h teeth, Heteroaryl (e.g., pyrazolyl) having 5 to 6 ring atoms, in which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4heteroaryl, optionally substituted with 1 to 2 substituents independently selected from the group consisting of haloalkoxy; Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 phenyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of haloalkoxy; is selected from the group consisting of:

[0304] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 1b teeth, Heteroaryl (e.g., pyrazolyl) having 5 to 6 ring atoms, in which 1 to 4 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 Heteroaryl optionally substituted with 1 to 2 substituents independently selected from the group consisting of haloalkoxy TIFF2023509421000124.tif15128, and Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 phenyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of haloalkoxy; TIFF2023509421000125.tif14128.

[0305] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 5 is H.

[0306] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 2 is H.

[0307] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 2 is one to three independently selected R a may be substituted with -C(O)(C 1~6 alkyl), or 1 to 3 independently selected R a -S(O) optionally substituted with 1~2 (C 1~4 alkyl) (e.g., S(O)Me).

[0308] As a non-limiting example, R 2 are C(=O)Me, S(O)2Me, TIFF2023509421000126.tif24128.

[0309] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 2 Ha-L 4 -L 5 -R i and L 4 is a bond and L 5 is a bond or C 1~4 alkylene (e.g., CH2), and R i teeth, (c) Heteroaryl having 5 to 6 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is independently selected from the group consisting of halo; OH; NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 Heteroaryl (e.g., halo, C 1~4 Alkyl, C 1~4 Haloalkyl, Cyano, C 1~4 Alkoxy, and C 1~4 pyridyl, pyrimidyl, or pyrazolyl, each optionally substituted with 1 to 2 substituents independently selected from haloalkoxy; and (d) Halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 6~10 Aryl (e.g., halo, C 1~4 Alkyl, C 1~4 Haloalkyl, Cyano, C 1~4 Alkoxy, and C 1~4 phenyl optionally substituted with 1 to 2 substituents independently selected from haloalkoxy) is selected from the group consisting of:

[0310] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 2 Ha-L 4 -L 5 -R i and L 4 is C(=O) or S(O)2, and L 5 is a bond or C 1~4 alkylene, and R i teeth, (c) Heteroaryl having 5 to 6 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2and the heteroaryl ring is independently selected from the group consisting of halo; OH; NR e R f ; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 Heteroaryl (e.g., halo, C 1~4 Alkyl, C 1~4 Haloalkyl, Cyano, C 1~4 Alkoxy, and C 1~4 pyridyl, pyrimidyl, or pyrazolyl, each optionally substituted with 1 to 2 substituents independently selected from haloalkoxy; and (d) Halo;OH;NR e R f 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy 6~10 Aryl (e.g., halo, C 1~4 Alkyl, C 1~4 Haloalkyl, Cyano, C 1~4 Alkoxy, and C 1~4 phenyl optionally substituted with 1 to 2 substituents independently selected from haloalkoxy) is selected from the group consisting of:

[0311] Non-limiting examples include R in formula (I-1a), (I-1b), or (I-2). 2 teeth, TIFF2023509421000127.tif30128, where R j H, halo, C 1~4 Alkyl, C 1~4Haloalkyl, Cyano, C 1~4 Alkoxy, or C 1~4 It is haloalkoxy.

[0312] In certain embodiments of formula (I-1a), (I-1b), or (I-2), R 6 is hydrogen.

[0313] In some embodiments, the compound of formula (I) has the formula (I-3a): TIFF2023509421000128.tif27128 or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , and R 1c each of which is H; halo; cyano; 1 to 2 R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 C optionally substituted with alkoxy 1~4 Alkoxy (e.g., C 1~4 alkoxy); and C 1~4 independently selected from the group consisting of haloalkoxy; Q 1 is N or CH, R 8 teeth, TIFF2023509421000129.tif34128; n2 is 0, 1, or 2, R c If there is, then each R c Halo, Cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; m1 and m2 are independently 0, 1, or 2, and m3, m4, m5, and m6 are independently 0 or 1; and T 1 is CH or N.

[0314] In some embodiments, the compound of formula (I) has the formula (I-3b): TIFF2023509421000130.tif30128 or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , and R 1c each of which is H; halo; cyano; 1 to 2 R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 C optionally substituted with alkoxy 1~4 Alkoxy (e.g., C 1~4 alkoxy); and C 1~4 independently selected from the group consisting of haloalkoxy; Q 1 is N or CH, R 8 teeth, TIFF2023509421000131.tif34128; n2 is 0, 1, or 2, R c If there is, then each R c Halo, Cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; m1 and m2 are independently 0, 1, or 2, and m3, m4, m5, and m6 are independently 0 or 1; and T 1 is CH or N.

[0315] In certain embodiments of formula (I-3a) or (I-3b), R 2 is H.

[0316] In certain embodiments of formula (I-3a) or (I-3b), R 1a and R 1c is H.

[0317] In certain embodiments of formula (I-3a) or (I-3b), R 1b is H.

[0318] In certain other embodiments, R 1b is other than H. For example, R 1b can be halo, such as F. As another non-limiting example, R 1b C such as methoxy 1~3 As another non-limiting example, R 1b is C 1~4 Haloalkoxy (e.g., C 2~4 As a further non-limiting example, R 1b is C 1~4 Alkoxy-substituted C 1~4 Alkoxy (e.g., C 1~4 Alkoxy-substituted C 2~4 alkoxy).

[0319] In certain embodiments of formula (I-3a) or (I-3b), each R 7 ' is a halo such as -F.

[0320] In certain embodiments of formula (I-3a) or (I-3b), R 8 teeth TIFF2023509421000132.tif22128. In certain of these embodiments, m1 = m2 = 1. In certain other embodiments, m1 = m2 = 0.

[0321] In certain embodiments of formula (I-3a) or (I-3b), T 1 is N. In certain other embodiments, T 1 is CH.

[0322] In certain embodiments of Formula (I-3a) or (I-3b), n2 is 1. In certain of these embodiments, R c is R 8 In certain such embodiments, R c is halo, such as -Cl. In certain embodiments, R c is C such as methyl or ethyl1~3 In certain embodiments, R c is cyano.

[0323] In certain embodiments of formula (I-3a) or (I-3b), Q 1 is N. In certain other embodiments, Q 1 is CH.

[0324] In certain embodiments of formula (I-3a) or (I-3b), R 7 If ' is present, then each R 7 ' is independently a halo.

[0325] Non-limiting exemplary compounds of formula I In certain embodiments, the compound is selected from the group consisting of the compounds shown in Table C1 or a pharmaceutically acceptable salt thereof.

[0326] [Table C1] TIFF2023509421000134.tif197138TIFF2023509421000135.tif189138TIFF202 3509421000136.tif186138TIFF2023509421000137.tif186138TIFF20235094210 00138.tif173138TIFF2023509421000139.tif221138TIFF2023509421000140.t if220138TIFF2023509421000141.tif199138TIFF2023509421000142.tif197138 TIFF2023509421000143.tif203138TIFF2023509421000144.tif187138TIFF202 3509421000145.tif177138TIFF2023509421000146.tif174138TIFF20235094210 00147.tif227138TIFF2023509421000148.tif227138TIFF2023509421000149.t if227138TIFF2023509421000150.tif227138TIFF2023509421000151.tif175138

[0327] 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 and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0328] 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).

[0329] 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).

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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 filtered.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.

[0334] 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.

[0335] 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.

[0336] 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.

[0337] 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).

[0338] 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.

[0339] 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.

[0340] 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.

[0341] 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.

[0342] 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.

[0343] Examples include upper GI targeting technologies such as the Accordion Pill (Intec Pharma), floating capsules, and materials that can adhere to mucosal walls.

[0344] 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.

[0345] 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.)).

[0346] 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.

[0347] 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.

[0348] 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.

[0349] In some embodiments, the compounds described herein are administered in a concentration of from about 0.001 mg / Kg to about 500 mg / Kg (e.g., from about 0.001 mg / Kg to about 200 mg / Kg, from about 0.01 mg / Kg to about 200 mg / Kg, from about 0.01 mg / Kg to about 150 mg / Kg, from about 0.01 mg / Kg to about 100 mg / Kg, from about 0.01 mg / Kg to about 50 mg / Kg, from about 0.01 mg / Kg to about 10 mg / Kg, from about 0.01 mg / Kg to about 5 mg / Kg, from about 0.01 mg / Kg to about 1 mg / Kg). g, about 0.01 mg / kg to about 0.5 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 200 mg / kg, about 0.1 mg / kg to about 150 mg / kg, about 0.1 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg).

[0350] 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).

[0351] 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 of time 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.

[0352] 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.

[0353] 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.

[0354] 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 such 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, cerebral cortical base Basilar degeneration, 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, encephalocele, cerebral trigeminal angiomatosis, epilepsy, Erb's palsy, essential tremor, Fabry's disease, Fahr's syndrome, syncope, familial spastic paraplegia,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, hereditary ataxia of the polyneuropathy type, varices zoster oticus Herpes zoster, Hirayama syndrome, HIV-associated dementia and neuropathy (also a neurological manifestation of AIDS), holoprosencephaly, Huntington's disease and other polyglutamine repeat diseases, 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, Juvenile encephalopathy, Lewy body 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 disability, 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, minor stroke, 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.

[0355] 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).

[0356] 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 infectious disease is a fungal infection (e.g., an infection caused by a mold, yeast, or higher fungus). In yet another embodiment, the infectious disease is a parasitic infection (e.g., an infection caused by a unicellular or multicellular parasite, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondiz). In yet another embodiment, the infectious disease is a viral infection (e.g., an infection caused by a virus associated with AIDS, avian influenza, chickenpox, cold sores, the common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and lower or upper respiratory tract infections (e.g., respiratory syncytial virus)).

[0357] In some embodiments, the condition, disease, or disorder is hepatitis B (see, e.g., WO 2015 / 061294).

[0358] In some embodiments, the condition, disease, or disorder is selected from cardiovascular diseases (including, for example, myocardial infarction).

[0359] In some embodiments, the condition, disease, or disorder is age-related macular degeneration.

[0360] 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.

[0361] 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).

[0362] In some embodiments, the condition, disease, or disorder is selected from the group consisting of cancer, a neurological disorder, an autoimmune disease, hepatitis B, uvetitis, cardiovascular disease, age-related macular degeneration, and mucositis.

[0363] Further examples include the indications discussed below herein and contemplated combination therapy regimens.

[0364] Combination therapy The present disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[0365] 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.

[0366] In certain embodiments, the methods described herein can further comprise administering one or more additional cancer therapies.

[0367] 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.

[0368] In some embodiments, the one or more additional cancer therapies is chemotherapy, which can include administering one or more additional chemotherapeutic agents.

[0369] 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.

[0370] 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.

[0371] 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.

[0372] 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.

[0373] 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 terpernoids are synthetic, semi-synthetic, or derivatives. In a further embodiment, the podophyllotoxins are, but are not limited to, etoposide and / or teniposide. In one embodiment, the taxanes are, but are not limited to, docetaxel and / or ortataxel.

[0021] In one embodiment, the cancer therapeutic agent is a topoisomerase. Topoisomerases are essential enzymes that maintain DNA topology. Inhibition of type I or type II topoisomerases interferes with both DNA transcription and replication by disrupting proper DNA supercoiling. In a further embodiment, the topoisomerase is, but is not limited to, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, the type I topoisomerase inhibitor is, but is not limited to, camptothecin.In another embodiment, the camptothecin is, but is not limited to, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67), and / or ST 1481. In one embodiment, the type II topoisomerase inhibitor is, but is not limited to, epipodophyllotoxin. In a further embodiment, the epipodophyllotoxin is, but is not limited to, amsacrine, etoposide, etoposide phosphate, and / or teniposide. In a further embodiment, the topoisomerase is synthetic, semi-synthetic, or a derivative, including those found in nature, such as, but not limited to, epipodophyllotoxin, a substance naturally occurring in the roots of American mayapple (Podophyllum peltatum).

[0374] 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.

[0375] 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.

[0376] 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).

[0377] 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.

[0378] 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.

[0379] 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.

[0380] 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.

[0381] 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®)).

[0382] 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.

[0383] 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).

[0384] 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).

[0385] 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.

[0386] 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.

[0387] 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).

[0388] 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.

[0389] 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.

[0390] 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.

[0391] 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.

[0392] 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.

[0393] 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.

[0394] 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.

[0395] 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.

[0396] 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.

[0397] 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.

[0398] 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.

[0399] 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.

[0400] 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.

[0401] 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.

[0402] 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.

[0403] 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.

[0404] 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.

[0405] 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®).

[0406] 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).

[0407] 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.

[0408] 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)).

[0409] 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).

[0410] 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.

[0411] 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).

[0412] 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.

[0413] 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).

[0414] 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).

[0415] 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.

[0416] 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.

[0417] The following abbreviations have the meanings indicated below: TIFF2023509421000152.tif118153 [Example]

[0418] material and method Reaction progress was frequently monitored by TLC or LC-MS. Product identity was frequently confirmed by LC-MS, which was recorded using one of the following methods:

[0419] LCMS Method A: XBridge Shield RP18, 50*4.6mm, injection volume 3.0μL, flow rate 1.5mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 0.04% NH3.H2O and mobile phase B (MPB): acetonitrile. Elution: 40% MPB to 70% in 2.80 min, to 95% in 0.20 min, hold at 95% MPB for 0.5 min, change from 95% MPB to 10% in 0.05 min, then equilibrate to 10% MPB for 0.25 min.

[0420] LCMS Method B: HALO C18, 30*3.0 mm, injection volume 0.1 μL, flow rate 1.2 mL / min, scan range 90-900 amu, UV detection 254 nm. Mobile phase A (MPA): water + 0.05% TFA and mobile phase B (MPB): acetonitrile + 0.05% TFA. Elution: 10% MPB to 100% in 1.30 min, hold at 100% MPB for 0.5 min, 100% MPB to 10% in 0.03 min, then equilibrate to 5% MPB for 0.17 min.

[0421] LCMS Method C: XBridge BEH Shield RP, 50*3.0mm, injection volume 0.5μL, flow rate 1.2mL / min, scan range 30~2000amu, UV detection 254nm. Mobile phase A (MPA): water + 5mM NH4HCO3 and mobile phase B (MPB): ACN. Elution: 10% MPB to 95% in 1.29 min, hold at 95% MPB for 0.3 min, change from 95% MPB to 10% in 0.1 min, then equilibrate to 5% MPB for 0.1 min.

[0422] LCMS Method D: XBridge BEH C18, 50*3mm, injection volume 0.7μL, flow rate 1.0mL / min, scan range 30-900amu, UV detection 254nm. Mobile phase A (MPA): water + 5mmol NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 5% MPB to 95% in 0.0.99 min, hold at 95% MPB for 0.7 min, change from 95% MPB to 5% in 0.10 min, then equilibrate to 5% MPB for 0.2 min.

[0423] LCMS Method E: Shim-pack Scepter C18, 50*3mm, injection volume 0.8μL, flow rate 1.5mL / 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% in 2.00min, hold at 95% MPB for 0.60min, change from 95% MPB to 10% in 0.20min, then equilibrate to 10% MPB for 0.20min.

[0424] LCMS Method F: Poroshell HPH-C18, 50*3mm, injection volume 2.7uL, flow rate 1.5mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A: water / 0.04% NH3.H2O and mobile phase B: acetonitrile. 1.0 min: 10% MPB to 95%, hold at 95% MPB for 0.5 min, 0.03 min: 95% MPB to 10%, then equilibrate to 10% MPB for 0.2 min.

[0425] LCMS Method G: Shim-pack XR-ODS, 50*3mm, injection volume 3.0 μL, flow rate 1.2 mL / min, scan range 90-900 amu, UV detection 254 nm. Mobile phase A (MPA): water / 0.05% TFA and mobile phase B (MPB): acetonitrile / 0.05% TFA. Elution: 5% MPB to 100% in 2.00 min, hold at 100% MPB for 0.7 min, change from 100% MPB to 5% in 0.05 min, then equilibrate to 5% MPB for 0.25 min.

[0426] LCMS Method H: EVO C18, 50*3mm, injection volume 2.0 μL, flow rate 1.2 mL / min, scan range 90-900 amu, UV detection 254 nm. Mobile phase A (MPA): water / 5 mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.6 min, change from 95% MPB to 10% in 0.05 min, then equilibrate to 10% MPB for 0.25 min.

[0427] LCMS Method I: Titan C18, 50*3mm, injection volume 2.0 μL, flow rate 1.2 mL / min, scan range 90-900 amu, UV detection 254 nm. Mobile phase A (MPA): water / 5 mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 40% MPB to 70% in 2.80 min, to 95% in 0.20 min, hold at 95% MPB for 0.5 min, change from 95% MPB to 10% in 0.05 min, then equilibrate to 10% MPB for 0.25 min.

[0428] LCMS Method J: Kinetex XB-C18 100A, 30*2.7mm, injection volume 0.6μL, flow rate 1.0mL / min, scan range 90-900amu, 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% in 1.50 min, hold at 100% MPB for 0.8 min, change from 100% MPB to 5% in 0.03 min, then equilibrate to 5% MPB for 0.17 min.

[0429] LCMS Method BA: Kinetex EVO C18 100A, 30*3mm, injection volume 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% in 2.0 min, hold at 95% MPB for 0.30 min, then change from 95% MPB to 10% in 0.10 min.

[0430] LCMS method BB: Xselect CSH C18, 50*3mm, injection volume 1.0 μL, flow rate 1.2 mL / min, scan range 90-900 amu, UV detection 254 nm. Mobile phase A (MPA): water / 0.1% FA and mobile phase B (MPB): acetonitrile / 0.1% FA. Elution: 5% MPB to 100% in 2.00 min, hold at 100% MPB for 0.70 min, change from 100% MPB to 5% in 0.05 min, then equilibrate to 5% MPB for 0.15 min.

[0431] LCMS method BC: XBridge Shield RP18, 50*4.6mm, injection volume 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 0.04% NH3.H2O and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.79 min, change from 95% MPB to 10% in 0.06 min, then equilibrate to 10% MPB for 0.15 min.

[0432] LCMS method: Shim-pack XR-ODS, 50*3mm, injection volume 0.3μL, flow rate 1.2mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 0.05% TFA and mobile phase B (MPB): acetonitrile / 0.05% TFA. Elution: 5% MPB to 100% in 1.10 min, hold at 100% MPB for 0.60 min, change from 100% MPB to 5% in 0.05 min, then equilibrate to 5% MPB for 0.25 min.

[0433] LCMS Method BE: Kinetex 2.6um EVO C18 100A, 50*3mm, injection volume 0.6μL, flow rate 1.2mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% in 1.20 min, hold at 95% MPB for 0.50 min, change from 95% MPB to 10% in 0.05 min, then equilibrate to 10% MPB for 0.10 min.

[0434] LCMS Method BF: EVO C18, 50*3mm, injection volume 0.1μL, flow rate 1.2mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% in 2.00min, hold at 95% MPB for 0.60min, change from 95% MPB to 10% in 0.15min, then equilibrate to 10% MPB for 0.25min.

[0435] LCMS Method BG: Titan C18, 50*3mm, injection volume 0.5μL, flow rate 1.5mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% in 1.80min, hold at 95% MPB for 0.80min, change from 95% MPB to 10% in 0.15min, then equilibrate to 10% MPB for 0.25min.

[0436] LCMS Method BH: Poroshell HPH C18, 50*3mm, injection volume 0.5μL, flow rate 1.2mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 + 5mM NH4OH and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% in 2.00min, hold at 95% MPB for 0.70min, change from 95% MPB to 5% in 0.05min, then equilibrate to 5% MPB for 0.25min.

[0437] LCMS method: HALOC18, 30*3mm, injection volume 0.5μL, flow rate 1.5mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 0.05% TFA and mobile phase B (MPB): acetonitrile / 0.05% TFA. Elution: 5% MPB to 100% in 1.20 min, hold at 100% MPB for 0.60 min, change from 100% MPB to 5% in 0.02 min, then equilibrate to 5% MPB for 0.18 min.

[0438] LCMS Method BJ: HALOC18, 30*3mm, injection volume 0.5μL, flow rate 1.5mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 0.1% FA and mobile phase B (MPB): acetonitrile / 0.1% FA. Elution: 5% MPB to 100% in 1.20 min, hold at 100% MPB for 0.60 min, change from 100% MPB to 5% in 0.02 min, then equilibrate to 5% MPB for 0.18 min.

[0439] 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.

[0440] Preparation example Schemes for the preparation of exemplary intermediates: The following schemes illustrate the preparation of exemplary intermediates.

[0441] Synthesis of Intermediate 1 (1-(3-((tert-butoxycarbonyl)(methyl)amino)cyclobutyl)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid) TIFF2023509421000153.tif80134Step 1: 5-Fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate methyl ester 5-Fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (3.0 g, 16.6 mmol, 1.0 equiv.) was dissolved in THF (50 mL), followed by the addition of HATU (9.5 g, 25.0 mmol, 1.5 equiv.), TEA (7.0 mL, 50.0 mmol, 3.0 equiv.), and MeOH (2.0 mL, 50.0 mmol, 3.0 equiv.). The resulting solution was stirred at rt for 6 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with DCM / methanol (100:1) to give methyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (1.8 g) as a white solid. LCMS Method A, MS-ESI: 195 [M+H] + 。

[0442] Step 2: tert-Butyl (3-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutyl)(methyl)carbamate Methyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (500.0 mg, 2.6 mmol, 1.0 equiv.) and tert-butyl N-(3-hydroxycyclobutyl)-N-methylcarbamate (777.4 mg, 3.9 mmol, 1.5 equiv.) were dissolved in toluene (10 mL), and then 2-(tributyl-λ5-phosphanylidene)acetonitrile (2.5 g, 10.3 mmol, 4.0 equiv.) was added portionwise under nitrogen. The mixture was stirred at 115 °C overnight and then concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN / water, gradient from 0% to 100% in 20 min; detector, UV 254 nm. This gave methyl 1-[3-[(tert-butoxycarbonyl)(methyl)amino]cyclobutyl]-5-fluoropyrrolo[2,3-b]pyridine-3-carboxylate (500 mg) as a yellow solid. LCMS Method C: [M+H] + =378.

[0443] Step 3: 1-(3-((tert-butoxycarbonyl)(methyl)amino)cyclobutyl)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid Methyl 1-[3-[(tert-butoxycarbonyl)(methyl)amino]cyclobutyl]-5-fluoropyrrolo[2,3-b]pyridine-3-carboxylate (400.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in methanol (4 mL) and water (4 mL), and then LiOH (84.8 mg, 2.1 mmol, 2.0 equiv.) was added. The solution was stirred at rt overnight and then concentrated in vacuo. The resulting aqueous layer was adjusted to pH = 5 by dropwise addition of HCl (2N). The solution was extracted with DCM, dried over anhydrous Na2SO4, and concentrated in vacuo to give 1-[3-[(tert-butoxycarbonyl)(methyl)amino]cyclobutyl]-5-fluoropyrrolo[2,3-b]pyridine-3-carboxylic acid (380 mg) as a yellow solid. LCMS Method C: [M+H] + =364.

[0444] Using the same method as described for Intermediate 1, the intermediates in Table E1 were prepared.

[0445] [Table E1]

[0446] Synthesis of Intermediate 4 (1-benzyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid) TIFF2023509421000155.tif29143Step 1: 1-Benzyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate methyl ester Methyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (500.0 mg, 2.5 mmol, 1.0 equiv.) was dissolved in DMF (40 mL), followed by the addition of DBU (411.6 mg, 2.7 mmol, 1.0 equiv.) and benzyl bromide (440.4 mg, 2.5 mmol, 1.0 equiv.). The resulting solution was stirred at ambient temperature for 2 hours and quenched by the addition of water. The mixture was extracted with EtOAc and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with EtOAc / petroleum ether (1:7) to give methyl 1-benzyl-5-fluoropyrrolo[2,3-b]pyridine-3-carboxylate (420 mg) as a white solid. LCMS Method A: TIFF2023509421000156.tif12142

[0447] Step 2: 1-benzyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid Methyl 1-benzyl-5-fluoropyrrolo[2,3-b]pyridine-3-carboxylate (400.0 mg, 1.4 mmol, 1.0 equiv) was dissolved in MeOH (15 mL) and HO (5 mL), and then NaOH (168.8 mg, 4.2 mmol, 3.0 equiv) was added. The resulting solution was stirred at 70 °C for 4 hours and cooled to rt. The solution was adjusted to pH = 6.5 with HCl (2 mol / L), and the solid was collected by filtration to give 1-benzyl-5-fluoropyrrolo[2,3-b]pyridine-3-carboxylic acid (300 mg) as a white solid. LCMS Method A: TIFF2023509421000157.tif19153

[0448] Synthesis of Intermediate 5 (5-Fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid) TIFF2023509421000158.tif27137Step 1: 5-Fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate methyl ester 5-Fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (200.0 mg, 1.0 mmol, 1.0 equiv) was dissolved in THF (10 mL), followed by the addition of NaH (60% wt., 40.0 mg, 1.0 mmol, 1.0 equiv). After 30 minutes, MeI (219.3 mg, 1.5 mmol, 1.5 equiv) was added. The resulting solution was stirred at ambient temperature for 8 hours and quenched with MeOH at 0 °C. After concentration in vacuo, the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; gradient from 10% B to 50% B in 10 minutes; detector, UV 254 nm. This gave methyl 5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (340.0 mg) as a yellow solid. LCMS Method A: [M+H] + =209.

[0449] Step 2: 5-Fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid Methyl 5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (300.0 mg, 1.4 mmol, 1.0 equiv.) was dissolved in MeOH (6 mL), THF (6 mL), and HO (2 mL), followed by the addition of NaOH (288.2 mg, 7.2 mmol, 5.0 equiv.). The solution was stirred at 50 °C overnight, cooled to ambient temperature, and the resulting mixture was adjusted to pH 6-7 with aqueous NaOH (1 mol / L). The solution was extracted with EtOAc and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with petroleum ether / EtOAc (1:1) to give 5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (240.0 mg) as a yellow solid. LCMS Method A: [M+H] + =195.

[0450] Synthesis of Intermediate 6 (6-(4,4-difluorocyclohexyl)pyridin-3-amine) TIFF2023509421000159.tif43134Step 1: 6-(4,4-Difluorocyclohex-1-en-1-yl)pyridin-3-amine 6-Iodopyridin-3-amine (5.0 g, 22.7 mmol, 1.0 equiv.) was dissolved in dioxane (80 mL) and HO (8 mL), followed by the addition of KCO (9.4 g, 68.2 mmol, 3.0 equiv.), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.5 g, 27.3 mmol, 1.2 equiv.), and Pd(dppf)ClCHCl (185.6 mg, 0.2 mmol, 0.1 equiv.) under nitrogen. The resulting solution was stirred at 90 °C for 12 h and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to give 6-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-amine (5.2 g) as a pale yellow solid. LCMS Method H: [M+H] + =211.

[0451] Step 2: 6-(4,4-difluorocyclohexyl)pyridin-3-amine 6-(4,4-Difluorocyclohex-1-en-1-yl)pyridin-3-amine (5.2 g, 14.3 mmol, 1.0 equiv) was dissolved in MeOH (50 mL), then Pd / C (10% wt, 1.5 g, 1.4 mmol, 0.1 equiv) was added. The reaction vessel was evacuated and refilled with hydrogen three times, then stirred under a hydrogen atmosphere for 16 h. Filtration and concentration gave 6-(4,4-difluorocyclohexyl)pyridin-3-amine (4.4 g) as an off-white solid. LCMS Method H: [M+H] + =213.

[0452] Using the same method as described for Intermediate 6, the intermediates in Table E2 were prepared.

[0453] [Table E2]

[0454] Synthesis of Intermediate 9 (Intermediate B1) (5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine) TIFF2023509421000161.tif31165Step 1: 3-chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine 2,3-Dichloro-5-nitropyridine (5.0 g, 26.0 mmol, 1.0 equiv.) and CsCO (42.2 g, 129.5 mmol, 5.0 equiv.) were dissolved in DMF (200 mL), followed by the addition of 4,4-difluoropiperidine (3.8 g, 31.1 mmol, 1.2 equiv.). The resulting solution was stirred at 110 °C 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 sodium sulfate, and concentrated in vacuo. The residue was purified by reverse-phase chromatography under the following conditions: column, C18 silica gel; A: acetonitrile; B: water (0.05% NHOH), 30% B to 60% B in 30 min; detector, UV 254 nm. This gave 3-chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (4.3 g) as a yellow solid. LCMS Method F: [M+H] + =278.

[0455] Step 2: 5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine 3-Chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (2.0 g, 7.2 mmol, 1.0 equiv.) was dissolved in HBr / HO (30 mL), and then SnCl.2HO (3.2 g, 14.4 mmol, 2.0 equiv.) was added. The resulting solution was stirred at ambient temperature for 2 hours. The solution was adjusted to pH 8 with aqueous NaOH (2 mol / L). The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine (2.0 g) as a white solid. LCMS Method A: [M+H] + =248.

[0456] Synthesis of Intermediate 10 (6-Cyclobutoxy-5-fluoropyridin-3-amine) TIFF2023509421000162.tif18159Step 1: 2-Cyclobutoxy-3-fluoro-5-nitropyridine 2-Chloro-3-fluoro-5-nitropyridine (500.0 mg, 2.8 mmol, 1.0 equiv.) and cyclobutanol (306.3 mg, 4.2 mmol, 1.5 equiv.) were dissolved in DMF (20 mL), and then CsCO (1.8 g, 5.7 mmol, 2.0 equiv.) was added. The resulting mixture was stirred at 120 °C overnight and then concentrated in vacuo. The residue was purified by reverse-phase chromatography under the following conditions: column, C18 silica gel; mobile phase, A: water, B: MeOH, 10% B to 50% B in 30 min; detector, UV 254 nm. This gave 2-cyclobutoxy-3-fluoro-5-nitropyridine (500 mg) as a yellow oil. LCMS Method B: [M+H] + =213.

[0457] Step 2: 6-Cyclobutoxy-5-fluoropyridin-3-amine 2-Cyclobutoxy-3-fluoro-5-nitropyridine (700.0 mg, 3.3 mmol, 1.0 equiv) was dissolved in MeOH (15 mL), then Pd / C (10% wt, 200 mg, 0.2 mmol, 0.1 equiv) was added. The reaction vessel was evacuated and refilled with hydrogen three times, then stirred under a hydrogen atmosphere for 8 hours. Filtration and concentration afforded 6-cyclobutoxy-5-fluoropyridin-3-amine (120 mg) as a black solid, which was used without further purification. LCMS Method A: [M+H] + =183.

[0458] Synthesis of Intermediate 12 (1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(6-(4,4-difluorocyclohexyl)pyridin-3-yl)urea) TIFF2023509421000163.tif30153Step 1: 5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl azide 5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (2.0 g, 8.3 mmol, 1.0 equiv.) was dissolved in THF (10 mL), and TEA (1.7 mL, 12.4 mmol, 1.5 equiv.) and DPPA (2.7 mL, 12.4 mmol, 1.5 equiv.) were added. The resulting solution was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to give 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl azide (1.5 g) as a white solid.

[0459] Step 2: 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(6-(4,4-difluorocyclohexyl)pyridin-3-yl)urea 5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl azide (500.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in toluene (3 mL), followed by the addition of TEA (0.5 mL, 3.8 mmol, 2.0 equiv.) and 6-(4,4-difluorocyclohexyl)pyridin-3-amine (478.6 mg, 2.3 mmol, 1.2 equiv.). The resulting solution was stirred at 90° C. for 2 hours 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 3-[5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-1-[6-(4,4-difluorocyclohexyl)pyridin-3-yl]urea (150 mg) as a white solid. LCMS Method B: [M+H] + =450.

[0460] Synthesis of Intermediate B1 (5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine) TIFF2023509421000164.tif27145Step 1: 3-chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine 2,3-Dichloro-5-nitropyridine (600.0 mg, 3.1 mmol, 1.0 equiv.) was dissolved in DMF (30 mL), and CsCO (4.1 g, 12.4 mmol, 4.0 equiv.) and 4,4-difluoropiperidine (375.1 mg, 3.1 mmol, 1.0 equiv.) were added. The reaction mixture was stirred at 60° C. 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 sodium sulfate, and concentrated in vacuo to give 3-chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (420 mg) as a yellow solid. LCMS Method BC: [M+H] + =278.

[0461] Step 2: 5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine 3-Chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (3.4 g, 12.2 mmol, 1.0 equiv.) was dissolved in 40% HBr (10.0 mL), and then SnCl (5.5 g, 29.0 mmol, 2.4 equiv.) was added. The resulting solution was stirred at ambient temperature for 2 hours and adjusted to pH 8 with aqueous NaOH (1 mol / L). The mixture 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 (10:1) to give 5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine (2.8 g) as a brown solid. LCMS Method BC: [M+H] + =248.

[0462] Using the method described for Intermediate B1, the intermediates in the table below were prepared. TIFF2023509421000165.tif105148TIFF2023509421000166.tif186148TIFF2023509421000167.tif212148TIFF20235094210 00168.tif187148TIFF2023509421000169.tif184148TIFF2023509421000170.tif200148TIFF2023509421000171.tif130148

[0463] Synthesis of Intermediate B18 (5-chloro-6-(4,4-difluorocyclohexyl)pyridin-3-amine) TIFF2023509421000172.tif43132Step 1: 5-chloro-6-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-amine 6-Bromo-5-chloropyridin-3-amine (2.0 g, 9.6 mmol, 1.0 equiv.) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.8 g, 11.6 mmol, 1.2 equiv.) were dissolved in dioxane (35 mL) and water (7 mL), followed by the addition of KCO (2.7 g, 19.3 mmol, 2.0 equiv.) and Pd(dppf)Cl (705.4 mg, 1.0 mmol, 0.1 equiv.) under nitrogen. The reaction mixture was heated to 80 °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 (1:1) to give 5-chloro-6-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-amine (2.1 g) as an off-white solid. LCMS Method BA: [M+H] + =245.

[0464] Step 2: 5-chloro-6-(4,4-difluorocyclohexyl)pyridin-3-amine 5-Chloro-6-(4,4-difluorocyclohex-1-en-1-yl)pyridin-3-amine (2.0 g, 8.2 mmol, 1.0 equiv) was dissolved in THF (50 mL), and then Pt / C (1.50 g, 3%) was added. The reaction mixture was a solution, and the reaction mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then heated to 80° C. for 36 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 5-chloro-6-(4,4-difluorocyclohexyl)pyridin-3-amine (300 mg) as a pale yellow solid. LCMS Method BE: [M+H] + =247.

[0465] Using the method described for intermediate B18, the intermediates in the following table were prepared. TIFF2023509421000173.tif64147TIFF2023509421000174.tif227147TIFF2023509421000175.tif88147

[0466] Synthesis of intermediate B24 (4-(3,3-difluorocyclobutyl)-3-fluoroaniline) TIFF2023509421000176.tif47152Step 1: 4-Bromo-1-(3,3-difluorocyclobutyl)-2-fluorobenzene 3-(4-Bromo-2-fluorophenyl)cyclobutan-1-one (1.3 g, 5.3 mmol, 1.0 equiv) was dissolved in DAST (30 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at ambient temperature overnight, then cooled to 0 °C and quenched by the addition of aqueous NaHCO. The resulting mixture was extracted with DCM, 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 4-bromo-1-(3,3-difluorocyclobutyl)-2-fluorobenzene (1.1 g) as a yellow oil. TIFF2023509421000177.tif18153

[0467] Step 2: tert-Butyl (4-(3,3-difluorocyclobutyl)-3-fluorophenyl)carbamate 4-Bromo-1-(3,3-difluorocyclobutyl)-2-fluorobenzene (1.1 g, 4.2 mmol, 1.0 equiv.) and BocNH (2.4 g, 20.7 mmol, 5.0 equiv.) were dissolved in toluene (11 mL). Pd(dba) (0.4 g, 0.4 mmol, 0.1 equiv.), XPhos (0.4 g, 0.8 mmol, 0.2 equiv.), and t-BuOK (2.3 g, 20.7 mmol, 5.0 equiv.) were added under a nitrogen atmosphere. The reaction mixture was heated to 100 °C overnight, cooled to ambient temperature, and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, 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 (1:8) to give tert-butyl [4-(3,3-difluorocyclobutyl)-3-fluorophenyl]carbamate (1.0 g) as a white solid. LCMS Method BA: [M+H] + =302.

[0468] Step 3: 4-(3,3-difluorocyclobutyl)-3-fluoroaniline Tert-Butyl [4-(3,3-difluorocyclobutyl)-3-fluorophenyl]carbamate (1.2 g, 4.0 mmol, 1.0 equiv) was dissolved in DCM (12 mL) and cooled to 0 °C, then TFA (3 mL) was added dropwise while maintaining the solution at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h and then concentrated in vacuo. The residue was dissolved in DCM and adjusted to pH 8 with aqueous NaHCO3. The resulting solution was extracted with DCM, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give crude 4-(3,3-difluorocyclobutyl)-3-fluoroaniline (800 mg) as a red oil. LCMS Method BA: [M+H] + =202.

[0469] Synthesis of Intermediate B25 (6-(4,4-difluoropiperidin-1-yl)pyridazin-3-amine) TIFF2023509421000178.tif27128 4,4-Difluoropiperidine (1.0 g, 8.3 mmol, 1.0 equiv.) was dissolved in EtOH (10 mL), and then 6-bromopyridazin-3-amine (1.4 g, 8.3 mmol, 1.0 equiv.) was added. The reaction mixture was heated to 80 °C overnight and concentrated in vacuo. The residue was purified by reverse-phase chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN / water, increasing from 0% ACN to 100% within 30 min; detector, UV 254 nm. This afforded 6-(4,4-difluoropiperidin-1-yl)pyridazin-3-amine (410 mg) as a brown solid. LCMS Method BD: [M+H] + =215.

[0470] Synthesis of Intermediate B27 (4-chloro-5-(4,4-difluoropiperidin-1-yl)pyridin-2-amine) TIFF2023509421000179.tif89165Step 1: 4-chloro-5-(4,4-difluoropiperidin-1-yl)picolinate methyl ester Methyl 5-bromo-4-chloropyridine-2-carboxylate (1.0 g, 3.9 mmol, 1.0 equiv.) was dissolved in dioxane (10 mL), followed by the addition of CsCO (2.6 g, 7.9 mmol, 2.0 equiv.), BINAP (248.5 mg, 0.4 mmol, 0.1 equiv.), Binap Palladacycle Gen. 2 (0.3 mg, 0.1 equiv.), and 4,4-difluoropiperidine (967.2 mg, 7.9 mmol, 2.0 equiv.) under a nitrogen atmosphere. The resulting solution was heated to 100° C. for 7 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 (1:3) to give methyl 4-chloro-5-(4,4-difluoropiperidin-1-yl)pyridine-2-carboxylate (711.2 mg) as a yellow solid. LCMS Method BA: [M+H] + =291.

[0471] Step 2: 4-chloro-5-(4,4-difluoropiperidin-1-yl)pyridine-2-carboxylic acid Methyl 4-chloro-5-(4,4-difluoropiperidin-1-yl)pyridine-2-carboxylate (700.0 mg, 2.4 mmol, 1.0 equiv.) was dissolved in MeOH (5 mL) and water (2 mL), and then LiOH (288.3 mg, 12.0 mmol, 5.0 equiv.) was added. The reaction mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo. The residue was diluted with water, and the solution was then adjusted to pH 5 with aqueous HCl (3 M). The solid was collected by filtration and dried to give 4-chloro-5-(4,4-difluoropiperidin-1-yl)pyridine-2-carboxylic acid (500.0 mg) as an off-white solid. LCMS Method BA: [MH] - =275.

[0472] Step 3: 4-chloro-5-(4,4-difluoropiperidin-1-yl)picolinoyl azide 4-Chloro-5-(4,4-difluoropiperidin-1-yl)pyridine-2-carboxylic acid (450.0 mg, 1.6 mmol, 1.0 equiv.) was dissolved in THF (5 mL), followed by the addition of TEA (0.5 mL, 3.5 mmol, 2.2 equiv.) and DPPA (671.4 mg, 2.4 mmol, 1.5 equiv.). The resulting mixture was stirred at ambient temperature for 6 hours and then concentrated in vacuo. This afforded 4-chloro-5-(4,4-difluoropiperidin-1-yl)picolinoyl azide (350.0 mg) as an off-white solid. LCMS Method BC: [M+H] + =302.

[0473] Step 4: tert-butyl (4-chloro-5-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)carbamate 4-Chloro-5-(4,4-difluoropiperidin-1-yl)pyridine-2-carbonyl azide (300.0 mg, 0.9 mmol, 1.0 equiv) was dissolved in t-BuOH (3 mL). The resulting solution was heated to 90° C. for 3 hours and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to give tert-butyl (4-chloro-5-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)carbamate (250.0 mg) as an off-white solid. LCMS Method BC: [M+H] + =348.

[0474] Step 5: 4-chloro-5-(4,4-difluoropiperidin-1-yl)pyridin-2-amine Tert-butyl [4-chloro-5-(4,4-difluoropiperidin-1-yl)pyridin-2-yl]carbamate (250.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in BF3.Et2O (3.0 mL). The resulting solution was stirred at ambient temperature for 3 hours and then quenched by the addition of water. The resulting solution was adjusted to pH 7 with aqueous NaOH (3 M). The resulting solution was extracted with DCM, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 4-chloro-5-(4,4-difluoropiperidin-1-yl)pyridin-2-amine (180.0 mg) as an off-white solid. LCMS Method BC: [M+H] + =248.

[0475] The following intermediates were prepared using the method described for intermediate B27. TIFF2023509421000180.tif57169

[0476] Synthesis of Intermediate B29 (4-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine) TIFF2023509421000181.tif58163Step 1: 2-(4,4-Difluoropiperidin-1-yl)-5-nitropyridin-4-amine 2-Chloro-5-nitropyridin-4-amine (1.0 g, 5.8 mmol, 1.0 equiv.) and 4,4-difluoropiperidine (1.1 g, 9.1 mmol, 2.0 equiv.) were dissolved in DMF (50 mL), followed by the addition of K2CO3 (2.4 g, 17.4 mmol, 3.0 equiv.). The reaction mixture was heated to 100 °C 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 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 2-(4,4-difluoropiperidin-1-yl)-5-nitropyridin-4-amine (949.2 mg) as an off-white solid. LCMS Method BA: [M+H] + =259.

[0477] Step 2: 4-chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine 2-(4,4-Difluoropiperidin-1-yl)-5-nitropyridin-4-amine (750.0 mg, 2.9 mmol, 1.0 equiv) was dissolved in aqueous HCl (6 M, 20 ml) and cooled to 0 °C. NaNO (550.0 mg, 8.0 mmol, 2.7 equiv) was then added while maintaining the solution at 0 °C. After 20 min at 0 °C, CuCl (781.5 mg, 5.8 mmol, 2.0 equiv) was added. The reaction mixture was stirred at 0 °C for an additional 1 h and then quenched by the addition of water. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 4-chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (220.0 mg) as an off-white solid. LCMS Method BA: [M+H] + =278.

[0478] Step 3: 4-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine 4-Chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (200.0 mg, 0.7 mmol, 1.0 equiv) was dissolved in aqueous HBr (40%, 20 ml) and cooled to 0 °C. SnCl2.2H2O (914.0 mg, 4.1 mmol, 5.8 equiv) was then added, and the solution was maintained at 0 °C. The reaction mixture was stirred at ambient temperature for 1 hour and concentrated in vacuo. The residue was diluted with water and adjusted to pH 8 with aqueous NaOH (4 M). The resulting mixture 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 ethyl acetate / petroleum ether (1:3) to give 4-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine (126.4 mg) as an off-white solid. LCMS Method BC: [M+H] + =248.

[0479] Synthesis of Intermediate B30 (5-(4,4-difluorocyclohexyl)-4-methoxypyridin-2-amine) TIFF2023509421000182.tif86150Step 1: 5-(4,4-difluorocyclohex-1-en-1-yl)-4-methoxypicolinate methyl ester Methyl 5-bromo-4-hydroxypyridine-2-carboxylate (1.5 g, 6.5 mmol, 1.0 equiv.) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.7 g, 19.4 mmol, 3.0 equiv.) were dissolved in 1,4-dioxane (15 mL) and water (1.5 mL), followed by the addition of Pd(dppf)Cl (0.5 g, 0.6 mmol, 0.1 equiv.) and NaCO (2.1 g, 19.4 mmol, 3.0 equiv.). The reaction mixture was heated to 70 °C overnight and then quenched by the addition of water. The resulting 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 methyl 5-(4,4-difluorocyclohex-1-en-1-yl)-4-hydroxypyridine-2-carboxylate (1.1 g) as a white solid. LCMS Method BD: [M+H] + =284.

[0480] Step 2: methyl 5-(4,4-difluorocyclohexyl)-4-methoxypicolinate Methyl 5-(4,4-difluorocyclohex-1-en-1-yl)-4-methoxypyridine-2-carboxylate (6.0 g, 21.2 mmol, 1.0 equiv.) was dissolved in ethyl acetate (60 mL), followed by the addition of Pd / C (10% wt., 1.2 g). The reaction mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature overnight. The solids were removed by filtration, and the filtrate was concentrated in vacuo to give methyl 5-(4,4-difluorocyclohexyl)-4-methoxypyridine-2-carboxylate (5.3 g) as an off-white solid. LCMS Method BD: [M+H] + =286.

[0481] Step 3: 5-(4,4-difluorocyclohexyl)-4-methoxypicolinic acid Methyl 5-(4,4-difluorocyclohexyl)-4-methoxypicolinate (800.0 mg, 2.8 mmol, 1.0 equiv.) was dissolved in MeOH (8 mL) and water (8 mL), and then NaOH (449.0 mg, 11.2 mmol, 4.0 equiv.) was added. The reaction mixture was stirred at ambient temperature overnight and then concentrated in vacuo. The residue was diluted with water, and the solution was adjusted to pH 6 with aqueous HCl (6 M). The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting solid was washed with ACN and dried to give 5-(4,4-difluorocyclohexyl)-4-methoxypicolinic acid (450.0 mg) as a white solid. LCMS Method BA: [M+H] + =272.

[0482] Step 4: tert-butyl (5-(4,4-difluorocyclohexyl)-4-methoxypyridin-2-yl)carbamate 5-(4,4-Difluorocyclohexyl)-4-methoxypicolinic acid (830.0 mg, 3.1 mmol, 1.0 equiv.) and TEA (0.5 mL, 3.7 mmol, 1.2 equiv.) were dissolved in t-BuOH (9 mL), and then DPPA (1.0 mg, 3.7 mmol, 1.2 equiv.) was added portionwise. The reaction mixture was heated to 90° C. overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting 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 DCM / MeOH (50:1) to give tert-butyl (5-(4,4-difluorocyclohexyl)-4-methoxypyridin-2-yl)carbamate (612.5 mg) as a white solid. LCMS Method BA: [M+H] + =343.

[0483] Step 5: 5-(4,4-difluorocyclohexyl)-4-methoxypyridin-2-amine tert-Butyl (5-(4,4-difluorocyclohexyl)-4-methoxypyridin-2-yl)carbamate (240.0 mg, 0.7 mmol, 1.0 equiv) was dissolved in DCM (4 mL) and cooled to 0 °C, then TFA (1 mL) was added dropwise while maintaining the solution at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h and concentrated in vacuo. The residue was diluted with water and then adjusted to pH 7 with saturated aqueous NaHCO3. 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 DCM / MeOH (20:1) to give 5-(4,4-difluorocyclohexyl)-4-methoxypyridin-2-amine (152.5 mg) as a brown solid. LCMS Method BA: [M+H] + =243.

[0484] Synthesis of Intermediate B31 (4-chloro-5-(4,4-difluorocyclohexyl)pyridin-2-amine) TIFF2023509421000183.tif75149Step 1: 4-chloro-5-(4,4-difluorocyclohexyl) methyl picolinate Methyl 5-(4,4-difluorocyclohexyl)-4-methoxypyridine-2-carboxylate (0.8 g, 2.6 mmol, 1.0 equiv.) was dissolved in toluene (30 mL) and DMF (1 mL) and cooled to 0 °C. POCl (1.1 mL, 13.1 mmol, 5.0 equiv.) was then added dropwise while maintaining the temperature at 0 °C. The reaction mixture was heated to 90 °C overnight, then cooled to 0 °C and quenched by the addition of ice water. The mixture was adjusted to pH 8 with saturated aqueous NaHCO, then 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 (1:3) to give methyl 4-chloro-5-(4,4-difluorocyclohexyl)pyridine-2-carboxylate (355.0 mg) as a white solid. LCMS Method BD: [M+H] + =290.

[0485] Step 2: 4-chloro-5-(4,4-difluorocyclohexyl)picolinic acid Methyl 4-chloro-5-(4,4-difluorocyclohexyl)pyridine-2-carboxylate (2.0 g, 6.9 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL) and water (20 mL), and then NaOH (1.1 g, 27.6 mmol, 4.0 equiv.) was added. The reaction mixture was stirred at ambient temperature overnight and concentrated in vacuo. The residue was diluted with water and then adjusted to pH 5 with aqueous HCl (6 M). The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give 4-chloro-5-(4,4-difluorocyclohexyl)pyridine-2-carboxylic acid (705.1 mg) as a white solid. LCMS Method BB: [MH] - =274.

[0486] Step 3: 4-chloro-5-(4,4-difluorocyclohexyl)picolinoyl azide 4-Chloro-5-(4,4-difluorocyclohexyl)pyridine-2-carboxylic acid (430.0 mg, 1.6 mmol, 1.0 equiv.) and TEA (189 mg, 1.9 mmol, 1.2 equiv.) were dissolved in toluene (6 mL), followed by the addition of DPPA (515.0 mg, 1.9 mmol, 1.2 equiv.). 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 saturated aqueous NaHCO3, dried over anhydrous Na2SO4, and concentrated in vacuo to give 4-chloro-5-(4,4-difluorocyclohexyl)pyridine-2-carbonyl azide (400.0 mg) as a light brown solid. LCMS Method BD: [M+H] + =301.

[0487] Step 4: tert-butyl (4-chloro-5-(4,4-difluorocyclohexyl)pyridin-2-yl)carbamate 4-Chloro-5-(4,4-difluorocyclohexyl)pyridine-2-carbonyl azide (400.0 mg, 1.3 mmol, 1.0 equiv) was dissolved in t-BuOH (4 mL). The solution was heated to 90° C. overnight. The precipitated solid was collected by filtration and washed with ethyl acetate to give tert-butyl N-[4-chloro-5-(4,4-difluorocyclohexyl)pyridin-2-yl]carbamate (380 mg) as a white solid. LCMS Method BD: [M+H] + =347.

[0488] Step 5: 4-chloro-5-(4,4-difluorocyclohexyl)pyridin-2-amine tert-Butyl N-[4-chloro-5-(4,4-difluorocyclohexyl)pyridin-2-yl]carbamate (190.0 mg, 0.5 mmol, 1.0 equiv) was dissolved in DCM (2 mL) and TFA (0.5 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in water and adjusted to pH = 7 with saturated aqueous NaHCO3. The resulting 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 DCM / MeOH (20:1) to give 4-chloro-5-(4,4-difluorocyclohexyl)pyridin-2-amine (130 mg) as a pale yellow solid. LCMS Method BD: [M+H] + =247.

[0489] Synthesis of Intermediate B32 (5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-amine) TIFF2023509421000184.tif84159Step 1: tert-Butyl 3,3-difluorocyclobutane-1-carboxylate 3,3-Difluorocyclobutanecarboxylic acid (1.0 g, 7.3 mmol, 1.0 equiv.) was dissolved in DCM (10 mL), and N,N-dimethylpyridin-4-amine (92.0 mg, 0.7 mmol, 0.1 equiv.), 2-methylpropan-2-ol (1.1 g, 14.7 mmol, 2.0 equiv.), and N,N'-dicyclohexylcarbodiimide (1.7 g, 8.1 mmol, 1.1 equiv.) were added at 10 °C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The solids were removed by filtration, and the filtrate was washed with aqueous HCl (2 N), saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give crude tert-butyl 3,3-difluorocyclobutane-1-carboxylate (896.1 mg) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ 2.83-2.78 (m, 5H), 1.47 (s, 9H).

[0490] Step 2: tert-butyl 1-(3-chloropyridin-2-yl)-3,3-difluorocyclobutane-1-carboxylate 3-Chloro-2-fluoropyridine (1.2 g, 10.4 mmol, 1.0 equiv.) and tert-butyl 3,3-difluorocyclobutane-1-carboxylate (2.0 g, 10.4 mmol, 1.0 equiv.) were dissolved in toluene (60 mL). Next, with stirring at 0°C, NaHMDS (2 M in THF, 6.2 mL, 12.4 mmol, 1.2 equiv.) was added dropwise over 10 minutes. The resulting solution was stirred at 0°C for 2 hours and then quenched by the addition of saturated aqueous NH4Cl. The resulting solution was extracted with ethyl acetate, 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 (1:5) to give tert-butyl 1-(3-chloropyridin-2-yl)-3,3-difluorocyclobutane-1-carboxylate (1.6 g) as a colorless oil. LCMS method BD:[M+H] + =304.

[0491] Step 3: 3-chloro-2-(3,3-difluorocyclobutyl)pyridine tert-Butyl 1-(3-chloropyridin-2-yl)-3,3-difluorocyclobutane-1-carboxylate (1.5 g, 5.2 mmol, 1.0 equiv.) was dissolved in DCM (30 mL) and TFA (3 ml). The resulting solution was stirred at ambient temperature for 10 hours and then concentrated under vacuum. The residue was dissolved in toluene (30 mL) and stirred at 90° C. for 18 hours. After cooling to ambient temperature and quenching by the addition of water, the pH value of the solution was adjusted to 7.5 with saturated aqueous Na2CO3 solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:7) to give 3-chloro-2-(3,3-difluorocyclobutyl)pyridine (700 mg) as a colorless oil. LCMS Method BD: TIFF2023509421000185.tif19152

[0492] Step 4: 3-chloro-2-(3,3-difluorocyclobutyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 3-Chloro-2-(3,3-difluorocyclobutyl)pyridine (700.0 mg, 3.7 mmol, 1.0 equiv.) was dissolved in heptane (30 mL), and bis(pinacolato)diborane (1.1 g, 4.4 mmol, 1.2 equiv.), 4,4-di-tert-butyl-2,2-dipyridyl (1.0 g, 3.7 mmol, 1.0 equiv.), and di-methanolatodiiridium(Ir-Ir)-cycloocta-1,5-diene (1:2) (495.8 mg, 0.7 mmol, 0.2 equiv.) were added under a nitrogen atmosphere. The resulting solution was stirred at ambient temperature for 18 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, 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 (1:5) to give 3-chloro-2-(3,3-difluorocyclobutyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300 mg) as a white solid. LCMS Method BD: [M+H] + =330.

[0493] Step 5: 5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-ol 3-Chloro-2-(3,3-difluorocyclobutyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (300.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL) and HO (3 mL). HO (30%, 0.14 mL, 1.4 mmol, 1.5 equiv.) was then added. The resulting solution was stirred at ambient temperature for 30 minutes and then quenched by the addition of saturated aqueous NaSO. The resulting solution was extracted with ethyl acetate, 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 5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-ol (160 mg) as a white solid. LCMS Method BD: TIFF2023509421000186.tif12128

[0494] Step 6: 5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl trifluoromethanesulfonate 5-Chloro-6-(3,3-difluorocyclobutyl)pyridin-3-ol (160.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in DCM (20 mL), and TEA (0.1 mL, 0.9 mmol, 1.2 equiv.) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonyl methanesulfonamide (309.4 mg, 0.8 mmol, 1.1 equiv.) were added. The resulting solution was stirred at ambient temperature for 30 minutes and then quenched by the addition of water. The solution was extracted with ethyl acetate, 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 (1:8) to give 5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl trifluoromethanesulfonate (220 mg) as a white solid. LCMS Method BD: [M+H] + =352.

[0495] Step 7: tert-Butyl (5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl)carbamate 5-Chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl trifluoromethanesulfonate (220.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (30 mL). NHBoc (230.3 mg, 1.9 mmol, 3.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (75.8 mg, 0.1 mmol, 0.2 equiv.), and Pd(dba) (120.1 mg, 0.1 mmol, 0.2 equiv.) were then added under a nitrogen atmosphere. The resulting solution was stirred at 90 °C under a nitrogen atmosphere for 3 hours and then 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-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl)carbamate (120 mg) as a white solid. LCMS Method BD: [M+H] + =319.

[0496] Step 8: 5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-amine tert-Butyl (5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl)carbamate (120.0 mg, 0.3 mmol, 1.0 equiv) was dissolved in DCM (10 mL) and TFA (2 ml). The resulting solution was stirred at ambient temperature for 30 minutes and then diluted with water. The pH of the solution was adjusted to 7.5 with saturated aqueous Na2CO3 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to give 5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-amine (60 mg) as a white solid. LCMS Method BD: [M+H] + =219.

[0497] Synthesis of Intermediate B33 (6-(3,3-difluorocyclobutyl)pyridin-3-amine) TIFF2023509421000187.tif41150 Step 1: tert-Butyl (6-(3,3-difluorocyclobutyl)pyridin-3-yl)carbamate tert-Butyl [5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-yl]carbamate (800.0 mg, 2.5 mmol, 1.0 equiv) was dissolved in MeOH (8 mL), and then Pd / C (267.1 mg, 10 wt%) was added under nitrogen. The mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and stirred at ambient temperature overnight. The solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel column eluted with ethyl acetate / petroleum ether (1:1) to afford tert-butyl (6-(3,3-difluorocyclobutyl)pyridin-3-yl)carbamate (500.0 mg) as an off-white solid. LCMS Method BA: [M+H] + =285.

[0498] Step 2: 6-(3,3-difluorocyclobutyl)pyridin-3-amine Tert-Butyl [6-(3,3-difluorocyclobutyl)pyridin-3-yl]carbamate (500.0 mg, 1.7 mmol, 1.0 equiv) was dissolved in DCM (5 mL) and cooled to 0 °C, then TFA (1.0 mL) was added while maintaining the solution at 0 °C. The reaction mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo. The residue was diluted with water, and the solution was adjusted to pH 7 with aqueous NaOH (3 mol / L). The resulting solution was extracted with DCM, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give 6-(3,3-difluorocyclobutyl)pyridin-3-amine (250.0 mg) as a yellow oil. LCMS Method BC: [M+H] + =185.

[0499] Synthesis of Intermediate B34 (6-(4,4-difluoropiperidin-1-yl)-5-ethylpyridin-3-amine) TIFF2023509421000188.tif28157Step 1: 6-(4,4-Difluoropiperidin-1-yl)-5-ethenylpyridin-3-amine 5-Chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine (3.0 g, 12.1 mmol, 1.0 equiv.) and KPO (5.1 g, 24.2 mmol, 2.0 equiv.) were dissolved in 1,4-dioxane (60 mL) and water (6 mL), and then Xphos Pd G (1.0 g, 1.2 mmol, 0.1 equiv.) and XPhos (577.4 mg, 1.2 mmol, 0.1 equiv.) were added under a nitrogen atmosphere. The resulting mixture was heated to 90 °C overnight, then cooled to ambient temperature and quenched by the addition of water. The resulting 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 6-(4,4-difluoropiperidin-1-yl)-5-ethenylpyridin-3-amine (5.1 g) as a yellow solid. LCMS Method BD: TIFF2023509421000189.tif20153

[0500] Step 2: 6-(4,4-difluoropiperidin-1-yl)-5-ethylpyridin-3-amine 6-(4,4-Difluoropiperidin-1-yl)-5-ethenylpyridin-3-amine (1.2 g, 2.5 mmol, 1.0 equiv.) was dissolved in THF (12 mL), and then Pd / C (0.2 g, 2.5 mmol, 1.0 equiv.) was added. The mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and stirred at ambient temperature overnight. The solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 6-(4,4-difluoropiperidin-1-yl)-5-ethylpyridin-3-amine (860 mg) as a dark yellow solid. LCMS Method BD: TIFF2023509421000190.tif12134

[0501] Synthesis of Intermediate B35 and Intermediate B36 (2-(5-amino-2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)ethan-1-ol and 1-(5-amino-2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)ethan-1-ol) TIFF2023509421000191.tif301506-(4,4-Difluoropiperidin-1-yl)-5-ethenylpyridin-3-amine (2.0 g, 8.4 mmol, 1.0 equiv.) was dissolved in THF (40 mL) and cooled to 0 °C. BH3.THF (1 M, 16.7 mL, 16.7 mmol, 2.0 equiv.) was then added dropwise while maintaining the solution at 0 °C. The resulting mixture was stirred at ambient temperature for 3 h. To the above mixture was added NaOH (5.0 g, 12.5 mmol, 1.5 equiv.) and HO2 (30%, 1.3 mL, 16.7 mmol, 2.0 equiv.). The resulting mixture was stirred at ambient temperature for an additional 4 h and quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18; mobile phase A: water / 0.1% NHHCO, mobile phase B: ACN; flow rate: 100 mL / min; gradient: 5% B to 35% B in 30 min; 254 nm. This gave 2-[5-amino-2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl]ethanol (first peak, 740 mg) as a yellow solid and 1-[5-amino-2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl]ethanol (second peak, 540 mg) as a yellow solid.

[0502] Intermediate B35: LCMS method BA: TIFF2023509421000192.tif19153

[0503] Intermediate B36: LCMS method BA: TIFF2023509421000193.tif19153

[0504] Synthesis of Intermediate B37 ((5-amino-2-(4,4-difluorocyclohexyl)pyridin-3-yl)methanol) TIFF2023509421000194.tif62145Step 1: Methyl 2-(4,4-difluorocyclohex-1-en-1-yl)-5-nitronicotinate 2-Chloro-5-nitropyridine-3-carboxylate (1.0 g, 4.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (30 mL) and water (5 mL), followed by the addition of KCO (1.0 g, 7.2 mmol, 1.5 equiv.), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.4 g, 5.7 mmol, 1.2 equiv.), and Pd(dppf)Cl (0.7 g, 1.0 mmol, 0.2 equiv.) under a nitrogen atmosphere. The resulting solution was heated to 90 °C for 2 h and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:6) to give methyl 2-(4,4-difluorocyclohex-1-en-1-yl)-5-nitropyridine-3-carboxylate (700 mg) as a white solid. LCMS Method BA: [M+H] + =299.

[0505] Step 2: methyl 5-amino-2-(4,4-difluorocyclohexyl)nicotinate 2-(4,4-Difluorocyclohex-1-en-1-yl)-5-nitropyridine-3-carboxylate (700.0 mg, 2.3 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL), followed by the addition of Pd / C (70.0 mg, 0.7 mmol, 0.3 equiv.) and AcOH (28.2 mg, 0.5 mmol, 0.2 equiv.). The reaction mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature for 3 days. 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 afford methyl 5-amino-2-(4,4-difluorocyclohexyl)pyridine-3-carboxylate (350 mg) as a white solid. LCMS Method BC: [M+H] + =271.

[0506] Step 3: (5-amino-2-(4,4-difluorocyclohexyl)pyridin-3-yl)methanol 5-Amino-2-(4,4-difluorocyclohexyl)pyridine-3-carboxylate (300.0 mg, 1.1 mmol, 1.0 equiv) was dissolved in THF (20 mL) and cooled to 0 °C. LiAlH (189.6 mg, 5.0 mmol, 4.5 equiv) was then added while maintaining the solution at 0 °C. The resulting solution was stirred at 0 °C for 10 min and then quenched by the addition of aqueous HCl (1 M). The solution was adjusted to pH 7 with aqueous NaCO. The resulting solution was extracted with DCM 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-amino-2-(4,4-difluorocyclohexyl)pyridin-3-yl]methanol (200 mg) as a white solid. LCMS Method BC: [M+H] + =243.

[0507] Synthesis of Intermediate B38 (5-amino-2-(4,4-difluoropiperidin-1-yl)nicotinonitrile) TIFF2023509421000195.tif291355-Chloro-6-(4,4-difluorocyclohexyl)pyridin-3-amine (300.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in DMF (20 mL), followed by P(t-Bu)3 Palladium Cycle Gen. 3 (69.5 mg, 0.1 mmol, 0.1 equiv.), P(t-Bu)3 . HBF (35.2 mg, 0.1 mmol, 0.1 equiv), Zn(CN) (285.6 mg, 2.4 mmol, 2.0 equiv), and Zn (11.9 mg, 0.2 mmol, 0.2 equiv) were added under a nitrogen atmosphere. The resulting mixture was heated to 120° C. overnight and then quenched with NHOH. The resulting 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 (1:2) to give 5-amino-2-(4,4-difluorocyclohexyl)pyridine-3-carbonitrile (160 mg) as a colorless oil. LCMS Method BD: TIFF2023509421000196.tif12128

[0508] Using the method described for intermediate 38, the following intermediates were prepared: TIFF2023509421000197.tif43159

[0509] Synthesis of Intermediate B42 (1-acetyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid) TIFF2023509421000198.tif291285-Fluoro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (500.0 mg, 2.8 mmol, 1.0 equiv.) and TEA (1.2 mL, 8.3 mmol, 3.0 equiv.) were dissolved in THF (50 mL), followed by the addition of AcCl (0.6 mL, 8.3 mmol, 3.0 equiv.). The reaction mixture was stirred at ambient temperature for 16 hours and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:10) to give 1-acetyl-5-fluoropyrrolo[2,3-b]pyridine-3-carboxylic acid (500.0 mg) as a yellow solid. LCMS Method BC: [M+H] + =223.

[0510] Synthesis of Intermediate B43 (5-chloro-1H-pyrrolo[3,2-b]pyridin-3-amine) TIFF2023509421000199.tif23143Step 1: 5-Chloro-3-nitro-1H-pyrrolo[3,2-b]pyridine 5-Chloro-1H-pyrrolo[3,2-b]pyridine (3.0 g, 19.7 mmol, 1.0 equiv) was dissolved in concentrated HSO (5 mL) and cooled to 0 °C, then KNO (2.4 g, 23.8 mmol, 1.2 equiv) was added portionwise 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 water. The resulting solution was adjusted to pH 9 with saturated aqueous NaHCO. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give 5-chloro-3-nitro-1H-pyrrolo[3,2-b]pyridine (3.1 g) as a yellow solid. LCMS Method BA: [M+H] + =198.

[0511] Step 2: 5-chloro-1H-pyrrolo[3,2-b]pyridin-3-amine 5-Chloro-3-nitro-1H-pyrrolo[3,2-b]pyridine (1.0 g, 5.1 mmol, 1.0 equiv) was dissolved in aqueous HBr (40%, 25 mL), and then SnCl.2H0 (6.7 g, 35.4 mmol, 7.0 equiv) was added. The reaction mixture was stirred at ambient temperature for 3 hours and then adjusted to pH 9 with saturated aqueous NaHCO. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give 5-chloro-1H-pyrrolo[3,2-b]pyridin-3-amine (850.0 mg) as a dark green solid. LCMS Method BC: [M+H] + =168.

[0512] The following intermediates were prepared using the method described for intermediate B43. TIFF2023509421000200.tif184144

[0513] Synthesis of Intermediate B50 (5-(4-ethylpiperazin-1-yl)-1H-pyrrolo[3,2-b]pyridin-3-amine) TIFF2023509421000201.tif59161 Step 1: tert-Butyl 4-[3-nitro-1H-pyrrolo[3,2-b]pyridin-5-yl]piperazine-1-carboxylate tert-Butyl 4-[1H-pyrrolo[3,2-b]pyridin-5-yl]piperazine-1-carboxylate (500.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in ACN (30 mL), and AgNO (421.3 mg, 2.5 mmol, 1.5 equiv.) and benzoyl chloride (348.7 mg, 2.5 mmol, 1.5 equiv.) were added. The reaction mixture was stirred at ambient temperature for 8 hours and then quenched by the addition of water. The resulting solution was adjusted to pH 10 with NaCO (2 M). 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 (1:3) to give tert-butyl 4-[3-nitro-1H-pyrrolo[3,2-b]pyridin-5-yl]piperazine-1-carboxylate (311.2 mg) as a yellow solid. LCMS Method BF: [M+H] + =348.

[0514] Step 2: 3-nitro-5-(piperazin-1-yl)-1H-pyrrolo[3,2-b]pyridine tert-Butyl 4-[3-nitro-1H-pyrrolo[3,2-b]pyridin-5-yl]piperazine-1-carboxylate (700.0 mg, 2.0 mmol, 1.0 equiv.) was dissolved in DCM (30 mL), and then TFA (0.8 mL, 10.1 mmol, 5.0 equiv.) was added. The reaction mixture was stirred at room temperature for 5 hours and then concentrated in vacuo to give 3-nitro-5-(piperazin-1-yl)-1H-pyrrolo[3,2-b]pyridine TFA salt (521.5 mg) as a yellow solid. LCMS Method BF: [M+H] + =248.

[0515] Step 3: 1-Ethyl-4-[3-nitro-1H-pyrrolo[3,2-b]pyridin-5-yl]piperazine 3-Nitro-5-(piperazin-1-yl)-1H-pyrrolo[3,2-b]pyridine TFA salt (500.0 mg, 1.4 mmol, 1.0 equiv.) and acetaldehyde (95.7 mg, 2.2 mmol, 1.5 equiv.) were dissolved in MeOH (30 mL), followed by the addition of NaBH (109.6 mg, 2.9 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 5 hours 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 1-ethyl-4-[3-nitro-1H-pyrrolo[3,2-b]pyridin-5-yl]piperazine (400 mg) as a yellow solid. LCMS Method BF: [M+H] + =276.

[0516] Step 4: 5-(4-ethylpiperazin-1-yl)-1H-pyrrolo[3,2-b]pyridin-3-amine 1-Ethyl-4-[3-nitro-1H-pyrrolo[3,2-b]pyridin-5-yl]piperazine (400.0 mg, 1.5 mmol, 1.0 equiv) was dissolved in MeOH (30 mL), and then Pt / C (56.9 mg, 3%) was added under nitrogen. The reaction mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (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 a silica gel column eluted with ethyl acetate / petroleum ether (1:3) to give 5-(4-ethylpiperazin-1-yl)-1H-pyrrolo[3,2-b]pyridin-3-amine (255.2 mg) as a pale yellow solid. LCMS Method BE: [M+H] + =246.

[0517] Synthesis of Intermediate B51 (5-ethyl-1H-pyrrolo[3,2-b]pyridin-3-amine) TIFF2023509421000202.tif37155Step 1: 5-Ethenyl-3-nitro-1H-pyrrolo[3,2-b]pyridine 5-Bromo-3-nitro-1H-pyrrolo[3,2-b]pyridine (200.0 mg, 0.8 mmol, 1.0 equiv) was dissolved in DMF (20 mL) and water (4 mL), followed by the addition of 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (190.9 mg, 1.2 mmol, 1.5 equiv), Pd(dppf)Cl (60.5 mg, 0.1 mmol, 0.1 equiv), and KCO (228.4 mg, 1.7 mmol, 2.0 equiv) under nitrogen. The reaction mixture was heated to 100 °C for 16 h and then concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel column eluted with ethyl acetate / petroleum ether (1:1) to give 5-ethenyl-3-nitro-1H-pyrrolo[3,2-b]pyridine (81.2 mg) as a yellow solid. LCMS Method BA: [M+H] + =190.

[0518] Step 2: 5-Ethyl-1H-pyrrolo[3,2-b]pyridin-3-amine 5-Ethenyl-3-nitro-1H-pyrrolo[3,2-b]pyridine (200.0 mg, 1.1 mmol, 1.0 equiv) was dissolved in MeOH (10 mL) and Pd / C (16.9 mg, 0.2 mmol, 0.2 equiv) was added. The mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and stirred at ambient temperature overnight. The solids were removed by filtration, and the filtrate was concentrated in vacuo to give crude 5-ethyl-1H-pyrrolo[3,2-b]pyridin-3-amine (110.1 mg) as a yellow solid. LCMS Method BA: [M+H] + =162.

[0519] Synthesis of Intermediate B52 (tert-butyl 4-(1H-pyrrolo[3,2-b]pyridin-5-yl)piperazine-1-carboxylate) TIFF2023509421000203.tif62156Step 1: tert-Butyl 4-(6-methyl-5-nitropyridin-2-yl)piperazine-1-carboxylate 6-Chloro-2-methyl-3-nitropyridine (500.0 mg, 2.9 mmol, 1.0 equiv.) was dissolved in ACN (30 mL), followed by the addition of tert-butyl piperazine-1-carboxylate (539.7 mg, 2.9 mmol, 1.0 equiv.) and DIEA (1.0 mL, 5.8 mmol, 2.0 equiv.). The reaction mixture was heated to 50° C. for 16 hours and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel column eluted with ethyl acetate / petroleum ether (1:1) to afford tert-butyl 4-(6-methyl-5-nitropyridin-2-yl)piperazine-1-carboxylate (552.3 mg) as a yellow solid. LCMS Method BF: [M+H] + =323.

[0520] Step 2: tert-butyl 4-(6-methyl-5-nitropyridin-2-yl)piperazine-1-carboxylate tert-Butyl 4-(6-methyl-5-nitropyridin-2-yl)piperazine-1-carboxylate (500.0 mg, 1.6 mmol, 1.0 equiv.) was dissolved in DMF (30 mL), and then (dimethoxymethyl)dimethylamine (0.6 mL, 4.7 mmol, 3.0 equiv.) was added. The resulting solution was heated to 90° C. for 16 hours and then quenched by the addition of water. The resulting solution was extracted with DCM, washed with brine, and concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel column eluted with ethyl acetate / petroleum ether (1:2) to give tert-butyl 4-(6-methyl-5-nitropyridin-2-yl)piperazine-1-carboxylate (352.3 mg) as a red solid. LCMS Method BC: [M+H] + =378.

[0521] Step 3: tert-Butyl [5-cyclobutoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]carbamate tert-Butyl 4-(6-methyl-5-nitropyridin-2-yl)piperazine-1-carboxylate (400.0 mg, 1.1 mmol, 1.0 equiv) was dissolved in MeOH (30 mL), then Pt / C (50.7 mg, 3%) was added under nitrogen. The reaction mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and 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 a silica gel column eluted with ethyl acetate / petroleum ether (1:3) to afford tert-butyl [5-cyclobutoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]carbamate (298.5 mg) as a yellow solid. LCMS Method BA: [M+H] + =303.

[0522] The following intermediates were prepared using the method described for intermediate B52. TIFF2023509421000204.tif39128

[0523] Synthesis of Intermediate B68 (1-(4,4-difluorocyclohexyl)-1H-pyrazol-4-amine) TIFF2023509421000205.tif50128Step 1: 1-(4,4-Difluorocyclohexyl)-4-nitropyrazole 4,4-Difluorocyclohexyl methanesulfonate (500.0 mg, 2.3 mmol, 1.0 equiv.) was dissolved in DMF (10 mL), followed by the addition of 4-nitropyrazole (316.7 mg, 2.8 mmol, 1.2 equiv.) and CsCO (1.5 g, 4.7 mmol, 2.0 equiv.). The reaction mixture was heated to 90° C. for 12 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 a silica gel column eluted with ethyl acetate / petroleum ether (1:10) to give 1-(4,4-difluorocyclohexyl)-4-nitropyrazole (420.0 mg) as an off-white solid. LCMS Method BC: [M+H] + =232.

[0524] Step 2: 1-(4,4-difluorocyclohexyl)pyrazol-4-amine 1-(4,4-Difluorocyclohexyl)-4-nitropyrazole (400.0 mg, 1.7 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL), followed by the addition of Pd / C (184.1 mg, 10% wt.). The reaction mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature overnight. The solids were removed by filtration, and the filtrate was concentrated in vacuo to give 1-(4,4-difluorocyclohexyl)pyrazol-4-amine (243.1 mg) as a yellow solid. LCMS Method BC: [M+H] + =202.

[0525] The following intermediates were synthesized using the method described above for intermediate B68. TIFF2023509421000206.tif30159

[0526] Synthesis of Intermediate B70 (5-chloro-6-(3,3-difluoro-1-oxa-9-azaspiro[5.5]undecan-9-yl)pyridin-3-amine) TIFF2023509421000207.tif60156Step 1: 1-Oxa-9-azaspiro[5.5]undecane-3-one tert-Butyl 3-oxo-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate (1.0 g, 3.7 mmol, 1.0 equiv.) was dissolved in DCM (6 mL) and TFA (4 mL). The reaction mixture was stirred at ambient temperature for 1 h and then quenched by the addition of water. The resulting solution was adjusted to pH 8 with aqueous Na2CO3, then extracted with ethyl acetate and concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel column eluted with ethyl acetate / petroleum ether (1:3) to give 1-oxa-9-azaspiro[5.5]undecan-3-one (512 mg) as a white solid. LCMS Method BA: [M+H] + =170.

[0527] Step 2: 9-(3-chloro-5-nitropyridin-2-yl)-1-oxa-9-azaspiro[5.5]undecan-3-one 1-Oxa-9-azaspiro[5.5]undecan-3-one (500.0 mg, 3.0 mmol, 1.0 equiv) was dissolved in ACN (40 mL), followed by the addition of 2,3-dichloro-5-nitropyridine (570.2 mg, 3.0 mmol, 1.0 equiv) and TEA (0.5 mL, 3.5 mmol, 1.2 equiv). The resulting solution was heated to 70° C. for 2 hours, then cooled to room temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash column chromatography on a silica gel column eluted with ethyl acetate / petroleum ether (1:6) to give 9-(3-chloro-5-nitropyridin-2-yl)-1-oxa-9-azaspiro[5.5]undecan-3-one (580.2 mg) as a white solid. LCMS Method BD: [M+H] + =326.

[0528] Step 3: 9-(3-chloro-5-nitropyridin-2-yl)-3,3-difluoro-1-oxa-9-azaspiro[5.5]undecane 9-(3-Chloro-5-nitropyridin-2-yl)-1-oxa-9-azaspiro[5.5]undecane-3-one (500.0 mg, 1.5 mmol, 1.0 equiv) was dissolved in DCM (12 mL) and cooled to -10 °C, followed by the addition of DAST (272.2 mg, 1.7 mmol, 1.1 equiv). The reaction mixture was stirred at -10 °C for 30 min and then quenched by the addition of water. The resulting solution was adjusted to pH 7.5 with aqueous NaCO, extracted with ethyl acetate, and concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel column eluted with ethyl acetate / petroleum ether (1:2) to give 9-(3-chloro-5-nitropyridin-2-yl)-3,3-difluoro-1-oxa-9-azaspiro[5.5]undecane (351.1 mg) as a white solid. LCMS method BA: [M+H] + =348.

[0529] Step 4: 5-chloro-6-[3,3-d...

Claims

1. Formula I: 【Chemical 1】 A compound, wherein, Z, Y 1 , Y 2 , and Y 3 Each of them is independently selected from the group consisting of CR 1 , N, and NR 2 provided that one to three of Z, Y 1 , Y 2 , and Y 3 are N, X 1 is NH, X 2 is CH and each [Chemical Formula 2] is independently a single bond or a double bond, provided that X 1 and X 2 containing 5-membered ring is heteroaryl, Z, Y 1 , Y 2 and Y 3 containing 6-membered ring is heteroaryl, and P 1 , P 2 , P 3 , P 4 and P 5 containing ring is aromatic, W is C(=O), Q is selected from the group consisting of NH, N(C 1～6 alkyl), *-NH-(C 1～3 alkylene)-, and *-N(C 1～6 alkyl)-(C 1～3 alkylene)-, where C 1～6 alkyl may be substituted with 1 to 2 independently selected R a and the asterisk represents the point of attachment to W, P 1 、P 2 、P 3 、P 4 、およびP 5 are defined according to (AA) or (BB): (AA) P 1 、P 2 、P 3 、P 4 、およびP 5 Each of them is independently selected from the group consisting of N, CH, CR 7 、およびCR c ; provided that 1 to 2 of P 1 、P 2 、P 3 、P 4 、およびP 5 are independently selected CR 7 ; or (BB) P 1 does not exist, thereby providing a 5-membered ring, P 2 、P 3 、P 4 、 and P 5 each of which is independently selected from the group consisting of O, S, N, NH, NR d 、NR 7 、CH, CR 7 、 and CR c and is independently selected from the group consisting of However, P 2 , P 3 , P 4 , and P 5 among 1 to 3 of them are O, S, N, NH, NR d , or NR 7 , and P 2 , P 3 , P 4 , and P 5 among 1 to 2 of them are independently selected NR 7 or CR 7 , Each R 7 is selected independently from the group consisting of -R 8 and -L 3 -R 9 and is selected independently from the group consisting of -R 8 is (a) C cycloalkyl or C cycloalkenyl, each independently selected from 1 to 4 R 7 ' and each substituted with 3～12 3～12 ​​ (b) a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom being independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 and one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring are substituted with 1 to 4 independently selected R 7 ', said heterocyclyl or heterocycloalkenyl, (c) C selected independently from 1 to 4 1～4 C, each of which may be substituted with 3 cycloalkyl, 3 cycloalkenyl, 5 cycloalkyl, or 5 cycloalkenyl, (d) C independently selected from 1 to 4 1～4 each of which may be substituted with C 7～12 cycloalkyl or C 7～12 cycloalkenyl, (e)A heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 provided that the heterocyclyl is other than tetrahydropyranyl and one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring may be substituted with 1 to 4 independently selected C 1～4 alkyl, said heterocyclyl or heterocycloalkenyl, (f)A heteroaryl having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 and one or more ring carbon atoms of the heteroaryl ring may be substituted with 1 to 4 independently selected R 7 ', said heteroaryl, and (g) C which may be substituted with 1 to 4 independently selected R 7 ’ and may be aryl 6～10 aryl is selected from the group consisting of, -L 3 is selected from the group consisting of -O-, -S-, -NH-, S(O) 1～2 , -CH 2 -, C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O) 2 , and S(O) 2 NH -R 9 is (a) C cycloalkyl or C cycloalkenyl which may be each independently selected from 1 to 4 Rs 7 ’ and may be each independently selected from 1 to 4 Rs 3～12 cycloalkyl or C 3～12 cycloalkenyl, (b)a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 wherein one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring may be substituted with one or more independently selected R 7 ', said heterocyclyl or heterocycloalkenyl (c) a heteroaryl having 5 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 and one or more ring carbon atoms of the heteroaryl ring may be substituted with 1 to 4 independently selected R 7 ', said heteroaryl, and (d) 1 to 4 independently selected R 7 optionally substituted with C 6～10 aryl is selected from the group consisting of, R 7 Each occurrence of 'is halo; -CN; -NO 2 ; -OH; one or two independently selected R a optionally substituted -C 1～4 alkyl; -C 2～4 alkenyl; -C 2～4 alkynyl; -C 1～4 haloalkyl; one or two independently selected R a optionally substituted -C 1～6 alkoxy; -C 1～6 haloalkoxy; S(O) 1～2 (C 1～4 alkyl); -NR'R''; oxo; S(O) 1～2 (NR'R''); -C 1～4 thioalkoxy; -C(=O)(C 1～4 alkyl); -C(=O)O(C 1～4 alkyl); -C(=O)OH; and -C(=O)N(R')(R'') and is independently selected from the group consisting of However, R 7 is R 8 and, R 8 is cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl, and when 1 to 4 R 7 's are substituted, R 8 is not monosubstituted with C 1～4 alkyl and However, when R 8 is replaced by 2 to 4 R 7 ', at least one R 7 ' must be a substituent other than C 1～4 alkyl; R 1 Each occurrence of which may be replaced by H; halo; cyano; 1 to 2 R a optionally substituted C 1～6 alkyl; C 2～6 alkenyl; C 2～6 alkynyl; C 1～4 haloalkyl; -OH, C 1～4 alkoxy, C 1～4 haloalkoxy, or -NR e R f optionally substituted C 1～4 alkoxy; C 1～4 haloalkoxy; -L 1 -L 2 -R h ; -S(O) 1～2 (C 1～4 alkyl); -S(O)(=NH)(C 1～4 alkyl); SF 5 ; -NR e R f ; -OH; oxo; -S(O) 1～2 (NR’R’’); -C 1～4 thioalkoxy; -NO 2 ; -C(=O)(C 1～4 alkyl); -C(=O)O(C 1～4 alkyl); -C(=O)OH; and -C(=O)N(R’)(R’’), independently selected from the group consisting of R 2 Each occurrence of (i) H, (ii)1 to 3 independently selected R a which may be substituted with 1～6 alkyl (iii) 1 to 3 independently selected Rs a which may be substituted with -C(O)(C 1～6 alkyl), (iv) 1 to 3 independently selected R a which may be replaced by -C(O)O(C 1～4 alkyl), (v) -CON(R’)(R’’), (vi)-S(O) 1～2 (NR’R’’)、 (vii) 1 to 3 independently selected R a which may be substituted with -S(O) 1～2 (C 1～4 alkyl), (viii) -OH, (ix)C 1～4 alkoxy, and (x)-L 4 -L 5 -R i is independently selected from the group consisting of, R 6 is H; 1 to 3 independently selected R a optionally substituted by C 1～6 alkyl; -OH; C 1～4 alkoxy; C(=O)H; C(=O)(C 1～4 alkyl); 1 to 4 independently selected C 1～4 optionally substituted by alkyl C 6～10 aryl; and heteroaryl having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, and each heteroatom is independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 and is independently selected from the group consisting of heteroaryl optionally substituted by 1 to 4 independently selected C 1～4 alkyl, selected from the group consisting of said heteroaryl, R a each occurrence of which is selected independently from the group consisting of -OH; -F; -Cl; -Br; -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; -CON(R')(R''); -S(O) 1～2 (NR'R''); -S(O) 1～2 (C 1～4 alkyl); cyano; and C 1～4 cycloalkyl or C 3～6 cycloalkenyl, each of which may be independently substituted with 1 to 4 C 3～6 alkyl, and is independently selected from the group consisting of R c each occurrence of which is independently selected from halo; cyano; C a alkyl which may be substituted with 1 to 6 independently selected R 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); -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)N(R’)(R’’); and -L 1 -L 2 -R h and is independently selected from the group consisting of, R d is C optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, C 1～4 alkoxy, and OH; C 1～6 alkyl optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo and OH; C 3～6 cycloalkyl or C 3～6 cycloalkenyl; -C(O)(C 1～4 alkyl); -C(O)O(C 1～4 alkyl); -CON(R’)(R’’); -S(O) 1～2 (NR’R’’); -S(O) 1～2 (C 1～4 alkyl); -OH; and C 1～4 selected from the group consisting of alkoxy, R e and R f each occurrence of which is independently selected from the group consisting of H; C 1～6 alkyl; C 1～6 haloalkyl; C 3～6 cycloalkyl or C 3～6 cycloalkenyl; -C(O)(C 1～4 alkyl); -C(O)O(C 1～4 alkyl); -CON(R')(R''); -S(O) 1～2 (NR'R''); -S(O) 1～2 (C 1～4 alkyl); -OH; and C 1～4 alkoxy, or R e and R f each, together with the nitrogen atom to which it is attached, form a ring having from 3 to 8 ring atoms, wherein said ring is (a) from 1 to 7 ring carbon atoms each substituted with 1 to 2 substituents independently selected from the group consisting of H and C 1～3 alkyl, and (b) 0 to 3 ring heteroatoms each independently selected from the group consisting of N(R d ), NH, O, and S (in addition to the nitrogen atom attached to R e and R f ), and -L 1 is a bond or C 1～3 alkylene, and -L 2 is -O-, -N(H)-, -S(O) 0～2 -, or a bond, R h is ・ Halo; 1 to 2 independently selected Rs a optionally substituted by C 1～4 alkyl; C 1～4 haloalkyl; cyano; C 1～4 alkoxy; and C 1～4 optionally substituted by 1 to 4 substituents independently selected from the group consisting of haloalkoxy, C 3～8 cycloalkyl or C 3～8 cycloalkenyl, ・ A heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 ), and the heterocyclyl or heterocycloalkenyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halo; 1 to 2 independently selected R a ; C 1～4 alkyl; C 1～4 haloalkyl; cyano; C 1～4 alkoxy; and C 1～4 haloalkoxy, said heterocyclyl or heterocycloalkenyl, ・A heteroaryl having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 independently selected from the group consisting of, and the heteroaryl ring is halo; 1 to 2 independently selected R a optionally substituted with C 1～4 alkyl; C 1～4 haloalkyl; cyano; C 1～4 alkoxy; and C 1～4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy, said heteroaryl, and ・ Halo; 1 to 2 independently selected Rs a Optionally substituted by C 1～4 Alkyl; C 1～4 Haloalkyl; cyano; C 1～4 Alkoxy; and C 1～4 Optionally substituted by 1 to 4 substituents independently selected from the group consisting of haloalkoxy 6～10 Aryl is selected from the group consisting of, -L 4 - is selected from the group consisting of a bond, -C(O)-, -C(O)O-, -C(O)NH-, C(O)NR d , S(O) 1～2 , S(O) 1～2 NH, and S(O) 1～2 NR d and is selected from the group consisting of: -L 5 - is selected from the group consisting of a bond and C 1～4 alkylene, R i is ・ Halo; OH; NR e R f ; 1 to 2 independently selected Rs a optionally substituted by C 1～4 alkyl; C 1～4 haloalkyl; cyano; C 1～4 alkoxy; and C 1～4 optionally each substituted by 1 to 4 substituents independently selected from the group consisting of haloalkoxy, C 3～8 cycloalkyl or C 3～8 cycloalkenyl, ・ A heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 independently selected from the group consisting of, and said heterocyclyl or heterocycloalkenyl is halo; OH; NR e R f ; 1 to 2 independently selected R a optionally substituted with C 1～4 alkyl; C 1～4 haloalkyl; cyano; C 1～4 alkoxy; and C 1～4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy, said heterocyclyl or heterocycloalkenyl, ・A heteroaryl having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 is independently selected from the group consisting of, and the heteroaryl ring is halo; OH; NR e R f ; 1 to 2 independently selected R a which may be substituted with C 1～4 alkyl; C 1～4 haloalkyl; cyano; C 1～4 alkoxy; and C 1～4 which may be substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy, said heteroaryl, and ・ Halo; OH; NR e R f ; 1 to 2 independently selected R a optionally substituted by C 1～4 alkyl; C 1～4 haloalkyl; cyano; C 1～4 alkoxy; and C 1～4 optionally substituted by 1 to 4 substituents independently selected from the group consisting of haloalkoxy C 6～10 aryl is selected from the group consisting of, Each occurrence of R’ and R’’ is H; -OH; C 1～4 alkyl; halo, C 1～4 alkyl, and C 1～4 aryl optionally substituted with 1 to 2 substituents selected from the group consisting of haloalkyl; and heteroaryl having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, and each heteroatom is independently selected from the group consisting of N, N(H), N(R 6～10 ), O, and S(O) d ), and the heteroaryl ring is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halo, -OH, NH 0～2 ), NH(C 2 alkyl), N(C 1～4 alkyl) 1～4 ), C 2 alkyl, and C 1～4 haloalkyl, and is independently selected from the group consisting of said heteroaryl optionally substituted with 1 to 4 substituents selected from the group consisting of 1～4 or R’ and R’’, together with the nitrogen atom to which each is attached, form a ring having 3 to 8 ring atoms, where the ring is (a) 1 to 7 ring carbon atoms each substituted with 1 to 2 substituents independently selected from the group consisting of H and C 1～3 alkyl, and (b) 0 to 3 ring heteroatoms (in addition to the nitrogen atom to which R’ and R’’ are attached) each independently selected from the group consisting of N(H), N(C 1～6 alkyl), O, and S, and having provided that the compound is 【Chemical Formula 3】 other than, the said compound, or a pharmaceutically acceptable salt or tautomer thereof.

2. P 1 、P 2 、P 3 、P 4 、and P 5 are as defined according to (AA), a compound according to claim 1.

3. P 1 、P 2 、P 3 、P 4 、and P 5 one or more of which is N, or P 1 、P 2 、P 3 、P 4 、and P 5 The compound according to claim 2, wherein one of them is N.

4. 【Fig. 4】 The moiety has the formula: 【Chemical Formula 5】 wherein n2 is 0, 1, or 2, the compound according to Claim 2 or Claim 3.

5. 【Fig. 6】 The moiety has the formula: [Chemical Formula 7] the compound according to any one of Claims 2 to 4.

6. P 1 、P 2 、P 3 、P 4 、and P 5 each of which is independently selected from the group consisting of CH, CR 7 、and CR c The compound according to claim 2, wherein the compound is independently selected from the group consisting of CH, CR

7. 【Fig. 8】 The moiety has the formula: 【Chemical Formula 9】 wherein n2 is 0, 1, or 2, the compound according to Claim 2 or Claim 6.

8. 【Fig. 10】 The moiety has the formula: 【Chemical 11】 the compound according to Claim 2, Claim 6, or Claim 7.

9. R 7 is R 8 The compound according to any one of claims 1 to 8, which is

10. R 8 is i) C cycloalkyl or C cycloalkenyl, each independently selected from 1 to 4 R 7 ' and each replaced by 3～12 cycloalkyl or C 3～12 cycloalkenyl, ii) 1 to 4 independently selected Rs 7 substituted with C 4～8 cycloalkyl, iii) cyclohexyl or cyclobutyl, each independently selected from 1 to 4 R 7 ’s, each of which is substituted with iv) each R 7 ’ is independently halo, 【Chemical Formula 12】 、 or v) each R 7 ’ is independently halo, and any one of R in i) to iv) 8 is, the compound according to any one of Claims 1 to 9.

11. R 8 is i) a heterocyclyl or heterocycloalkenyl having 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, and each heteroatom is independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 and one or more ring atoms of the heterocyclyl ring or heterocycloalkenyl ring are optionally substituted with 1 to 4 independently selected R 7 ', said heterocyclyl or heterocycloalkenyl ii) a heterocyclyl having 4 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom being independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 and one or more ring carbon atoms of the heterocyclyl ring are substituted with 1 to 4 independently selected R 7 ', said heterocyclyl iii) A heterocyclyl having 4 to 6 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, and each heteroatom is independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 and one or more ring carbon atoms of the heterocyclyl ring are substituted with 2 to 4 independently selected R 7 ', said heterocyclyl iv) 【Chemical Formula 13】 、 v) a spirocyclic heterocyclyl having 6 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each heteroatom being independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 and one or more ring carbon atoms of the heterocyclyl ring may be substituted with 1 to 4 independently selected R 7 ', said spirocyclic heterocyclyl vi) 【Chemical 14】 、 or vii) Each R 7 ’ is independently a halo, and any one of R in i) to vi) 8 is, the compound according to any one of Claims 1 to 9.

12. R c The compound according to any one of claims 1 to 11, wherein each occurrence of is a halo independently selected.

13. Q is NH and W is C(=O), the compound according to any one of Claims 1 to 12.

14. Y 1 、 Y 2 、 and Y 3 one of which is independently N, and the remaining Y 1 、 Y 2 、 and Y 3 each of which is independently selected CR 1 is, or Z is N and Y 1 , Y 2 , and Y 3 each of which is independently selected CR 1 is The compound according to any one of Claims 1 to 13.

15. 【Fig. 15】 The moiety is 【Chemical Formula 16】 selected from the group consisting of, the compound according to any one of Claims 1 to 14.

16. Formula (Ia): 【Chemical 17】 a compound or a pharmaceutically acceptable salt thereof, the compound according to any one of Claims 1 to 15.

17. Formula (Id): 【Chemical 18】 a compound or a pharmaceutically acceptable salt thereof, the compound according to any one of Claims 1 to 15.

18. i) Formula (Ia-1), (Ia-2), or (Ia-3): 【Chemical 19】 a compound, or a pharmaceutically acceptable salt thereof, ii) Formula (Id-1), (Id-2), or (Id-3): 【Chemical 20】 a compound, or a pharmaceutically acceptable salt thereof, or iii) R 2 is H and R 5 is H, a compound of either i) or ii) is, the compound according to any one of Claims 1 to 15.

19. i) R 1 each occurrence of which is H, or ii) R 1 one or two occurrences of are other than H, or iii) R 1 one occurrence of which is other than H, or or iv) R 1 One occurrence of which may be replaced by halo; cyano; one or two Rs a Optionally substituted by C 1～6 Alkyl; C 2～6 Alkenyl; C 2～6 Alkynyl; C 1～4 Haloalkyl; C 1～4 Alkoxy; C 1～4 Haloalkoxy; -S(O) 1～2 (C 1～4 Alkyl); -S(O) 1～2 (NR’R’’); -NO 2 ; -L 1 ; -L 2 ; -R h ; -C(=O)(C 1～4 Alkyl); -C(=O)O(C 1～4 Alkyl); -C(=O)OH; and C(=O)N(R’)(R’’) selected from the group consisting of the compound according to any one of Claims 1 to 18.

20. Formula (I-3a) or (I-3b): 【Chemical 21】 【Chemical 22】 a compound or a pharmaceutically acceptable salt thereof, wherein, R 1a 、R 1b 、and R 1c each is independently selected from the group consisting of H; halo; cyano; C a alkyl optionally substituted with 1 to 2 R 1～6 groups; C 1～4 haloalkyl; C 1～4 alkoxy; and C 1～4 haloalkoxy, Q 1 is N or CH, R 8 is 【Chemical 23】 is selected from the group consisting of, n2 is 0, 1, or 2, R c When R exists, each R c is independently selected from the group consisting of halo, cyano, C 1～3 alkyl, and C 1～3 alkoxy, m1 and m2 are independently 0, 1, or 2, m3, m4, m5, and m6 are independently 0 or 1, and T 1 is CH or N, the compound according to Claim 1.

21. R 2 is H, n2 is 1, and R c is R 8 is ortho to each other, and each R 7 ’ is independently halo, the compound according to claim 20.

22. R 8 is 【Chemical Formula 24】 The compound according to claim 20 or claim 21, selected from the group consisting of

23. The following table: 【Chemical 25】 【Chemical 26】 【Chemical 27】 【Chemical 28】 【Chemical 29】 【Chemical Formula 30】 【Chemical 31】 【Chemical Formula 32】 【Chemical 33】 【Chemical Formula 34】 【Chemical 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical Formula 39】 【Chemical 40】 【Chemical 41】 【Chemical 42】 【Chemical Formula 43】 The compound according to claim 1, selected from the group consisting of compounds having the structure shown in

24. A pharmaceutical composition comprising the compound according to any one of claims 1 to 23 and one or more pharmaceutically acceptable excipients.

25. The pharmaceutical composition according to claim 24, for use in inhibiting STING activity.

26. The pharmaceutical composition according to claim 25, for use in the treatment of a disease, disorder, or condition associated with STING.

27. The pharmaceutical composition according to claim 26, wherein the disease, disorder, or condition is selected from the group consisting of type I interferonopathy, Ehlers-Danlos syndrome (EDS), systemic lupus erythematosus, inflammation-related disorders, and rheumatoid arthritis.

28. The pharmaceutical composition according to claim 26, wherein the disease, disorder, or condition is amyotrophic lateral sclerosis or Parkinson's disease.

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