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. TIFF2023509422000703.tif52135

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 955,839, filed December 31, 2019, and U.S. Provisional Patent Application No. 63 / 090,538, 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 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. [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): TIFF0007756643000001.tif45128, or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 1c , R 1d , 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) is featured, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a tautomer thereof, or any combination of the foregoing. "Prodrug" is intended to refer to a compound that can be converted into a biologically active compound described herein (e.g., a compound of formula (I)) under physiological conditions or by solvolysis. Thus, the term "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 into an active compound in vivo, for example, by solvolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammals (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. 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] In another aspect, featured is 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, featured is a method of treatment, 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] In another aspect, described herein are compounds, or pharmaceutically acceptable salts or tautomers thereof, for use in the treatment of diseases, conditions, or disorders that are modulated by STING inhibition.

[0020] In another aspect, described herein are compounds, or pharmaceutically acceptable salts or tautomers thereof, for use in treating conditions, diseases, or disorders associated with increased (e.g., hyperactivity) of STING activation.

[0021] In another aspect, described herein are compounds, or pharmaceutically acceptable salts or tautomers thereof, for use in the treatment of cancer.

[0022] In another aspect, described herein is a compound, 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 cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor, or hepatocellular carcinoma.

[0023] In another aspect, described herein are compounds, or pharmaceutically acceptable salts or tautomers thereof, for use in the treatment of type I interferonopathy.

[0024] In another aspect, described herein are compounds, or pharmaceutically acceptable salts or tautomers thereof, for use in treating a type I interferonopathy selected from 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.

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

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

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

[0030] In another aspect, described herein is the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, for the treatment of a disease, condition, or disorder modulated by STING inhibition.

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

[0032] In another aspect, described herein is the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, for the treatment of cancer.

[0033] In another aspect, described herein is the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, 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.

[0034] In another aspect, described herein is the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, for the treatment of type I interferonopathy.

[0035] In another aspect, described herein is the use of a compound, or a pharmaceutically acceptable salt or tautomer thereof, for the treatment of a type I interferonopathy selected from 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.

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

[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. Pharmacologically acceptable salts are not particularly limited as long as they 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 radical, which may be straight or branched, containing the specified number of carbon atoms. For example, C 1~10 indicates that the group may have 1 to 10 (inclusive) carbon atoms in it. Alkyl groups may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. The term "saturated," as used in this context, means that there are only single bonds between the constituent carbon atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

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

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

[0059] The term "alkylene" refers to a divalent alkyl (eg, --CH.sub.2--).

[0060] The term "alkenyl" refers to an acyclic hydrocarbon chain that may be straight or branched and has one or more carbon-carbon double bonds. The alkenyl moiety contains the specified 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 may be unsubstituted or substituted with one or more substituents.

[0061] The term "alkynyl" refers to an acyclic hydrocarbon chain that may be straight or branched and has one or more carbon-carbon triple bonds. The alkynyl moiety contains the specified 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, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and 0, 1, 2, 3, or 4 atoms in each ring may be substituted by 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, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl 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. Cycloalkyls also include spirocyclic rings (e.g., spirocyclic bicycles in which two rings are connected through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, etc. The term "saturated," as used in this context, means that only single bonds exist between the constituent carbon atoms.

[0064] The term "cycloalkenyl," as used herein, 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 or 3 to 10 ring carbons or 3 to 6 ring carbons, and the cycloalkenyl group may be 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 within the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group as a whole is not fully saturated. The cycloalkenyl may contain multiple fused and / or bridged and / or spirocyclic rings.

[0065] The term "heteroaryl," as used herein, refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, or 5, 6, 9, 10, or 14 ring atoms; and having 6, 10, or 14 pi electrons shared in the cyclic array; in which at least one ring in the system is aromatic and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (although rings containing heteroatoms are not required, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolyl). 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, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriarolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolidinyl, and pyrrolidinyl. Examples include bro[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, isoindolinyl, and the like. 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 N, O, or S in the monocyclic, bicyclic, or tricyclic ring systems, respectively), having 1 to 3 heteroatoms in the monocyclic, 1 to 6 heteroatoms in the bicyclic, or 1 to 9 heteroatoms in the tricyclic or polycyclic ring systems, wherein the heteroatoms are selected from O, N, or S, and 0, 1, 2, or 3 atoms of each ring are 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 heteorocyclyls 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 (e.g., spirocyclic bicycles in which two rings are connected through only one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-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]undecane, 3-oxa-9-azaspiro[5.5]undecanyl, etc. The term "saturated," when 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 N, O, or S in the monocyclic, bicyclic, or tricyclic ring systems, respectively) containing 1 to 3 heteroatoms in the monocyclic, 1 to 6 heteroatoms in the bicyclic, or 1 to 9 heteroatoms in the tricyclic or polycyclic ring systems, wherein the heteroatoms are selected from O, N, or S, and 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, the heterocycloalkenyl group can have any degree of unsaturation, provided that one or more double bonds are within the ring, none of the rings in the ring system are aromatic, and the heterocycloalkenyl group as a whole is not fully saturated. Heterocycloalkenyls can include multiple fused and / or bridged and / or spirocyclic rings.

[0068] As used herein, if a ring is described 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] As used herein, if a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation due to the ring itself; e.g., one or more double or triple bonds between the 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 stated, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form a bicyclic or higher ring system (e.g., tricyclic, polycyclic ring system), such rings and cyclic groups are defined as rings whose points of fusion are (i) adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents a zero atom bridge). TIFF0007756643000002.tif13128); (ii) a single ring atom (spiro-fused ring system) (e.g., TIFF0007756643000003.tif17128), or (iii) a series of vicinal ring atoms (bridged ring systems where all bridge lengths are >0). It is understood that this encompasses those with fused rings, including those located on TIFF0007756643000004.tif14128.

[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 TIFF0007756643000005.tif15128 is the moiety: TIFF0007756643000006.tif16128. Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxyl encompass pyridone or pyrimidone tautomers.

[0073] [The present invention 1001] Formula I: TIFF0007756643000007.tif44128 A compound of the formula: During the ceremony, X 1 are O, S, N, NR 2 , and C.R. 1 selected from the group consisting of: X 2 are O, S, N, NR 4 , and C.R. 5 selected from the group consisting of: each TIFF0007756643000008.tif2128 are independently a single bond or a double bond, provided that: X 1 and X 2 is a heteroaryl; 6-membered ring TIFF0007756643000009.tif30128 is aromatic; and P 1 、P 2 、P 3 、P 4 , and P 5 The ring containing is aromatic; P 1 、P 2 、P 3 、P 4 , and P 5 is defined according to (AA) or (BB): (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: 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 independently selected from the group consisting of: R 8 and R 9 teeth, (a) 1 to 4 independently selected R 7 ', each of which may be replaced by C 3~12 Cycloalkyl or C 3~12 cycloalkenyl; (b) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 the heterocyclyl or heterocycloalkenyl optionally substituted by '; (c) Heteroaryl of 5 to 12 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 the heteroaryl, optionally substituted by ; and (d) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl independently selected from the group consisting of: -L 3 -O-, -C 1~4 Alkylene, -S-, -NH-, S(O) 1~2 , C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O) 2 , and S(O) 2 selected from the group consisting of NH; R 7 Each occurrence of ' is halo;-CN;-NO2 -OH; 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; one to two 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''); 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-NO 2 );(vii)S(=O)(=N(R d )); and (viii) S(=O)(=NH) selected from the group consisting of: 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; R 1a 、R 1b 、R 1c , and R 1d Each of the groups is H; halo; cyano; one to 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;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);SF 5 ;-NR e R f ;-OH;-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''); 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 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 independently selected from the group consisting of: R 4 is H; and one to three independently selected R a C optionally substituted with 1~6 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; one to three 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 of 5 to 10 ring atoms, wherein 1 to 4 ring atoms are selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is a heteroatom selected from the group consisting of 1 to 4 independently selected C 1~4 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 (C1~4 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 independently selected from the group consisting of: cycloalkenyl; R b Each occurrence of is selected from 1 to 6 independently selected R 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 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;-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 -L2 -R h independently selected from the group consisting of: R d Ha, Halo, C 1~3 Alkoxy, C 1~3 Haloalkoxy, OH, and C 3~6 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl 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 selected from the group consisting of 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; 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, wherein 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; -L 2 -O-, -N(H)-, -S(O) 0~2 - or in conjunction; 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 each optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; C 3~8 Cycloalkyl or C 3~8 cycloalkenyl; Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of 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 the heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo; a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 the heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; and ·C 6~10 aryl, halo; one to two independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 The C may be substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy. 6~10 Aryl selected from the group consisting of: -L4 - 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 each optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; C 3~8 Cycloalkyl or C 3~8 cycloalkenyl; Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of 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 the heterocyclyl or heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 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 the heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; and ·C 6~10 aryl, 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 The C may be 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 of 5 to 10 ring atoms, wherein 1 to 4 ring atoms are selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo, —OH, NH 2 , NH(C 1~4 alkyl), N(C 1~4 alkyl) 2 、C 1~4 Alkyl, and C 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; or R' and R'' together with the nitrogen atom to which they are each attached form a ring of 3 to 8 ring atoms, wherein said ring is selected from the group consisting of (a) H and C 1~3 (b) 1 to 7 ring carbon atoms, each substituted with 1 to 2 substituents independently selected from the group consisting of alkyl; and (b) N(H), N(C 1~6 having 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; however, (a)X 1 NR 2 and X 2 is CH;R 1a 、R 1b 、R 1c 、R 1d , and R 6 each of is H; W is C(=O); Q is NH; and P1 、P 2 、P 3 、P 4 , and P 5 If is defined according to (AA), then · TIFF0007756643000010.tif18128 Part TIFF0007756643000011.tif15128 If R 2 is CH 2 CH 2 OCH 3 But CH 3 But CH 2 CH 3 But SO 2 -(p-tolyl) or not; and -L 3 is -O-, -NH-, or C(=O), and · TIFF0007756643000012.tif18128 The part is one R 7 R is pyrimidinyl or pyridyl, each substituted with 2 is CH 2 CH 2 CH 2 N(CH 3 ) 2 But CH 2 CH 2 CH 2 N(CH 2 CH 3 ) 2 Or not, here R 7 is R 8 and R 8 is unsubstituted phenyl; and (b) the compound is TIFF0007756643000013.tif82158 But not, The compound, or a pharmaceutically acceptable salt thereof, or a tautomer thereof. [The present invention 1002] P 1 、P 2 、P 3、P 4 , and P 5 The compound of the present invention 1001, wherein is defined according to (AA). [The present invention 1003] P 1 、P 2 、P 3 、P 4 , and P 5 One or two of these are N, or P 1 、P 2 、P 3 、P 4 , and P 5 The compound of the present invention 1002, wherein one of the groups is N. [The present invention 1004] TIFF0007756643000014.tif18128 The part is the expression: TIFF0007756643000015.tif13128 The compound of claim 1002 or 1003, having the formula: [The present invention 1005] TIFF0007756643000016.tif18128 The part is the expression: TIFF0007756643000017.tif17128 The compound of any one of claims 1002 to 1004 of the present invention, [The present invention 1006] TIFF0007756643000018.tif18128 The part is the expression: TIFF0007756643000019.tif14128 where n2 is 0, 1, or 2; or TIFF0007756643000020.tif18128 The part is the expression: TIFF0007756643000021.tif17128 where n2 is 0, 1, or 2; The compound of the present invention 1002 or 1003. [The present invention 1007] TIFF0007756643000022.tif18128 The part is the expression: TIFF0007756643000023.tif23128 The compound of claim 1002, 1003, or 1006, having the formula: [The present invention 1008] P 1 、P 2 、P 3 、P 4 , and P 5 Each of these is CH, CR 7 , and C.R. c 1002. A compound of the present invention, independently selected from the group consisting of: [The present invention 1009] TIFF0007756643000024.tif18128 The part is the expression: TIFF0007756643000025.tif13128 wherein n2 is 0, 1, or 2. [The present invention 1010] TIFF0007756643000026.tif18128 The part is the expression: TIFF0007756643000027.tif16128 The compound of the present invention 1002, 1008, or 1009, having the formula: [The present invention 1011] R 7 R 8 The compound of any one of 1001 to 1010 of the present invention, [The present invention 1012] R 8 but, i) 1 to 4 independently selected R 7 ', each of which is replaced by C 3~12 Cycloalkyl or C 3~12 cycloalkenyl; ii) 1 to 4 independently selected R 7 ', C 4~8 cycloalkyl; iii) 1 to 4 independently selected R 7 cyclohexyl or cyclobutyl, each substituted by '; or iv) Each R 7 ' is independently halo, TIFF0007756643000028.tif23128 The compound of any one of claims 1001 to 1011 of the present invention, [The present invention 1013] R 8 but, i) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 the heterocyclyl or heterocycloalkenyl optionally substituted by '; ii) heterocyclyl of 4 to 6 ring atoms, in which 1 to 2 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 3 independently selected R 7 the heterocyclyl substituted by '; iii) TIFF0007756643000029.tif24128 ; iv) spirocyclic heterocyclyl of 6 to 12 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 the spirocyclic heterocyclyl optionally substituted by '; v) TIFF0007756643000030.tif26128 ; or vi) Each R 7 ' is independently halo or C 1~3 Any one of R i) to R v) is alkyl. 8 The compound of any one of claims 1001 to 1011 of the present invention, [The present invention 1014] Each R c is an independently selected halo. [The present invention 1015] Q is NH; and W is C(=O), and optionally R 6 The compound of any one of claims 1001 to 1014, wherein is H. [The present invention 1016] X 1 NR 2 and X 2 is CR 5 or X 1 is NH; and X 2 The compound of any one of claims 1001 to 1015, wherein is CH. [The present invention 1017] i)R 1a 、R 1b 、R 1c , and R 1d one or two of which are other than H; and R 1a 、R 1b 、R 1c , and R 1d each of the remainder is H; ii)R 1b and R 1c each of which is other than H; and R 1a and R 1d whether each of is H; iii)R 1b and R 1c are independently selected halo groups, and R 1a and R 1d whether each of is H; iv) R 1b is other than H; and R 1a 、R 1c , and R 1d whether each of is H; v)R 1b But, halo; 1 to 2 R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl; -CN; -SF 5 ;C 1~4 Thioalkoxy;S(O) 2 (C1~4 alkyl); and C 1~4 Alkoxy or C 1~4 haloalkoxy; and R 1a 、R 1c , and R 1d whether each of is H; or vi)R 1b is a halo; and R 1a 、R 1c , and R 1d each of which is H, Any of compounds 1001 to 1016 of the present invention. [The present invention 1018] Formula (I-1a), (I-2a), or (I-3a): TIFF0007756643000031.tif89128 or a pharmaceutically acceptable salt thereof, During the ceremony, R 1a 、R 1b 、R 1c , and R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth, m1 and m2 are independently 0, 1, or 2, and T 1 is CH or N; TIFF0007756643000032.tif24128 ; and Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 The spirocyclic heterocyclyl may be substituted by '. selected from the group consisting of: Arbitrarily, where each R 7 ' is independently a halo or C 1~3 is alkyl; and Arbitrarily, here R d C optionally substituted with 1 to 3 independently selected halo 1~6 is alkyl, 1001 compounds of the present invention. [The present invention 1019] R 8 but, TIFF0007756643000033.tif28128 selected from the group consisting of Arbitrarily, where each R 7 ' is independently halo or C 1~3 alkyl, e.g., -F or methyl, and Arbitrarily, here R d C optionally substituted with 1 to 3 independently selected halo 1~6 Alkyl, for example, C optionally substituted with 1 to 3 -F 2~4 is alkyl, Compound 1018 of the present invention. [The present invention 1020] Each R 7' independently halo or C 1~3 alkyl, and R d C optionally substituted with 1 to 3 independently selected halo 1~6 The compound of the present invention 1018 or 1019, which is alkyl. [The present invention 1021] 1001. A compound of the present invention selected from the group consisting of the compounds set forth in Table C1 or a pharmaceutically acceptable salt thereof. [The present invention 1022] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1021 and one or more pharmaceutically acceptable excipients. [The present invention 1023] A method for inhibiting STING activity, comprising the step of contacting STING with any of the compounds of the present invention 1001 to 1021 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention 1022. [The present invention 1024] A method for inducing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of any of the compounds of the present inventions 1001 to 1021 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention 1022. [The present invention 1025] A method for treating a STING-related disease, disorder, or condition, for example, a disease, disorder, or condition in which increased STING signaling, such as enhanced STING signaling, contributes to the pathology and / or symptoms and / or progression of the disease, said method comprising the step of administering to a subject in need of such treatment an effective amount of any of the compounds of present inventions 1001 to 1021 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of present invention 1022. 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): TIFF0007756643000034.tif44128, or a pharmaceutically acceptable salt thereof or a tautomer thereof, During the ceremony, X 1 are O, S, N, NR 2 , and C.R. 1 selected from the group consisting of: X 2 are O, S, N, NR 4 , and C.R. 5 selected from the group consisting of: each TIFF0007756643000035.tif2128 are independently single or double bonds, provided that: X 1 and X 2 is a heteroaryl; 6-membered ring TIFF0007756643000036.tif30128 is aromatic; and P 1 , P 2 , P 3 , P 4 , and P 5 The ring containing is aromatic; P 1 , P 2 , P 3 , P 4 , and P 5 is defined according to (AA) or (BB): (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: 2 , P 3 , P4 , 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 independently selected from the group consisting of: R 8 and R 9 teeth, (a) 1 to 4 independently selected R 7 ', each of which may be replaced by C 3~12 Cycloalkyl or C 3~12 cycloalkenyl; (b) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', optionally substituted with heterocyclyl or heterocycloalkenyl; (c) Heteroaryl of 5 to 12 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', optionally substituted with heteroaryl; and (d) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl independently selected from the group consisting of: -L 3 -O-, -C 1~4 Alkylene, -S-, -NH-, S(O) 1~2 , C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2, and S(O)2NH; R 7 Each occurrence of ' is selected from the group consisting of halo; -CN; -NO; -OH; and one to two independently selected R a may be substituted with -C 1~4 Alkyl;-C 2~4 Alkenyl;-C 2~4 Alkynyl;-C 1~4 Haloalkyl; one to two 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''); 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) selected from the group consisting of: 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; R 1a , R 1b , R 1c , and R 1d Each of the groups is H; halo; cyano; one to 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;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);SF5;-NR e R f ;-OH;-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 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 1~4alkyl); (viii) -OH; (ix) C 1~4 Alkoxy; and (x)-L 4 -L 5 -R i independently selected from the group consisting of: R 4 is H; and one to three independently selected R a C optionally substituted with 1~6 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; one to three 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 of 5 to 10 ring atoms, wherein 1 to 4 ring atoms are selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is a heteroatom selected from the group consisting of 1 to 4 independently selected C1~4 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 independently selected from the group consisting of: cycloalkenyl; R b Each occurrence of is selected from 1 to 6 independently selected R 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 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 1~4Haloalkoxy;-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; -C(=O)N(R')(R''); and -L 1 -L 2 -R h independently selected from the group consisting of: R d Ha, Halo, C 1~3 Alkoxy, C 1~3 Haloalkoxy, OH, and C 3~6 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl 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 N(R')(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 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 N(R')(R'');-S(O) 1~2 (C 1~4 alkyl); -OH; and C1~4 independently selected from the group consisting of 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 (a) H and C 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; -L 2 -O-, -N(H)-, -S(O) 0~2 - or in conjunction; 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 each optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; C 3~8 Cycloalkyl or C 3~8 cycloalkenyl; Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of halo; a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo; 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; and C 6~10 aryl, halo; one to two 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 is 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; C1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 each optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; C 3~8 Cycloalkyl or C 3~8 cycloalkenyl; Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of 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 of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 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; and C 6~10 aryl, halo; OH; NR e R f ; 1 to 2 independently selected R a C optionally substituted with1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 C is 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 of 5 to 10 ring atoms, wherein 1 to 4 ring atoms are selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 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 optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; or R' and R'' together with the nitrogen atom to which they are each attached form a ring of 3 to 8 ring atoms, wherein the ring is (a) H and C 1~3 (b) 1 to 7 ring carbon atoms, each substituted with 1 to 2 substituents independently selected from the group consisting of alkyl; and (b) N(H), N(C 1~6 and has 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 compound of formula (I): TIFF0007756643000037.tif44128, or a pharmaceutically acceptable salt thereof or a tautomer thereof, During the ceremony, X1 are O, S, N, NR 2 , and C.R. 1 selected from the group consisting of: X 2 are O, S, N, NR 4 , and C.R. 5 selected from the group consisting of: each TIFF0007756643000038.tif2128 are independently single or double bonds, provided that: X 1 and X 2 is a heteroaryl; 6-membered ring TIFF0007756643000039.tif30128 is aromatic; and P 1 , P 2 , P 3 , P 4 , and P 5 The ring containing is aromatic; P 1 , P 2 , P 3 , P 4 , and P 5 is defined according to (AA) or (BB): (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 , P4 , 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: 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 is; Each R 7 -R 8 and -L 3 -R 9 independently selected from the group consisting of: R 8 and R 9 teeth, (a) 1 to 4 independently selected R 7 ', each of which may be replaced by C 3~12 Cycloalkyl or C 3~12 cycloalkenyl; (b) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', optionally substituted with heterocyclyl or heterocycloalkenyl; (c) Heteroaryl of 5 to 12 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2and one or more ring carbon atoms of the heteroaryl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', optionally substituted with heteroaryl; and (d) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl independently selected from the group consisting of: -L 3 -O-, -CH2, -S-, -NH-, S(O) 1~2 , C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2, and S(O)2NH; R 7 Each occurrence of ' is selected from the group consisting of halo; -CN; -NO; -OH; and one to two independently selected R a may be substituted with -C 1~4 Alkyl;-C 2~4 Alkenyl;-C 2~4 Alkynyl;-C 1~4 haloalkyl; one to two 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''); 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) selected from the group consisting of: 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; R 1a , R 1b , R 1c , and R 1d Each of the groups is H; halo; cyano; one to 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;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);SF5;-NR e R f ;-OH;-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 R a may be substituted with -C(O)O(C1~4 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 independently selected from the group consisting of: R 4 is H; and one to three independently selected R a C optionally substituted with 1~6 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; one to three 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 1~4C optionally substituted with alkyl 6~10 aryl; and heteroaryl of 5 to 10 ring atoms, wherein 1 to 4 ring atoms are selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is a heteroatom selected from the group consisting of 1 to 4 independently selected C 1~4 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 each optionally substituted with alkyl, C 3~6 Cycloalkyl or C 3~6 independently selected from the group consisting of: cycloalkenyl; R b Each occurrence of is selected from 1 to 6 independently selected R 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 hindependently 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 1~4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); and -L 1 -L 2 -R h independently selected from the group consisting of: R d Ha, Halo, C 1~3 Alkoxy, C 1~3 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy 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 selected from the group consisting of alkoxy; R e and R f Each occurrence of H;C 1~6 Alkyl; C 1~6 Haloalkyl;C 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 independently selected from the group consisting of 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 (a) H and C 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; -L 2 -O-, -N(H)-, -S(O) 0~2 - or in conjunction; 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 each optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; C 3~8 Cycloalkyl or C 3~8 cycloalkenyl; Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of halo; 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 of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo; 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; and C 6~10 aryl, halo; one to two 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 is 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 C1~4 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 each optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; C 3~8 Cycloalkyl or C 3~8 cycloalkenyl; Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of 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 of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 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 1~4heteroaryl optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; C 6~10 aryl, 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 is 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 of 5 to 10 ring atoms, wherein 1 to 4 ring atoms are selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 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 haloalkyl; or R′ and R″, together with the nitrogen atom to which they are each attached, form a ring of 3 to 8 ring atoms, wherein the ring is selected from the group consisting of: (a) H and C 1~3 (b) 1 to 7 ring carbon atoms, each substituted with 1 to 2 substituents independently selected from the group consisting of alkyl; and (b) N(H), N(C 1~6 and has 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): TIFF0007756643000040.tif45128, or a pharmaceutically acceptable salt thereof or a tautomer thereof, X 1 are O, S, N, NR 2 , and C.R. 1 selected from the group consisting of: X 2 are O, S, N, NR 4 , and C.R. 5 selected from the group consisting of: each TIFF0007756643000041.tif2128 are independently single or double bonds, provided that: X 1 and X 2 is a heteroaryl; Six-membered rings are aromatic: TIFF0007756643000042.tif30128; and P 1 , P 2 , P 3 , P 4 , and P 5 The ring containing is aromatic; P 1 , P 2 , P 3 , P 4 , and P 5 is defined according to (AA) or (BB): (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: P 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 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 independently selected from the group consisting of: R 8 and R 9 teeth, (a) 1 to 4 independently selected R 7 ', each of which may be replaced by C 3~12 Cycloalkyl or C 3~12 cycloalkenyl; (b) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7', optionally substituted with heterocyclyl or heterocycloalkenyl; (c) Heteroaryl of 5 to 12 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heteroaryl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', optionally substituted with heteroaryl; and (d) 1 to 4 independently selected R 7 ' may be substituted with C 6~10 Aryl independently selected from the group consisting of: -L 3 -O-, -CH2, -S-, -NH-, S(O) 1~2 , C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O)2, and S(O)2NH; R 7 Each occurrence of ' is selected from the group consisting of halo; -CN; -NO; -OH; and one to two independently selected R a may be substituted with -C 1~4 Alkyl;-C 2~4 Alkenyl;-C 2~4 Alkynyl;-C 1~4 Haloalkyl; one to two 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''); 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) selected from the group consisting of: 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; R 1a , R 1b , R 1c , and R 1d Each of the groups is H; halo; cyano; one to 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;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);SF5;-NR e R f ;-OH;-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 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 independently selected from the group consisting of: R 4 is H; and one to three independently selected R a C optionally substituted with 1~6 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; one to three independently selected Ra 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 of 5 to 10 ring atoms, wherein 1 to 4 ring atoms are selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is a heteroatom selected from the group consisting of 1 to 4 independently selected C 1~4 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 independently selected from the group consisting of: cycloalkenyl; R b Each occurrence of is selected from 1 to 6 independently selected R 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 1~4alkyl);-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 independently selected from the group consisting of: R c Each occurrence of (a) halo; (b) cyano; (c) one to six 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 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 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 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 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 (a) H and C 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; -L 2 -O-, -N(H)-, -S(O) 0~2 - or in conjunction; 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 each optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; C 3~8 Cycloalkyl or C3~8 cycloalkenyl; Heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of halo; 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 of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo; 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; and C 6~10 aryl, halo; one to two 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 is 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)NRd , 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, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heterocyclyl or heterocycloalkenyl is selected from the group consisting of 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 of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is selected from the group consisting of halo; OH; NR e Rf ; 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; C 6~10 aryl, 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 is 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 of 5 to 10 ring atoms, wherein 1 to 4 ring atoms are selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 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 haloalkyl; or R′ and R″, together with the nitrogen atom to which they are each attached, form a ring of 3 to 8 ring atoms, wherein the ring is selected from the group consisting of: (a) H and C 1~3(b) 1 to 7 ring carbon atoms, each substituted with 1 to 2 substituents independently selected from the group consisting of alkyl; and (b) N(H), N(C 1~6 and has 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] In some embodiments, the following are provided: (a)X 1 NR 2 and X 2 is CH;R 1a , R 1b , R 1c , R 1d , and R 6 each of is H; W is C(=O); Q is NH; and P 1 , P 2 , P 3 , P 4 , and P 5 If is defined according to (AA), then · TIFF0007756643000043.tif18128 part TIFF0007756643000044.tif17128 is R 2 may not be CH2CH2OCH3, CH3, CH2CH3, or SO2-(p-tolyl); and -L 3 is -O-, -NH-, or C(=O), and · TIFF0007756643000045.tif18128 If the moiety is pyrimidinyl or pyridyl, use R 2 may be neither CH2CH2CH2N(CH3)2 nor CH2CH2CH2N(CH2CH3)2, and R 7 R 8 and R 8 is unsubstituted phenyl; and (b) The compound is It is not TIFF0007756643000046.tif82158 either.

[0079] Variable symbol P 1 , P 2 , P 3 , P 4 , and P 5 P 1 、P 2 、P 3 、P 4 , and P 5 When is defined according to (AA) In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 is defined according to (AA).

[0080] In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 One of them is N.

[0081] In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 Two of them are N.

[0082] 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:

[0083] In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 One of them is CR 7 is.

[0084] In some of these embodiments, P 3 is CR 7 is.

[0085] In some embodiments, P 4 is N. In certain embodiments, P 3 is CR 7 and P 4 is N.

[0086] In some embodiments, P 1 , P 2 , and P 5 are CH and CR c In certain embodiments, P 3 is CR 7 And ;P 4 is N; and P 1 , P 2 , and P 5 are CH and CR c are independently selected from the group consisting of:

[0087] In some embodiments, P 1 , P 2 , and P 5 one of which is N; and P 1 , P 2 , and P 5 The remaining ones are CH and CR c In certain embodiments, P 3 is CR 7 And ;P 4 is N; and P 1 , P 2 , and P 5 one of which is N; and P 1 , P 2 , and P 5 The remaining ones are CH and CR c are independently selected from the group consisting of:

[0088] In some embodiments, P 1 is N.

[0089] In some of these embodiments, P 2 , P 4 , and P 5 are CH and CR c are independently selected from the group consisting of:

[0090] In certain other embodiments, P 2 , P 4 , and P 5 one of which is N; and P 2 , P 4 , and P 5 The remaining ones are CH and CR c are independently selected from the group consisting of:

[0091] In certain embodiments, P 3 is CR 7 And ;P 4 is N; and P 1 , P 2 , and P 5 are CH and CR c are independently selected from the group consisting of:

[0092] In certain embodiments, P 3 is CR 7 And ;P 4 is N;P 1 is N; and P 2 and P 5 are CH and CR c are independently selected from the group consisting of:

[0093] In certain embodiments, P 3 is CR 7 And ;P 4 is N;P 5 is N; and P 2 and P 1 are CH and CR c are independently selected from the group consisting of:

[0094] In certain embodiments, P 3 is CR 7 and P 1, P 2 , P 4 and P 5 are CH and CR c are independently selected from the group consisting of:

[0095] In certain embodiments, P 3 is CR 7 And ;P 1 is N; and P 2 , P 4 , and P 5 are CH and CR c are independently selected from the group consisting of:

[0096] In certain embodiments, P 3 is CR 7 And ;P 4 and P 2 is N; and P 1 and P 5 are CH and CR c are independently selected from the group consisting of:

[0097] In some embodiments, P 4 is CR 7 is.

[0098] In some of these embodiments, P 1 , P 2 , P 3 , and P 5 are N, CH, and CR, respectively. c Non-limiting examples include P 1 , P 2 , P 3 , and P 5 are CH and CR c and the hydroxyl group may be independently selected from the group consisting of:

[0099] In certain other embodiments, P 1 , P 2 , P 3 , and P 5 one of which is N; and 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:

[0100] In certain embodiments, P 4 is CR 7 And ;P 3 is N; and P 1 , P 2 , and P 5 are CH and CR c are independently selected from the group consisting of:

[0101] In certain embodiments, P 4 is CR 7 And ;P 2 is N; and P 1 , P 3 , and P 5 are CH and CR c are independently selected from the group consisting of:

[0102] P 1 、P 2 、P 3 、P 4 , and P 5 When is defined according to (BB) In some embodiments, P 1 , P 2 , P 3 , P 4 , and P 5 is defined according to (BB).

[0103] 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 some of these embodiments, each of the remaining P 2 , P 3, P 4 , and P 5 , CH, CR c , S, N, NH, and NR d independently selected from the group consisting of: 2 , P 3 , P 4 , and P 5 1 to 3 (e.g., 1 to 2) of the d is.

[0104] In certain embodiments, P 3 is CR 7 or NR 7 and P 2 , P 4 , and P 5 are O, S, N, NH, and NR d , CH, and CR c independently selected from the group consisting of: 2 , P 3 , P 4 , and P 5 1 to 3 of these are O, S, N, NH, NR d , or NR 7 is.

[0105] In some of these embodiments, P 3 is NR 7 and P 2 , P 4 , and P 5 are O, S, N, NH, and NR d , CH, and CR c are independently selected from the group consisting of:

[0106] In some of the aforementioned embodiments, P 3 is NR 7 and P 2 , P 4 , and P 5 are N, CH, and CR, respectively. c are independently selected from the group consisting of:

[0107] In certain embodiments, P 3 is NR7 And ;P 2 is CH or CR c (e.g., CH); P 4 is N; and P 5 is CH or CR c (e.g., CH).

[0108] In certain embodiments, P 3 is NR 7 And ;P 2 is N;P 4 is CH or CR c , for example CH; and P 5 is CH or CR c , for example CH.

[0109] In certain embodiments, P 3 is NR 7 And ;P 2 is CH or CR c , for example, C;P 4 is CH or CR c , for example CH; and P 5 is N.

[0110] In certain embodiments, P 3 is CR 7 and P 2 , P 4 , and P 5 Each of these is CH, CR c , S, N, NH, and NR d independently selected from the group consisting of: 2 , P 4 , and P 5 One to two (e.g., two) of the d is.

[0111] In certain embodiments, P 3 is CR 7 And ;P 2 NH, NR d or S (e.g., S); P 5 is N; and P 4 is CH or CR c(e.g., CH).

[0112] In certain embodiments, P 3 is CR 7 And ;P 2 NH, NR d , or S (e.g., S); P 5 is CH or CR c and P 4 is N.

[0113] P 1 、P 2 、P 3 、P 4 , and P 5 Non-limiting combinations of In some aspects, The TIFF0007756643000047.tif18128 part is the formula: TIFF0007756643000048.tif14128, where n2 is 0, 1, or 2.

[0114] In certain embodiments, The TIFF0007756643000049.tif18128 part is the formula: I have TIFF0007756643000050.tif14128.

[0115] In certain embodiments, The TIFF0007756643000051.tif18128 part is the formula: I have TIFF0007756643000052.tif16128.

[0116] In some aspects, The TIFF0007756643000053.tif18128 part is the formula: TIFF0007756643000054.tif13128, where n2 is 0, 1, or 2.

[0117] In some of these aspects, The TIFF0007756643000055.tif18128 part is the formula: I have TIFF0007756643000056.tif13128.

[0118] In certain embodiments, The TIFF0007756643000057.tif18128 part is the formula: I have TIFF0007756643000058.tif15128.

[0119] In some aspects, The TIFF0007756643000059.tif18128 part is the formula: TIFF0007756643000060.tif15128, where n2 is 0, 1, or 2.

[0120] In some aspects, The TIFF0007756643000061.tif18128 part is the formula: TIFF0007756643000062.tif14128, where n2 is 0, 1, or 2.

[0121] In some of these aspects, The TIFF0007756643000063.tif18128 part is the formula: I have TIFF0007756643000064.tif23128.

[0122] In some aspects, The TIFF0007756643000065.tif18128 part is the formula: TIFF0007756643000066.tif14128, where n2 is 0, 1, or 2.

[0123] In some aspects, The TIFF0007756643000067.tif18128 part is the formula: TIFF0007756643000068.tif21128, where n2 is 0, 1, or 2.

[0124] In some of these aspects, The TIFF0007756643000069.tif18128 part is the formula: I have TIFF0007756643000070.tif24128.

[0125] In certain embodiments, The TIFF0007756643000071.tif18128 part is the formula: I have TIFF0007756643000072.tif21128.

[0126] In some aspects, The TIFF0007756643000073.tif18128 part is the formula: I have TIFF0007756643000074.tif21128.

[0127] In some of these aspects, The TIFF0007756643000075.tif18128 part is the formula: I have TIFF0007756643000076.tif21128.

[0128] In some aspects, The TIFF0007756643000077.tif18128 part is the formula: TIFF0007756643000078.tif14128, where n2 is 0 or 1, for example 0.

[0129] In some of these aspects, The TIFF0007756643000079.tif18128 part is the formula: I have TIFF0007756643000080.tif13128.

[0130] In some aspects, The TIFF0007756643000081.tif18128 part is the formula: TIFF0007756643000082.tif13128, where n2 is 0 or 1, for example 0.

[0131] In some aspects, The TIFF0007756643000083.tif18128 part is the formula: TIFF0007756643000084.tif14128, where n2 is 0 or 1, for example 0.

[0132] Variable symbol R 7 In some embodiments, R 7 is R 8 is.

[0133] In some embodiments, R 8 teeth, (a) 1 to 4 independently selected R 7 ', each of which may be replaced by C 3~12 Cycloalkyl or C 3~12 cycloalkenyl; and (b) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring or heterocycloalkenyl ring are each 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:

[0134] In certain embodiments, R 8 teeth, (a) 1 to 4 independently selected R 7 ', each of which is replaced by C 3~12 Cycloalkyl or C 3~12 cycloalkenyl; and (b) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring or heterocycloalkenyl ring are each 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:

[0135] In certain embodiments, R 8 is one to four independently selected R 7 ', each of which is replaced by C 3~12 Cycloalkyl or C 3~12 It is a cycloalkenyl.

[0136] In certain embodiments, R 8 is one to four independently selected R 7 ', each of which is replaced by C 4~10 Cycloalkyl or C 4~10 It is a cycloalkenyl.

[0137] In some of these aspects, R 8 is one to four independently selected R 7 ', each of which is replaced by C 4~8 Cycloalkyl or C 4~8 It is a cycloalkenyl.

[0138] In some of these aspects, R 8 is one to four independently selected R 7 ', C 4~8 It is cycloalkyl.

[0139] In certain embodiments, R 8 is 1 to 3 R 7 ', C 4~8 It is cycloalkyl.

[0140] In some of these aspects, R 8 is one to three (e.g., one or two) R 7 ', and cyclohexyl.

[0141] As a non-limiting example of the foregoing embodiment, R 8 teeth It could be TIFF0007756643000085.tif24128.

[0142] In certain embodiments, R 8 is one to three (e.g., one or two) R 7 ', cyclobutyl.

[0143] As a non-limiting example of the foregoing embodiment, R 8 teeth It could be TIFF0007756643000086.tif21128.

[0144] Another non-limiting example is R 8 teeth It could be TIFF0007756643000087.tif25128.

[0145] In certain embodiments, R 8 is one to four independently selected R 7 ', spirocyclic C 6~12 In some of these embodiments, R is cycloalkyl. 8 teeth TIFF0007756643000088.tif28128.

[0146] In certain embodiments, R 8 is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 It has been replaced with '.

[0147] In certain embodiments, R 8 is a heterocyclyl or heterocycloalkenyl of 4 to 10 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 It has been replaced with '.

[0148] In certain embodiments, R 8 is a heterocyclyl or heterocycloalkenyl of 4 to 8 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 It has been replaced with '.

[0149] In some of these aspects, R 8 is a heterocyclyl of 4 to 8 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 It has been replaced with '.

[0150] In certain embodiments, R 8 is a heterocyclyl of 4-6 ring atoms, where 1-2 ring atoms are N, N(H), N(R d), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 3 independently selected R 7 It has been replaced with '.

[0151] In some of these aspects, R 8 is one to three (e.g., one or two) independently selected R 7 The aryl group is selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, dioxanyl (eg, 1,3-dioxanyl), piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, each of which is substituted by '.

[0152] In some of the foregoing embodiments, R 8 is one to three (e.g., one or two) independently selected R 7 and n is 0 or 1. The radicals are selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, each of which is substituted by '.

[0153] In certain embodiments, R 8 is one to three (e.g., one or two) independently selected R 7 ' is selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl, each of which is substituted with '.

[0154] In certain embodiments, R 8 is one to three (e.g., one or two) independently selected R 7 The aryl group is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl, each of which is substituted by '.

[0155] As a non-limiting example, R 8 teeth, TIFF0007756643000089.tif24128.

[0156] As a non-limiting example of the foregoing embodiment, R 8 teeth, TIFF0007756643000090.tif24128.

[0157] As a further non-limiting example, R 8 teeth, TIFF0007756643000091.tif44167.

[0158] Another non-limiting example is R 8 teeth, TIFF0007756643000092.tif25128 and TIFF0007756643000093.tif21128 (e.g., R 7 ' is C 1~4 haloalkyl, e.g., -CF3 TIFF0007756643000094.tif21128).

[0159] Another non-limiting example is R 8 is R 8 R 8 teeth It could be TIFF0007756643000095.tif24128.

[0160] As a further non-limiting example, R 8 teeth, TIFF0007756643000096.tif53166, wherein R d2 is H or R d is.

[0161] In certain embodiments, R 8 is a spirocyclic heterocyclyl of 6-12 ring atoms, where 1-3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0~2and wherein one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 It may be substituted with '.

[0162] In some of the foregoing embodiments, R 8 is one to four independently selected R 7 and 2,6-diazaspiro[3.3]heptanyl, 1-oxa-9-azaspiro[5.5]undecanyl, 6-azaspiro[2.5]octanyl, 1,5-dioxaspiro[5.5]undecanyl, 7-azaspiro[3.5]nonanyl, and 2,6-diazaspiro[3.3]heptanyl, each of which is optionally substituted by R d may be substituted with.

[0163] In some of these aspects, R 8 is one to four independently selected R 7 2-azaspiro[3.3]heptanyl, 1-oxa-9-azaspiro[5.5]undecanyl, and 6-azaspiro[2.5]octanyl, each of which is optionally substituted by 2-azaspiro[3.3]heptanyl, 1-oxa-9-azaspiro[5.5]undecanyl, and 6-azaspiro[2.5]octanyl.

[0164] As a non-limiting example of the foregoing embodiment, R 8 teeth TIFF0007756643000097.tif26128, for example, It could be TIFF0007756643000098.tif26128.

[0165] As a further non-limiting example, R 8 teeth, TIFF0007756643000099.tif31136.

[0166] As a further non-limiting example, R 8 teeth It could be TIFF0007756643000100.tif34128.

[0167] As a further non-limiting example, R 8 teeth TIFF0007756643000101.tif27128, and optionally R d Ha, Halo, C 1~3 Alkoxy, and C 1~3 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~6 alkyl, for example, where R d C is substituted with one to three independently selected halo groups. 2~4 Alkyl The file is TIFF0007756643000102.tif12128.

[0168] In certain embodiments, R 8 is a bridged heterocyclyl of 6 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 For example, R 8 is one or two R at one or more ring carbon atoms. 7 may be substituted with ' It could be TIFF0007756643000103.tif17128.

[0169] In certain embodiments, R 8 is unsubstituted C 3~12 Cycloalkyl or C 3~12 It is a cycloalkenyl.

[0170] In some of these aspects, R 8 is unsubstituted C 3~8 (For example, C 3~5 or C 7~8 ) monocyclic cycloalkyl. For example, R 8 is unsubstituted C 4~6It can be a monocyclic cycloalkyl, such as cyclobutyl or cyclopentyl. As another non-limiting example, R 8 can be cyclohexyl.

[0171] In certain embodiments, R 8 is unsubstituted C 7~12 It is a bicyclic cycloalkyl.

[0172] In some of these aspects, R 8 is unsubstituted C 7~12 As a non-limiting example of the foregoing embodiment, R 8 teeth It could be TIFF0007756643000104.tif22128.

[0173] In certain embodiments, R 8 is unsubstituted C 7~12 A non-limiting example of the foregoing embodiment is R 8 teeth It could be TIFF0007756643000105.tif13128.

[0174] In certain embodiments, R 8 is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 are heteroatoms independently selected from the group consisting of:

[0175] In certain embodiments, R 8 is a monocyclic heterocyclyl of 3 to 8 ring atoms, where 1 to 2 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 are heteroatoms independently selected from the group consisting of:

[0176] In some of these aspects, R 8is selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, and oxepanyl, wherein the ring nitrogen atom is R d may be substituted with.

[0177] In some of the foregoing embodiments, R 8 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxepanyl, where the ring nitrogen atom is R d may be substituted with.

[0178] As a non-limiting example of the foregoing embodiment, R 8 is morpholinyl, piperidinyl (e.g., TIFF0007756643000106.tif25128, etc. TIFF0007756643000107.tif23128), or oxepanyl, where the ring nitrogen atom is R d may be substituted with.

[0179] In certain embodiments, R 8 Azetidinyl TIFF0007756643000108.tif22128, Pyrrolidinyl TIFF0007756643000109.tif21128, piperidinyl (e.g., TIFF0007756643000110.tif25128, etc. TIFF0007756643000111.tif23128), or piperazinyl TIFF0007756643000112.tif24128, where the ring nitrogen atom is R d may be substituted with Arbitrarily, here R d Ha, Halo, C 1~3 Alkoxy, and C 1~3 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~6alkyl, for example, where R d C is substituted with one to three independently selected halo groups. 2~4 Alkyl The file is TIFF0007756643000113.tif12128.

[0180] In certain embodiments, R 8 is pyrrolidinyl, piperidinyl, or piperazinyl, where the ring nitrogen atom is R d may be substituted with.

[0181] In some of these aspects, R 8 is piperidinyl (e.g., TIFF0007756643000114.tif25128, etc. TIFF0007756643000115.tif23128), or piperazinyl TIFF0007756643000116.tif24128, where the ring nitrogen atom is R d optionally substituted with, where R d Ha, Halo, C 1~3 Alkoxy, C 1~3 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~6 alkyl, for example, where R d C is substituted with one to three independently selected halo groups. 2~4 Alkyl The file is TIFF0007756643000117.tif9128.

[0182] In certain embodiments, R 8 teeth, m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; and T 2 CH2, NH, NR d , or O, TIFF0007756643000118.tif51128; Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 spirocyclic heterocyclyl, optionally substituted by '; and 1 to 4 independently selected R 7 Optionally substituted by ', spirocyclic C 6~12 cycloalkyl selected from the group consisting of Arbitrarily, where each R 7 ' is C 1~3 Alkyl; C 1~3 haloalkyl; and halo, e.g., where each R 7 ' are independently selected from the group consisting of methyl, CF3, and -F; and Arbitrarily, here R d is optionally substituted with 1 to 3 independently selected halo, e.g., —F; C 1~6 Alkyl, e.g., C 2~4 It is alkyl.

[0183] In certain embodiments, R 8 teeth, m1 and m2 are independently 0, 1, or 2; and T 1 is CH or N; TIFF0007756643000119.tif24128; and Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', spirocyclic heterocyclyl, for example, TIFF0007756643000120.tif26128; Arbitrarily, where each R 7 ' is C 1~3 independently selected from the group consisting of alkyl and halo, e.g., methyl and -F; and optionally wherein R d is optionally substituted with 1 to 3 independently selected halo, e.g., —F; C 1~6 Alkyl, e.g., C 2~4 It is alkyl.

[0184] In some of these aspects, R 8 teeth, TIFF0007756643000121.tif58166.

[0185] In certain embodiments, R 8 teeth TIFF0007756643000122.tif22128, where m1 and m2 are independently 0, 1, or 2, and T 1 is CH or N, for example, R 8 teeth, Selected from the group consisting of TIFF0007756643000123.tif24128; Arbitrarily, where each R 7 ' is C 1~3 Alkyl; C 1~3 haloalkyl; and halo, e.g., where each R 7 ' are independently selected from the group consisting of methyl, CF3, and -F, e.g., where each R 7 ' is an independently selected halo, e.g., -F.

[0186] In certain embodiments, R 8 teeth TIFF0007756643000124.tif23128, where m1 and m2 are independently 0, 1, or 2, and T 1 is CH or N, e.g., R 8 teeth, Selected from the group consisting of TIFF0007756643000125.tif24128; Arbitrarily, here R d is optionally substituted with 1 to 3 independently selected halo, e.g., —F; C 1~6 Alkyl, e.g., C 2~4 It is alkyl.

[0187] In certain embodiments, R 8 teeth, TIFF0007756643000126.tif24128, wherein m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; and T 2 are CH2, NH, NR d or O; e.g., R 8 teeth, Selected from the group consisting of TIFF0007756643000127.tif24128; Arbitrarily, where each R 7 ' is C 1~3 Alkyl and C 1~3 haloalkyl.

[0188] In certain embodiments, R 8 teeth, Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 spirocyclic heterocyclyl, optionally substituted by '; and 1 to 4 independently selected R 7 Optionally substituted by ', spirocyclic C 6~12 cycloalkyl selected from the group consisting of Arbitrarily, where each R 7 ' is C 1~3 Alkyl; C 1~3haloalkyl; and halo, e.g., where each R 7 ' are independently selected from the group consisting of methyl, CF3, and -F.

[0189] In some of these aspects, R 8 teeth TIFF0007756643000128.tif31128, wherein m1, m2, m3, and m4 are independently 0, 1, or 2, provided that m1+m2+m3+m4≦6, and T 1 is CH or N, e.g., R 8 teeth, Selected from the group consisting of TIFF0007756643000129.tif31128; Arbitrarily, where each R 7 ' is C 1~3 Alkyl; C 1~3 haloalkyl; and halo, e.g., where each R 7 ' are independently selected from the group consisting of methyl, CF3, and -F, e.g., where each R 7 ' is an independently selected halo, e.g., -F.

[0190] In certain embodiments, R 8 teeth TIFF0007756643000130.tif30128, wherein m1, m2, m3, and m4 are independently 0, 1, or 2, provided that m1+m2+m3+m4≦6, and T 1 is CH or N, e.g., R 8 teeth TIFF0007756643000131.tif27128; Arbitrarily, here R d is optionally substituted with 1 to 3 independently selected halo, e.g., —F; C 1~6 Alkyl, e.g., C 2~4 It is alkyl.

[0191] In certain embodiments, R 8 teeth TIFF0007756643000132.tif31128, where m3 and m4 are independently 0, 1, or 2, provided that m3 + m4 ≦ 4, e.g., R 8 teeth TIFF0007756643000133.tif33128; Arbitrarily, where each R 7 ' is C 1~3 Alkyl; C 1~3 haloalkyl; and halo, e.g., where each R 7 R′ is independently selected from the group consisting of methyl, CF3, and —F, e.g., where each R 7 ' is an independently selected halo, e.g., -F.

[0192] In certain embodiments, R 8 is a bicyclic or polycyclic heterocyclyl or heterocycloalkenyl of 7 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 are heteroatoms independently selected from the group consisting of:

[0193] In some of these aspects, R 8 is a bicyclic or polycyclic heterocyclyl of 7 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 are heteroatoms independently selected from the group consisting of:

[0194] As a non-limiting example of the foregoing embodiment, R 8 teeth It could be TIFF0007756643000134.tif21128.

[0195] In certain embodiments, R 8 is a heteroaryl of 5 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2and wherein one or more ring carbon atoms of the heteroaryl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 It may be substituted with '.

[0196] In certain embodiments, R 8 is a heteroaryl of 5-6 ring atoms, where 1-3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heteroaryl ring are each independently selected from the group consisting of 1 to 2 independently selected R 7 It may be substituted with '.

[0197] In some of these aspects, R 8 is a heteroaryl of 5 ring atoms, where 1-3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heteroaryl ring are each independently selected from the group consisting of 1 to 2 independently selected R 7 It may be substituted with '.

[0198] In some of the foregoing embodiments, R 8 is one to two independently selected R 7 ', and one R at the ring nitrogen atom d and pyrazolyl, imidazolyl, thiazolyl, oxazolyl, triazolyl, optionally substituted by.

[0199] As a non-limiting example of the foregoing embodiment, R 8 is one to two independently selected R 7 ', optionally substituted thiazolyl It could be TIFF0007756643000135.tif16128.

[0200] In certain embodiments, R8 is a bicyclic heteroaryl of 7 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heteroaryl ring are each independently selected from the group consisting of 1 to 2 independently selected R 7 It may be substituted with '.

[0201] As a non-limiting example of the foregoing embodiment, R 8 teeth It could be TIFF0007756643000136.tif23128.

[0202] In certain embodiments, R 8 is one to four independently selected R 7 ' may be substituted with C 6~10 It is aryl.

[0203] In some of these aspects, R 8 is one to two independently selected R 7 ' is optionally substituted phenyl (for example, unsubstituted phenyl).

[0204] In some embodiments, R 7 Ha-L 3 -R 9 is.

[0205] In some of these embodiments, -L 3 is -O-. In certain embodiments, -L 3 is -NH-. In certain embodiments, -L 3 is -S- or S(O) 1~2 In certain embodiments, -L 3 is -CH2-. 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. 3 is C 1~4 Alkylene, e.g. CH2 or TIFF0007756643000137.tif9128, where aa is R 9 It is the connection point to

[0206] Specific Aspects (R 7 Ga-L 3 -R 9 In this case, R 9 teeth, (a) 1 to 4 independently selected R 7 ', each of which may be replaced by C 3~12 Cycloalkyl or C 3~12 cycloalkenyl, and (b) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring or heterocycloalkenyl ring are each 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:

[0207] In certain embodiments, R 9 is one to four independently selected R 7 ', each of which may be replaced by C 3~12 Cycloalkyl or C 3~12 It is a cycloalkenyl.

[0208] In some of these aspects, R 9 is 1 to 2 R 7 Optionally substituted with C 4~8 It is cycloalkyl.

[0209] As a non-limiting example, R 9 is 1 to 2 R 7' may be cyclobutyl, cyclopentyl, cyclohexyl, or spiro[3.3]heptanyl, each of which may be substituted (eg, unsubstituted).

[0210] In certain embodiments, R 9 is a heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 It may be substituted with '.

[0211] In some of these aspects, R 9 is a heterocyclyl of 4 to 8 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 2 independently selected R 7 It may be substituted with '.

[0212] As a non-limiting example of the foregoing embodiment, R 9 is one to two independently selected R 7 and azepinyl, each of which is optionally substituted (eg, unsubstituted) by '.

[0213] In certain embodiments, R 7 is L 3 -R 9 and;L 3 is -O- or -NH-; and R 9 teeth, 1-2 R 7 Optionally substituted with C 4~8 cycloalkyl; and Heterocyclyl of 4 to 8 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 2 independently selected R 7 Optionally substituted heterocyclyl is selected from the group consisting of:

[0214] In some of these aspects, R 7 is L 3 -R 9 and;L 3 is -O- or -NH-; and R 9 is one to two independently selected R 7 cyclobutyl, cyclopentyl, cyclohexyl, and oxetanyl, each of which may be substituted (e.g., unsubstituted) by L'. 3 can be -O-.

[0215] R 7 Ga-L 3 -R 9 If R 7 Non-limiting examples of TIFF0007756643000138.tif65157 is an example.

[0216] In certain embodiments, The TIFF0007756643000139.tif18128 part is the formula: TIFF0007756643000140.tif19128, where n2 is 0, 1, or 2; and R 7 is R 8 where R 8 teeth, 1 to 4 independently selected R 7 Optionally substituted with C 4~8 cycloalkyl; and Heterocyclyl of 4 to 12 (e.g., 4 to 8) ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 Optionally substituted heterocyclyl is selected from the group consisting of:

[0217] In certain embodiments, The TIFF0007756643000141.tif18128 part is the formula: TIFF0007756643000142.tif23165, where n2 is 0, 1, or 2; and R 7 is R 8 where R 8 teeth, 1 to 4 independently selected R 7 Optionally substituted with C 4~8 cycloalkyl; and Heterocyclyl of 4 to 12 (e.g., 4 to 8) ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 Optionally substituted heterocyclyl is selected from the group consisting of:

[0218] In certain embodiments, The TIFF0007756643000143.tif18128 part is the formula: TIFF0007756643000144.tif26164, where n2 is 0, 1, or 2; and R 7 is R 8 where R 8 teeth, 1 to 4 independently selected R 7Optionally substituted with C 4~8 cycloalkyl; and Heterocyclyl of 4 to 8 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 Optionally substituted heterocyclyl is selected from the group consisting of:

[0219] In certain embodiments, The TIFF0007756643000145.tif18128 part is the formula: TIFF0007756643000146.tif14128, where n2 is 0 or 1 (e.g., 0); and R 7 is R 8 where R 8 teeth, 1 to 4 independently selected R 7 Optionally substituted with C 4~8 cycloalkyl; and Heterocyclyl of 4 to 8 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 Optionally substituted heterocyclyl is selected from the group consisting of:

[0220] Specific aspects ( The TIFF0007756643000147.tif18128 part is the formula: TIFF0007756643000148.tif47152), n2 is 0.

[0221] Specific aspects ( The TIFF0007756643000149.tif18128 part is the formula: TIFF0007756643000150.tif47152), n2 is 1.

[0222] In some of these aspects, R c is R 7 It is located ortho to the

[0223] Specific aspects ( The TIFF0007756643000151.tif18128 part is the formula: TIFF0007756643000152.tif47152) in R 7 is R 8 and R 8 is 1 to 3 R 7 C replaced with ' 4~8 It is cycloalkyl.

[0224] In some of these aspects, R 8 is 1 to 3 R 7 cyclohexyl substituted with ', e.g. TIFF0007756643000153.tif23128. In certain embodiments, R 8 is 1 to 3 R 7 'substituted cyclobutyl, e.g. TIFF0007756643000154.tif19128, for example The file is TIFF0007756643000155.tif18128.

[0225] Specific aspects ( The TIFF0007756643000156.tif18128 part is the formula: TIFF0007756643000157.tif47152) in R 7 is R 8 and R 8 is a heterocyclyl of 4 to 8 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O)0~2 and wherein one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 It has been replaced with '.

[0226] In some of these aspects, R 8 is a heterocyclyl of 4-6 ring atoms, where 1-2 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 3 independently selected R 7 It has been replaced with '.

[0227] In certain embodiments, R 8 is one to three (e.g., one or two) independently selected R 7 and n is 0 or 1. The radicals are selected from the group consisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl, each of which is substituted by '.

[0228] In certain embodiments, R 8 is two to four (e.g., two) independently selected R 7 ' is selected from the group consisting of azetidinyl, pyrrolidinyl, and piperidinyl, each of which is substituted with '.

[0229] As a non-limiting example of the foregoing embodiment, R 8 teeth, TIFF0007756643000158.tif78169. For example, R 8 teeth It could be TIFF0007756643000159.tif24140.

[0230] Specific aspects ( The TIFF0007756643000160.tif18128 part is the formula: TIFF0007756643000161.tif47152) in R 7 is R 8 and R 8 is a spirocyclic heterocyclyl of 6 to 12 (e.g., 6 to 8) ring atoms, e.g., TIFF0007756643000162.tif28128, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 It has been replaced with '.

[0231] Specific aspects ( The TIFF0007756643000163.tif18128 part is the formula: TIFF0007756643000164.tif47152) in R 7 is R 8 and R 8 is a heterocyclyl of 4 to 8 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 are heteroatoms independently selected from the group consisting of 8 is the ring N(R d ) groups.

[0232] In some of these aspects, R 8 is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and 2,6-diazaspiro[3.3]heptanyl, wherein the ring nitrogen atom is R d are substituted with, for example, R 8 teeth TIFF0007756643000165.tif28128, and optionally R d Ha, Halo, C 1~3 Alkoxy, and C 1~3C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~6 alkyl, for example, where R d C is substituted with one to three independently selected halo groups. 2~4 Alkyl The file is TIFF0007756643000166.tif12128.

[0233] Specific aspects ( The TIFF0007756643000167.tif18128 part is the formula: TIFF0007756643000168.tif15128) in R 7 is R 8 and R 8 is unsubstituted C 4~6 monocyclic cycloalkyl (e.g., cyclopentyl, cyclobutyl, or cyclohexyl); or R 8 is unsubstituted C 7~8 Bicyclic (e.g., spirocyclic) cycloalkyl The file is TIFF0007756643000169.tif23128.

[0234] In certain embodiments, The TIFF0007756643000170.tif18128 part is the formula: TIFF0007756643000171.tif14128, 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, 1-2 R 7 Optionally substituted with C 4~8 cycloalkyl; and Heterocyclyl of 4 to 8 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 2 independently selected R 7 Optionally substituted heterocyclyl is selected from the group consisting of:

[0235] In certain embodiments, The TIFF0007756643000172.tif18128 part is the formula: TIFF0007756643000173.tif14128, 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, 1-2 R 7 Optionally substituted with C 4~8 cycloalkyl; and Heterocyclyl of 4 to 8 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 2 independently selected R 7 Optionally substituted heterocyclyl is selected from the group consisting of:

[0236] Specific aspects ( The TIFF0007756643000174.tif18128 part is the formula: TIFF0007756643000175.tif15128) in R 7 is L 3 -R 9 and;L 3 is -O- or -NH-; and R 9 is one to two independently selected R 7In some of these embodiments, L is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and oxetanyl, each of which is optionally substituted (e.g., unsubstituted) by . 3 is -O-.

[0237] Specific aspects ( The TIFF0007756643000176.tif18128 part is the formula: TIFF0007756643000177.tif15128), R 7 teeth TIFF0007756643000178.tif50158.

[0238] Variable symbol R 7 ' In certain embodiments, each R 7 ', if present, halo, -CN, -OH, R a may be substituted with -C 1~4 Alkyl, -C 1~4 Haloalkyl, R a may be substituted with -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″).

[0239] In certain embodiments, each R 7 ', if present, halo, -CN, R a may be substituted with -C 1~4 Alkyl, -C 1~4 Haloalkyl, R a may be substituted with -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″).

[0240] In certain embodiments, each R 7 ', if present, is independently halo. For example, each R 7 ', if present, may be -F.

[0241] In certain embodiments, each R 7 ', if present, independently C 1~3 Alkyl, for example methyl.

[0242] In certain embodiments, each R 7 ', if present, are independently selected C 1~3 Haloalkyl, for example -CF3.

[0243] In certain embodiments, R 7 One occurrence of 'R' a may be substituted with -C 1~4 Alkyl, e.g., unsubstituted C 1~4 alkyl (e.g., methyl, ethyl, n-propyl) or R 7 ' is R a -C is substituted with 1~4 Alkyl (e.g., OH or C 3~6 -C substituted with cycloalkyl 1~4 alkyl).

[0244] In certain embodiments, R 7 One occurrence of ' is -CN.

[0245] In certain embodiments, R 7 One occurrence of 'R' a C optionally substituted with 1~6 Alkoxy, e.g., unsubstituted C1~6 alkoxy (e.g., methoxy); or R a C is replaced by 1~6 Alkoxy (e.g., OH or C 3~6 -C substituted with cycloalkyl 1~4 alkoxy).

[0246] R 7 In some of the aforementioned aspects of one occurrence of 'R 7 Each remaining occurrence of ', if present, is independently halo (eg, -F).

[0247] In certain embodiments, each R c is, if present, (a) halo; (b) cyano; (c) one to six independently selected R a C optionally substituted with 1~10 Alkyl; (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; and (r) —C(═O)N(R′)(R″).

[0248] In certain embodiments, each R c is, when present, (a) halo; (b) cyano; (c) C optionally substituted with 1 to 6 independently selected -F or -Cl; 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).

[0249] In certain embodiments, each R c Halo, Cyano, C 1~3 Alkyl, and C 1~3 alkoxy is independently selected from the group consisting of:

[0250] In certain embodiments, each R c are independently selected halo (e.g., —F or —Cl), C 1~4 alkyl (e.g., CH), or CF. For example, each R c As another non-limiting example, each R c can be —Cl.

[0251] Variable symbols Q and W In some embodiments, Q is NH.

[0252] In some embodiments, Q is N(C 1~3 alkyl), where C 1~3 Alkyl is one to two independently selected R a (e.g., Q is NMe or NCH2CH2CH2OH).

[0253] In some embodiments, Q is —NH—(C 1~3 alkylene)-, where the asterisk indicates the point of attachment to W.

[0254] In some embodiments, W is C(=O).

[0255] In some embodiments, W is S(O)2, C(=S), or C(=NR d )

[0256] In some embodiments, W is C(=C-NO2) or C(=N-CN).

[0257] In certain embodiments, Q is NH; and W is C(=O).

[0258] Variable symbol X 1 , X2 In some embodiments, X 1 is NR 2 In certain embodiments, X 1 is NH.

[0259] In some embodiments, X 2 is CR 5 In certain embodiments, X 2 is CH.

[0260] In certain embodiments, X 1 is NR 2 and X 2 is CR 5 In some of these embodiments, X 1 is NH; and X 2 is CH.

[0261] R 1a , R 1b , R 1c , and R 1d In some embodiments, R 1a , R 1b , R 1c , and R 1d Each of the groups is H; halo; cyano; one to 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;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);SF5;-NR e R f ;-OH;-S(O) 1~2 (NR'R'');-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl);-C(=O)O(C 1~4 alkyl); and —C(═O)N(R′)(R″).

[0262] In certain embodiments, R 1a , R 1b , R 1c , and R 1d Each of is H.

[0263] In certain other embodiments, R 1a , R 1b , R 1c , and R 1d one or two of which are other than H; and R 1a , R 1b , R 1c , and R 1d The rest of each is H.

[0264] In certain embodiments, R 1a , R 1b , R 1c , and R 1d one of which is other than H; and R 1a , R 1b , R 1c , and R 1d The rest of each is H.

[0265] In certain embodiments, R 1a , R 1b , R 1c , and R 1d two of which are other than H; and R 1a , R 1b , R 1c , and R 1d The rest of each is H.

[0266] In certain embodiments, R 1a is H or halo. For example, R 1a can be H.

[0267] In certain embodiments, R 1d is H or halo. For example, R 1d can be H.

[0268] In certain embodiments, R 1b is other than H; R 1a , R1c , and R 1d Each of is H.

[0269] In certain embodiments, R 1b and R 1c each of which is other than H; and R 1a and R 1d Each of is H.

[0270] In certain embodiments, R 1b is halo, e.g., -F, -Cl, or -Br. For example, R 1b can be -F or -Cl (e.g., -F). For example, R 1b can be -F. As another non-limiting example, R 1b can be —Cl.

[0271] In certain embodiments, R 1b is 1 to 2 R a C optionally substituted with 1~6 Alkyl, e.g., unsubstituted C 1~6 It is alkyl.

[0272] In certain embodiments, R 1b is C 1~4 It is haloalkyl (e.g., -CF3 or -CHF2).

[0273] In certain embodiments, R 1b is -CN.

[0274] In certain embodiments, R 1b is -SF5.

[0275] In certain embodiments, R 1b is C 1~4 Thioalkoxy (eg, SMe).

[0276] In certain embodiments, R 1b is S(O)2(C 1~4 alkyl) (e.g., S(O)Me).

[0277] In certain embodiments, R1b is C 1~4 Alkoxy or C 1~4 haloalkoxy (eg, OCHF2).

[0278] In certain embodiments, R 1c is halo (e.g., -F).

[0279] In certain embodiments, R 1c is C 1~6 Alkyl and C 1~4 haloalkyl.

[0280] In certain embodiments, R 1c is C 1~4 Alkoxy, C 1~4 Haloalkoxy (e.g., OCHF2), -CN, -SF5, C 1~4 Thioalkoxy (e.g., SMe), and S(O)2(C 1~4 alkyl) (e.g., S(O)Me).

[0281] In certain embodiments, R 1b and R 1c each of which is an independently selected halo; and R 1a and R 1d Each of is H. For example, R 1b and R 1c Each of may be -F.

[0282] In certain embodiments, R 1c is H; and R 1b is halo, e.g., —F or —Cl, e.g., —Cl; and R 1a and R 1d Each of is H.

[0283] In certain embodiments, R 1c is the halo; R 1b is C 1~6 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4Haloalkoxy (e.g., OCHF2), -CN, -SF5, C 1~4 Thioalkoxy (e.g., SMe), and S(O)2(C 1~4 alkyl) (e.g., S(O)Me); and R 1a and R 1d Each of is H. For example, R 1c is -F.

[0284] In certain embodiments, R 1c is H;R 1b is C 1~6 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy (e.g., OCHF2), -CN, -SF5, C 1~4 Thioalkoxy (e.g., SMe), and S(O)2(C 1~4 alkyl) (e.g., S(O)Me); and R 1a and R 1d Each of is H.

[0285] Variable symbol R 2 In some embodiments, R 2 is H.

[0286] In some aspects, R 2 teeth, (iii) 1 to 3 independently selected R a may be substituted with -C(O)(C 1~6 alkyl); (iv) 1 to 3 independently 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:

[0287] In certain embodiments, R 2 is one to three independently selected R a may be substituted with -C(O)(C 1~6 In some of these embodiments, R 2 Each R a The substituents are independently -F, -Cl, -OH, or -NR e R f is.

[0288] As a non-limiting example of the foregoing embodiment, R 2 is C(=O)Me, TIFF0007756643000179.tif23128.

[0289] 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).

[0290] In certain embodiments, R 2 Ha-L 4 -L 5 -R i In some of these embodiments, -L 4 is a bond. In certain embodiments, -L 4 is C(=O). In certain embodiments, -L 4 is S(O)2. In certain embodiments, -L 5 is a bond. In certain other embodiments, -L 5 is C 1~4 Alkylene (e.g., C 1~2 alkylene).

[0291] Specific Aspects (R 2 Ga-L 4 -L 5 -R i In this case, R i teeth, (a) 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 is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; 3~8 Cycloalkyl (e.g., R i but TIFF0007756643000180.tif19128, where "Boc" represents tert-butoxycarbonyl; and (b) heterocyclyl having 3 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and heteroatoms 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 (e.g., R i but TIFF0007756643000181.tif22128, where "Boc" stands for tert-butoxycarbonyl) is selected from the group consisting of:

[0292] Specific Aspects (R 2 Ga-L 4 -L 5 -R i In this case, R i teeth, (a) Heteroaryl of 5 to 6 ring atoms, wherein 1 to 2 ring atoms are N, N(H), N(R d ), O, and S(O)0~2 and the heteroaryl ring is 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., R i But, 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; and (b)C 6~10 aryl, 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 is 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:

[0293] In certain embodiments, R 2 Ha-L 4 -L 5 -R i and;L 4 is a bond; L 5 is a bond or C1~4 alkylene; and R i teeth, (a) 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 is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; 3~8 Cycloalkyl (e.g., "Boc" represents tert-butoxycarbonyl) TIFF0007756643000182.tif19128); (b) heterocyclyl having 3 to 8 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and heteroatoms 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); TIFF0007756643000183.tif22128) (c) Heteroaryl of 5 to 6 ring atoms, wherein 1 to 2 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and the heteroaryl ring is 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, optionally substituted with 1 to 2 substituents independently selected from haloalkoxy; and (d)C 6~10 aryl, 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 is 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:

[0294] Specific Aspects (R 2 Ga-L 4 -L 5 -R i In this case, R 2 Ha-L 4 -L 5 -R i and;L 4 is C(=O) or S(O)2; L 5 is a bond or C 1~4 alkylene; and R i teeth, (c) Heteroaryl of 5 to 6 ring atoms, wherein 1 to 2 ring atoms are N, N(H), N(Rd ), O, and S(O) 0~2 and the heteroaryl ring is 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; and (d)C 6~10 aryl, 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 is 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:

[0295] As a non-limiting example, R 2 teeth, TIFF0007756643000184.tif30128, wherein R j is H; halo; C 1~4Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; or C 1~4 It is haloalkoxy.

[0296] Variable symbol R 5 In some embodiments, R 5 is H.

[0297] Variable symbol R 6 In some embodiments, R 6 is H.

[0298] In some embodiments, R 6 is C 1~3 It is alkyl.

[0299] Non-limiting combinations In some embodiments, the compound has formula (I-1): TIFF0007756643000185.tif38128, or a pharmaceutically acceptable salt thereof, wherein n2 is 0, 1, or 2.

[0300] In some of these embodiments, the compound has formula (I-1-1): The compound is TIFF0007756643000186.tif30128.

[0301] In some embodiments, the compound has formula (I-2): TIFF0007756643000187.tif38128, or a pharmaceutically acceptable salt thereof, wherein n2 is 0, 1, or 2.

[0302] In some of these embodiments, the compound has formula (I-2-1): The compound is TIFF0007756643000188.tif30128.

[0303] In some embodiments, the compound has formula (I-3): TIFF0007756643000189.tif38128, or a pharmaceutically acceptable salt thereof, wherein n2 is 0, 1, or 2.

[0304] In some of these embodiments, the compound has formula (I-3-1): The compound is TIFF0007756643000190.tif30128.

[0305] In some embodiments, the compound has formula (I-4): TIFF0007756643000191.tif38128, or a pharmaceutically acceptable salt thereof, wherein n2 is 0, 1, or 2.

[0306] In some of these embodiments, the compound has formula (I-4-1): The compound is TIFF0007756643000192.tif30128.

[0307] In some embodiments, the compound has formula (I-5): TIFF0007756643000193.tif38128, or a pharmaceutically acceptable salt thereof, wherein n2 is 0, 1, or 2.

[0308] In some of these embodiments, the compound has formula (I-5-1): The compound is TIFF0007756643000194.tif30128.

[0309] In some embodiments, the compound has formula (I-6): TIFF0007756643000195.tif36128, or a pharmaceutically acceptable salt thereof, wherein n2 is 0 or 1.

[0310] In some of these embodiments, the compound has formula (I-6-1): The compound is TIFF0007756643000196.tif30128.

[0311] In some embodiments, the compound has formula (I-7): TIFF0007756643000197.tif37128, or a pharmaceutically acceptable salt thereof, wherein: P 1 and P 2 one of which is N; and P 1 and P 2 The other is CH or CR c (e.g., CH).

[0312] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 7 Ha-R 8 is.

[0313] Certain embodiments (R 7 Ga-R 8 In this case, R 8 is one to four independently selected R 7 ', each of which may be replaced by C 3~12 Cycloalkyl or C 3~12 It is a cycloalkenyl.

[0314] Certain embodiments (R 7 Ga-R 8 In this case, R 8 is 1 to 3 R 7 C replaced with ' 4~8 It is cycloalkyl.

[0315] In some of these aspects, R 8 is 1 to 3 R 7 In certain embodiments, R is cyclohexyl substituted with '. 8 is 1 to 3 R 7 ' is a cyclobutyl substituted with '.

[0316] As a non-limiting example of the foregoing embodiment, R 8 teeth TIFF0007756643000198.tif24128. As another non-limiting example, R 8 teeth TIFF0007756643000199.tif19128, for example It could be TIFF0007756643000200.tif18128.

[0317] In certain embodiments, R 8 is unsubstituted C 4~6 monocyclic cycloalkyl (e.g., cyclopentyl, cyclobutyl, or cyclohexyl); or R 8 is unsubstituted C 7~8 Bicyclic (e.g., spirocyclic) cycloalkyl The file is TIFF0007756643000201.tif23128.

[0318] Certain embodiments (R 7 Ga-R 8 In this case, R 8 is a heterocyclyl or heterocycloalkenyl of 4 to 12 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7It has been replaced with '.

[0319] In some of these aspects, R 8 is a heterocyclyl of 4 to 8 ring atoms, where 1 to 2 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 3 independently selected R 7 It has been replaced with '.

[0320] Certain embodiments (R 7 Ga-R 8 In this case, R 8 is one to three (e.g., two) independently selected R 7 and tetrahydropyranyl, each of which is substituted with ' (e.g., R 8 teeth, TIFF0007756643000202.tif25128).

[0321] Certain embodiments (R 7 Ga-R 8 In this case, R 8 is one to three (e.g., two) independently selected R 7and tetrahydropyranyl, each of which is substituted with ' (e.g., R 8 teeth, TIFF0007756643000203.tif25170).

[0322] For example, R 8 may be selected from the group consisting of, for example, R 8 teeth, TIFF0007756643000204.tif52165.

[0323] R 7 Ga-R 8 In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), where 8 is a spirocyclic heterocyclyl of 6 to 12 ring atoms, e.g., TIFF0007756643000205.tif28128, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 ', where each R 7 ' is an independently selected halo, e.g., -F.

[0324] R 7 Ga-R 8 In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), where8 is a monocyclic heterocyclyl of 3 to 8 ring atoms, where 1 to 2 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 are heteroatoms independently selected from the group consisting of:

[0325] In some of these aspects, R 8 Azetidinyl TIFF0007756643000206.tif21128, Oxetanyl, Pyrrolidinyl TIFF0007756643000207.tif23128, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl (e.g., TIFF0007756643000208.tif25128, etc. TIFF0007756643000209.tif23128), piperazinyl TIFF0007756643000210.tif24128, morpholinyl, and azepinyl, where the ring nitrogen atom is R d may be substituted with.

[0326] In some of these aspects, R d Ha, Halo, C 1~3 Alkoxy, and C 1~3 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy 1~6 alkyl, for example, where R d C is substituted with one to three independently selected halo groups. 2~4 Alkyl The file is TIFF0007756643000211.tif12128.

[0327] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 7 Ha-L 3 -R9 is.

[0328] In some of these embodiments, L 3 is -O-.

[0329] In certain embodiments, L 3 is -NH-.

[0330] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 7 Ga-L 3 -R 9 If R 9 is one to four independently selected R 7 ', each of which may be replaced by C 3~12 Cycloalkyl or C 3~12 It is a cycloalkenyl.

[0331] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 7 Ga-L 3 -R 9 If R 9 is one to two independently selected R 7 ' may be substituted with C 4~8 It is cycloalkyl.

[0332] In some of these aspects, R 9 is one to two independently selected R 7 ' is cyclobutyl, cyclopentyl, cyclohexyl, or spiro[3.3]heptanyl, each of which may be substituted (e.g., unsubstituted).

[0333] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 7 Ga-L 3 -R 9 If R 9 is a heterocyclyl of 4 to 8 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0~2 and wherein one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 2 independently selected R 7 It may be substituted with '.

[0334] In certain embodiments, R 9 is one to two independently selected R 7 and azepinyl, each of which is optionally substituted (eg, unsubstituted) by '.

[0335] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 7 Ga-L 3 -R 9 If R 7 teeth The file is TIFF0007756643000212.tif33148.

[0336] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 7', if present, halo, -CN, -OH, R a may be substituted with -C 1~4 Alkyl, -C 1~4 Haloalkyl, R a may be substituted with -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″).

[0337] In some of these embodiments, each R 7 ', if present, halo, -CN, R a may be substituted with -C 1~4 Alkyl, -C 1~4 Haloalkyl, R a may be substituted with -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″). For example, each R 7 ', when present, can be -F. As another non-limiting example, each R 7 ', if present, are independently selected C 1~3 alkyl, e.g., methyl. As a further non-limiting example, each R 7 ', if present, are independently selected C 1~3 Haloalkyl, for example -CF3.

[0338] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 7 One occurrence of ' R a may be substituted with -C 1~4 Alkyl, e.g., unsubstituted C 1~4 alkyl (e.g., methyl, ethyl, n-propyl); R a -C is substituted with 1~4 Alkyl (e.g., OH or C 3~6 -C substituted with cycloalkyl 1~4 alkyl);-CN;R a may be substituted with -C 1~6 Alkoxy, e.g., unsubstituted C 1~6 alkoxy (e.g., methoxy); or R a C is replaced by 1~6 Alkoxy (e.g., OH or C 3~6 -C substituted with cycloalkyl 1~4 alkoxy) and R 7 Each remainder of ', if present, is independently halo (e.g., -F).

[0339] In certain embodiments of formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), or (I-7), n2 is 0.

[0340] In certain embodiments of formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), or (I-7), n2 is 1 or 2. For example, n2 can be 1.

[0341] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), each R c If present, halo; cyano; C 1~10 Alkyl; C 1~4 Alkoxy;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-C(=O)(C 1~10 alkyl); and -C(=O)O(C 1~4 alkyl).

[0342] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), when n2 is 1 or 2, each R c If present, (a) halo; (b) cyano; (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).

[0343] In some of these embodiments, each R c When present, is halo (e.g., -F, -Br, or -Cl) or cyano. For example, R c As another non-limiting example, R c can be —Cl.

[0344] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), Q is NH.

[0345] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), Q is N(C 1~3 alkyl), where C 1~3 Alkyl is R a may be substituted with.

[0346] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), Q is *—NH—(C 1~3 alkylene), where the asterisk indicates the point of attachment to W.

[0347] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), W is C(=O).

[0348] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), W is C(=C-NO2) or C(=N-CN).

[0349] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), W is S(O), C(=S), or C(=NR d )

[0350] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), Q is NH; and W is C(=O).

[0351] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 1a , R 1b , R 1c , and R 1d Each of the groups is H; halo; cyano; one to 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;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 alkyl);-S(O)(=NH)(C 1~4 alkyl);SF5;-NR e R f ;-OH;-S(O) 1~2 (NR'R'');-C 1~4 Thioalkoxy; -NO2; -C(=O)(C 1~4 alkyl);-C(=O)O(C 1~4 alkyl); and —C(═O)N(R′)(R″).

[0352] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 1a , R 1b , R 1c , and R 1d Each of is H.

[0353] In certain other embodiments, R 1a , R 1b , R 1c , and R 1d one or two of which are other than H; and R 1a , R 1b , R 1c , and R 1d The rest of each is H.

[0354] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 1a and R 1d Each of R is independently selected from the group consisting of H and halo. For example, R 1a and R 1d Each of may be H.

[0355] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 1b is other than H;R 1a , R 1c , and R 1d Each of is H.

[0356] In some of these aspects, R 1bis halo (e.g., —F or —Cl (e.g., —F)).

[0357] In certain other embodiments, R 1b is C 1~6 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy (e.g., OCHF2), -CN, -SF5, C 1~4 Thioalkoxy (e.g., SMe), and S(O)2(C 1~4 alkyl) (e.g., S(O)Me); and R 1a and R 1d Each of is H.

[0358] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 1b and R 1c each of which is other than H; and R 1a and R 1d Each of is H.

[0359] In some of these aspects, R 1c is halo (e.g., -F); R 1b is C 1~6 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy (e.g., OCHF2), -CN, -SF5, C 1~4 Thioalkoxy (e.g., SMe), and S(O)2(C 1~4 alkyl) (e.g., S(O)Me); and R 1a and R 1d Each of is H.

[0360] In certain other embodiments, R 1b and R 1cEach of R is an independently selected halo. For example, R 1b and R 1c Each of these is -F.

[0361] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 2 is H.

[0362] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), 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).

[0363] As a non-limiting example of the foregoing embodiment, R 2 are C(=O)Me, S(O)2Me, TIFF0007756643000213.tif23128.

[0364] In certain embodiments of formula (I-1) (e.g., I-1-1), (I-2) (e.g., I-2-1), (I-3) (e.g., I-3-1), (I-4) (e.g., I-4-1), (I-5) (e.g., I-5-1), (I-6) (e.g., I-6-1), or (I-7), R 6 is H.

[0365] In certain embodiments, the compound of Formula (I) has the formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a): TIFF0007756643000214.tif20363, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth, m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; and T 2 CH2, NH, NR d , or O, TIFF0007756643000215.tif51128; Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 spirocyclic heterocyclyl, optionally substituted by '; and 1 to 4 independently selected R 7 Optionally substituted by ', spirocyclic C 6~12 cycloalkyl is selected from the group consisting of:

[0366] In certain embodiments, the compound of Formula (I) has the formula (I-1a), (I-2a), or (I-3a): TIFF0007756643000216.tif89128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth, m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; TIFF0007756643000217.tif24128; and Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 Optionally substituted spirocyclic heterocyclyl is selected from the group consisting of:

[0367] In certain embodiments, the compound has the formula (I-1a): In certain embodiments, the compound has the formula (I-2a): In certain embodiments, the compound has the formula (I-3a):

[0368] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 2 is H. In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 6 is H.

[0369] In certain embodiments of Formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), n2 is 1; and R c is R 8 In certain embodiments, R c is halo, e.g., —Cl. In certain embodiments, R c is C 1~3 Alkyl, for example methyl.

[0370] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 1a and R 1d is H; and R 1c is H or halo.

[0371] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 1b is halo, e.g., —F or —Cl. In certain embodiments of formula (I-1a), (I-2a), or (I-3a), R 1b is C 1~6 Alkyl or C 1~4 Haloalkyl, for example methyl or -CHF2.

[0372] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 8 teeth TIFF0007756643000218.tif22128, where m1 and m2 are independently 0, 1, or 2, and T1 is CH or N. For example, R 8 teeth, TIFF0007756643000219.tif24128.

[0373] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 8 teeth TIFF0007756643000220.tif23128, where m1 and m2 are independently 0, 1, or 2, and T 1 is CH or N. For example, R 8 teeth, TIFF0007756643000221.tif24128.

[0374] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 8 teeth, TIFF0007756643000222.tif24128, wherein m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; and T 2 are CH2, NH, NR d , or O. For example, R 8 teeth, TIFF0007756643000223.tif24128.

[0375] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 8 teeth TIFF0007756643000224.tif31128, wherein m1, m2, m3, and m4 are independently 0, 1, or 2, with the proviso that m1+m2+m3+m4≦6, and T 1 is CH or N. For example, R 8 teeth, TIFF0007756643000225.tif31128.

[0376] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 8 teeth TIFF0007756643000226.tif30128, wherein m1, m2, m3, and m4 are independently 0, 1, or 2, with the proviso that m1+m2+m3+m4≦6, and T 1 is CH or N. For example, R 8 teeth It could be TIFF0007756643000227.tif27128.

[0377] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R 8 teeth, TIFF0007756643000228.tif28128.

[0378] In certain embodiments of Formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), each R 7 ' is C 1~3 Alkyl; C 1~3 haloalkyl; and halo, e.g., where each R 7 ' are independently selected from the group consisting of methyl, CF3, and -F; and R d is optionally substituted with 1 to 3 independently selected halo, e.g., —F; C 1~6 Alkyl, e.g., C 2~4 It is alkyl.

[0379] In certain embodiments of Formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), each R 7' is C 1~3 Independently selected from the group consisting of alkyl and halo, such as methyl and -F.

[0380] In certain embodiments of formula (I-1a), (I-2a), (I-3a), (I-4a), (I-5a), or (I-6a), R d is optionally substituted with 1 to 3 independently selected halo, e.g., —F; C 1~6 Alkyl, e.g., C 2~4 It is alkyl.

[0381] In certain embodiments, the compound of formula (I) has formula (I-3a): TIFF0007756643000229.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth, m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; and T 2 CH2, NH, NR d , or O, TIFF0007756643000230.tif51128; Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 spirocyclic heterocyclyl, optionally substituted by '; and 1 to 4 independently selected R 7 Optionally substituted by ', spirocyclic C 6~12 cycloalkyl is selected from the group consisting of:

[0382] In certain embodiments of formula (I-3a), R 8 teeth TIFF0007756643000231.tif22128; and optionally, where each R 7 In some of these embodiments, R ' is an independently selected halo, e.g., -F. 8 teeth, TIFF0007756643000232.tif24128, and optionally wherein each R 7 ' is -F. For example, R 8 teeth It could be TIFF0007756643000233.tif22128.

[0383] In certain embodiments of formula (I-3a), R 1a and R 1d is H;R 1b is halo, e.g., -F; R 1c is -H or halo, e.g., -H or -F; and R 2 is H.

[0384] In certain embodiments of Formula (I-3a), the compound has the formula (I-3a-1): I have TIFF0007756643000234.tif32128.

[0385] In certain embodiments of Formula (I-3a) or Formula (I-3a-1), R c is halo, for example, —F or —Cl.

[0386] In certain embodiments of Formula (I-3a) or Formula (I-3a-1), R 8 teeth TIFF0007756643000235.tif22128; and / or R 1a and R 1d is H; and / or R 1b is -F; and / or R 1c is -H or -F; and / or R 2 is H; and / or R c is a halo.

[0387] In certain embodiments, the compound of formula (I) has formula (I-2a): TIFF0007756643000236.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth, m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; and T 2 CH2, NH, NR d , or O, TIFF0007756643000237.tif51128; Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 spirocyclic heterocyclyl, optionally substituted by '; and 1 to 4 independently selected R 7 Optionally substituted by ', spirocyclic C 6~12 cycloalkyl is selected from the group consisting of:

[0388] In certain embodiments of formula (I-2a), R 8 teeth TIFF0007756643000238.tif23128; and optionally, where each R 7 ' is an independently selected halo, e.g., -F; and optionally, where R d is C substituted with 1 to 3 independently selected halo, e.g., -F 2~4 In some of these embodiments, R 8 teeth, TIFF0007756643000239.tif24147; and optionally wherein each R 7 ' is -F; and optionally where R d C substituted with 1 to 3 -F 2~4 alkyl. For example, R 8 teeth It could be TIFF0007756643000240.tif27128.

[0389] In certain embodiments of formula (I-2a), R 1a , R 1d , and R 1c are H and R respectively. 1b is —H or halo, e.g., —H, —Cl, or —F; and R 2 is H.

[0390] In certain embodiments of Formula (I-2a), the compound has the formula (I-2a-1): I have TIFF0007756643000241.tif32128.

[0391] In certain embodiments of Formula (I-2a) or Formula (I-2a-1), R c is -halo.

[0392] In certain embodiments of Formula (I-2a) or Formula (I-2a-1), R 8 teeth TIFF0007756643000242.tif27128; and / or R 1a , R 1d , and R 1c is H; and / or R 1b is -H, -Cl, or -F; and / or R 2 is H; and / or R c is a halo.

[0393] In certain embodiments, the compound of formula (I) has formula (I-7a): TIFF0007756643000243.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, P 1 and P 2 one of which is N; and P 1 and P 2 The other is CH; R 1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; R 8 teeth, m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; and T 2 CH2, NH, NR d , or O, TIFF0007756643000244.tif51128; Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 spirocyclic heterocyclyl, optionally substituted by '; and 1 to 4 independently selected R 7 Optionally substituted by ', spirocyclic C 6~12 cycloalkyl is selected from the group consisting of:

[0394] In certain embodiments of formula (I-7a), R 8 teeth TIFF0007756643000245.tif22128; and optionally, where each R 7 In some of these embodiments, R ' is an independently selected halo, e.g., -F. 8 teeth, TIFF0007756643000246.tif24128; and optionally wherein each R 7 ' is -F. For example, R 8 teeth The file is TIFF0007756643000247.tif22128.

[0395] In certain embodiments of formula (I-7a), R 1a , R 1d , and R 1c is H;R 1b is halo, e.g., —Cl; and R 2 is H.

[0396] In certain embodiments of formula (I-7a), R 8 teeth TIFF0007756643000248.tif22128; and / or R 1a , R1d , and R 1c is H; and / or R 1b is -Cl; and / or R 2 is H.

[0397] In certain embodiments, the compound of formula (I) has formula (I-1a): TIFF0007756643000249.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth, m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; and T 2 CH2, NH, NR d , or O, TIFF0007756643000250.tif51128; Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 spirocyclic heterocyclyl, optionally substituted by '; and 1 to 4 independently selected R 7 Optionally substituted by ', spirocyclic C 6~12 cycloalkyl is selected from the group consisting of:

[0398] In certain embodiments of formula (I-1a), R 8 teeth TIFF0007756643000251.tif22128; and optionally, where each R 7 In some of these embodiments, R ' is an independently selected halo, e.g., -F. 8 teeth, TIFF0007756643000252.tif24128; and optionally wherein each R 7 ' is -F. For example, R 8 teeth, TIFF0007756643000253.tif23128.

[0399] In certain embodiments of formula (I-1a), R 8 teeth TIFF0007756643000254.tif31128, wherein m1, m2, m3, and m4 are independently 0, 1, or 2, with the proviso that m1 + m2 + m3 + m4 ≦ 6; T 1 is CH or N; and each R 7 ' is C 1~3 Alkyl; C 1~3 haloalkyl; and halo, e.g., methyl, CF, and -F. In some of these embodiments, R 8 teeth, TIFF0007756643000255.tif31128; and optionally wherein each R 7 ' is -F. For example, R 8 teeth, TIFF0007756643000256.tif27128.

[0400] In certain embodiments of formula (I-1a), R 1a and R1d is H;R 1b is halo, e.g., —F or —Cl; R 1c is —H or halo, e.g., —H, —F, or —Cl; and R 2 is H.

[0401] In certain embodiments of Formula (I-1a), the compound has the formula (I-1a-1): I have TIFF0007756643000257.tif28128.

[0402] In certain embodiments of Formula (I-1a) or Formula (I-1a-1), R c is halo, for example, —F or —Cl.

[0403] In certain embodiments of Formula (I-1a) or Formula (I-1a-1), R 8 teeth, TIFF0007756643000258.tif23128; and / or R 1a and R 1d is H; and / or R 1b is -F or -Cl; and / or R 1c is -H, -F, or -Cl; and / or R 2 is H; and / or R c is a halo.

[0404] In certain embodiments of Formula (I-1a) or Formula (I-1a-1), R 8 teeth, TIFF0007756643000259.tif27128; and / or R 1a and R 1d is H; and / or R 1b is -F or -Cl; and / or R 1c is -H, -F, or -Cl; and / or R 2 is H; and / or R c is a halo.

[0405] In certain embodiments, the compound of formula (I) has formula (I-1a): TIFF0007756643000260.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; R 2 is H; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth TIFF0007756643000261.tif22128, where: m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; and Each R 7 ' is C 1~3 Alkyl; C 1~3 haloalkyl; and halo, such as methyl, CF3, and -F.

[0406] In some of these embodiments, the compound has formula (I-1a): TIFF0007756643000262.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a and R 1d is H; R 1b and R 1cEach of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; R 2 is H; n2 is 0, 1; R c is, when present, selected from the group consisting of halo and cyano; R 8 teeth, TIFF0007756643000263.tif24128; and Each R 7 ' is independently a halo or C 1~3 Alkyl, e.g., -F or -C 1~3 It is alkyl.

[0407] In some of the foregoing embodiments, the compound has formula (I-1a-1): TIFF0007756643000264.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a and R 1d is H; R 1b is a halo; R 1c is H or halo; R 2 is H; R c is selected from the group consisting of -F, -Cl, -Br, and cyano; and R 8 teeth, TIFF0007756643000265.tif23128.

[0408] In certain embodiments, the compound of formula (I) has formula (I-1a): TIFF0007756643000266.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; R 2 is H; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth TIFF0007756643000267.tif23128, where: m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; and R d is optionally substituted with 1 to 3 independently selected halo, e.g., —F; C 1~6 Alkyl, e.g., C 2~4 It is alkyl.

[0409] In some of these embodiments, the compound has formula (I-1a): TIFF0007756643000268.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a and R 1d is H; R 1b and R 1c Each of the groups is H; halo; cyano; one to two R a C optionally substituted with1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; R 2 is H; n2 is 0, 1; R c is, when present, selected from the group consisting of halo and cyano; R 8 teeth, TIFF0007756643000269.tif24128; and R d is optionally substituted with 1 to 3 independently selected halo, e.g., —F; C 2~4 It is alkyl.

[0410] In some of the foregoing embodiments, the compound has formula (I-1a-1): TIFF0007756643000270.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a and R 1d is H; R 1b is a halo; R 1c is H or halo; R 2 is H; R c is selected from the group consisting of -F, -Cl, -Br, and cyano; R 8 teeth, TIFF0007756643000271.tif24128; and R d is optionally substituted with 1 to 3 independently selected halo, e.g., —F; C 2~4 It is alkyl.

[0411] In certain embodiments, the compound of formula (I) has formula (I-1a): TIFF0007756643000272.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; R 2 is H; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth, TIFF0007756643000273.tif24128, wherein m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; T 2 are CH2, NH, NR d , or O; and Each R 7 ' is C 1~3 Alkyl and C 1~3 haloalkyl.

[0412] In some of these embodiments, the compound has formula (I-1a): TIFF0007756643000274.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a and R 1d is H; R 1b and R 1cEach of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; R 2 is H; n2 is 0, 1; R c is, when present, selected from the group consisting of halo and cyano; R 8 teeth, TIFF0007756643000275.tif24128; and Each R 7 ' is C 1~3 Alkyl and C 1~3 haloalkyl.

[0413] In some of the foregoing embodiments, the compound has formula (I-1a-1): TIFF0007756643000276.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a and R 1d is H; R 1b is a halo; R 1c is H or halo; R 2 is H; R c is selected from the group consisting of -F, -Cl, -Br, and cyano; R 8 teeth, TIFF0007756643000277.tif24128; and Each R 7 ' is C 1~3 Alkyl and C 1~3 haloalkyl.

[0414] In certain embodiments, the compound of formula (I) has formula (I-1a): TIFF0007756643000278.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; R 2 is H; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth TIFF0007756643000279.tif31128, where: m1, m2, m3, and m4 are independently 0, 1, or 2, provided that m1+m2+m3+m4≦6; T 1 is CH or N; and Each R 7 ' is C 1~3 Alkyl; C 1~3 haloalkyl; and halo, such as methyl, CF3, and -F.

[0415] In some of these embodiments, the compound has formula (I-1a): TIFF0007756643000280.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a and R 1d is H; R 1band R 1c Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; R 2 is H; n2 is 0, 1; R c is, when present, selected from the group consisting of halo and cyano; R 8 teeth, TIFF0007756643000281.tif31128; and Each R 7 ' is C 1~3 Independently selected from the group consisting of alkyl and halo, such as methyl and -F.

[0416] In some of the foregoing embodiments, the compound has formula (I-1a-1): TIFF0007756643000282.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a and R 1d is H; R 1b is a halo; R 1c is H or halo; R 2 is H; R c is selected from the group consisting of -F, -Cl, -Br, and cyano; and R 8 teeth, TIFF0007756643000283.tif31128.

[0417] In certain embodiments, the compound of formula (I) has formula (I-1a): TIFF0007756643000284.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; R 2 is H; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth TIFF0007756643000285.tif30128, where: m1, m2, m3, and m4 are independently 0, 1, or 2, provided that m1+m2+m3+m4≦6; T 1 is CH or N; and R d is optionally substituted with 1 to 3 independently selected halo, e.g., —F; C 1~6 Alkyl, e.g., C 2~4 It is alkyl.

[0418] In some of these embodiments, the compound has formula (I-1a): TIFF0007756643000286.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a and R 1d is H; R 1b and R 1c Each of the groups is H; halo; cyano; one to two Ra C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; R 2 is H; n2 is 0, 1; R c is, when present, selected from the group consisting of halo and cyano; R 8 teeth TIFF0007756643000287.tif27128; and R d is optionally substituted with 1 to 3 independently selected halo, e.g., —F; C 2~4 It is alkyl.

[0419] In some of the foregoing embodiments, the compound has formula (I-1a-1): TIFF0007756643000288.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a and R 1d is H; R 1b is a halo; R 1c is H or halo; R 2 is H; R c is selected from the group consisting of -F, -Cl, -Br, and cyano; and R 8 teeth TIFF0007756643000289.tif27128; and R d is substituted with 1 to 3 independently selected halo, e.g., -F; C 2~4 It is alkyl.

[0420] In certain embodiments, the compound of formula (I) has formula (I-6a): TIFF0007756643000290.tif29128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth, m1 and m2 are independently 0, 1, or 2; and T 2 CH2, NH, NR d , or O, TIFF0007756643000291.tif51128; Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 spirocyclic heterocyclyl, optionally substituted by '; and 1 to 4 independently selected R 7 Optionally substituted by ', spirocyclic C 6~12 cycloalkyl is selected from the group consisting of:

[0421] In certain embodiments of formula (I-6a), R 8 teeth TIFF0007756643000292.tif32128, wherein m1, m2, m3, and m4 are independently 0, 1, or 2, with the proviso that m1 + m2 + m3 + m4 ≦ 6; and Each R 7 ' is C 1~3 Alkyl; C 1~3 haloalkyl; and halo, such as methyl, CF3, and -F.

[0422] In some of these aspects, R 8 teeth TIFF0007756643000293.tif27128. For example, R 8 teeth It could be TIFF0007756643000294.tif27128.

[0423] In certain embodiments of formula (I-6a), R 1a , R 1d , and R 1c is H;R 1b is halo, e.g., —Cl; and R 2 is H.

[0424] In certain embodiments of Formula (I-6a), n2 is 0.

[0425] In certain embodiments of Formula (I-6a), n2 is 0; and / or R 8 teeth TIFF0007756643000295.tif27128; and / or R 1a , R 1d , and R 1c is H; and / or R 1b is -Cl; and / or R 2 is H.

[0426] In certain embodiments, the compound of formula (I) has formula (I-4a): TIFF0007756643000296.tif34128, or a pharmaceutically acceptable salt thereof; During the ceremony, R1a , R 1b , R 1c , R 1d Each of the groups is H; halo; cyano; one to two R a C optionally substituted with 1~6 Alkyl; C 1~4 Haloalkyl;C 1~4 Alkoxy; and C 1~4 independently selected from the group consisting of haloalkoxy; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1~3 Alkyl, and C 1~3 independently selected from the group consisting of alkoxy; R 8 teeth, m1 and m2 are independently 0, 1, or 2; T 1 is CH or N; and T 2 CH2, NH, NR d , or O, TIFF0007756643000297.tif51128; Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0~2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 spirocyclic heterocyclyl, optionally substituted by '; and 1 to 4 independently selected R 7 Optionally substituted by ', spirocyclic C 6~12 cycloalkyl is selected from the group consisting of:

[0427] In certain embodiments of formula (I-4a), R 8 teeth TIFF0007756643000298.tif22128; and optionally, where each R 7In some of these embodiments, R ' is an independently selected halo, e.g., -F. 8 teeth, TIFF0007756643000299.tif24128; and optionally wherein each R 7 ' is -F. For example, R 8 teeth It could be TIFF0007756643000300.tif22128.

[0428] In certain embodiments of formula (I-4a), R 1a and R 1d is H;R 1b is halo, e.g., —F or —Cl; R 1c is H or halo, e.g., -H or -F; and R 2 is H.

[0429] In certain embodiments of Formula (I-4a), n2 is 1; and the compound has the formula (I-4a-1): I have TIFF0007756643000301.tif32128.

[0430] In certain embodiments of Formula (I-4a) or Formula (I-4a-1), R c is a halo.

[0431] In certain embodiments of Formula (I-4a), n2 is 0.

[0432] In certain embodiments of Formula (I-4a) or Formula (I-4a-1), R 8 teeth TIFF0007756643000302.tif22128; and / or R 1a and R 1d is H; and / or R 1b is -F or -Cl; and / or R 1c is -H or -F; and / or R 2 is H.

[0433] In certain embodiments of formula (I-1a) (e.g., I-1a-1), (I-2a) (e.g., I-2a-1), (I-3a) (e.g., I-3a-1), (I-4a) (e.g., I-4a-1), (I-5a), (I-6a), or (I-7a), R 6 is H.

[0434] Non-limiting examples of compounds of formula I In some embodiments, the compound is selected from the group consisting of the compounds set forth in Table C1 or a pharmaceutically acceptable salt thereof.

[0435] [Table C1] TIFF0007756643000304.tif227129TIFF0007756643000305.tif214129TIFF0007756643000306.tif214129TIFF0007756643000307.tif200129TIFF0007756643000308.tif223129TIFF0007756643000309.tif199126TIFF0007756643000310.tif211126TIFF0007756643000311.tif203126TIFF0007756643000312.tif203126TIFF0007756643000313.tif199126TIFF0007756643000314.tif197126TIFF0007756643000315.tif220126TIFF0007756643000316.tif221126TIFF0007756643000317.tif217126TIFF0007756643000318.tif176128TIFF0007756643000319.tif180128TIFF0007756643000320.tif184128TIFF0007756643000321.tif180128TIFF0007756643000322.tif176128TIFF0007756643000323.tif178128TIFF0007756643000324.tif178128TIFF0007756643000325.tif174128TIFF0007756643000326.tif173128TIFF0007756643000327.tif227126TIFF0007756643000328.tif174128TIFF0007756643000329.tif185128TIFF0007756643000330.tif175128TIFF0007756643000331.tif114128

[0436] Pharmaceutical Compositions and Administration Summary 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.

[0437] 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).

[0438] 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).

[0439] 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.

[0440] 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.

[0441] 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.

[0442] 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.

[0443] 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.

[0444] 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.

[0445] 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.

[0446] 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).

[0447] Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar-agar, calcium carbonate, and the like. The formulation may be mixed with a variety of additives, including but not limited to: potato, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardants, 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, the dosage form may also contain buffering agents. Solid compositions of a similar type may 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.

[0448] 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.

[0449] 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.

[0450] 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.

[0451] 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.

[0452] Examples include upper GI targeting technologies such as the Accordion Pill (Intec Pharma), floating capsules, and materials that can adhere to mucosal walls.

[0453] 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.

[0454] 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.)).

[0455] 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.

[0456] 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.

[0457] 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.

[0458] 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).

[0459] 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).

[0460] 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.

[0461] 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.

[0462] 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.

[0463] 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.

[0464] 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 some specific 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).

[0465] 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)).

[0466] In some embodiments, the condition, disease, or disorder is hepatitis B (see, e.g., WO 2015 / 061294).

[0467] In some embodiments, the condition, disease, or disorder is selected from cardiovascular diseases (including, for example, myocardial infarction).

[0468] In some embodiments, the condition, disease, or disorder is age-related macular degeneration.

[0469] 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.

[0470] 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).

[0471] 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.

[0472] Further examples may include the indications discussed below herein and contemplated combination therapy regimens.

[0473] Combination therapy The present disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[0474] 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.

[0475] In certain embodiments, the methods described herein can further comprise administering one or more additional cancer therapies.

[0476] 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.

[0477] In some embodiments, the one or more additional cancer therapies is chemotherapy, which can include administering one or more additional chemotherapeutic agents.

[0478] In certain embodiments, the additional chemotherapeutic agent is an immunomodulatory moiety, e.g., an immune checkpoint inhibitor. In some specific 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), gastrointestinal tract infection (GTI), or leukemia (LEU). Lectin 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-CD1 60, 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 NKG 2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1). See, e.g., Postow, MJ Clin. Oncol. 2015, 33, 1.

[0479] In some specific 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.

[0480] 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.

[0481] 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.

[0482] 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).

[0483] 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.

[0484] 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.

[0485] 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 (IP -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).

[0486] 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.

[0487] 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.

[0488] 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.

[0489] 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.

[0490] 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®)).

[0491] 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.

[0492] 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).

[0493] 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).

[0494] 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.

[0495] 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.

[0496] 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).

[0497] 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.

[0498] 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.

[0499] 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.

[0500] 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.

[0501] 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.

[0502] 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.

[0503] 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.

[0504] 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.

[0505] 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.

[0506] 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.

[0507] 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.

[0508] 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.

[0509] 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.

[0510] 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.

[0511] 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.

[0512] 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.

[0513] 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.

[0514] 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®).

[0515] 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).

[0516] 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.

[0517] 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)).

[0518] 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).

[0519] 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.

[0520] 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).

[0521] 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.

[0522] 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).

[0523] 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).

[0524] 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.

[0525] To further illustrate the foregoing, the following non-limiting, exemplary synthetic schemes are included. Variations of these examples that fall 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.

[0526] The following abbreviations have the indicated meanings: TIFF0007756643000332.tif78157 [Example]

[0527] material and method Reaction progress was often monitored by TLC or LC-MS. Product identity was often confirmed by LC-MS. LC-MS was recorded using one of the following methods:

[0528] Method AB: Poroshell HPH-C18, 50*3.0mm, 2.7μm, injection 4μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A: water / 0.04% NH₃·H₂O and mobile phase B (MPB): ACN. 10% MPB ~ 95% / 1.99min, hold at 95% MPB for 0.6min, 95% MPB ~ 10% / 0.2min, then equilibrate to 10% MPB for 0.5min.

[0529] Method AH: EVO C18, 50*3mm, injection 2.0μL, 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% / 2.00min, hold at 95% MPB for 0.6min, 95% MPB to 10% / 0.05min, then equilibrate to 10% MPB for 0.25min.

[0530] LCMS Method A: Kinetex EVO C18 100A, 30*3mm, injection 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% MPB for 2.0 min, hold at 95% MPB for 0.30 min, 95% MPB to 10% MPB for 0.10 min.

[0531] LCMS Method B: Xselect CSH C18, 50*3mm, injection 1.0 μL, flow rate 1.2 mL / min, scan range 90-900 amu, UV detection 254 nm. Mobile phase A (MPA): water / 0.1% FA and mobile phase B (MPB): acetonitrile / 0.1% FA. Elution: 5% MPB to 100% for 2.00 min, hold at 100% MPB for 0.70 min, 100% MPB to 5% for 0.05 min, then equilibrate to 5% MPB for 0.15 min.

[0532] LCMS Method C: XBridge Shield RP18, 50*4.6mm, injection 0.5μL, flow rate 1.2mL / min, scan range 90-900amu, UV detection 254nm. Mobile phase A (MPA): water / 0.04% NH3.H2O and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% / 2.00min, hold at 95% MPB for 0.79min, 95% MPB to 10% / 0.06min, then equilibrate to 10% MPB for 0.15min.

[0533] LCMS Method D: Shim-pack XR-ODS, 50*3mm, injection 0.3 μL, flow rate 1.2 mL / min, scan range 30-2000 amu, UV detection 254 nm. Mobile phase A (MPA): water / 0.05% TFA and mobile phase B (MPB): acetonitrile / 0.05% TFA. Elution: 5% MPB to 100% / 1.10 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% / 0.05 min, then equilibrate to 5% MPB for 0.25 min.

[0534] LCMS Method E: Kinetex 2.6um EVO C18 100A, 50*3mm, injection 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% / 1.20min, hold at 95% MPB for 0.50min, 95% MPB to 10% / 0.05min, then equilibrate to 10% MPB for 0.10min.

[0535] LCMS Method F: EVO C18, 50*3mm, injection 0.1 μL, flow rate 1.2 mL / min, scan range 30-2000 amu, UV detection 254 nm. Mobile phase A (MPA): water / 5 mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% / 2.00 min, hold at 95% MPB for 0.60 min, 95% MPB to 10% / 0.15 min, then equilibrate to 10% MPB for 0.25 min.

[0536] LCMS Method G: Titan C18, 50*3mm, injection 0.5μL, flow rate 1.5mL / min, scan range 30-2000amu, UV detection 254nm. Mobile phase A (MPA): water / 5mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 10% MPB to 95% / 1.80min, hold at 95% MPB for 0.80min, 95% MPB to 10% / 0.15min, then equilibrate to 10% MPB for 0.25min.

[0537] LCMS Method H: Poroshell HPH C18, 50*3mm, 0.5μL injection, 1.2mL / min flow rate, 30-2000amu scan range, UV detection at 254nm. Mobile Phase A (MPA): water / 5mM NH4HCO3 + 5mM NH4OH and Mobile Phase B (MPB): acetonitrile. Elution: 10% MPB to 95% / 2.00min, hold at 95% MPB for 0.70min, 95% MPB to 5% / 0.05min, then equilibrate to 5% MPB for 0.25min.

[0538] LCMS method I: HALOC18, 30*3 mm, injection 0.5 μL, flow rate 1.5 mL / min, scan range 30-2000 amu, UV detection 254 nm. Mobile phase A (MPA): water / 0.05% TFA and mobile phase B (MPB): acetonitrile / 0.05% TFA. Elution: 5% MPB to 100% MPB for 1.20 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% MPB for 0.02 min, then equilibrate to 5% MPB for 0.18 min.

[0539] LCMS Method J: HALOC18, 30*3mm, injection 0.5 μL, flow rate 1.5 mL / min, scan range 30-2000 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% MPB for 1.20 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% MPB for 0.02 min, then equilibrate to 5% MPB for 0.18 min.

[0540] 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.

[0541] Synthesis of exemplary intermediates Intermediate 1: 5,6-difluoro-1H-indol-3-amine TIFF0007756643000333.tif24147 Step 1 - Synthesis of 5,6-difluoro-3-nitrol-1H-indole:5,6-Difluoro-1H-indole (5.0 g, 32.7 mmol, 1.0 equiv.) was dissolved in CH3CN (50.0 mL) and AgNO3 (6.1 g, 36.0 mmol, 1.1 equiv.) was added portionwise. The resulting solution was then cooled to 0 °C, and after 5 min, benzoyl chloride (4.1 mL, 36.0 mmol, 1.1 equiv.) was added. The resulting solution was allowed to warm to room temperature over 2 h, and then the pH of the reaction mixture was adjusted to pH 8 by the dropwise addition of 1 M aqueous Na2CO3. The mixture was extracted with EtOAc (150 mL × 3), and the organic layers were combined and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (5 / 95) to give 5,6-difluoro-3-nitro-1H-indole (3.5 g, 17.7 mmol) as a yellow solid. LC-MS method B, MS-ESI: 199.1 [M+H + Alternatively, the residue can be purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, 0-100% EtOAc / petroleum ether gradient eluent @ 30 mL / min) to give 5,6-difluoro-3-nitro-1H-indole (2.9 g, 13.5 mmol) as a yellow solid. MS-ESI, 199.1 [M+H + ].

[0542] Step 2 - Synthesis of 5,6-difluoro-1H-indol-3-amine (Intermediate 1): 5,6-Difluoro-3-nitro-1H-indole (3.5 g, 17.7 mmol, 1.0 equiv.) was dissolved in 40% HBr / HO (40 mL), then SnCl (16.8 g, 88.5 mmol, 5.0 equiv.) was added, and the reaction mixture was heated at 70 °C for 30 min. The reaction mixture was cooled to room temperature, and the pH was adjusted to pH 8 by dropwise addition of 1 M aqueous NaOH. The mixture was extracted with DCM (150 mL x 5), and the combined organic layers were concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS Method B, MS-ESI: 169.1 [M+H + ].

[0543] Intermediate 2: Synthesis of (6-(4,4-difluorocyclohexyl)pyridin-3-amine) TIFF0007756643000334.tif27145Step 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 a nitrogen atmosphere. The resulting solution was stirred at 90 °C for 12 h and then concentrated under reduced pressure. 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.

[0544] 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), followed by the addition of Pd / C (10 wt%, 1.5 g, 1.4 mmol, 0.1 equiv.). The reaction vessel was evacuated and then refilled with hydrogen three times, then stirred under a hydrogen atmosphere for 16 hours. 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.

[0545] Intermediate 3: 2-(4,4-difluorocyclohexyl)-5-isocyanatopyridine TIFF0007756643000335.tif161286-(4,4-Difluorocyclohexyl)pyridin-3-amine (1 mmol) was dissolved in 5 mL of DCM / water (1:1 mixture) and cooled to 0 °C. Triphosgene (0.5 mmol) was dissolved in 2 mL of DCM and slowly added to the DCM layer. The solution was stirred for 30 minutes, and the two layers were separated. The organic layer was washed with brine and dried over anhydrous MgSO. The organic layer was rotary evaporated and used directly in the next step.

[0546] Synthesis of Intermediate 5 (5-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-amine) TIFF0007756643000336.tif25154 Step 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 under reduced pressure to give 3-chloro-2-(4,4-difluoropiperidin-1-yl)-5-nitropyridine (420 mg) as a yellow solid. LCMS Method C: [M+H] + = 278.

[0547] 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) followed by SnCl (5.5 g, 29.0 mmol, 2.4 equiv.). 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 under reduced pressure. 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 C: [M+H] + = 248.

[0548] The following intermediates were prepared using the same method as described for intermediate 5. TIFF0007756643000337.tif153161TIFF0007756643000338.tif202161TIFF0007756643000339.tif224161TIFF00077566430 00340.tif218161TIFF0007756643000341.tif191161TIFF0007756643000342.tif226161TIFF0007756643000343.tif196161 TIFF0007756643000344.tif226161TIFF0007756643000345.tif187161TIFF0007756643000346.tif192161TIFF00077566430 00347.tif191161TIFF0007756643000348.tif197161TIFF0007756643000349.tif182161TIFF0007756643000350.tif151161

[0549] Synthesis of intermediate 43 (6-(4,4-difluorocyclohexyl)pyridin-3-amine) TIFF0007756643000351.tif68132Step 1: 6-(4,4-Difluorocyclohex-1-en-1-yl)pyridin-3-amine 6-Iodopyridin-3-amine (4.0 g, 18.2 mmol, 1.0 equiv.) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.3 g, 21.8 mmol, 1.2 equiv.) were dissolved in 1,4-dixoane (40 mL) and water (8 mL), followed by the addition of KCO (7.5 g, 54.5 mmol, 3.0 equiv.) and Pd(dppf)Cl (1.5 g, 1.8 mmol, 0.1 equiv.) under a nitrogen atmosphere. The reaction mixture was heated at 90 °C for 12 h and then concentrated under reduced pressure. 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 (2.7 g) as a pale yellow solid. LCMS Method D: [M+H] + = 211.

[0550] Step 2: 6-(4,4-difluorocyclohexyl)pyridin-3-amine 6-(4,4-Difluorocyclohex-1-en-1-yl)pyridin-3-amine (10.0 g, 47.6 mmol, 1.0 equiv.) was dissolved in MeOH (40 mL) and Pd / C (1.0 g, 9.5 mmol, 0.2 equiv.) was added. The mixture was sparged with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature for 2 hours. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure to give 6-(4,4-difluorocyclohexyl)pyridin-3-amine (9.1 g) as an off-white solid. LCMS Method C: [M+H] + = 213.

[0551] The following intermediates were prepared using the same method as described for intermediate 43. TIFF0007756643000352.tif202163TIFF0007756643000353.tif210163TIFF0007756643000354.tif225163

[0552] Synthesis of intermediate 49 (6-(4,4-difluoropiperidin-1-yl)pyridazin-3-amine) TIFF0007756643000355.tif30128 4,4-Difluoropiperidine (1.0 g, 8.3 mmol, 1.0 equiv.) was dissolved in EtOH (10 mL), followed by the addition of 6-bromopyridazin-3-amine (1.4 g, 8.3 mmol, 1.0 equiv.). The reaction mixture was heated at 80° C. overnight and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN / water, increasing from 0% ACN to 100% within 30 minutes; detector, UV 254 nm. This afforded 6-(4,4-difluoropiperidin-1-yl)pyridazin-3-amine (410 mg) as a brown solid. LCMS Method D: [M+H] + = 215.

[0553] Synthesis of Intermediate 50 (4-(3,3-difluorocyclobutyl)-3-fluoroaniline) TIFF0007756643000356.tif55138Step 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 added to DAST (30.0 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight and then quenched at 0 °C by the addition of aqueous NaHCO3. The resulting mixture was extracted with DCM, dried over anhydrous Na2SO4, and concentrated under reduced pressure. 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. TIFF0007756643000357.tif20153

[0554] 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 (11.0 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 at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:8) to give tert-butyl [4-(3,3-difluorocyclobutyl)-3-fluorophenyl]carbamate (1.0 g, 80.0%) as a white solid. LCMS Method A: [M+H] + = 302.

[0555] 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 (12.0 mL) and TFA (3.0 mL) was added dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in DCM, and the solution was washed with saturated aqueous NaHCO and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 4-(3,3-difluorocyclobutyl)-3-fluoroaniline (800 mg) as a red oil. LCMS Method A: [M+H] + = 202.

[0556] Synthesis of Intermediate 51 (5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-amine) TIFF0007756643000358.tif76155Step 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 warmed to room temperature and stirred for 18 h. The solids were removed by filtration, and the filtrate was washed with 2 N aqueous HCl, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude tert-butyl 3,3-difluorocyclobutane-1-carboxylate (896.1 mg) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 2.83-2.78 (m, 5H), 1.47 (s, 9H).

[0557] 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). NaHMDS (2 M in THF, 6.2 mL, 12.4 mmol, 1.2 equiv.) was then added dropwise over 10 min with stirring at 0 °C. The resulting solution was stirred at 0 °C for 2 h 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 under reduced pressure. 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 D:[M+H] + = 304.

[0558] 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 reduced pressure. The residue was dissolved in toluene (30 mL) and stirred at 90° C. for 18 hours. After cooling to ambient temperature and quenching by adding water, the pH 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 reduced pressure. 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 D: TIFF0007756643000359.tif12152

[0559] 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)diboron (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 under reduced pressure. 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 D: [M+H] + = 330.

[0560] 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 under reduced pressure. 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 D: TIFF0007756643000360.tif12128

[0561] 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 under reduced pressure. 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 D: [M+H] + = 352.

[0562] 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 under reduced pressure. 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 D: [M+H] + = 319.

[0563] 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 value of the solution was adjusted to 7.5 with saturated aqueous Na2CO3 solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to give 5-chloro-6-(3,3-difluorocyclobutyl)pyridin-3-amine (60 mg) as a white solid. LCMS Method D: [M+H] + = 219.

[0564] The following intermediates were synthesized using the method described for intermediate 51. TIFF0007756643000361.tif55159

[0565] Synthesis of intermediate 52 (6-(4,4-difluoropiperidin-1-yl)-5-ethylpyridin-3-amine) TIFF0007756643000362.tif26151 Step 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), followed by the addition of Xphos Pd G (1.0 g, 1.2 mmol, 0.1 equiv.) and XPhos (577.4 mg, 1.2 mmol, 0.1 equiv.) under a nitrogen atmosphere. The resulting mixture was heated at 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 under reduced pressure. 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 D: TIFF0007756643000363.tif19153

[0566] 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 flushed with nitrogen, placed under a hydrogen gas atmosphere (balloon), and then stirred at ambient temperature overnight. The solids were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:1) to give 6-(4,4-difluoropiperidin-1-yl)-5-ethylpyridin-3-amine (860 mg) as a dark yellow solid. LCMS Method D: TIFF0007756643000364.tif12128

[0567] Synthesis of intermediate 53 (2-(5-amino-2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)ethan-1-ol) TIFF0007756643000365.tif311376-(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 mixture was added NaOH (5.0 g, 12.5 mmol, 1.5 equiv.) and HO (30%, 1.3 mL, 16.7 mmol, 2.0 equiv.). The resulting mixture was stirred at ambient temperature for an additional 4 h and then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column: C18; mobile phase A: water / 0.1% NH3HCO3, mobile phase B: ACN; flow rate: 100 mL / min; gradient: 5% B to 35% B / 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. LCMS Method A: TIFF0007756643000366.tif19153

[0568] Synthesis of Intermediate 54 ((5-amino-2-(4,4-difluorocyclohexyl)pyridin-3-yl)methanol) TIFF0007756643000367.tif61128Step 1: Methyl 2-(4,4-difluorocyclohex-1-en-1-yl)-5-nitronicotinate 2-Chloro-5-nitropyridine-3-carboxylic acid ester (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 at 90 °C for 2 h and concentrated under reduced pressure. 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 A: [M+H] + = 299.

[0569] Step 2: methyl 5-amino-2-(4,4-difluorocyclohexyl)nicotinate 2-(4,4-Difluorocyclohex-1-en-1-yl)-5-nitropyridine-3-carboxylic acid ester (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 mixture was flushed 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 under reduced pressure. The residue...

Claims

1. Formula I: 【Chemical 1】 A compound of the formula During the ceremony, X 1 is NH; X 2 is CH; each 【Chemistry 2】 are independently a single bond or a double bond, provided that: X 1 and X 2 is a heteroaryl; 6-membered ring 【Chemistry 3】 is aromatic; and P 1 , P 2 , P 3 , P 4 , and P 5 the ring containing is aromatic; 【Chemistry 4】 The part is 【Chemistry 5】 [Wherein, n2 is 0, 1 or 2] or 【Chemistry 6】 [Wherein, n2 is 0 or 1] and Each R 7 -R 8 and -L 3 -R 9 are independently selected from the group consisting of: R 8 and R 9 teeth, (a) 1 to 4 independently selected R 7 ', each of which may be replaced by C 3～12 Cycloalkyl or C 3～12 cycloalkenyl; and (b) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0～2 and one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 the heterocyclyl or heterocycloalkenyl optionally substituted by '; are independently selected from the group consisting of: -L 3 -O-, -C 1～4 Alkylene, -S-, -NH-, S(O) 1～2 , C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O) 2 , and S(O) 2 selected from the group consisting of NH; R 7 Each occurrence of ' is a halo; -CN; -NO 2 -OH; 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; one to two 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 -C(=O)N(R')(R''); -C(=O)OH; and -C(=O)N(R')(R''); W is C(=O); Q is NH or N(C 1-6 alkyl), where C 1～6 Alkyl is one to two independently selected R a optionally substituted with; R 1a , R 1b , R 1c , and R 1d each of which is H; halo; cyano; one to 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; C 1～4 Haloalkoxy; -S(O) 1～2 (C 1～4 alkyl); -S(O)(=NH)(C 1～4 alkyl); SF 5 ;-NR e R f ; -OH; -S(O) 1～2 (NR'R'');-C 1～4 Thioalkoxy; -NO 2 ;-C(=O)(C 1～4 alkyl); -C(=O)O(C 1～4 independently selected from the group consisting of -C(=O)OH; -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 R a may be substituted with -C(O)O(C 1～4 alkyl); (v) -CON(R')(R''); (we)-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 selected from the group consisting of alkyl; R 6 is H; one to three 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 of 5 to 10 ring atoms, wherein 1 to 4 ring atoms are selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 and the heteroaryl ring is selected from 1 to 4 independently selected C 1～4 optionally substituted with alkyl; R a Each occurrence of represents -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 independently selected from the group consisting of: cycloalkenyl; 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; -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 are independently selected from the group consisting of: R d Ha, Halo, C 1～3 Alkoxy, C 1～3 Haloalkoxy, OH, and C 3～6 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl 1～6 C, each of which is optionally 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 selected from the group consisting of 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; 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, wherein said ring is 1～3 (b) 1 to 7 ring carbon atoms, each substituted with 1 to 2 substituents independently selected from the group consisting of alkyl; and (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; -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 each optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; C 3～8 Cycloalkyl or C 3～8 cycloalkenyl; heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0～2 and wherein the heterocyclyl or heterocycloalkenyl is selected from the group consisting of halo; one to two independently selected R a C optionally substituted with 1～4 Alkyl; C 1～4 Haloalkyl; Cyano; C 1～4 Alkoxy; and C 1～4 the heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0～2 and the heteroaryl ring is selected from the group consisting of halo; a C optionally substituted with 1～4 Alkyl; C 1～4 Haloalkyl; Cyano; C 1～4 Alkoxy; and C 1～4 the heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; and ・C 6～10 aryl, halo; one to two independently selected R a C optionally substituted with 1～4 Alkyl; C 1～4 Haloalkyl; Cyano; C 1～4 Alkoxy; and C 1～4 The C may be 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 each optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; C 3～8 Cycloalkyl or C 3～8 cycloalkenyl; heterocyclyl or heterocycloalkenyl having 3 to 16 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0～2 and wherein the heterocyclyl or heterocycloalkenyl is selected from the group consisting of 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 the heterocyclyl or heterocycloalkenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; Heteroaryl of 5 to 10 ring atoms, 1 to 4 of which are N, N(H), N(R d ), O, and S(O) 0～2 and the heteroaryl ring is 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 the heteroaryl, optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; and ・C 6～10 Aryl, 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 The C may be 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 of 5 to 10 ring atoms, wherein 1 to 4 ring atoms are selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0～2 and the heteroaryl ring is selected from the group consisting of halo, —OH, NH 2 , NH(C 1～4 alkyl), N(C 1～4 alkyl) 2 , C 1～4 Alkyl, and C 1～4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; or R' and R'' together with the nitrogen atom to which each is attached form a ring of 3 to 8 ring atoms, wherein said ring is selected from the group consisting of (a) H and C 1～3 (b) 1 to 7 ring carbon atoms, each substituted with 1 to 2 substituents independently selected from the group consisting of alkyl; and (b) N(H), N(C 1～6 having 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; however, The compound is 【Chemistry 7】 isn't it, The compound, or a pharmaceutically acceptable salt thereof, or a tautomer thereof. 【Request 2】 【Chemical 8】 The part is the formula 【Chemistry 9】 wherein n2 is 0 or 1; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof. 【Request 3】 【Chemical 10】 The part is the formula 【Chemistry 11】 wherein n2 is 0 or 1; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof.

4. 【Catalog 12】 The moiety has the formula: 【Chemistry 13】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein n2 is 0, 1, or 2.

5. 【Catalog 14】 The moiety has the formula: 【Chemistry 15】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, having the formula:

6. 【Catalog 16】 The moiety has the formula: 【Chemistry 17】 where n2 is 0, 1, or 2; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof.

7.

18. The moiety has the formula: 【Chemistry 19】 where n2 is 0, 1, or 2; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof. 【Request 8】 【Chemical 20】 The moiety has the formula: 【Chemical 21】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, having the formula:

9. 【Chemical 22】 The moiety has the formula: 【Chemical 23】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein n2 is 0, 1, or 2.

10.

24. The moiety has the formula: 【Chemistry 25】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, having the formula:

11. R 7 R 8 11. The compound of any one of claims 1 to 10, wherein:

12. R 8 but, i) 1 to 4 independently selected R 7 ', each of which is replaced by C 3～12 Cycloalkyl or C 3～12 cycloalkenyl; ii) 1 to 4 independently selected R 7 ', C 4～8 cycloalkyl; iii) 1 to 4 independently selected R 7 cyclohexyl or cyclobutyl, each substituted by '; or iv) Each R 7 ' is independently halo, 【Chemical 26】 12. The compound of any one of claims 1 to 11, wherein:

13. R 8 but, i) heterocyclyl or heterocycloalkenyl of 3 to 12 ring atoms, wherein 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0～2 and one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 may be replaced with ' the heterocyclyl or heterocycloalkenyl; ii) Heterocyclyl of 4 to 6 ring atoms, in which 1 to 2 ring atoms are N, N(H), N(R d ), O, and S(O) 0～2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 3 independently selected R 7 the heterocyclyl substituted by '; iii) 【Chemical 27】 ； iv) spirocyclic heterocyclyl of 6 to 12 ring atoms, in which 1 to 3 ring atoms are N, N(H), N(R d ), O, and S(O) 0～2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 the spirocyclic heterocyclyl optionally substituted by '; v） 【Chemical formula 28】 ； or vi) Each R 7 ' is independently halo or C 1～3 Any one of R i) to R v) is alkyl. 8 12. The compound of any one of claims 1 to 11, wherein:

14. Each R c is an independently selected halo, or a pharmaceutically acceptable salt or tautomer thereof.

15. 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt or tautomer thereof, wherein Q is NH.

16. The compound according to any one of claims 1 to 15, wherein R 6 is H, or a pharmaceutically acceptable salt or tautomer thereof.

17. i) R 1a , R 1b , R 1c , and R 1d one or two of which are other than H; and R 1a , R 1b , R 1c , and R 1d each of the remainder is H; ii) R 1b and R 1c each of which is other than H; and R 1a and R 1d each of which is H; iii) R 1b and R 1c are independently selected halo groups, and R 1a and R 1d each of which is H; iv) R 1b is other than H; and R 1a , R 1c , and R 1d each of which is H; v) R 1b But, halo; 1-2 R a C optionally substituted with 1～6 Alkyl; C 1～4 Haloalkyl; -CN; -SF 5 ;C 1～4 Thioalkoxy; S(O) 2 (C 1～4 alkyl); and C 1～4 Alkoxy or C 1～4 haloalkoxy; and R 1a , R 1c , and R 1d each of which is H; or vi) R 1b is halo; and R 1a , R 1c , and R 1d each of which is H, 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a tautomer thereof.

18. Formula (I-1a), (I-2a), or (I-3a): 【Chemical 29】 or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, R 1a , R 1b , R 1c , and R 1d each of which is H; halo; cyano; one to two R a C optionally substituted with 1～6 Alkyl; C 1～4 Haloalkyl; C 1～4 Alkoxy; and C 1～4 independently selected from the group consisting of haloalkoxy; n2 is 0, 1, or 2; Each R c If present, halo, cyano, C 1～3 Alkyl, and C 1～3 independently selected from the group consisting of alkoxy; R 8 teeth, m1 and m2 are independently 0, 1, or 2, and T 1 is CH or N; 【Chemistry 30】 and Spirocyclic heterocyclyl of 6 to 12 ring atoms, 1 to 3 of which are N, N(H), N(R d ), O, and S(O) 0～2 and one or more ring carbon atoms of the heterocyclyl ring are each independently selected from the group consisting of 1 to 4 independently selected R 7 The spirocyclic heterocyclyl may be substituted by '. selected from the group consisting of: Arbitrarily, where each R 7 ' is independently a halo or C 1～3 is alkyl; and Arbitrarily, here R d is optionally substituted with 1 to 3 independently selected halo; 1～6 is alkyl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof.

19. R 8 but, 【Chemical Formula 31】 selected from the group consisting of Arbitrarily, where each R 7 ' is independently halo or C 1～3 alkyl, and Arbitrarily, here R d C optionally substituted with 1 to 3 independently selected halo 1～6 is alkyl, 19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, or a tautomer thereof.

20. Each R 7' independently halo or C 1～3 alkyl, and R d C optionally substituted with 1 to 3 independently selected halo 1～6 20. The compound of claim 18 or 19, or a pharmaceutically acceptable salt or tautomer thereof, wherein R is alkyl.

21. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, selected from the group consisting of compounds listed in the table below, or a pharmaceutically acceptable salt thereof, or a tautomer thereof. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】

22. 22. A pharmaceutical composition comprising the compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or tautomer thereof, and one or more pharmaceutically acceptable excipients.

23. A pharmaceutical composition described in claim 22 for inhibiting STING activity.

24. 23. The pharmaceutical composition of claim 22 for treating a disease, disorder, or condition associated with STING.

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