Compounds and compositions for treating diseases associated with STING activity

Abstract

The present invention provides compounds and compositions for the treatment of diseases associated with STING activity, in particular chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or co-crystals and / or pharmaceutical combinations of compounds) that inhibit (e.g., antagonize) interferon gene stimulants (STINGs). The chemical entities are useful, for example, in the treatment of a condition, disease or condition in which an increase (e.g., excess) of STING activation (e.g., STING signaling) results in a condition / or symptom and / or progression of a condition, disease or condition (e.g., cancer) in a subject (e.g., a human). Compositions comprising the chemical entities and methods of using and making the compositions are also provided.

Description

[0001] This application is a divisional application of the international application with application number PCT / US2019 / 062238 filed on November 19, 2019 and invention name “Compounds and compositions for treating diseases associated with STING activity”. The international application entered the Chinese national phase on July 16, 2021 with application number 201980089438.2.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 769,327, filed on November 19, 2018, and U.S. Provisional Application No. 62 / 861,781, filed on June 14, 2019, which are incorporated herein by reference in their entireties. Technical Field

[0004] The present invention provides a chemical entity (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or co-crystal and / or a pharmaceutical combination of compounds) that inhibits (e.g., antagonizes) stimulator of interferon genes (STING). The chemical entity can be used, for example, to treat a condition, disease or disorder in which STING activation (e.g., STING signal transduction) is increased (e.g., excessive) leading to a morbid state / or symptom and / or progression of a condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). The present invention also provides a composition comprising the chemical entity and a method of using and preparing the composition. Background Art

[0005] 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. When cells are infected with intracellular pathogens such as viruses, mycobacteria, and intracellular parasites, STING induces type I interferon production. Type I interferons mediated by STING protect infected cells and nearby cells from local infection in an autocrine and paracrine manner.

[0006] The STING pathway is crucial in mediating the recognition of cytosolic DNA. In this context, STING is a transmembrane protein localized in the endoplasmic reticulum (ER) that acts as a second messenger receptor for 2',3' cyclic GMP-AMP (hereafter cGAMP), produced by cGAS after dsDNA binding. In addition, STING can also serve as a primary pattern recognition receptor for bacterial cyclic dinucleotides (CDNs) and small molecule agonists. The recognition of endogenous or prokaryotic CDNs occurs through the carboxyl-terminal domain of STING, which faces the cytoplasm and generates a V-shaped binding pocket formed by STING homodimers. Ligand-induced activation of STING triggers its relocalization to the Golgi apparatus, a process that is essential for promoting the interaction of STING with TBK1. In turn, this protein complex signals through the transcription factor IRF-3, thereby inducing type I interferons (IFNs) and other co-regulated antiviral factors. In addition, STING has been shown to trigger NF-κB and MAP kinase activation. After the initiation of signal transduction, STING is rapidly degraded, which is important in terminating the inflammatory response.

[0007] Hyperactivation of STING is associated with a subset of monogenic autoinflammatory disorders, the so-called type I interferonopathies. Examples of these diseases include a clinical syndrome called STING-associated vasculopathy of infancy (SAVI), which is caused by gain-of-function mutations in TMEM173 (the gene name for STING). In addition, STING is involved in the pathogenesis of Aicardi-Goutières Syndrome (AGS) and inherited forms of lupus. Unlike SAVI, continuous innate immune activation in AGS underlies dysregulated nucleic acid metabolism. In addition to these genetic diseases, emerging evidence suggests that STING has a more general pathogenic role in a range of inflammation-related diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and cancer. Therefore, small molecule-based pharmacological interventions on the STING signaling pathway have great potential in the treatment of a variety of diseases. Summary of the invention

[0008] The present invention provides chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or co-crystals and / or drug combinations of compounds) that inhibit (e.g., antagonize) stimulators of interferon genes (STING). The chemical entity can be used, for example, to treat such a condition, disease or disorder in which STING activation (e.g., STING signal transduction) increases (e.g., excessively) leading to the morbidity / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) of a subject (e.g., a human). The present invention also provides compositions comprising the chemical entity and methods of using and preparing the composition.

[0009] "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 inhibiting, blocking or attenuating agonist-mediated responses, altering distribution or otherwise. STING antagonists include chemical entities that interfere with or inhibit STING signal transduction.

[0010] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0011]

[0012] Among them, A, B, W and R N May be as defined anywhere herein.

[0013] In one aspect, the invention provides pharmaceutical compositions comprising a chemical entity described herein (eg, a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound) and one or more pharmaceutically acceptable excipients.

[0014] In one aspect, the present invention provides a method of inhibiting (e.g., antagonizing) STING activity, comprising contacting STING with a chemical entity as described herein (e.g., a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound). The method includes an in vitro method, such as contacting a sample comprising one or more cells comprising STING (e.g., innate immune cells, such as mast cells, macrophages, dendritic cells (DCs), and natural killer cells) with a chemical entity. The method may also include an in vivo method; for example, administering a chemical entity to a subject (e.g., a human) suffering from a disease in which STING signaling is increased (e.g., excessive) thereby causing the pathology and / or symptoms and / or progression of the disease.

[0015] In one aspect, the invention provides a method for treating a condition, disease or disorder that is improved by antagonizing STING, wherein increased (e.g., excessive) STING activation (e.g., STING signaling) results in morbidity and / or symptoms and / or progression of the condition, disease or disorder in a subject (e.g., a human). The method comprises administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

[0016] In another aspect, the invention provides a method of treating cancer comprising administering to a subject in need of such treatment an effective amount of a chemical entity described herein (eg, a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

[0017] In another aspect, the present invention provides methods for treating other diseases associated with STING, such as type I interferon diseases (e.g., STING-associated vasculopathy of infancy (SAVI)), Aicardi-Goutières Syndrome (AGS), hereditary forms of lupus, and inflammation-related diseases such as systemic lupus erythematosus and rheumatoid arthritis. The method comprises administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

[0018] In another aspect, the invention provides a method of inhibiting STING-dependent type I interferon production in a subject in need thereof, comprising administering to the subject an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

[0019] In another aspect, the invention provides a method for treating a disease in which increased (e.g., excessive) STING activation (e.g., STING signaling) results in a disease state and / or symptom and / or progression. The method comprises administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

[0020] In another aspect, the invention provides a method of treatment comprising administering to a subject an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising the same); wherein the subject suffers from (or is susceptible to suffering from) a disease in which increased (e.g., excessive) STING activation (e.g., STING signaling) leads to pathology and / or symptoms and / or progression of the disease.

[0021] In another aspect, the invention provides methods of treatment comprising administering to a subject a chemical entity described herein (e.g., a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising the same), wherein the chemical entity is administered in an amount effective to treat a disease in which increased (e.g., excessive) STING activation (e.g., STING signaling) leads to a morbid state and / or symptom and / or progression of the disease, thereby treating the disease.

[0022] Implementations may include one or more of the following features.

[0023] The chemical entity can be administered in combination with one or more other therapeutic agents and / or regimens. For example, the method can further include administering one or more (e.g., two, three, four, five, six or more) other agents.

[0024] The chemical entity can be administered in combination with one or more other therapeutic agents and / or regimens useful for treating other STING-associated diseases, for example, type I interferonopathies (e.g., STING-associated vasculopathy of infancy (SAVI)), Aicardi-Goutières Syndrome (AGS), hereditary forms of lupus, and inflammation-related diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

[0025] 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); for example, chemotherapy comprising administration of one or more (e.g., two, three, four, five, six or more) other chemotherapeutic agents. Non-limiting examples of other chemotherapeutic agents are selected from: alkylating agents (e.g., cisplatin, carboplatin, nitrogen mustard, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); antimetabolites (e.g., azathioprine and / or mercaptopurine); terpenoids (e.g., vinca alkaloids and / or taxanes; e.g., vincristine, vinblastine, vinorelbine and / or vindesine, taxol, paclitaxel and / or docetaxel); topoisomerases (e.g., type I topoisomerases and / or type 2 topoisomerases; e.g., camptothecins, e.g., irinotecan and / or topotecan); amsacrine (e.g., tadalafil ... msacrine, etoposide, etoposide phosphate and / or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); hormones (e.g., luteinizing hormone-releasing hormone agonists; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide);Antibodies (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Brentuximab Vedotin, Canakinumab, Cetuximab, Certolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Ibritumomabtiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab umab), rituximab, tocilizumab, tositumomab and / or trastuzumab; antiangiogenic agents; cytokines; thrombotic agents; growth inhibitors; anthelmintics; and immune checkpoint inhibitors targeting immune checkpoint receptors selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1–PD-L1, PD-1–PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T-cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC Class II–LAG3, 4-1BB–4-1BB ligand, OX40–OX40 ligand, GITR, GITR ligand–GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25–TL1A, CD40L, CD40–CD40 ligand, HVEM–LIGHT–LTA, HVEM, HVEM–BTLA, HVEM–CD160, HVEM–;

[0026] 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, butyrophilin including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NK G2A, MICA and MICB, CD244, CD28, CD86–CD28, CD86–CTLA, CD80–CD28, CD39, CD73 adenosine–CD39–CD73, CXCR4–CXCL12, phosphatidylserine, TIM3, phosphatidylserine–TIM3, SIRPA–CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

[0027] The subject may have cancer; for example, the subject has undergone and / or is undergoing and / or will undergo one or more cancer treatments.

[0028] Non-limiting examples of cancer include melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms tumor or hepatocellular carcinoma. In some embodiments, the cancer can be a refractory cancer.

[0029] The chemical entity can be administered intratumorally.

[0030] The method may further include identifying the object.

[0031] Other implementations include what is described in the detailed description and / or claims.

[0032] Other definitions

[0033] In order to promote the understanding of the disclosure set forth herein, a plurality of other terms are defined below. Generally, the nomenclature used herein and the laboratory procedures of organic chemistry, medicinal chemistry and pharmacology described herein are well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which this paper belongs. Each patent, application, disclosed application and other publications and attached appendix mentioned in the entire specification are incorporated herein by reference in their entirety.

[0034] As used herein, the term "STING" is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, 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.

[0035] As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the subject being treated.

[0036] “API” means active pharmaceutical ingredient.

[0037] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a chemical entity sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. Results include reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired changes in a biological system. For example, an "effective amount" for therapeutic use is an amount comprising a compound disclosed herein to provide a clinically significant alleviation of disease symptoms. In any case, any appropriate technique (e.g., a dose escalation study) may be used to determine a suitable "effective" amount.

[0038] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., 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).

[0039] The term "pharmaceutically acceptable salt" refers to a preparation of a compound that does not cause significant irritation to the organism to which it is administered and does not eliminate the biological activity and properties of the compound. In some cases, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some cases, a salt is formed by reacting a compound having an acidic group described herein with a base, 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 salt or a magnesium salt, a salt of an organic base, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt formed with an amino acid, such as arginine, lysine, and the like, or by other methods previously determined. There is no particular limitation on the pharmaceutically acceptable salt, as long as it can be used in medicine. Examples of salts formed with bases of the compounds described herein include the following: salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, specifically exemplified by addition salts formed with the following acids: inorganic 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; acidic amino acids such as aspartic acid and glutamic acid.

[0040] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents and / or thickeners. Pharmaceutical compositions facilitate administration of compounds to an organism. There are a variety of techniques for administering compounds in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0041] The term "subject" may refer to an animal, including but not limited to a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., to refer to a mammalian subject, e.g., a human subject.

[0042] In the context of treating a disease, disorder or condition, the terms "treat," "treat," and "therapy" are intended to include alleviating or eliminating the disease, disorder or condition, or one or more symptoms associated with the disease, disease or condition; or slowing the progression, spread, or worsening of the disease, disorder or condition, or one or more symptoms thereof. "Cancer treatment" refers to one or more of the following effects: (1) inhibiting tumor growth to some extent, including (i) slowing and (ii) complete arrest of growth; (2) reducing the number of tumor cells; (3) maintaining tumor size; (4) reducing tumor size; (5) inhibiting, including (i) reducing, (ii) slowing, or (iii) completely preventing tumor cell infiltration into peripheral organs; (6) inhibiting, including (i) reducing, (ii) slowing, or (iii) completely preventing cancer metastasis; (7) enhancing anti-tumor immune responses, which can (i) maintain tumor size, (ii) reduce tumor size, (iii) slow tumor growth, (iv) reduce, slow, or prevent invasion and / or (8) reducing to some extent the severity or number of one or more symptoms associated with the disorder.

[0043] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0044] The term "alkyl" refers to a hydrocarbon chain which may be straight or branched and contains the indicated number of carbon atoms. -10 Indicates that the group may have 1 to 10 (inclusive) carbon atoms. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.

[0045] The term "haloalkyl" refers to an alkyl group wherein one or more hydrogen atoms are replaced by independently selected halogens.

[0046] The term "alkoxy" refers to an -O-alkyl group (e.g., -OCH 3 ).

[0047] The term "alkylene" refers to a divalent alkyl group (e.g., -CH 2 -).

[0048] The term "alkenyl" refers to a 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 It means that the group may have 2 to 6 (inclusive) carbon atoms.

[0049] The term "alkynyl" refers to a 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 It means that the group may have 2 to 6 (inclusive) carbon atoms.

[0050] The term "aryl" refers to a monocyclic, bicyclic, tricyclic or polycyclic group of 6-20 carbons, wherein 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 wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted with a substituent. Examples of aryl also include phenyl, naphthyl, tetrahydronaphthyl, etc.

[0051] The term "cycloalkyl" as used herein includes cycloalkyl groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 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. Cycloalkyl groups may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyls also include spirocycles (e.g., spirobicycles in which the two rings are connected by only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0052] The term ring "alkenyl" as used herein includes partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. The cycloalkenyl group may have any degree of saturation, provided that all rings in the ring system are not aromatic; and the cycloalkenyl group is generally not fully saturated. The cycloalkenyl group may include multiple condensed rings and / or bridged rings and / or spiro rings.

[0053] As used herein, the term "heteroaryl" refers to a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, or 5, 6, 9, 10 or 14 ring atoms; and sharing 6, 10 or 14 π electrons in the ring array; wherein at least one ring in the system is aromatic (but not necessarily a ring containing heteroatoms, such as tetrahydroisoquinolyl, such as tetrahydroquinolyl), and at least one ring in the system contains one or more independently selected from N, O and S(O) 0-2heteroatoms. A heteroaryl group may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include: thienyl, pyridyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quino[2,3-d]pyrimidinyl, oxazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiine, isoindole, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furanyl, pyrazolyl, imidazolyl, isoindole, pyranyl, pyrazinyl and pyrimidinyl.

[0054] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic non-aromatic ring system having 3-16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic), having 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic) or 1-9 heteroatoms (if tricyclic or polycyclic), the heteroatoms being selected from O, N or S (e.g., having carbon atoms and 1-3, 1-6 or 1-9 heteroatoms selected from N, O or S (O) if monocyclic, bicyclic or tricyclic, respectively). 0-2) wherein 0, 1, 2 or 3 atoms of each ring may be substituted with a substituent. Examples of heterocyclic groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, etc. Heterocyclic groups may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, Azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclyl also includes spirocycles (e.g., spirobicycles in which the two rings are connected by only one atom). Non-limiting examples of spirocyclic heterocyclyls include: 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-azaspiro[3.5]decane, 2-azaspiro[4.4]decane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-azaspiro[3.5]decane, 2-azaspiro[3.5]decane, 2-azaspiro[3.5]decane, 2-azaspiro[3.5]decane, 2-azaspiro[4.4]decane, 2-azaspiro[3.5 ... Oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like.

[0055] In addition, the atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. As a general example and not limitation, isotopes of hydrogen include tritium and deuterium, while isotopes of carbon include 13 C and14 C.

[0056] Non-limiting exemplary compounds of the formulae described herein include a stereogenic sulfur atom and optionally one or more stereogenic carbon atoms. Examples of stereoisomeric mixtures are provided herein (e.g., a racemic mixture of enantiomers; a diastereomeric mixture). Methods of separating the individual components of the stereoisomeric mixtures are also described and exemplified herein (e.g., resolving the enantiomers of a racemic mixture). For compounds containing only stereogenic sulfur atoms, the resolved enantiomers are depicted using one of the following two formats: Formula A / B (hashed and stereowedge three-dimensional representations); and Formula C ("flat structure with stereogenic sulfur marked with a *).

[0057]

[0058] In reaction schemes showing resolution of racemic mixtures, Formulas A / B and C are intended only to convey that the component enantiomers are resolved in enantiomerically pure form (about 98% ee or higher). The use of the schemes showing the resolution of products in Formula A / B format is not intended to disclose or imply any correlation between absolute configuration and elution order. Some of the compounds shown in the following table are shown in Formula A / B format.

[0059] In addition, compounds generally or specifically disclosed herein are intended to include all tautomeric forms. Thus, for example, The compounds include Similarly, a pyridinyl or pyrimidinyl moiety described as optionally substituted with hydroxy includes pyridone or pyrimidone tautomeric forms.

[0060] The following description further details one or more embodiments of the present invention. Other features, objectives and advantages of the present invention are apparent from the description and claims. DETAILED DESCRIPTION

[0061] The present invention provides a chemical entity (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or co-crystal and / or a pharmaceutical combination of compounds) that inhibits (e.g., antagonizes) stimulator of interferon genes (STING). The chemical entity can be used, for example, to treat a condition, disease or disorder in which STING activation (e.g., STING signal transduction) is increased (e.g., excessive) leading to a morbid state / or symptom and / or progression of a condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). The present invention also provides a composition comprising the chemical entity and a method of using and preparing the composition.

[0062] Compounds of formula I

[0063] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt or tautomer thereof:

[0064]

[0065] in:

[0066] A is selected from the following group:

[0067] (i) a heteroaryl group containing 5-6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O, S and S(O) 2 , and wherein 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 and CR 3 , provided that at least one ring atom is R 1 Replacement; and

[0068] (ii) a heteroaryl group containing 7 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 3-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 and C(R 3 ) 2 ;

[0069] B and each occurrence of R N according to (A) and (B) definition:

[0070] (A)

[0071] B is:

[0072] (a)C 1-15 Alkyl, which is optionally substituted by 1 to 6 R a replace;

[0073] (b)C 3-20 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace;

[0074] (c) 1-4 Rs cSubstituted phenyl;

[0075] (d)C 8-20 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0076] (e) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl ring is optionally replaced by 1-4 independently selected R c replace; or

[0077] (f) a heterocyclic group containing 3 to 16 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace;

[0078] Each R N Independently for:

[0079] (i) H,

[0080] (ii)C 1-6 Alkyl, optionally with 1-3 R a replace,

[0081] (iii)C 3-6 Cycloalkyl, optionally substituted with 1 to 3 R a replace,

[0082] (iv)-C(O)(C 1-4 alkyl), and

[0083] (v) -C(O)O(C 1-4 alkyl),

[0084] (B)

[0085] B and an R N Together with the atoms to which they are attached, they form a ring containing 5-20 ring atoms, wherein the ring contains: (a) 0-4 ring heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 (Except for the moiety) and (b) 2 to 17 ring carbon atoms, each of which is optionally substituted with 1 to 2 substituents independently selected from the following:

[0086] (i) H;

[0087] (ii) oxo;

[0088] (iii) halogen;

[0089] (iv) hydroxyl group;

[0090] (v)C 1-6 alkyl;

[0091] (vi)C 1-6 Haloalkyl;

[0092] (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c replace;

[0093] (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace;

[0094] (ix) a heterocyclic group containing 3 to 16 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b Replacement; and

[0095] (x)C 3-20 Cycloalkyl, which is optionally substituted by 1 to 4 R b Replacement; and

[0096] The remaining R N Is H or C 1-6 alkyl;

[0097] W is O, NH or N(R d );

[0098] R1 is:

[0099] (i)-(U 1 ) q -U 2 ,in:

[0100] q is 0 or 1;

[0101] ●U 1 It is C 1-6 Alkylene, which is optionally substituted by 1 to 6 R a Replacement; and

[0102] ●U 2 yes:

[0103] (a)C 3-12 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace,

[0104] (b)C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0105] (c) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl ring is optionally replaced by 1-4 independently selected R c Replace, or

[0106] (d) a heterocyclic group containing 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace,

[0107] or,

[0108] (ii)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace;

[0109] Each occurrence of R 2 Independently selected from:

[0110] (i)C 1-6 Alkyl, which is optionally substituted by 1-4 independently selected R a replace;

[0111] (ii)C 3-6 Cycloalkyl;

[0112] (iii) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 ;

[0113] (iv)-C(O)(C 1-4 alkyl);

[0114] (v) -C(O)O(C 1-4 alkyl);

[0115] (vi) -CON(R')(R');

[0116] (vii)-S(O) 1-2 (NR'R");

[0117] (viii)-S(O) 1-2 (C 1-4 alkyl);

[0118] (ix) -OH; and

[0119] (x)C 1-4 Alkoxy;

[0120] Each occurrence of R 3 independently selected from the group consisting of halogen, cyano, optionally substituted by 1-2 R a Substituted C 1-6 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, oxo, -S(O) 1-2 (NR'R"), -C 1-4 Thioalkoxy, -NO 2 ,-C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R");

[0121] Each occurrence of R a Independently selected from the group consisting of: -OH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); cyano; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution;

[0122] Each occurrence of Rb Independently selected from: optionally 1-6 independently selected R a Substituted C 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 1-4 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 ;

[0123] Each occurrence of R c Independently selected from:

[0124] (a) halogen;

[0125] (b) cyano;

[0126] (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace;

[0127] (d)C 2-6 alkenyl;

[0128] (e)C 2-6 Alkynyl;

[0129] (g)C 1-4 Alkoxy;

[0130] (h)C 1-4 Haloalkoxy;

[0131] (i)-S(O) 1-2 (C 1-4 alkyl);

[0132] (j)-NR e R f ;

[0133] (k)–OH;

[0134] (l)-S(O) 1-2 (NR'R");

[0135] (m)-C 1-4Thioalkoxy;

[0136] (n)-NO 2 ;

[0137] (o)-C(=O)(C 1-4 alkyl);

[0138] (p)-C(=O)O(C 1-4 alkyl);

[0139] (q) -C(=O)OH;

[0140] (r)-C(═O)N(R′)(R″); and

[0141] (s)-L 1 -L 2 -R h ;

[0142] R d Select from the following group: C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy;

[0143] Each occurrence of R e and R f Independently selected from: H; C 1-6 Alkyl; C 1-6 Haloalkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy; or R e and R f Together with the nitrogen atoms to which they are attached, they form a ring containing 3-8 ring atoms, wherein the ring contains: (a) 1-7 ring carbon atoms, each carbon atom being independently selected from H and C 1-3 1-2 substituents of the alkyl group; (b) 0-3 ring heteroatoms (except for R e and R f connected nitrogen atoms), each of which is independently selected from N(Rd ), NH, O and S;

[0144] -L 1 Is a chemical bond or C1 -3 Alkylene;

[0145] -L 2 is –O-, -N(H)-, -S-, or a bond;

[0146] R h Selected from:

[0147] ●C 3-8 Cycloalkyl, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl and C 1-4 haloalkyl (in some embodiments, provided that when R h is optionally 1-4 independently selected C 1-4 Alkyl substituted C 3-6 When cycloalkyl, -L 1 is key, or -L 2 is –O-, -N(H)-, or -S-);

[0148] ● Heterocyclyl, wherein the heterocyclyl contains 3-16 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 wherein the heterocyclyl ring is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0149] ● Heteroaryl containing 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl and C 1-4 haloalkyl; and

[0150] ●C 6-10 Aryl, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl or C 1-4 haloalkyl; and

[0151] Each occurrence of R' and R" is independently selected from the group consisting of H, C 1-4 Alkyl and C 6-10 Aryl, which is optionally selected from halogen, C1-4 Alkyl and C 1-4 or R' and R" together with the nitrogen atom to which they are attached form a ring containing 3-8 ring atoms, wherein the ring contains: (a) 1-7 ring carbon atoms, each carbon atom being substituted by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms (except the nitrogen atom connected to R' and R "), each of which is independently selected from the following groups: N (H), N (R d ), O and S;

[0152] Provided that the compound is not:

[0153]

[0154] Implementations may include any one or more of the features described below and / or in the claims.

[0155] Ring A

[0156] In some embodiments, A is: a heteroaryl group containing 7-20 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 3-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 and C(R 3 ) 2 .

[0157] In some embodiments, A is: a heteroaryl group containing 8-16 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 4-15 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 and C(R 3 ) 2 .

[0158] In some embodiments, A is: a heteroaryl group containing 8-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 4-9 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 and C(R 3 ) 2 .

[0159] In some embodiments, A is: a heteroaryl group containing 8-9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 4-8 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 and C(R 3 ) 2 .

[0160] [C6] In some embodiments, A has formula (A-1):

[0161]

[0162] in,

[0163] Z is selected from the following group: bond, CH, CR 1 , CR 3 、N、NH、N(R 1 ) and N(R 2 );

[0164] Y 1 , Y 2 and Y 3 Each independently selected from the following group: O, S, CH, CR 1 , CR 3 、N、NH、N(R 1 ) and NR2 ;

[0165] Y 4 is C or N;

[0166] X 1 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;

[0167] X 2 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;and

[0168] each are independently single bonds or double bonds, provided that Y 4 , X 1 and X 2 The five-membered ring is a heteroaryl group; and contains Z, Y 1 , Y 2 , Y 3 and Y 4 The ring is aromatic (ie, an aromatic carbocyclic or heterocyclic ring).

[0169] As used herein, when including Z, Y 1 , Y 2 , Y 3 and Y 4 The ring is described as aromatic, which means that it contains Z, Y 1 , Y 2 , Y 3 and Y 4 (Right now, The 6-membered or 5-membered ring of the 4-membered ring (part) has a continuous delocalized π-electron system. In general, the number of out-of-plane π-electrons corresponds to the Hückel rule (4n+2). Examples of such rings include: each of which is optionally replaced by one or more R as described anywhere herein 1 and / or R 3 replace.

[0170] [C7] In some of these embodiments, Z is selected from the group consisting of CH, CR 1 , CR 3 , N and N(R 2 ).

[0171] [C8] For example, Z can be selected from the group consisting of CH, CR 1 , CR3 and N.

[0172] [C9] For example, Z is selected from the following group: CH, CR 1 and CR 3 (eg, Z is CH).

[0173] [C10] In some of the foregoing embodiments, Y 1 , Y 2 and Y 3 Each independently selected from the following group: CH, CR 1 , CR 3 and N.

[0174] [C11] In some of these embodiments, Y 1 , Y 2 and Y 3 Each independently selected from the following group: CH, CR 1 , CR 3 and N.

[0175] [C12] For example, Some are possible wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (e.g., m1=0 or 1; and m3=0, 1 or 2).

[0176] [C13] In other aforementioned embodiments, 1-2 Y 1 , Y 2 and Y 3 Independently is N.

[0177] [C14] In some embodiments, Y 1 , Y 2 and Y 3 One of can independently be N.

[0178] [C15] In some of the foregoing embodiments, the remaining Y 1 , Y 2 and Y 3 Each independently selected from the following group: CH, CR 1 and CR 3 , the condition is one or more Y 1 , Y 2 and Y 3 independently CH.

[0179] [C16] For example, Part can be The asterisk indicates the connection to Y 4 point; and m3=0, 1 or 2; and m3=0, 1 or 2 (for example, m1=0 or 1; and m3=0 or 1).

[0180] [C17] For example, Part can be The asterisk indicates the connection to Y 4 point; and m1=0, 1 or 2; and m3=0, 1 or 2 (for example, m1=0 or 1; and m3=0 or 1).

[0181] [C17a] For example, Part can be The asterisk indicates the connection to Y 4 point; and m1=0, 1 or 2; and m3=0, 1 or 2 (for example, m1=0 or 1; and m3=0 or 1).

[0182] [C18] In some embodiments, Y 1 , Y 2 and Y 3 Two of them are independently N.

[0183] [C19] In some of the foregoing embodiments, the remaining Y 1 , Y 2 and Y 3 independently CH or CR 1 .

[0184] [C20] In some embodiments, Z is N.

[0185] [C21] In some of these embodiments, Y 1 , Y 2 and Y 3 Each independently selected from the following group: CH, CR 1 , CR 3 and N.

[0186] [C22] In some embodiments, Y 1 , Y 2 and Y 3 one of them may independently be N; and the remaining Y 1 , Y 2 and Y 3 Each can be independently CH, CR 1 , CR 3 and N; or

[0187] [C23] Remaining Y 1 , Y 2 and Y 3 Each independently can be CH, CR 1 and CR 3 .

[0188] [C24] For example, Part can be The asterisk indicates the connection Y 4 point; and m1=0, 1 or 2; and m3=0, 1 or 2 (for example, m1=0 or 1; and m3=0 or 1).

[0189] [C25] In some of the foregoing embodiments, Z is a bond.

[0190] [C26] In some of these embodiments, Y 1 , Y 2 and Y 3 Each independently selected from the following group: O, S, CH, CR 1 , CR 3 , N, NH and NR 2 .

[0191] [C27] In some embodiments, 1-2 Y 1 , Y 2 and Y 3 Independently selected from the group consisting of O, S, N, NH and NR 2 (e.g., S, N, and NR 2 ).

[0192] [C28] For example, Part can be The asterisk indicates 4 Connected points; and m1=0 or 1; and m3=0, 1 or 2.

[0193] [C29] For example, Part can be (For example, ), where the asterisk indicates the connection Y 4 point.

[0194] [C30] In some of the aforementioned embodiments, Y 4 It is C.

[0195] [C31] In some of the foregoing embodiments, X 1 Selected from the group consisting of O, S, NH, NR 1 and NR 2 .

[0196] [C32] In some embodiments, X 1 Selected from the group consisting of NH, NR 1 and NR 2 (For example, X 1 It can be NH).

[0197] [C33] In some of the foregoing embodiments, X 2 Selected from the group consisting of N, CH, CR 1and CR 3 ;

[0198] [C34] For example, X 2 Selected from the following group: N, C(C 1-3 alkyl) and CH;

[0199] [C35] For example, X 2 It can be CH.

[0200] [C36] For example, X 1 and X 2 Together can be Among them, the asterisk indicates 4 Connect the dots.

[0201] [C37] Non-limiting examples of A include:

[0202] (For example, ), wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (e.g., m1=0 or 1; and m3=0, 1 or 2).

[0203] [C38] Another non-limiting example of A includes:

[0204] wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[0205] [C39] Another non-limiting example of A includes:

[0206] wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[0207] Another non-limiting example of [C40]A includes:

[0208] Wherein m1=0, 1 or 2; and m3=0, 1 or 2.

[0209] [C41] Another non-limiting example of A includes:

[0210] Wherein m1=0 or 1; and m3=0, 1 or 2.

[0211] Other non-limiting examples of [C42]A include:

[0212] (For example, ).

[0213] [C43] In some embodiments, A is: a heteroaryl group containing 8-20 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 4-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 and C(R 3 ) 2 .

[0214] [C44] In some embodiments, A is: a heteroaryl group (e.g., a tricyclic heteroaryl group) containing 10-16 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 6-15 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 and C(R 3 ) 2 .

[0215] [C45] In some embodiments, A is (A-2):

[0216]

[0217] in:

[0218] Z is selected from the following group:

[0219] Key, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 , C(R 3 ) 2 、O、N、NH、N(R 1 ) and N(R 2 );

[0220] Y 1 and Y 2 Each is independently selected from the following group: O, S, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 , C(R 3 ) 2 、N、NH、N(R 1 ) and NR 2 ;

[0221] Q 1 and Q 2 One of the does not exist, and Q 1 and Q 2 The other one is C 2-5 Alkylene, which is optionally interrupted by a heteroatom selected from: -NH-, -N(R 1 )-、-N(R 2 )- and –O-; and

[0222] each is independently a single bond or a double bond.

[0223] [C46] In some embodiments (when A is (A-2)), Z is selected from CH, CR 1 , CR 3 and N.

[0224] [C47] In some of the foregoing embodiments, Z is selected from CH and N (eg, Z is CH).

[0225] [C48] In some of these embodiments (when A is (A-2)), Y 1 and Y 2 Each independently selected from the following group: CH, CR 1 , CR 3 and N.

[0226] [C49] In some of these embodiments (when A is (A-2)), Y 1 and Y 2 Each independently selected from the following group: CH, CR 1 and CR 3 .

[0227] [C50] In some embodiments (when A is (A-2)), Q 1 It is C 2-5Alkylene, which is optionally interrupted by a heteroatom selected from: -NH-, -N(R 1 )-、-N(R 2 )- and –O-; and Q 2 Does not exist.

[0228] [C51] As a non-limiting example, Q 1 Can be C 2-3 Alkylene (e.g., C 2 ).

[0229] [C52] In some embodiments (when A is (A-2)), Q 2 It is C 2-5 Alkylene, which is optionally interrupted by a heteroatom selected from: -NH-, -N(R 1 )-、-N(R 2 )- and –O-; and Q 1 Does not exist.

[0230] [C53] As a non-limiting example, Q 2 It is C 3-4 Alkylene (e.g., C 3 ).

[0231] [C54] In some embodiments (if A is (A-2)), A is:

[0232]

[0233] wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (eg, m1=0; and m3=0).

[0234] [C55] In some embodiments (if A is (A-2)), A is:

[0235]

[0236] wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (eg, m1=0; and m3=0).

[0237] [C56] In some embodiments, A is (A-3):

[0238]

[0239] in,

[0240] Ring A 3A is a monocyclic or bicyclic ring containing 5-12 ring atoms, wherein 0-2 ring atoms are cumulative and selected for Y 4wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and 2-12 are ring carbon atoms, each independently selected from: C, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 and C(R 3 ) 2 , provided that ring A 3A is non-aromatic;

[0241] X 1 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;

[0242] X 2 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ; The condition is to contain Y 4 , X 1 and X 2 The ring of is heteroaromatic; and

[0243] Y 4 Selected from: N or C.

[0244] [C57] In some embodiments (when A is (A-3)), Y 4 It is C

[0245] [C58] In some embodiments (when A is (A-3)), Ring A 3A is a monocyclic ring containing 5-8 ring atoms, of which 0-2 ring atoms are cumulative and selected for Y 4 wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and 2-8 are ring carbon atoms, each independently selected from: C, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR3 , CHR 3 and C(R 3 ) 2 , provided that ring A 3A It is non-aromatic.

[0246] [C59] In some embodiments (when A is (A-3)), Ring A 3A is a monocyclic ring containing 5-6 ring atoms, wherein 0-2 (e.g., 0 or 1, e.g., 0) ring atoms are cumulatively selected for Y 4 wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and 2-6 are ring carbon atoms, each independently selected from: C, CH 2 , CHR 1 , C(R 1 ) 2 , CHR 3 and C(R 3 ) 2 , provided that ring A 3A It is non-aromatic.

[0247] [C60] In some embodiments (if A is (A-3)), A is:

[0248] wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[0249] [C61] In some embodiments (when A is (A-3)), Ring A 3A is a bicyclic ring (eg, a spirobicyclic ring) containing 7-12 ring atoms, wherein 0-2 (eg, 0 or 1, eg, 1) ring atoms are cumulatively selected for Y 4 wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and 4-12 are ring carbon atoms, each independently selected from: C, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 and C(R 3 ) 2 , provided that ring A 3AIt is non-aromatic.

[0250] [C62] In some embodiments (when A is (A-3)), Ring A 3A is a bicyclic ring (eg, a spirobicyclic ring) containing 7-9 (eg, 8) ring atoms, wherein 0-2 (eg, 0 or 1, eg, 1) ring atoms are cumulatively selected for Y 4 wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and 4-9 are ring carbon atoms, each independently selected from: C, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 and C(R 3 ) 2 , provided that ring A 3A It is non-aromatic.

[0251] [C63] In some embodiments (when A is (A-3)), Ring A 3A is a bicyclic ring (eg, a spirobicyclic ring) containing 7-9 (eg, 8) ring atoms, wherein 0-2 (eg, 0 or 1, eg, 1) ring atoms are cumulatively selected for Y 4 wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R d ) and O, and 4-9 are ring carbon atoms, each independently selected from: C, CH 2 , CHR 1 , C(R 1 ) 2 , CHR 3 and C(R 3 ) 2 , provided that ring A 3A It is non-aromatic.

[0252] [C64] In some embodiments (if A is (A-3)), A is:

[0253] wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[0254] [C65] In some embodiments (when A is (A-3)), X 1 Selected from NH, N(R 2 ), O and S.

[0255] [C66] As a non-limiting example of the above embodiment, X 1 It can be NH.

[0256] [C67] In some embodiments (when A is (A-3)), X 2 Selected from N, CH and CR 1 .

[0257] [C68] As a non-limiting example of the above embodiment, X 2 It is CH.

[0258] [C69] In some embodiments (if A is (A-3)), A is:

[0259] wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[0260] [C70] In some embodiments (if A is (A-3)), A is:

[0261] wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[0262] [C71] In some embodiments, A is: a heteroaryl group containing 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O, S and S(O) 2 , and wherein 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 and CR 3 , provided that at least one ring atom is substituted by R1.

[0263] [C72] In some of the aforementioned embodiments, A is: a heteroaryl group containing 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S, and wherein 1-4 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 and CR 3 , provided that at least one ring atom is R 1 replace.

[0264] [C73] In some embodiments, A is: a heteroaryl group containing 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S, and wherein 1-4 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 and CR 3 , provided that a ring atom is occupied by 1-2 R 1 (e.g., 1) substitution.

[0265] [C74] In some embodiments, A is (A-4):

[0266]

[0267] in:

[0268] Z 2 Selected from: CH, R 2 and N;

[0269] X 3 Selected from: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;

[0270] Y 5 and Y 6 Each independently selected from O, S, CH, CR 1 , CR 3 NR 1 NR 2 , NH and N; and

[0271] Each are independently single bonds or double bonds, provided that Y 5 , Y 6 , X 3 and Z 2 The five-membered ring of is a heteroaryl group.

[0272] [C75] In some of the foregoing embodiments,

[0273] When X 3 YesNR 1 or CR 1 When Y 5 and Y 6 Each independently selected from O, S, CH, CR 1 , CR 3 NR 1 NR 2 , NH and N; and

[0274] When X 3 Selected from O, S, N, NH, NR 2 , CH and CR 3 When Y 5 and Y 6 One of them is CR 1 or NR 1 (In some embodiments, Y 5 and Y 6 The other one is selected from O, S, CH, CR 3 NR 2 , NH and N).

[0275] [C76] In some embodiments (when A is (A-4)), Z 2 is selected from CH and N.

[0276] [C77] As a non-limiting example, Z 2 It can be CH.

[0277] [C78] In some embodiments (when A is (A-4)), Z 2 selected from CH and N), Y 6 Selected from N, CH and CR 3 .

[0278] [C79] As a non-limiting example, Y 6 It can be N.

[0279] [C80] In some embodiments (when A is (A-4)), Z 2 is selected from CH and N; and / or Y 6 Selected from N, CH and CR 3 ), Y 5 Yes CR 1 .

[0280] [C81] In some embodiments (when A is (A-4)), Z 2 Selected from CH and N; Y 6 Selected from N, CH and CR 3 , and / or Y 5 Yes CR 1 ), X 3 Selected from S, O, NH and N(R 2 ).

[0281] [C82] Non-limiting examples of A include:

[0282] [C83] As a non-limiting example, A may be

[0283] [C84] As another non-limiting example, A may be

[0284] [C85] In some embodiments (when A is (A-4)), Z 2 It is N.

[0285] [C86] In some embodiments (when A is (A-4); and / or Z 2 is N), Y 6 Selected from N, CH and CR 3 .

[0286] [C87] As a non-limiting example, Y 6 It can be CH.

[0287] [C88] In some embodiments (when A is (A-4); Z 2 is N; and / or Y 6 Selected from N, CH and CR 3 ), Y 5 Yes CR 1 .

[0288] [C89] In some embodiments (when A is (A-4), Z 2 Yes N; Y 6 Selected from N, CH and CR 3 , and / or Y 5 Yes CR 1 ), X 3 Selected from O, S, NH and NR 2 .

[0289] Non-limiting examples of [C90]A include:

[0290] [C91] As a non-limiting example, A may be Variable R 1

[0291] [C92] In some embodiments, R 1 Independently selected from: (i)-(U 1 ) q -U 2 ,in:

[0292] q is 0 or 1;

[0293] ·U 1 It is C 1-6 Alkylene, which is optionally substituted by 1 to 6 R a Replacement; and

[0294] ·U2 yes:

[0295] (a)C 3-10 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace,

[0296] (b)C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0297] (c) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl ring is optionally replaced by 1-4 independently selected R c Replace, or

[0298] (d) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace,

[0299] and

[0300] (ii)C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

[0301] [C93] In some embodiments, R 1 Yes-(U 1 ) q -U 2 .

[0302] [C94] In some embodiments, q is 0.

[0303] [C95] In some embodiments, U 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace.

[0304] [C96] In some embodiments, U 2 It is C 6-10 Aryl, which is optionally substituted by 1-2 R c replace.

[0305] [C97] As a non-limiting example, U 2 It may be a phenyl group, which is optionally substituted by 1-2 (eg, 1) R creplace.

[0306] [C98] In some embodiments, U 2 is a heteroaryl group containing 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring is optionally replaced by 1-4 independently selected R c replace.

[0307] [C99] In some embodiments, U 2 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c replace.

[0308] [C100] In some embodiments, U 2 is a heteroaryl group containing 6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c replace.

[0309] [C101] As a non-limiting example of the foregoing embodiment, U 2 It can be pyridyl (e.g., 2-pyridyl) or pyrimidinyl (2-pyrimidinyl), each of which is optionally substituted by 1-2 independently selected R c substituted (eg, unsubstituted).

[0310] [C102] In some embodiments, each occurrence of U 2 R c The substituents are selected from:

[0311] (a) halogen (e.g., Cl, F);

[0312] (b) cyano;

[0313] (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace;

[0314] (f)C 1-4 Haloalkyl;

[0315] (g)C 1-4 Alkoxy;

[0316] (h)C 1-4haloalkoxy; and

[0317] (m)-C 1-4 Thioalkoxy.

[0318] [C103] In some embodiments, each occurrence of U 2 R c The substituents are selected from: halogen (e.g., Cl, F; e.g., F), cyano, C 1-6 Alkyl and C 1-4 Halogenated alkyl.

[0319] [C104] As a non-limiting example, each occurrence of U 2 R c Substituents may be selected from halogen (eg, Cl, F; eg, F).

[0320] [C105] In some embodiments, U 2 is a heterocyclic group containing 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace.

[0321] [C106] In some embodiments, U 2 is a heterocyclic group containing 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace.

[0322] [C107] In some embodiments, U 2 is a heterocyclic group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b replace.

[0323] [C108] In some embodiments, U 2 is a heterocyclic group containing 5 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by an independently selected R bReplace (for example, U 2 is tetrahydrofuranyl).

[0324] [C109] In some embodiments (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c replace.

[0325] [C110] In some of the foregoing embodiments, each R 1 As defined in any of paragraphs [C102]-[C104].

[0326] [C110a] In some of these embodiments, each occurrence of U 2 R c The substituents are selected from:

[0327] (a) halogen (e.g., Cl, F);

[0328] (b) cyano;

[0329] (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace;

[0330] (f)C 1-4 Haloalkyl;

[0331] (g)C 1-4 Alkoxy;

[0332] (h)C 1-4 haloalkoxy; and

[0333] (m)-C 1-4 Thioalkoxy.

[0334] [C110b] As a non-limiting example, each occurrence of U 2 R c The substituents may be selected from: halogen (eg, Cl, F; eg, F), cyano, C 1-6 Alkyl and C 1-4 Halogenated alkyl.

[0335] [C110c] For example, each occurrence of U 2 R c Substituents may be selected from halogen (eg, Cl, F; eg, F).

[0336] [C111] In some embodiments (when R 1 Yes-(U1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is substituted with pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl).

[0337] [C112] In some of the foregoing embodiments, each R 1 As defined in any of paragraphs [C102]-[C104].

[0338] [C112a] In some of these embodiments, each occurrence of U 2 R c The substituents are selected from:

[0339] (a) halogen (e.g., Cl, F);

[0340] (b) cyano;

[0341] (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace;

[0342] (f)C 1-4 Haloalkyl;

[0343] (g)C 1-4 Alkoxy;

[0344] (h)C 1-4 haloalkoxy; and

[0345] (m)-C 1-4 Thioalkoxy.

[0346] [C112b] As a non-limiting example, each occurrence of U 2 R c The substituents may be selected from: halogen (eg, Cl, F; eg, F), cyano, C 1-6 Alkyl and C 1-4 Halogenated alkyl.

[0347] [C112c] For example, each occurrence of U 2 R c Substituents may be selected from halogen (eg, Cl, F; eg, F).

[0348] [C113] In some embodiments, R1 It is C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

[0349] [C114] In some embodiments, R 1 It is C 1-6 Alkyl, which is optionally substituted by 1-4 independently selected R a replace.

[0350] [C115] In some embodiments, R 1 It is C 1-3 Alkyl, which is optionally substituted by 1-4 independently selected R a replace.

[0351] [C116] As a non-limiting example, R 1 Can be C 1-3 Alkyl, which is optionally substituted with 1-3 (e.g., 1, 2 or 3) independently selected R a replace.

[0352] [C117] In some embodiments, each occurrence of R 1 R a The substituents are independently selected from: -OH; -F; -Cl; -NR e R f ; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); cyano; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution;

[0353] [C118] In some embodiments, each occurrence of R 1 R a The substituents are independently selected from: -OH; -F; -Cl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)OH, and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution.

[0354] [C119] In some embodiments, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH.

[0355] [C120] As a non-limiting example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0356] Variable R 3

[0357] In some embodiments, each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0358] In some embodiments, each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0359] In some embodiments (e.g., when Ring A is a heteroaryl group containing 10 ring atoms), each occurrence of R 3 Independently selected from the group consisting of fluorine, bromine, iodine, cyano, 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"), -C1-4 Thioalkoxy, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0360] As a non-limiting example, each occurrence of R 3 Can be independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

[0361] Variable R 2

[0362] In some embodiments, each occurrence of R 2 Independently selected from:

[0363] (i)C 1-6 Alkyl (e.g., methyl);

[0364] (ii)C 3-6 Cycloalkyl;

[0365] (iv)-C(O)(C 1-4 alkyl) (e.g., C(O)Me);

[0366] (v) -C(O)O(C 1-4 alkyl);

[0367] (vi) -CON(R')(R');

[0368] (vii)-S(O) 1-2 (NR'R"); and

[0369] (viii)-S(O) 1-2 (C 1-4 alkyl) (e.g., S(O) 2 Me).

[0370] In some embodiments, each occurrence of R 2 Independently C 1-6 Alkyl (eg, methyl).

[0371] In some embodiments, each occurrence of R 2 are independently -C(O)(C 1-4 alkyl) (e.g., C(O)Me).

[0372] In some embodiments, each occurrence of R 2 Independently -S(O) 1-2 (C 1-4 alkyl) (e.g., S(O)2 Me).

[0373] R 1 , R 3 Non-limiting combinations of and Ring A

[0374] Non-limiting combinations when Ring A is (A-1):

[0375] In some embodiments, when Ring A is (A-1); and (A-1) is as defined in any of paragraphs [C12], [C16], [C17] and [C24], m1=1.

[0376] In some of the foregoing embodiments, m3=0.

[0377] In some embodiments (when Ring A is (A-1); and (A-1) is as defined in any of paragraphs [C12], [C16], [C17], and [C24]), m1=0; and m3=0.

[0378] In some embodiments (when Ring A is (A-1); and (A-1) is as defined in paragraph [C28]), m1=1; and m3=0.

[0379] In some embodiments (when Ring A is (A-1); and (A-1) is as defined in any of paragraphs [C12], [C16], [C17], [C24], and [C37]-[C42]), m3=1 or 2.

[0380] In some of the foregoing embodiments, m1=0.

[0381] In some embodiments (when Ring A is (A-1); and (A-1) is as defined in any of paragraphs [C12], [C16], [C17], [C24], and [C37]-[C42]; m3 = 1 or 2; and / or m1 = 0), each occurrence of R 3 Independently as defined in any of paragraphs [C121]-[C123].

[0382] [A-1a]

[0383] In some embodiments, Ring A is (A-1); and Part is wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (e.g., m1=0 or 1; and m3=0, 1 or 2).

[0384] In some of these embodiments, m1=1.

[0385] In some embodiments of [A-1a], R 1 Yes-(U1 ) q -U 2 In some of these embodiments, q is 0.

[0386] In some embodiments of [A-1a], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0387] In some embodiments of [A-1a], U 2 As defined in paragraph [C99].

[0388] In some embodiments of [A-1a], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0389] In some embodiments of [A-1a], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0390] In some embodiments of [A-1a] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0391] In some embodiments of [A-1a] (when R 1 Yes-(U 1 ) q -U 2 ), R 1is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0392] In some embodiments of [A-1a] (when R 1 Yes-(U 1 ) q -U 2 ; and q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0393] In some embodiments of [A-1a], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0394] In some embodiments of [A-1a], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0395] In some embodiments of [A-1a], m3=0.

[0396] In some other embodiments, m3=1 or 2.

[0397] In some embodiments of [A-1a], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0398] In some embodiments of [A-1a], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0399] In some embodiments of [A-1a], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0400] In some of the foregoing embodiments, m1=0.

[0401] In some embodiments, m1=0; and m3=0.

[0402] [A-1b]

[0403] In some embodiments, Ring A is (A-1); Part is Among them: the asterisk indicates the connection Y 4 point; and m3=0, 1 or 2; and m3=0, 1 or 2 (for example, m1=0 or 1; and m3=0 or 1).

[0404] In some of these embodiments, m1=1.

[0405] In some embodiments of [A-1b], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0406] In some embodiments of [A-1b], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0407] In some embodiments of [A-1b], U 2 As defined in paragraph [C99].

[0408] In some embodiments of [A-1b], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0409] In some embodiments of [A-1b], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0410] In some embodiments of [A-1b] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0411] In some embodiments of [A-1b] (when R 1 Yes-(U1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0412] In some embodiments of [A-1b] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0413] In some embodiments of [A-1b], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0414] In some embodiments of [A-1b], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0415] In some embodiments of [A-1b], m3=0.

[0416] In some other embodiments, m3=1 or 2.

[0417] In some embodiments of [A-1b], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0418] In some embodiments of [A-1b], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0419] In some embodiments of [A-1b], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0420] In some of the foregoing embodiments, m1=0.

[0421] In some embodiments, m1=0; and m3=0.

[0422] [A-1c]

[0423] In some embodiments, Ring A is (A-1); Part is Among them: the asterisk indicates the connection Y 4point; and m3=0, 1 or 2; and m3=0, 1 or 2 (for example, m1=0 or 1; and m3=0 or 1).

[0424] In some of these embodiments, m1=1.

[0425] In some embodiments of [A-1c], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0426] In some embodiments of [A-1c], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0427] In some embodiments of [A-1c], U 2 As defined in paragraph [C99].

[0428] In some embodiments of [A-1c], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0429] In some embodiments of [A-1c], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0430] In some embodiments of [A-1c] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0431] In some embodiments of [A-1c] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0432] In some embodiments of [A-1c] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0433] In some embodiments of [A-1c], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0434] In some embodiments of [A-1c], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF3 or CH 2 CO 2 H.

[0435] In some embodiments of [A-1c], m3=0.

[0436] In some other embodiments, m3=1 or 2.

[0437] In some embodiments of [A-1c], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0438] In some embodiments of [A-1c], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0439] In some embodiments of [A-1c], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0440] In some of the foregoing embodiments, m1=0.

[0441] In some embodiments, m1=0; and m3=0.

[0442] [A-1d]

[0443] In some embodiments, Ring A is (A-1); Part is Among them: the asterisk indicates the connection Y 4 point; and m1=0, 1 or 2; and m3=0, 1 or 2 (for example, m1=0 or 1; and m3=0 or 1).

[0444] In some of these embodiments, m1=1.

[0445] In some embodiments of [A-1d], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0446] In some embodiments of [A-1d], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0447] In some embodiments of [A-1d], U 2 As defined in paragraph [C99].

[0448] In some embodiments of [A-1d], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0449] In some embodiments of [A-1d], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0450] In some embodiments of [A-1d] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R cThe substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0451] In some embodiments of [A-1d] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0452] In some embodiments of [A-1d] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0453] In some embodiments of [A-1d], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0454] In some embodiments of [A-1d], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0455] In some embodiments of [A-1d], m3=0.

[0456] In some other embodiments, m3=1 or 2.

[0457] In some embodiments of [A-1d], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0458] In some embodiments of [A-1d], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0459] In some embodiments of [A-1d], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0460] In some of the foregoing embodiments, m1=0.

[0461] In some embodiments, m1=0; and m3=0.

[0462] [A-1e]

[0463] In some embodiments, Ring A is (A-1); Part is Among them: Asterisk indicates 4 Connected points; and m1=0 or 1; and m3=0, 1 or 2.

[0464] In some of these embodiments, m1=1.

[0465] In some embodiments of [A-1e], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0466] In some embodiments of [A-1e], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0467] In some embodiments of [A-1e], U 2 As defined in paragraph [C99].

[0468] In some embodiments of [A-1e], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0469] In some embodiments of [A-1e], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0470] In some embodiments of [A-1e] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0471] In some embodiments of [A-1e] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0472] In some embodiments of [A-1e] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0473] In some embodiments of [A-1e], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0474] In some embodiments of [A-1e], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R aSubstituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0475] In some embodiments of [A-1e], m3=0.

[0476] In some other embodiments, m3=1 or 2.

[0477] In some embodiments of [A-1e], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0478] In some embodiments of [A-1e], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0479] In some embodiments of [A-1e], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0480] In some of the foregoing embodiments, m1=0.

[0481] In some embodiments, m1=0; and m3=0.

[0482] [A-1f]

[0483] In some embodiments, Ring A is (A-1); and Part is (For example, ), where the asterisk indicates the connection Y 4 point.

[0484] In some embodiments of [A-1f], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0485] In some embodiments of [A-1f], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0486] In some embodiments of [A-1f], U 2 As defined in paragraph [C99].

[0487] In some embodiments of [A-1f], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0488] In some embodiments of [A-1f], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0489] In some embodiments of [A-1f] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R cThe substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0490] In some embodiments of [A-1f] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0491] In some embodiments of [A-1f] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0492] In some embodiments of [A-1f], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0493] In some embodiments of [A-1f], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 Ra Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0494] In some embodiments (when Ring A is as defined in any of paragraphs [C37]-[C41]), m1=1. In some of the foregoing embodiments, m3=0.

[0495] In some other embodiments (when Ring A is as defined in any of paragraphs [C37]-[C41]), m1=0; and m3=0.

[0496] [A-1g]

[0497] In some embodiments, A is: (For example, ), wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (e.g., m1=0 or 1; and m3=0, 1 or 2).

[0498] In some of these embodiments, m1=1.

[0499] In some embodiments of [A-1g], R1 is -(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0500] In some embodiments of [A-1g], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0501] In some embodiments of [A-1g], U 2 As defined in paragraph [C99].

[0502] In some embodiments of [A-1g], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0503] In some embodiments of [A-1g], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0504] In some embodiments of [A-1g] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0505] In some embodiments of [A-1g] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0506] In some embodiments of [A-1g] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0507] In some embodiments of [A-1g], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0508] In some embodiments of [A-1g], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0509] In some embodiments of [A-1g], m3=0.

[0510] In some other embodiments, m3=1 or 2.

[0511] In some embodiments of [A-1g], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0512] In some embodiments of [A-1g], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0513] In some embodiments of [A-1g], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0514] In some of the foregoing embodiments, m1=0.

[0515] In some embodiments, m1=0; and m3=0.

[0516] [A-1h]

[0517] In some embodiments, A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[0518] In some of these embodiments, m1=1.

[0519] In some embodiments of [A-1h], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0520] In some embodiments of [A-1h], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0521] In some embodiments of [A-1h], U 2 As defined in paragraph [C99].

[0522] In some embodiments of [A-1h], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0523] In some embodiments of [A-1h], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0524] In some embodiments of [A-1h] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0525] In some embodiments of [A-1h] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0526] In some embodiments of [A-1h] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0527] In some embodiments of [A-1h], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0528] In some embodiments of [A-1h], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0529] In some embodiments of [A-1h], m3=0.

[0530] In some other embodiments, m3=1 or 2.

[0531] In some embodiments of [A-1h], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0532] In some embodiments of [A-1h], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O)1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0533] In some embodiments of [A-1h], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0534] In some of the foregoing embodiments, m1=0.

[0535] In some embodiments, m1=0; and m3=0.

[0536] [A-1i]

[0537] In some embodiments, A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[0538] In some of these embodiments, m1=1.

[0539] In some embodiments of [A-1i], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0540] In some embodiments of [A-1i], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0541] In some embodiments of [A-1i], U 2 As defined in paragraph [C99].

[0542] In some embodiments of [A-1i], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0543] In some embodiments of [A-1i], U 2 Each R cSubstituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0544] In some embodiments of [A-1i] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0545] In some embodiments of [A-1i] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0546] In some embodiments of [A-1i] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0547] In some embodiments of [A-1i], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0548] In some embodiments of [A-1i], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0549] In some embodiments of [A-1i], m3=0.

[0550] In some other embodiments, m3=1 or 2.

[0551] In some embodiments of [A-1i], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0552] In some embodiments of [A-1i], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0553] In some embodiments of [A-1i], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0554] In some of the foregoing embodiments, m1=0.

[0555] In some embodiments, m1=0; and m3=0.

[0556] [A-1j]

[0557] In some embodiments, A is Wherein m1=0, 1 or 2; and m3=0, 1 or 2.

[0558] In some of these embodiments, m1=1.

[0559] In some embodiments of [A-1j], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0560] In some embodiments of [A-1j], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0561] In some embodiments of [A-1j], U 2 As defined in paragraph [C99].

[0562] In some embodiments of [A-1j], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0563] In some embodiments of [A-1j], U 2 Each R cSubstituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0564] In some embodiments of [A-1j] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0565] In some embodiments of [A-1e] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0566] In some embodiments of [A-1j] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0567] In some embodiments of [A-1j], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0568] In some embodiments of [A-1j], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0569] In some embodiments of [A-1j], m3=0.

[0570] In some other embodiments, m3=1 or 2.

[0571] In some embodiments of [A-1j], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0572] In some embodiments of [A-1j], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0573] In some embodiments of [A-1j], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0574] In some of the foregoing embodiments, m1=0.

[0575] In some embodiments, m1=0; and m3=0.

[0576] [A-1k]

[0577] In some embodiments, A is Wherein m1=0 or 1; and m3=0, 1 or 2.

[0578] In some of these embodiments, m1=1.

[0579] In some embodiments of [A-1k], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0580] In some embodiments of [A-1k], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0581] In some embodiments of [A-1k], U 2 As defined in paragraph [C99].

[0582] In some embodiments of [A-1k], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0583] In some embodiments of [A-1k], U 2 Each R cSubstituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0584] In some embodiments of [A-1k] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0585] In some embodiments of [A-1k] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0586] In some embodiments of [A-1k] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0587] In some embodiments of [A-1k], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0588] In some embodiments of [A-1k], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0589] In some embodiments of [A-1k], m3=0.

[0590] In some other embodiments, m3=1 or 2.

[0591] In some embodiments of [A-1k], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0592] In some embodiments of [A-1k], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0593] In some embodiments of [A-1k], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0594] In some of the foregoing embodiments, m1=0.

[0595] In some embodiments, m1=0; and m3=0.

[0596] [A-1l]

[0597] In some embodiments, A is (For example, ).

[0598] In some embodiments of [A-11], R1 is -(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0599] In some embodiments of [A-11], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0600] In some embodiments of [A-11], U 2 As defined in paragraph [C99].

[0601] In some embodiments of [A-11], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0602] In some embodiments of [A-11], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R cSubstituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0603] In some embodiments of [A-11] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0604] In some embodiments of [A-11] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0605] In some embodiments of [A-11] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0606] In some embodiments of [A-11], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0607] In some embodiments of [A-11], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0608] Non-limiting combinations when Ring A is (A-3):

[0609] In some embodiments (when Ring A is as defined in any of paragraphs [C60], [C64], and [C69]-[C70]), m1=1.

[0610] In some embodiments (when Ring A is as defined in any of paragraphs [C60], [C64], and [C69]-[C70]), m1=0; and m3=0.

[0611] [A-3a]

[0612] In some embodiments, A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[0613] In some of these embodiments, m1=1.

[0614] In some embodiments of [A-3a], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0615] In some embodiments of [A-3a], U 2As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0616] In some embodiments of [A-3a], U 2 As defined in paragraph [C99].

[0617] In some embodiments of [A-3a], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0618] In some embodiments of [A-3a], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0619] In some embodiments of [A-3a] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0620] In some embodiments of [A-3a] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0621] In some embodiments of [A-3a] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0622] In some embodiments of [A-3a], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0623] In some embodiments of [A-3a], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0624] In some embodiments of [A-3a], m3=0.

[0625] In some other embodiments, m3=1 or 2.

[0626] In some embodiments of [A-3a], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0627] In some embodiments of [A-3a], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0628] In some embodiments of [A-3a], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0629] In some of the foregoing embodiments, m1=0.

[0630] In some embodiments, m1=0; and m3=0.

[0631] [A-3b]

[0632] In some embodiments, A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[0633] In some of these embodiments, m1=1.

[0634] In some embodiments of [A-3b], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0635] In some embodiments of [A-3b], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0636] In some embodiments of [A-3b], U 2 As defined in paragraph [C99].

[0637] In some embodiments of [A-3b], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0638] In some embodiments of [A-3b], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0639] In some embodiments of [A-3b] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0640] In some embodiments of [A-3b] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0641] In some embodiments of [A-3b] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0642] In some embodiments of [A-3b], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0643] In some embodiments of [A-3b], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0644] In some embodiments of [A-3b], m3=0.

[0645] In some other embodiments, m3=1 or 2.

[0646] In some embodiments of [A-3b], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -NR e R f , –OH, -S(O) 1-2 (NR'R"), -C 1-4 Thioalkoxy, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0647] In some embodiments of [A-3b], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0648] In some embodiments of [A-3b], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0649] In some of the foregoing embodiments, m1=0.

[0650] In some embodiments, m1=0; and m3=0.

[0651] [A-3c]

[0652] In some embodiments, A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[0653] In some of these embodiments, m1=1.

[0654] In some embodiments of [A-3c], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0655] In some embodiments of [A-3c], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0656] In some embodiments of [A-3c], U 2 As defined in paragraph [C99].

[0657] In some embodiments of [A-3c], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0658] In some embodiments of [A-3c], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0659] In some embodiments of [A-3c] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0660] In some embodiments of [A-1c] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c(For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0661] In some embodiments of [A-3c] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0662] In some embodiments of [A-3c], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0663] In some embodiments of [A-3c], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0664] In some embodiments of [A-3c], m3=0.

[0665] In some other embodiments, m3=1 or 2.

[0666] In some embodiments of [A-3c], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4Alkoxy, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0667] In some embodiments of [A-3c], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0668] In some embodiments of [A-3c], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0669] In some of the foregoing embodiments, m1=0.

[0670] In some embodiments, m1=0; and m3=0.

[0671] [A-3d]

[0672] In some embodiments, A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[0673] In some of these embodiments, m1=1.

[0674] In some embodiments of [A-3d], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0675] In some embodiments of [A-3d], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0676] In some embodiments of [A-3d], U 2 As defined in paragraph [C99].

[0677] In some embodiments of [A-3d], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0678] In some embodiments of [A-3d], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0679] In some embodiments of [A-3d] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0680] In some embodiments of [A-3d] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c(For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0681] In some embodiments of [A-3d] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0682] In some embodiments of [A-3d], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0683] In some embodiments of [A-3d], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0684] In some embodiments of [A-3d], m3=0.

[0685] In some other embodiments, m3=1 or 2.

[0686] In some embodiments of [A-3d], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4Alkoxy, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0687] In some embodiments of [A-3d], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0688] In some embodiments of [A-3d], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0689] In some of the foregoing embodiments, m1=0.

[0690] In some embodiments, m1=0; and m3=0.

[0691] Non-limiting combinations when Ring A is (A-2):

[0692] In some embodiments (when Ring A is as defined in any of paragraphs [C54]-[C55]), m1 = 0. In some of the foregoing embodiments, m3 = 0 or 1 (eg, 0).

[0693] [A-2a]

[0694] In some embodiments, A is: wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (eg, m1=0; and m3=0).

[0695] In some of these embodiments, m1=1.

[0696] In some embodiments of [A-2a], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0697] In some embodiments of [A-2a], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0698] In some embodiments of [A-2a], U 2 As defined in paragraph [C99].

[0699] In some embodiments of [A-2a], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0700] In some embodiments of [A-2a], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0701] In some embodiments of [A-2a] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0702] In some embodiments of [A-2a] (when R 1 Yes-(U 1) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0703] In some embodiments of [A-2a] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0704] In some embodiments of [A-2a], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0705] In some embodiments of [A-2a], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0706] In some embodiments of [A-2a], m3=0.

[0707] In some other embodiments, m3=1 or 2.

[0708] In some embodiments of [A-2a], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0709] In some embodiments of [A-2a], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0710] In some embodiments of [A-2a], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0711] In some of the foregoing embodiments, m1=0.

[0712] In some embodiments, m1=0; and m3=0.

[0713] [A-2b]

[0714] In some embodiments, A is: wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (eg, m1=0; and m3=0).

[0715] In some of these embodiments, m1=1.

[0716] In some embodiments of [A-2b], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0717] In some embodiments of [A-2b], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0718] In some embodiments of [A-2b], U 2 As defined in paragraph [C99].

[0719] In some embodiments of [A-2b], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0720] In some embodiments of [A-2], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0721] In some embodiments of [A-2] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0722] In some embodiments of [A-2b] (when R 1 Yes-(U1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0723] In some embodiments of [A-2b] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0724] In some embodiments of [A-2b], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0725] In some embodiments of [A-2b], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0726] In some embodiments of [A-2b], m3=0.

[0727] In some other embodiments, m3=1 or 2.

[0728] In some embodiments of [A-2b], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0729] In some embodiments of [A-2b], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[0730] In some embodiments of [A-2b], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[0731] In some of the foregoing embodiments, m1=0.

[0732] In some embodiments, m1=0; and m3=0.

[0733] Non-limiting combinations when Ring A is (A-4):

[0734] [A-4a]

[0735] In some embodiments, A is selected from:

[0736] In some embodiments of [A-4a], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0737] In some embodiments of [A-4a], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0738] In some embodiments of [A-4a], U 2 As defined in paragraph [C99].

[0739] In some embodiments of [A-4a], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0740] In some embodiments of [A-4a], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0741] In some embodiments of [A-4a] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0742] In some embodiments of [A-4a] (when R 1 Yes-(U 1 ) q -U 2), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0743] In some embodiments of [A-4a] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0744] In some embodiments of [A-4a], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0745] In some embodiments of [A-4a], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0746] [A-4b]

[0747] In some embodiments, A is

[0748] In some embodiments of [A-4b], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0749] In some embodiments of [A-4b], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0750] In some embodiments of [A-4b], U 2 As defined in paragraph [C99].

[0751] In some embodiments of [A-4b], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0752] In some embodiments of [A-4b], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0753] In some embodiments of [A-4b] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0754] In some embodiments of [A-4b] (when R 1 Yes-(U1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0755] In some embodiments of [A-4b] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0756] In some embodiments of [A-4b], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0757] In some embodiments of [A-4b], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0758] [A-4c]

[0759] In some embodiments, A is

[0760] In some embodiments of [A-4c], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0761] In some embodiments of [A-4c], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0762] In some embodiments of [A-4c], U 2 As defined in paragraph [C99].

[0763] In some embodiments of [A-4c], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0764] In some embodiments of [A-4c], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0765] In some embodiments of [A-4c] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0766] In some embodiments of [A-4c] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0767] In some embodiments of [A-4c] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0768] In some embodiments of [A-4c], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0769] In some embodiments of [A-4c], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO2 H.

[0770] [A-4d]

[0771] In some embodiments, A is selected from:

[0772] In some embodiments of [A-4d], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0773] In some embodiments of [A-4d], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0774] In some embodiments of [A-4d], U 2 As defined in paragraph [C99].

[0775] In some embodiments of [A-4d], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0776] In some embodiments of [A-4d], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0777] In some embodiments of [A-4d] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R cThe substituents may be as defined in paragraph [C110c].

[0778] In some embodiments of [A-4d] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0779] In some embodiments of [A-4d] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0780] In some embodiments of [A-4d], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0781] In some embodiments of [A-4d], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R1 Can be CF 3 or CH 2 CO 2 H.

[0782] [A-4e]

[0783] In some embodiments, A is

[0784] In some embodiments of [A-4e], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[0785] In some embodiments of [A-4e], U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[0786] In some embodiments of [A-4e], U 2 As defined in paragraph [C99].

[0787] In some embodiments of [A-4e], U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[0788] In some embodiments of [A-4e], U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[0789] In some embodiments of [A-4e] (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R cThe substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[0790] In some embodiments of [A-4e] (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[0791] In some embodiments of [A-4e] (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[0792] In some embodiments of [A-4e], R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[0793] In some embodiments of [A-4e], each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[0794] [AR 1 ]R 1 Exemplary embodiments of

[0795] In some embodiments (when Ring A is (A-1); and (A-1) is as defined in any of paragraphs [C12], [C16], [C17], and [C24]; and / or m1=1 (e.g., when m3=0)), R 1 As defined in any of paragraphs [C93]-[C104] and [C109]-[C112].

[0796] In some embodiments (when Ring A is (A-1); and (A-1) is as defined in any of paragraphs [C12], [C16], [C17], and [C24]; and / or m1=1 (e.g., when m3=0)), R 1 As defined in any of paragraphs [C93]-[C94] and [C105]-[C108].

[0797] In some embodiments (when Ring A is (A-1); and (A-1) is as defined in any of paragraphs [C12], [C16], [C17], and [C24]; and / or m1=1 (e.g., when m3=0)), R 1 As defined in any of paragraphs [C113]-[C120].

[0798] In some embodiments (when Ring A is (A-1); and (A-1) is as defined in any of paragraphs [C28]-[C29]; m1=1; and / or m3=0), R 1 As defined in any of paragraphs [C93]-[C104] and [C109]-[C112].

[0799] In some embodiments (when Ring A is (A-1); and (A-1) is as defined in any of paragraphs [C28]-[C29]; m1=1; and / or m3=0), R 1 As defined in any of paragraphs [C93]-[C94] and [C105]-[C108].

[0800] In some embodiments (when Ring A is (A-1); and (A-1) is as defined in paragraph [C28]; m1 = 1; and / or m3 = 0), R1 As defined in any of paragraphs [C113]-[C120].

[0801] In some embodiments (when Ring A is as defined in any of paragraphs [C37]-[C41]; m1=1; and / or m3=0), R 1 As defined in any of paragraphs [C93]-[C104] and [C109]-[C112].

[0802] In some embodiments (when Ring A is as defined in any of paragraphs [C37]-[C41]; m1=1; and / or m3=0), R 1 As defined in any of paragraphs [C93]-[C94] and [C105]-[C108].

[0803] In some embodiments (when Ring A is as defined in any of paragraphs [C37]-[C41]; m1=1; and / or m3=0), R 1 As defined in any of paragraphs [C113]-[C120].

[0804] In some embodiments (when Ring A is as defined in any of paragraphs [C60], [C64] and [C69-70]; and / or m1=1), R 1 As defined in any of paragraphs [C93]-[C104] and [C109]-[C112].

[0805] In some embodiments (when Ring A is as defined in any of paragraphs [C60], [C64] and [C69-70]; and / or m1 = -70), R 1 As defined in any of paragraphs [C93]-[C94] and [C105]-[C108].

[0806] In some embodiments (when Ring A is as defined in any of paragraphs [C60], [C64] and [C69-70]; and / or m1 = -70), R 1 As defined in any of paragraphs [C113]-[C120].

[0807] In some embodiments (when Ring A is as defined in any of paragraphs [C82]-[C84] and [C90]-[C91]), R 1 As defined in any of paragraphs [C93]-[C104] and [C109]-[C112].

[0808] In some embodiments (when Ring A is as defined in any of paragraphs [C82]-[C84] and [C90]-[C91]), R 1As defined in any of paragraphs [C93]-[C94] and [C105]-[C108].

[0809] In some embodiments (when Ring A is as defined in any of paragraphs [C82]-[C84] and [C90]-[C91]), R 1 As defined in any of paragraphs [C113]-[C120].

[0810] Ring B and variable R N

[0811] When ring B and R N according to (A) How to implement the definition

[0812] [C154] In some embodiments, B and each occurrence of R N according to (A) definition.

[0813] Ring B

[0814] [C155] In some embodiments, B is replaced by 1-4 R c Substituted phenyl.

[0815] [C156] In some embodiments, B is replaced by 1-2 R c Substituted phenyl, 1-2 R c In formula I, -S(O)(=N(R N ) 2 )-part of the ring carbon (e.g., an R c The ring carbon is located in the para position).

[0816] [C156a] In some embodiments, B is replaced by 1-2 R c Substituted phenyl, one of which is R c In formula I, -S(O)(=N(R N ) 2 In some of the foregoing embodiments, B is not further substituted. In some other embodiments, B is located in the ring carbon of formula I connected to -S(O)(=N(R N ) 2 )-part of the other R of the ring carbon at the meta position c replace.

[0817] [C157] In some embodiments, B is a heteroaryl group containing 5-20 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2, and wherein the heteroaryl ring is optionally replaced by 1-4 independently selected R c replace.

[0818] [C158] In some of these embodiments, B is a heteroaryl group containing 5-6 ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally substituted by 1-3 independently selected R c replace.

[0819] [C159] In some of the aforementioned embodiments, B is a heteroaryl group containing 5 ring atoms, wherein 1-3 (e.g., 2) of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally substituted by 1-3 independently selected R c replace.

[0820] [C160] As a non-limiting example, B can be pyrazolyl or imidazolyl, each of which is optionally substituted with 1-2 independently selected R c replace.

[0821] [C161] In some other embodiments, B is a heteroaryl group containing 6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c replace.

[0822] [C162] As a non-limiting example, B can be pyrazolyl (e.g., 2-pyrazolyl, 3-pyrazolyl, and 4-pyrazolyl), each of which is optionally substituted with 1-2 independently selected R c replace.

[0823] [C163] In some embodiments, B is a heteroaryl group containing 9-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring is optionally replaced by 1-3 independently selected R c replace.

[0824] [C164] In some of the aforementioned embodiments, B is a tricyclic heteroaryl group containing 12-15 (e.g., 13) ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2, and wherein the heteroaryl ring is optionally replaced by 1-3 independently selected R c replace.

[0825] [C165] As a non-limiting example, B may be It is optionally replaced by 1-2 independently selected R c replace.

[0826] [C166a] In some embodiments, each occurrence of R of B c The substituents are selected from:

[0827] (a) halogen;

[0828] (b) cyano;

[0829] (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace;

[0830] (d)C 2-6 alkenyl;

[0831] (e)C 2-6 Alkynyl;

[0832] (g)C 1-4 Alkoxy;

[0833] (h)C 1-4 Haloalkoxy;

[0834] (i)-S(O) 1-2 (C 1-4 alkyl);

[0835] (j)-NR e R f , where R e and R f One is besides H;

[0836] (k)–OH;

[0837] (l)-S(O) 1-2 (NR'R");

[0838] (m)-C 1-4 Thioalkoxy;

[0839] (n)-NO 2 ;

[0840] (o)-C(=O)(C 1-4 alkyl);

[0841] (p)-C(=O)O(C 1-4 alkyl);

[0842] (q) -C(=O)OH;

[0843] (r)-C(═O)N(R′)(R″); and

[0844] (s)-L 1 -L 2 -R h ;

[0845] [C166] In some embodiments, each occurrence of R of B c The substituents are selected from:

[0846] (a) halogen;

[0847] (b) cyano;

[0848] (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace;

[0849] (g)C 1-4 Alkoxy;

[0850] (h)C 1-4 Haloalkoxy;

[0851] (i)-S(O) 1-2 (C 1-4 alkyl);

[0852] (m)-C 1-4 Thioalkoxy;

[0853] (o)-C(=O)(C 1-4 alkyl);

[0854] (p)-C(=O)O(C 1-4 alkyl);

[0855] (r)-C(═O)N(R′)(R″); and

[0856] (s)-L 1 -L 2 -R h .

[0857] [C167] In some embodiments, each occurrence of R of B c The substituents are selected from:

[0858] (a) halogen;

[0859] (b) cyano;

[0860] (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R areplace;

[0861] (g)C 1-4 Alkoxy;

[0862] (h)C 1-4 haloalkoxy; and

[0863] (s)-L 1 -L 2 -R h .

[0864] [C168] In some embodiments, each occurrence of R of B c The substituents are selected from:

[0865] (a) halogen;

[0866] (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a Replacement; and

[0867] (s)-L 1 -L 2 -R h .

[0868] [C169] In some of these embodiments, one occurrence of R C It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

[0869] [C170] In some embodiments, one occurrence of R c It is C 1-3 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

[0870] [C171] In some of the foregoing embodiments, each occurrence of R a Independently selected from: -F; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy.

[0871] [C172] As a non-limiting example, R c It is CF 3 or (For example, R c Can be CF 3 ).

[0872] [C173] In some embodiments (when one occurrence of R c It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a Replacement), Rc is unsubstituted C 1-10 Alkyl (e.g., unsubstituted C 1-6 (For example, C 1-3 )alkyl.

[0873] [C174] In some embodiments, one occurrence of R c Yes-L 1 -L 2 -R h .

[0874] [C175] In some of these embodiments, -L 1 is the key.

[0875] [C176] In some of these embodiments, -L 1 It is C 1-3 Alkylene.

[0876] [C177] In some embodiments (when one occurrence of R c Yes-L 1 -L 2 -R h ), -L 2 is the key.

[0877] [C178] In some other embodiments (when one occurrence of R c Yes-L 1 -L 2 -R h ), -L 2 It's –O-.

[0878] [C179] In some embodiments (when one occurrence of R c Yes-L 1 -L 2 -R h ), -L 1 is the key; and –L 2 is the key.

[0879] [C180] In some embodiments (when one occurrence of R c Yes-L 1 -L 2 -R h ), -L 1 is the key; and –L 2 It's –O-.

[0880] [C181] In some embodiments (when one occurrence of R c Yes-L 1 -L 2 -R h ), -L 1 It is C1-3 Alkylene; and –L 2 It's –O-.

[0881] [C182] In some embodiments (when one occurrence of R c Yes-L 1 -L 2 -R h ), R h Selected from:

[0882] ·C 3-8 Cycloalkyl, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl and C 1-4 haloalkyl, provided that when R h is optionally 1-4 independently selected C 1-4 Alkyl substituted C 3-6 When cycloalkyl, -L 1 is key, or -L 2 is –O-, -N(H)-, or -S-; and

[0883] ·C 6-10 Aryl, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0884] [C183] In some embodiments (when one occurrence of R c Yes-L 1 -L 2 -R h ), R h Selected from:

[0885] ·C 6-8 Cycloalkyl, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl and C 1-4 haloalkyl, provided that when R h is optionally 1-4 independently selected C 1-4 Alkyl substituted C 3-6 When cycloalkyl, -L 1 is key, or -L 2 is –O-, -N(H)-, or -S-; and

[0886] phenyl, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0887] [C184] As a non-limiting example (when one occurrence of R cYes-L 1 -L 2 -R h ), one occurrence of R c Can be selected from:

[0888]

[0889] [C185] In some embodiments, one occurrence of R c is unsubstituted C 1-3 alkyl.

[0890] [C186] In some embodiments, one occurrence of R c is a halogen (eg, -F or -Cl).

[0891] [C187] In some of the foregoing embodiments, the second occurrence of R c When present is independently halogen.

[0892] [C188] In some embodiments, B is C 3-20 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace.

[0893] [C189] In some embodiments, B is C 3-12 Cycloalkyl, which is optionally substituted by 1-2 R b replace.

[0894] [C190] In some embodiments, B is C 6-12 Cycloalkyl, which is optionally substituted by 1-2 R b replace.

[0895] [C191] In some of the foregoing embodiments, B is C 6-12 Cycloalkyl (for example, B can be ).

[0896] [C192] In some embodiments, B is a heterocyclic group containing 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace.

[0897] [C193] In some embodiments, B is a heterocyclic group containing 3-12 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2, and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace.

[0898] [C194] In some of these embodiments, B is a heterocyclyl group containing 3-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b Substitution (for example, B can be It is further optionally represented by 1 R b replace).

[0899] [C195] In some other embodiments, B is a heterocyclic group containing 7-12 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b Substitution (for example, B can be Each of which is further optionally represented by 1 R b replace).

[0900] [C196] In some of the foregoing embodiments (when B is a heterocyclyl or cycloalkyl group as defined in any of the above embodiments), each occurrence of R b Independently selected from the following group: C 1-10 Alkyl; C 1-4 Haloalkyl; –OH; oxo; -F; -Cl; –NR e R f ; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)(C 1-4 alkyl); -C(=O)O(C 1-4 Alkyl); -S(O) 1-2 (C 1-4 alkyl); cyano; and -L 1 -L 2 -R h .

[0901] [C197] In some embodiments, each occurrence of R b Independently selected from the following group: C 1-10 Alkyl; C 1-4 Haloalkyl; -F; C 1-4 Alkoxy; C 1-4 Haloalkoxy; and -L 1 -L2 -R h .

[0902] [C198] In some embodiments, R b Independently selected from the following group: C 1-10 Alkyl; C 1-4 haloalkyl; -F; and -L 1 -L 2 -R h .

[0903] [C199] In some embodiments, one occurrence of R b Independently -L 1 -L 2 -R h .

[0904] [C200] In some of these embodiments, -L 1 is the key; and -L 2 is the key.

[0905] [C201] In some of the foregoing embodiments, R h It is C 6-10 Aryl, which is optionally substituted by 1-4 (eg, 1-2, eg, 1) substituents independently selected from the group consisting of halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0906] In some embodiments, B is in:

[0907] n1 = 0 or 1; and

[0908] R cA and R cB Each is independently selected R c .

[0909] In some of these embodiments, R cB It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

[0910] In some embodiments, R cB It is C 1-3 Alkyl, which is optionally substituted by 1-6 independently selected R a For example, R cB Can be CF 3 or (For example, R cB Can be CF 3 ).

[0911] In some of these embodiments, each occurrence of R a Independently selected from: -F; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy.

[0912] In some embodiments (when one occurrence of R cB It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a Replacement), R cB is unsubstituted C 1-10 Alkyl (e.g., unsubstituted C 1-6 (For example, C 1-3 )alkyl.

[0913] In some embodiments, R cA It is CF 3 .

[0914] In some embodiments (when B is ), R cB is R as defined in any of paragraphs [C174]-[C184] c .

[0915] In some embodiments, R cB Yes-L 1 -L 2 -R h .

[0916] In some of these embodiments, -L 1 is a bond. In some other embodiments, -L 1 It is C 1-3 Alkylene.

[0917] In some embodiments (when R cB Yes-L 1 -L 2 -R h ), -L 2 is a bond. In some other embodiments, -L2 is -O-.

[0918] In some embodiments (when R cB Yes-L 1 -L 2 -R h ), -L 1 is the key; and –L 2 is a bond. In some other embodiments, -L 1 is the key; and -L 2 is -O-. In some other embodiments, -L 1 It is C 1-3 Alkylene; and -L2 It's –O-.

[0919] In some embodiments (when R cB Yes-L 1 -L 2 -R h ), R h As defined in paragraph [C182]. In some embodiments, R h As defined in paragraph [C183]. For example, R h May be as defined in paragraph [C184].

[0920] In some embodiments (when B is ), R cB is unsubstituted C 1-10 Alkyl (e.g., C 1-3 alkyl).

[0921] In some embodiments (when B is ), R cB It's a halogen.

[0922] In some embodiments (when B is ), n1 is 0.

[0923] In some other embodiments (when B is ), n1 is 1; and R cA It's a halogen.

[0924] In some other embodiments, B is a heteroaryl group containing from 6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c Replacement; and

[0925] R c As defined in any of paragraphs [C169]-[C173] (e.g., R c Can be CF 3 ).

[0926] In some of these embodiments, R c It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

[0927] In some embodiments, R cB It is C 1-3 Alkyl, which is optionally substituted by 1-6 independently selected R a For example, R c Can be CF3 or (For example, R c Can be CF 3 ).

[0928] In some of these embodiments, each occurrence of R a Independently selected from: -F; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy.

[0929] In some embodiments (when one occurrence of R c It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a Replacement), R c is unsubstituted C 1-10 Alkyl (e.g., unsubstituted C 1-6 (For example, C 1-3 )alkyl.

[0930] In some other embodiments, B is a heteroaryl group containing from 6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c Replacement; and R c As defined in any of paragraphs [C174]-[C184].

[0931] In some of these embodiments, R c Yes-L 1 -L 2 -R h .

[0932] In some of these embodiments, -L 1 is a bond. In some other embodiments, -L 1 It is C 1-3 Alkylene.

[0933] In some embodiments (when R c Yes-L 1 -L 2 -R h ), -L 2 is a bond. In some other embodiments, -L 2 It's –O-.

[0934] In some embodiments (when R c Yes-L 1 -L 2 -R h ), -L 1 is the key; and –L2 is a bond. In some other embodiments, -L 1 is the key; and -L 2 is -O-. In some other embodiments, -L 1 It is C 1-3 Alkylene; and -L 2 It's –O-.

[0935] In some embodiments (when R c Yes-L 1 -L 2 -R h ), R h As defined in paragraph [C182]. In some embodiments, R h As defined in paragraph [C183]. For example, R h May be as defined in paragraph [C184].

[0936] In some other embodiments, B is a heteroaryl group containing 5 ring atoms, wherein 1-3 (e.g., 2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c Replacement; and R c As defined in any of paragraphs [C174]-[C184].

[0937] In some of these embodiments, R c Yes-L 1 -L 2 -R h .

[0938] In some of these embodiments, -L 1 is a bond. In some other embodiments, -L 1 It is C 1-3 Alkylene.

[0939] In some embodiments (when R c Yes-L 1 -L 2 -R h ), -L 2 is a bond. In some other embodiments, -L 2 It's –O-.

[0940] In some embodiments (when R c Yes-L 1 -L 2 -R h ), -L 1 is the key; and –L 2is a bond. In some other embodiments, -L 1 is the key; and -L 2 is -O-. In some other embodiments, -L 1 It is C 1-3 Alkylene; and -L 2 It's –O-.

[0941] In some embodiments (when R c Yes-L 1 -L 2 -R h ), R h As defined in paragraph [C182]. In some embodiments, R h As defined in paragraph [C183]. For example, R h May be as defined in paragraph [C184].

[0942] As non-limiting examples, B can be imidazolyl or pyrazolyl, each of which is optionally substituted with 1-2 independently selected R c replace.

[0943] In some embodiments (when B is a heteroaryl group containing from 5 ring atoms, wherein 1-3 (e.g., 2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c Replacement; and R c As defined in any of paragraphs [C174]-[C184]), one occurrence of R c Yes-L 1 -L 2 -R h , where -L 1 is a key; and / or –L 2 is the key.

[0944] Variable R N

[0945] [C214] In some embodiments, each R N Independently selected from:

[0946] (i) H,

[0947] (ii)C 1-6 Alkyl, optionally with 1-3 R a replace,

[0948] (iii)C 3-6 Cycloalkyl, optionally substituted with 1-2 R a replace,

[0949] (iv)-C(O)(C 1-4 alkyl), and

[0950] (v) -C(O)O(C 1-4 alkyl).

[0951] [C215] In some embodiments, one occurrence of R N It's H.

[0952] [C216] In some embodiments (when one occurrence of R N is H), the second occurrence of R N It's H.

[0953] [C217] In some other embodiments, the second occurrence of R N Selected from:

[0954] (ii)C 1-6 Alkyl, optionally with 1-3 R a replace,

[0955] (iii)C 3-6 Cycloalkyl, optionally substituted with 1-2 R a replace,

[0956] (iv)-C(O)(C 1-4 alkyl), and

[0957] (v) -C(O)O(C 1-4 alkyl).

[0958] [C218] In some of these embodiments, R N The second occurrence of C 1-6 Alkyl, optionally with 1-3 R a (e.g., 1-2, e.g., 1) substitutions.

[0959] [C219] In some of these embodiments, each occurrence of R a Selected from C 1-4 Alkoxy, C 3-6 Cycloalkyl and hydroxy.

[0960] [C220] In some embodiments (when one occurrence of R N is H), the second occurrence of R N Yes -C(O)O(C 1-4 alkyl) (e.g., -C(O)Me).

[0961] [C221] In some embodiments (when one occurrence of R N is H), the second occurrence of R N is unsubstituted C1-6 alkyl.

[0962] [C222] In some embodiments, one occurrence of R N It is C 1-6 alkyl.

[0963] [C223] In some of these embodiments, the second occurrence of R N Selected from:

[0964] (ii)C 1-6 Alkyl, optionally with 1-3 R a replace,

[0965] (iii)C 3-6 Cycloalkyl, optionally substituted with 1-2 R a replace,

[0966] (iv)-C(O)(C 1-4 alkyl), and

[0967] (v) -C(O)O(C 1-4 alkyl).

[0968] [C224] In some embodiments (when one occurrence of R N It is C 1-6 Alkyl), the second occurrence of R N It is C 1-6 alkyl.

[0969] [C225] In some embodiments (when one occurrence of R N It is C 1-6 Alkyl), the second occurrence of R N It is C 1-3 alkyl.

[0970] When ring B and R N according to (B) How to implement the definition+

[0971] In some embodiments, B and each occurrence of R N according to (B) definition.

[0972] In some embodiments, B and an R N Together with the atoms to which they are attached, they form a ring containing 5-15 ring atoms, wherein the ring contains: (a) 0-4 ring heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 (Except for the moiety) and (b) 2 to 12 ring carbon atoms, each of which is optionally substituted with 1 to 2 substituents independently selected from the following:

[0973] (i) H;

[0974] (ii) oxo;

[0975] (iii) halogen;

[0976] (iv) hydroxyl group;

[0977] (v)C 1-6 alkyl;

[0978] (vi)C 1-6 Haloalkyl;

[0979] (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c replace;

[0980] (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 , and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace;

[0981] (ix) a heterocyclic group containing 3 to 16 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b Replacement; and

[0982] (x)C 3-20 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace.

[0983] In some embodiments, B and an R N Together with the atoms to which they are attached, they form a ring containing 5-15 ring atoms, wherein the ring contains: (a) 0-4 ring heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 (Except for the (a) 2 to 12 ring carbon atoms, each of which is optionally substituted with 1 to 2 substituents independently selected from the following:

[0984] (i) H;

[0985] (ii) oxo;

[0986] (iii) halogen;

[0987] (iv) hydroxyl group;

[0988] (v)C 1-6 alkyl;

[0989] (vi)C 1-6 Haloalkyl;

[0990] (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c Replacement; and

[0991] (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 , and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

[0992] In some embodiments, B and an R N Together with the atoms to which they are attached, they form a ring containing 8-15 ring atoms, wherein the ring contains: (a) 0-4 ring heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 (Except for the moiety) and (b) 2 to 12 ring carbon atoms, each of which is optionally substituted with 1 to 2 substituents independently selected from the following:

[0993] (i) H;

[0994] (ii) oxo;

[0995] (iii) halogen;

[0996] (iv) hydroxyl group;

[0997] (v)C 1-6 Alkyl; and

[0998] (vi)C 1-6 Halogenated alkyl.

[0999] In some embodiments, B and an R N Together with the atoms to which it is attached, it forms: It is optionally substituted with 1 to 3 substituents independently selected from the following:

[1000] (ii) oxo;

[1001] (iii) halogen;

[1002] (iv) hydroxyl group;

[1003] (v)C 1-6 Alkyl; and

[1004] (vi)C 1-6 Halogenated alkyl.

[1005] In some of these embodiments, B and an R N Together with the atoms to which it is attached, it forms: It is further optionally substituted by 1-2 substituents independently selected from the following:

[1006] (ii) oxo;

[1007] (v)C 1-6 Alkyl; and

[1008] (vi)C 1-6 Halogenated alkyl.

[1009] In some embodiments, B and an R N Together with the atoms to which they are attached, they form a ring containing 5-7 ring atoms, wherein the ring contains: (a) 0-4 ring heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 (Except for the moiety) and (b) 2-3 ring carbon atoms, each of which is optionally substituted with 1-2 substituents independently selected from the following:

[1010] (i) H;

[1011] (ii) oxo;

[1012] (iii) halogen;

[1013] (iv) hydroxyl group;

[1014] (v)C 1-6 alkyl;

[1015] (vi)C 1-6 Haloalkyl;

[1016] (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c Replacement; and

[1017] (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(Rd ), O and S(O) 0-2 , and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

[1018] In some of these embodiments, B and an R N Together with the atoms to which it is attached, it forms: It is optionally substituted by 1 to 3 substituents independently selected from the following: (ii) oxo; (iii) halogen; (iv) hydroxyl; and (v) C 1-6 alkyl;

[1019] Among them, Ar N Selected from:

[1020] (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c Replacement; and

[1021] (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein one or more of the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c Substitution (e.g., Ar N It is C 6-10 Aryl, optionally substituted with 1-2 R c Substitution (e.g., R c Can be a halogenated alkyl group, such as CF 3 )).

[1022] In some embodiments, R N It's hydrogen.

[1023] Variable W

[1024] In some embodiments, W is O.

[1025] In some embodiments, W is NH.

[1026] In some embodiments, W is NR d .

[1027] Non-restricted combinations

[1028] [AA]

[1029] In some embodiments, the compound has formula (I-1):

[1030] Where n1 = 0 or 1; and

[1031] R cA and R cB Each is independently selected R c .

[1032] In some embodiments of formula (I-1), A is (A-1):

[1033]

[1034] in,

[1035] Z is selected from the following group:

[1036] key, CH, CR 1 , CR 3 、N、NH、N(R 1 ) and N(R 2 );

[1037] Y 1 , Y 2 and Y 3 Each independently selected from the following group: O, S, CH, CR 1 , CR 3 、N、NH、N(R 1 ) and NR 2 ;

[1038] Y 4 is C or N;

[1039] X 1 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;

[1040] X 2 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;and

[1041] each are independently single bonds or double bonds, provided that Y 4 , X 1 and X 2 The five-membered ring is a heteroaryl group; and contains Z, Y 1 , Y 2 , Y 3 and Y 4 The ring is aromatic (ie, an aromatic carbocyclic or heterocyclic ring).

[1042] In some embodiments of formula (I-1), A is:

[1043] (For example, ), wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (e.g., m1=0 or 1; and m3=0, 1 or 2).

[1044] In some embodiments of formula (I-1), A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[1045] In some embodiments of formula (I-1), A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[1046] In some embodiments of formula (I-1), A is Wherein m1=0, 1 or 2; and m3=0, 1 or 2.

[1047] In some embodiments of formula (I-1), A is Wherein m1=0 or 1; and m3=0, 1 or 2.

[1048] In some embodiments of formula (I-1), A is: (For example, ).

[1049] In some embodiments of formula (I-1), A is (A-2):

[1050]

[1051] Z is selected from the following group:

[1052] Key, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 , C(R 3 ) 2 、O、N、NH、N(R 1 ) and N(R 2 );

[1053] Y 1 and Y 2 Each is independently selected from the following group: O, S, CH, CH 2 , CR 1 , CHR 1, C(R 1 ) 2 , CR 3 , CHR 3 , C(R 3 ) 2 、N、NH、N(R 1 ) and NR 2 ;

[1054] Q 1 and Q 2 One of the does not exist, and Q 1 and Q 2 The other one is C 2-5 Alkylene, which is optionally interrupted by a heteroatom selected from: -NH-, -N(R 1 )-、-N(R 2 )- and –O-; and

[1055] each is independently a single bond or a double bond.

[1056] In some embodiments of formula (I-1), A is: wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (eg, m1=0; and m3=0).

[1057] In some embodiments of formula (I-1), A is: wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (eg, m1=0; and m3=0).

[1058] In some embodiments of formula (I-1), A is (A-3):

[1059]

[1060] in,

[1061] Ring A 3A is a monocyclic or bicyclic ring containing 5-12 ring atoms, wherein 0-2 ring atoms are cumulative and selected for Y 4 wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and 2-12 are ring carbon atoms, each independently selected from: C, CH, CH 2 , CR 1 , CHR 1 , C(R 1 ) 2 , CR 3 , CHR 3 and C(R3 ) 2 , provided that ring A 3A is non-aromatic;

[1062] X 1 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;

[1063] X 2 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ; The condition is to contain Y 4 , X 1 and X 2 The ring of is heteroaromatic; and

[1064] Y 4 Selected from: N or C.

[1065] In some embodiments of formula (I-1), A is: wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[1066] In some embodiments of formula (I-1), A is: wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[1067] In some embodiments of formula (I-1), A is: wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[1068] In some embodiments of formula (I-1), A is: wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[1069] In some embodiments of formula (I-1), A is (A-4):

[1070]

[1071] in:

[1072] Z 2 Selected from: CH, R 2 and N;

[1073] X3 Selected from: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;

[1074] Y 5 and Y 6 Each independently selected from O, S, CH, CR 1 , CR 3 NR 1 NR 2 , NH and N; and

[1075] Each are independently single bonds or double bonds, provided that Y 5 , Y 6 , X 3 and Z 2 The five-membered ring of is a heteroaryl group.

[1076] In some embodiments of formula (I-1), A is selected from:

[1077] In some embodiments of formula (I-1), A is:

[1078] In some embodiments of formula (I-1), A is:

[1079] In some embodiments of formula (I-1), A is selected from: For example, A can be

[1080] In some embodiments of Formula (I-1), each R 1 As defined in any of paragraphs [C92]-[C120].

[1081] In some embodiments of Formula (I-1), R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[1082] In some embodiments of Formula (I-1), U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[1083] In some embodiments of Formula (I-1), U 2 As defined in paragraph [C99].

[1084] In some embodiments of Formula (I-1), U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[1085] In some embodiments of Formula (I-1), U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[1086] In some embodiments of formula (I-1) (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[1087] In some embodiments of formula (I-1) (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R cThe substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[1088] In some embodiments of formula (I-1) (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[1089] In some embodiments of Formula (I-1), R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[1090] In some embodiments of Formula (I-1), each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[1091] In some embodiments of Formula (I-1), each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[1092] In some embodiments of Formula (I-1), each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[1093] In some embodiments of Formula (I-1), each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[1094] In some of these embodiments, R cB It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

[1095] In some embodiments, R cB It is C 1-3 Alkyl, which is optionally substituted by 1-6 independently selected R a For example, R cB Can be CF 3 or (For example, R cB Can be CF 3 ).

[1096] In some of these embodiments, each occurrence of R a Independently selected from: -F; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy.

[1097] In some embodiments (when one occurrence of R cB It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a Replacement), R cB is unsubstituted C 1-10 Alkyl (e.g., unsubstituted C 1-6 (For example, C 1-3 )alkyl.

[1098] In some embodiments of Formula (I-1), RcB is R as defined in any of paragraphs [C174]-[C184] c .

[1099] In some embodiments, R cB Yes-L 1 -L 2 -R h .

[1100] In some of these embodiments, -L 1 is a bond. In some other embodiments, -L 1 It is C 1-3 Alkylene.

[1101] In some embodiments (when R cB Yes-L 1 -L 2 -R h ), -L 2 is a bond. In some other embodiments, -L2 is -O-.

[1102] In some embodiments (when R cB Yes-L 1 -L 2 -R h ), -L 1 is the key; and –L 2 is a bond. In some other embodiments, -L 1 is the key; and -L 2 is -O-. In some other embodiments, -L 1 It is C 1-3 Alkylene; and -L 2 It's –O-.

[1103] In some embodiments (when R cB Yes-L 1 -L 2 -R h ), R h As defined in paragraph [C182]. In some embodiments, R h As defined in paragraph [C183]. For example, R h May be as defined in paragraph [C184].

[1104] In some embodiments of Formula (I-1), R cB YesR c Unsubstituted C1 -6 Alkyl (e.g., C 1-3 alkyl).

[1105] In some embodiments of Formula (I-1), R cB It's a halogen.

[1106] In some embodiments of formula (I-1), n1=0.

[1107] In some embodiments of formula (I-1), n1=1.

[1108] In some of the foregoing embodiments, R cA It's a halogen.

[1109] In some embodiments of Formula (I-1), each R N As defined in any of paragraphs [C214]-[C225].

[1110] In some embodiments, one occurrence of R N It's H.

[1111] In some embodiments (when one occurrence of R N is H), the second occurrence of R N It's H.

[1112] In some other embodiments, the second occurrence of R N Selected from:

[1113] (ii)C 1-6 Alkyl, optionally with 1-3 R a replace,

[1114] (iii)C 3-6 Cycloalkyl, optionally substituted with 1-2 R a replace,

[1115] (iv)-C(O)(C 1-4 alkyl), and

[1116] (v) -C(O)O(C 1-4 alkyl).

[1117] In some of these embodiments, R N The second occurrence of C 1-6 Alkyl, optionally with 1-3 R a (e.g., 1-2, e.g., 1) substitutions. For example, the second occurrence of R N Can be unsubstituted C 1-6 alkyl.

[1118] In some of these embodiments, each occurrence of R a Selected from C 1-4 Alkoxy, C 3-6 Cycloalkyl and hydroxy.

[1119] In some embodiments (when one occurrence of R Nis H), the second occurrence of R N Yes -C(O)O(C 1-4 alkyl) (e.g., -C(O)Me).

[1120] In some embodiments, each R N It's H.

[1121] [BB]

[1122] In some embodiments, the compound has formula (I-2):

[1123]

[1124] Wherein B2 is selected from:

[1125] a) a heteroaryl group containing from 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl ring is optionally substituted by 1-2 independently selected R c Replacement; and

[1126] b) a heteroaryl group containing from 5 ring atoms, wherein 1 to 3 (e.g., 2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl ring is optionally substituted by 1-2 independently selected R c replace.

[1127] In some embodiments (I-2), B 2 is a heteroaryl group containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally substituted by 1-2 independently selected R c Replacement; and R c As defined in any of paragraphs [C169]-[C173] (e.g., R c Can be CF 3 ).

[1128] In some of these embodiments, R c It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

[1129] In some embodiments, R c It is C 1-3 Alkyl, which is optionally substituted by 1-6 independently selected R a For example, R cCan be CF 3 or (For example, R cB Can be CF 3 ).

[1130] In some of these embodiments, each occurrence of R a Independently selected from: -F; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy.

[1131] In some embodiments (when one occurrence of R c It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a Replacement), R c is unsubstituted C 1-10 Alkyl (e.g., unsubstituted C 1-6 (For example, C 1-3 )alkyl.

[1132] In some embodiments (I-2), B 2 is a heteroaryl group (e.g., pyrazolyl or imidazolyl) containing from 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c Replacement; and R c As defined in any of paragraphs [C174]-[C184].

[1133] In some embodiments, R c Yes-L 1 -L 2 -R h .

[1134] In some of these embodiments, -L 1 is a bond. In some other embodiments, -L 1 It is C 1-3 Alkylene.

[1135] In some embodiments (when R c Yes-L 1 -L 2 -R h ), -L 2 is a bond. In some other embodiments, -L2 is -O-.

[1136] In some embodiments (when R c Yes-L 1 -L 2 -R h), -L 1 is the key; and –L 2 is a bond. In some other embodiments, -L 1 is the key; and -L 2 is -O-. In some other embodiments, -L 1 It is C 1-3 Alkylene; and -L 2 It's –O-.

[1137] In some embodiments (when R c Yes-L 1 -L 2 -R h ), R h As defined in paragraph [C182]. In some embodiments, R h As defined in paragraph [C183]. For example, R h May be as defined in paragraph [C184].

[1138] In some embodiments of formula (I-2), A is (A-1):

[1139]

[1140]

[1141] in,

[1142] Z is selected from the following group:

[1143] key, CH, CR 1 , CR 3 、N、NH、N(R 1 ) and N(R 2 );

[1144] Y 1 , Y 2 and Y 3 Each independently selected from the following group: O, S, CH, CR 1 , CR 3 、N、NH、N(R 1 ) and NR 2 ;

[1145] Y 4 is C or N;

[1146] X 1 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;

[1147] X2 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;and

[1148] each are independently single bonds or double bonds, provided that Y 4 , X 1 and X 2 The five-membered ring is a heteroaryl group; and contains Z, Y 1 , Y 2 , Y 3 and Y 4 The ring is aromatic (ie, an aromatic carbocyclic or heterocyclic ring).

[1149] In some embodiments of formula (I-2), A is: (For example, ),

[1150] wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (e.g., m1=0 or 1; and m3=0, 1 or 2).

[1151] In some embodiments of formula (I-2), A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[1152] In some embodiments of formula (I-2), A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[1153] In some embodiments of formula (I-2), A is Wherein m1=0, 1 or 2; and m3=0, 1 or 2.

[1154] In some embodiments of formula (I-2), A is Wherein m1=0 or 1; and m3=0, 1 or 2.

[1155] In some embodiments of formula (I-2), A is: (For example, ).

[1156] In some embodiments of Formula (I-2), each R 1 As defined in any of paragraphs [C92]-[C120].

[1157] In some embodiments of Formula (I-2), R1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[1158] In some embodiments of Formula (I-2), U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[1159] In some embodiments of Formula (I-2), U 2 As defined in paragraph [C99].

[1160] In some embodiments of Formula (I-2), U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[1161] In some embodiments of Formula (I-2), U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[1162] In some embodiments of formula (I-2) (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[1163] In some embodiments of formula (I-2) (when R 1 Yes-(U 1 ) q -U 2 ), R 1is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[1164] In some embodiments of formula (I-2) (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[1165] In some embodiments of Formula (I-2), R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[1166] In some embodiments of Formula (I-2), each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[1167] In some embodiments of Formula (I-2), each R3 is as defined in any of paragraphs [C121]-[C123].

[1168] In some embodiments of Formula (I-2), each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[1169] In some embodiments of formula (I-2), each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[1170] In some embodiments of Formula (I-2), each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[1171] In some embodiments of Formula (I-2), each R N As defined in any of paragraphs [C214]-[C225].

[1172] In some embodiments of Formula (I-2), one occurrence of R N It's H.

[1173] In some embodiments (when one occurrence of R N is H), the second occurrence of R N It's H.

[1174] In some other embodiments, the second occurrence of R N Selected from:

[1175] (ii)C 1-6 Alkyl, optionally with 1-3 R a replace,

[1176] (iii)C 3-6 Cycloalkyl, optionally substituted with 1-2 R a replace,

[1177] (iv)-C(O)(C 1-4 alkyl), and

[1178] (v) -C(O)O(C 1-4 alkyl).

[1179] In some of these embodiments, R N The second occurrence of C 1-6 Alkyl, optionally with 1-3 R a (e.g., 1-2, e.g., 1) substitutions. For example, the second occurrence of R N Can be unsubstituted C 1-6 alkyl.

[1180] In some of these embodiments, each occurrence of R a Selected from C 1-4 Alkoxy, C 3-6 Cycloalkyl and hydroxy.

[1181] In some embodiments (when one occurrence of R N is H), the second occurrence of R N Yes -C(O)O(C 1-4 alkyl) (e.g., -C(O)Me).

[1182] In some embodiments of Formula (I-2), each R N It's H.

[1183] [CC]

[1184] In some embodiments, the compound has formula (I-3):

[1185]

[1186] Among them B 3 Selected from:

[1187] a)C 6-12 Cycloalkyl, which is optionally substituted by 1-2 R b replace;

[1188] b) a heterocyclic group containing 3 to 6 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b Replacement; and

[1189] c) a heterocyclic group containing 7 to 12 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b replace.

[1190] In some embodiments of formula (I-3), B 3 It is C 6-12 Cycloalkyl, which is optionally substituted with one R b replace.

[1191] In some embodiments of formula (I-3), B 3 is a heterocyclic group containing 3-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b Replace; one occurrence of R b As defined in paragraphs [C196]-[C201]

[1192] In some of the foregoing embodiments, one occurrence of R b As defined in paragraph [C196]. In some embodiments, one occurrence of R b As defined in paragraph [C197]. In some embodiments, one occurrence of R b As defined in paragraph [C198]. In some embodiments, one occurrence of R b Yes-L 1 -L 2 -R h In some of these embodiments, -L 1 is the key; and -L 2 In some embodiments of formula (I-2) (when one occurrence of R b Yes-L 1 -L 2 -R h ), R h It is C 6-10 Aryl, which is optionally substituted by 1-4 (eg, 1-2, eg, 1) substituents independently selected from the group consisting of halogen, C 1-4 Alkyl or C1-4 Halogenated alkyl.

[1193] In some embodiments of formula (I-3), B 3 is a heterocyclic group containing 7-12 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b replace.

[1194] In some of the foregoing embodiments, B 3 is unsubstituted.

[1195] In some embodiments of formula (I-3), A is (A-1):

[1196]

[1197] in,

[1198] Z is selected from the following group:

[1199] key, CH, CR 1 , CR 3 、N、NH、N(R 1 ) and N(R 2 );

[1200] Y 1 , Y 2 and Y 3 Each independently selected from the following group: O, S, CH, CR 1 , CR 3 、N、NH、N(R 1 ) and NR 2 ;

[1201] Y 4 is C or N;

[1202] X 1 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;

[1203] X 2 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;and

[1204] each are independently single bonds or double bonds, provided that Y 4 , X 1 and X 2 The five-membered ring is a heteroaryl group; and contains Z, Y 1 , Y 2 , Y 3 and Y 4 The ring is aromatic (ie, an aromatic carbocyclic or heterocyclic ring).

[1205] In some embodiments of formula (I-3), A is: (For example, ), wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (e.g., m1=0 or 1; and m3=0, 1 or 2).

[1206] In some embodiments of formula (I-3), A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[1207] In some embodiments of formula (I-3), A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[1208] In some embodiments of formula (I-3), A is Wherein m1=0, 1 or 2; and m3=0, 1 or 2.

[1209] In some embodiments of formula (I-3), A is Wherein m1=0 or 1; and m3=0, 1 or 2.

[1210] In some embodiments of formula (I-3), A is: (For example, ).

[1211] In some embodiments of formula (I-3), A is (A-4):

[1212]

[1213] in:

[1214] Z 2 Selected from: CH, R 2 and N;

[1215] X 3 Selected from: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR3 ;

[1216] Y 5 and Y 6 Each independently selected from O, S, CH, CR 1 , CR 3 NR 1 NR 2 , NH and N; and

[1217] Each are independently single bonds or double bonds, provided that Y 5 , Y 6 , X 3 and Z 2 The five-membered ring of is a heteroaryl group.

[1218] In some embodiments of formula (I-3), A is selected from: For example, A can be As a non-limiting example, A may be

[1219] In some embodiments of formula (I-3), A is selected from: For example, A can be

[1220] In some embodiments of formula (I-3), each R 1 As defined in any of paragraphs [C92]-[C120].

[1221] In some embodiments of formula (I-3), R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[1222] In some embodiments of Formula (I-3), U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[1223] In some embodiments of Formula (I-3), U 2 As defined in paragraph [C99].

[1224] In some embodiments of Formula (I-3), U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[1225] In some embodiments of Formula (I-3), U2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[1226] In some embodiments of formula (I-3) (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[1227] In some embodiments of formula (I-3) (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[1228] In some embodiments of formula (I-3) (when R 1 Yes-(U 1 ) q-U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U 2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[1229] In some embodiments of formula (I-3), R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[1230] In some embodiments of formula (I-3), each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[1231] In some embodiments of formula (I-3), each R3 is as defined in any of paragraphs [C121]-[C123].

[1232] In some embodiments of formula (I-3), each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[1233] In some embodiments of formula (I-3), each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[1234] In some embodiments of formula (I-3), each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[1235] In some embodiments of formula (I-3), each R N As defined in any of paragraphs [C214]-[C225].

[1236] In some embodiments of Formula (I-3), one occurrence of R N It's H.

[1237] In some embodiments (when one occurrence of R N is H), the second occurrence of R N It's H.

[1238] In some other embodiments, the second occurrence of R N Selected from:

[1239] (ii)C 1-6 Alkyl, optionally with 1-3 R a replace,

[1240] (iii)C 3-6 Cycloalkyl, optionally substituted with 1-2 R a replace,

[1241] (iv)-C(O)(C 1-4 alkyl), and

[1242] (v) -C(O)O(C 1-4 alkyl).

[1243] In some of these embodiments, R N The second occurrence of C 1-6 Alkyl, optionally with 1-3 R a (e.g., 1-2, e.g., 1) substitutions. For example, the second occurrence of R N Can be unsubstituted C 1-6 alkyl.

[1244] In some of these embodiments, each occurrence of R a Selected from C 1-4 Alkoxy, C 3-6 Cycloalkyl and hydroxy.

[1245] In some embodiments (when one occurrence of R N is H), the second occurrence of R N Yes -C(O)O(C 1-4 alkyl) (e.g., -C(O)Me).

[1246] In some embodiments of formula (I-3), each R N It's H.

[1247] [DD]

[1248] In some embodiments, A is (A-1):

[1249]

[1250] in,

[1251] Z is selected from the following group:

[1252] key, CH, CR 1 , CR 3 、N、NH、N(R 1 ) and N(R 2 );

[1253] Y 1 , Y 2 and Y 3 Each independently selected from the following group: O, S, CH, CR 1 , CR 3 、N、NH、N(R 1 ) and NR 2 ;

[1254] Y 4 is C or N;

[1255] X 1 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;

[1256] X 2 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;and

[1257] each are independently single bonds or double bonds, provided that Y 4 , X 1 and X 2 The five-membered ring is a heteroaryl group; and contains Z, Y 1 , Y 2 , Y 3 and Y 4 The ring is aromatic (i.e., an aromatic carbocyclic or heterocyclic ring);

[1258] B and an R N Together with the atoms to which they are attached, they form a ring containing 5-20 ring atoms, wherein the ring contains: (a) 0-4 ring heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 (Except for the moiety) and (b) 2 to 17 ring carbon atoms, each of which is optionally substituted with 1 to 2 substituents independently selected from the following:

[1259] (i) H;

[1260] (ii) oxo;

[1261] (iii) halogen;

[1262] (iv) hydroxyl group;

[1263] (v)C 1-6 alkyl;

[1264] (vi)C 1-6 Haloalkyl;

[1265] (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c replace;

[1266] (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace;

[1267] (ix) a heterocyclic group containing 3 to 16 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected Rb Replacement; and

[1268] (x)C 3-20 Cycloalkyl, which is optionally substituted by 1 to 4 R b Replacement; and

[1269] The remaining R N Is H or C 1-6 alkyl.

[1270] In some embodiments of [DD], A is: (For example, ),

[1271] wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (e.g., m1=0 or 1; and m3=0, 1 or 2).

[1272] In some embodiments of [DD], A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[1273] In some embodiments of [DD], A is wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

[1274] In some embodiments of [DD], A is Wherein m1=0, 1 or 2; and m3=0, 1 or 2.

[1275] In some embodiments of [DD], A is Wherein m1=0 or 1; and m3=0, 1 or 2.

[1276] In some embodiments of [DD], A is (For example, ).

[1277] In some embodiments of [DD], B and an R N Together with the atoms to which it is attached, it forms: It is optionally substituted with 1 to 3 substituents independently selected from the following:

[1278] (ii) oxo;

[1279] (iii) halogen;

[1280] (iv) hydroxyl group;

[1281] (v)C 1-6 Alkyl; and

[1282] (vi)C1-6 Halogenated alkyl.

[1283] In some embodiments of [DD], B and an R N Together with the atoms to which it is attached, it forms: It is optionally substituted by 1 to 3 substituents independently selected from the following: (ii) oxo; (iii) halogen; (iv) hydroxyl; and (v) C 1-6 alkyl;

[1284] Among them, Ar N Selected from:

[1285] (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c Replacement; and

[1286] (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 , and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

[1287] In some embodiments of [DD], each R 1 As defined in any of paragraphs [C92]-[C120].

[1288] In some embodiments of [DD], R 1 Yes-(U 1 ) q -U 2 In some of these embodiments, q is 0.

[1289] In some embodiments of (DD), U 2 As defined in paragraph [C96]. For example, U 2 May be as defined in paragraph [C97].

[1290] In some embodiments of (DD), U 2 As defined in paragraph [C99].

[1291] In some embodiments of (DD), U 2 As defined in paragraph [C100]. For example, U 2 May be as defined in paragraph [C101].

[1292] In some embodiments of (DD), U 2 Each R c Substituents, when present, are as defined in paragraph [C102]. For example, U2 Each R c Substituents, when present, may be as defined in paragraph [C103]. For example, U 2 Each R c Substituents, when present, may be as defined in paragraph [C104].

[1293] In some embodiments of (DD) (when R 1 Yes-(U 1 ) q -U 2) , R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C110a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C110b]. 2 Each R c The substituents may be as defined in paragraph [C110c].

[1294] In some embodiments of (DD) (when R 1 Yes-(U 1 ) q -U 2 ), R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c (For example, R 1 is pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl). In some of these embodiments, U 2 Each R c The substituents are as defined in paragraph [C112a]. For example, U 2 Each R c The substituents may be as defined in paragraph [C112b]. 2 Each R c The substituents may be as defined in paragraph [C112c].

[1295] In some embodiments of (DD) (when R 1 Yes-(U 1 ) q -U 2 ; when q=0), U 2 As defined in paragraph [C106]. For example, U2 It can be as defined in paragraph [C107]. For example, U 2 May be as defined in paragraph [C108].

[1296] In some embodiments of (DD), R 1 As defined in paragraph [C114] (e.g., as defined in paragraph [C115]). As a non-limiting example, R 1 May be as defined in paragraph [C116].

[1297] In some embodiments of (DD), each occurrence of R 1 R a Substituents are as defined in paragraph [C117]. For example, each occurrence of R 1 R a Substituents may be as defined in paragraph [C118]. As a non-limiting example, each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH. For example, R 1 Can be CF 3 or CH 2 CO 2 H.

[1298] In some embodiments of [DD], each R 3 As defined in any of paragraphs [C121]-[C123].

[1299] In some embodiments of [DD], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[1300] In some embodiments of [DD], each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O)1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

[1301] In some embodiments of [DD], each occurrence of R 3 Independently selected from the following groups: halogen, cyano, C 1-4 Alkoxy and C 1-4 For example, each occurrence of R 3 It may be a halogen (eg, F).

[1302] In some embodiments, the compound is selected from the following or a pharmaceutically acceptable salt thereof:

[1303] Table 1A

[1304]

[1305]

[1306]

[1307]

[1308]

[1309]

[1310] In some embodiments, the compound is selected from the following or a pharmaceutically acceptable salt thereof:

[1311] Table 1B

[1312]

[1313]

[1314]

[1315]

[1316]

[1317]

[1318]

[1319]

[1320] (R N )2 NS(O)(=N)-part (when W is O)

[1321] In some embodiments, (R N ) 2 The sulfur atom in the NS(O)(=N)- moiety has a (S) stereochemistry.

[1322] In some embodiments, (R N ) 2 The sulfur atom in the NS(O)(=N)- moiety has an (R) stereochemistry.

[1323] Pharmaceutical compositions and administration

[1324] Overview

[1325] 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 pharmaceutical combination 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 described herein.

[1326] In some embodiments, the chemical entity can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tweens, poloxamers or other similar polymer delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or dielectrics, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and lanolin. Cyclodextrins such as α-, β- and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to provide delivery of the compounds described herein. Dosage forms or compositions containing chemical entities described herein in the range of 0.005%-100% can be prepared, with the remainder being made up by non-toxic excipients. The contemplated composition may contain 0.001%-100% of the chemical entities provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, and in yet another embodiment 20-80%. The actual method of preparing such a dosage form is known or understood by those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, England, 2012).

[1327] Routes of administration and composition components

[1328] In some embodiments, the chemical entities described herein or pharmaceutical compositions thereof can be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, transdermal, intracervical, intrasinus, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumor, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, transdermal, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In some embodiments, the preferred route of administration is parenteral (eg, intratumoral).

[1329] The composition can be formulated for parenteral administration, for example, for injection by intravenous, intramuscular, subcutaneous or even intraperitoneal routes. Generally, such compositions can be prepared as injections, in the form of liquid solutions or suspensions; solid forms suitable for adding liquids to prepare solutions or suspensions before injection can also be prepared; and the preparations can also be emulsified. In light of the present disclosure, the preparation of such preparations is known to those skilled in the art.

[1330] Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; including sesame oil, peanut oil or propylene glycol aqueous solution preparations; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it is easy to inject. It should also be stable under the conditions of manufacture and storage, and must be able to resist the contaminating effects of microorganisms such as bacteria and fungi during storage.

[1331] The carrier can also be a solvent or dispersion medium comprising, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof, and vegetable oils. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion system, and by using a surfactant. The action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, isotonic agents such as sugars or sodium chloride are preferably included. The absorption of the injectable composition can be prolonged by using agents that delay absorption, such as aluminum monostearate and gelatin in the composition.

[1332] Sterile injections are prepared by mixing the required amount of active compound in a suitable solvent with the various other components mentioned above and then filtering and sterilizing as needed. Typically, the various sterile active components are incorporated into a sterile carrier containing an alkaline dispersion medium and the other required ingredients mentioned above to prepare a dispersion. When preparing sterile powders required for sterile injections, the preferred preparation method is vacuum drying and freeze drying techniques to obtain a powder of the active component and any other required components from a previously sterile filtered solution.

[1333] For intratumoral injection, see, e.g., 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.

[1334] Pharmaceutically acceptable excipients that can be used as gels, creams, enemas or rectal suppositories in rectal compositions include, but are not limited to, one or more of the following: cocoa butter glycerides, synthetic polymers such as polyvinyl pyrrolidone, PEG (such as PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, Anoxid SBN, vanilla essential oil, parabens in aerosol, phenoxyethanol, sodium methylparaben, sodium propylparaben, diethylamine, carbomer, carbopol, methyl methoxybenzoate, polyethylene glycol cetearyl ether, decyl cocoate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-disulfite, sodium EDTA, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamin A and E), and potassium acetate.

[1335] In some embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of enemas.

[1336] In other embodiments, the compounds described herein, or pharmaceutical compositions thereof, are suitable for local delivery to the digestive or gastrointestinal tract via oral administration (eg, solid or liquid dosage forms).

[1337] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates and sodium carbonate, e) solubilizers, such as paraffin, f) absorption promoters, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glyceryl monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or lactose fractions as well as high molecular weight polyethylene glycols.

[1338] In one embodiment, the composition can take the form of a unit dosage form such as a pill or tablet, so the composition can also include, in addition to the chemical entity provided herein: a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate, etc.; a binder such as starch, gum arabic, polyvinyl pyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, a powder, a pill, a solution or a suspension (e.g., in propylene carbonate, vegetable oil, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). It is also possible to consider a unit dosage form in which one or more chemical entities or other active agents provided herein are physically separated, such as a capsule containing each drug particle (or a tablet in a capsule); a double-layer tablet; a double-chamber gel capsule, etc. Enteric-coated or delayed-release oral dosage forms are also considered.

[1339] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersants or preservatives, which are especially useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[1340] In some embodiments, the excipient is sterile and generally free of undesirable substances. The composition can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients, such as tablets and capsules, sterility is not required. USP / NF standards are generally sufficient.

[1341] In some embodiments, the solid oral dosage form may further include one or more components that chemically and / or structurally facilitate the composition to deliver the chemical entity to the stomach or lower GI; for example, the ascending colon and / or transverse colon and / or distal colon and / or small intestine. Exemplary formulation techniques are described in, for example, Filipski, KJ et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

[1342] Examples include upper GI targeting technologies such as the Accordion Pill (Intec Pharma), floating capsules and materials that are able to adhere to the mucosal wall.

[1343] Other examples include lower GI targeting technologies. To target various areas of the intestine, several enteric / pH responsive coatings and excipients can be used. These materials are typically polymers designed to dissolve or erode within a specific pH range, selected based on the GI region where drug release is desired. In cases where the active ingredient may irritate the upper GI, these materials also serve to protect acid-labile drugs from gastric fluid erosion or limit exposure (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (vinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers) and Marcoat. Other technologies include dosage forms that respond to the local flora of the gastrointestinal tract, pressure-controlled colon delivery capsules and Pulsincap.

[1344] Ophthalmic compositions may include, but are not limited to, any one or more of the following: viscogens (e.g., carboxymethylcellulose, glycerol, 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 chlorine oxide complex; Allergan, Inc.).

[1345] Topical compositions may include ointments and creams. Ointments are semisolid preparations, usually based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are usually viscous liquids or semisolid emulsions, usually oil-in-water or water-in-oil. The cream base is usually washable and comprises an oil phase, an emulsifier and an aqueous phase. The oil phase is sometimes also referred to as the "internal phase", which is usually composed of petrolatum and fatty alcohols (such as cetyl alcohol or stearyl alcohol); although not necessarily, the aqueous phase usually exceeds the volume of the oil phase and usually contains a wetting agent. The emulsifier in the cream formulation is usually a nonionic, anionic, cationic or amphoteric surfactant. Like other carriers or vehicles, the ointment base should be inert, stable, non-irritating and insensitive.

[1346] In any of the foregoing embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipids, multilamellar vesicles with crosslinks between bilayers, biodegradable poly (D, L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-loaded lipid bilayers.

[1347] dose

[1348] The dosage can vary depending on the needs of the patient, the severity of the disease being treated and the specific compound being used. The determination of the appropriate dosage for a particular situation can be determined by a person skilled in the art of medicine. The total daily dosage can be divided and administered in portions throughout the day or by providing continuous delivery.

[1349] In some embodiments, the compound described herein is administered at a dose of about 0.001 mg / Kg to about 500 mg / Kg (e.g., about 0.001 mg / Kg to about 200 mg / Kg; about 0.01 mg / Kg to about 200 mg / Kg; about 0.01 mg / Kg to about 150 mg / Kg; about 0.01 mg / Kg to about 100 mg / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 mg / Kg to about 1mg / Kg; about 0.01mg / Kg to about 0.5mg / Kg; about 0.01mg / Kg to about 0.1mg / Kg; about 0.1mg / Kg to about 200mg / Kg; about 0.1mg / Kg to about 150mg / Kg; about 0.1mg / Kg to about 100mg / Kg; about 0.1mg / Kg to about 50mg / Kg; about 0.1mg / Kg to about 10mg / Kg; about 0.1mg / Kg to about 5mg / Kg; about 0.1mg / Kg to about 1mg / Kg; about 0.1mg / Kg to about 0.5mg / Kg).

[1350] Dosage

[1351] The foregoing doses can be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[1352] In some embodiments, the compound described herein is administered for 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 longer. In another embodiment, the dosing stop time 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 longer. In one embodiment, individual treatment compounds are given for a period of time, followed by separate time periods. In another embodiment, treatment compounds are given in the first period of time, and administration is stopped in the second period of time after the first period of time, and then treatment compounds are restarted in the third period of time, and then administration is stopped in the fourth period of time after the third period of time. In one aspect of this embodiment, the administration period of the treatment compound and the subsequent time period of stopping administration are repeated in a determined or undetermined time period. In another embodiment, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In another embodiment, the time of stopping 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 longer.

[1353] Treatment

[1354] In some embodiments, methods are provided for treating a subject having a condition, disease, or disorder in which increased (e.g., excess) STING activity (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., immune disorder, cancer).

[1355] Indications

[1356] In some embodiments, the condition, disease or disorder is cancer. Non-limiting examples of cancer include: melanoma, carcinoma, lymphoma, blastoma, sarcoma and leukemia or lymphoid malignancies. More specific examples of such cancers include: breast cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, clear cell carcinoma lung cancer, including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), cervical cancer, ovarian cancer, prostate cancer, prostate tumors, liver cancer, bladder cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, including gastrointestinal cancer, gastrointestinal stromal tumors, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytic leukemia ... hepatoma, hepatoma, hematologic malignancies including non-Hodgkin lymphoma (NHL), multiple myeloma, myelodysplastic disease, myeloid proliferative disorders, chronic myeloid leukemia, and acute hematologic malignancies, endometrial or uterine cancer, endometriosis, endometrial stromal sarcoma, fibrosarcoma, choriocarcinoma, salivary gland cancer, vulvar cancer, thyroid cancer, esophageal cancer, hepatoma In some cases, the cancer is melanoma.

[1357] 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 cranial nerves), and the autonomic nervous system (parts of which are located in both the central and peripheral nervous systems). Non-limiting examples of cancer include: acquired epileptic aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; corpus callosum dysgenesis; agnosia; Aicardi syndrome; Alexander disease; Alpers' disease; alternating hemiplegia; Alzheimer's disease; vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; hypoxia; aphasia; apraxia; arachnoid cyst; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy palsy; benign essential blepharospasm; benign focus; amyotrophy; benign intracranial hypertension; Binswanger disease; blepharospasm; Bloch-Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma); spinal tumors; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis; headache; cerebral aneurysm; cerebral arteriosclerosis; brain 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 palsy; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease disease; cumulative trauma disease; Cushing's syndrome; cytomegalovirus infection; dancing eyes and feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome; Dejerine-Klumke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia;Dyslexia; dystonia; epileptic encephalopathy of early infancy; empty sella syndrome; encephalitis; encephalocele; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry's disease; Fahr's syndrome; syncope; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich's ataxia; frontotemporal dementia and other "tauopathies"; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barré syndrome syndrome; HTLV-1-associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (also a neurologic manifestation of AIDS); holoprosencephaly; Huntington's disease and other glutamine repeat disorders; hydrocephalus; hydrocortisonephritis; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; phytic acid storage disease of infancy; infantile nasal discharge; infantile spasms; inflammatory myopathy; intracranial cysts; intracranial hypertension; Jobart syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease disease); Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome;

[1358] Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh's 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 disc disease; Lyme disease-neurological sequelae; Machado-Joseph disease; hydrocephalus; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-stroke; mitochondrial myopathy; Mobius syndrome syndrome; monosomic muscular atrophy; motor neuron disease; Moyamoya disease; mucopolysaccharidosis; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating diseases; multiple system atrophy with postural hypotension; p-muscular dystrophy; myasthenia gravis; diffuse myelofractionated sclerosis; infantile myoclonic encephalopathy; myoclonus; myopathy; myotonia congenita; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurologic manifestations of AIDS; neurologic sequelae of lupus; neuromyotonia; neuronal lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; recessive spondylodysplasia sequence; Ohtahara syndrome syndrome; oligopontine cerebellar atrophy; myoclonus-myoclonus; optic neuritis; postural hypotension; overuse syndrome; paresthesias; Parkinson's disease; myotonia congenita; paraneoplastic disorders; paroxysmal seizures; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralysis; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorder; sneeze reflex; phytic acid storage disease; Pick's disease; pinched nerve; pituitary tumor; polymyositis; foramen; post-polio syndrome; postherpetic neuralgia; postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome;Primary lateral sclerosis; Prions; Progressive hemifacial atrophy; Progressive multifocal leukoencephalopathy; Progressive sclerosing poliomyelitis; Progressive supranuclear palsy; Pseudoencephalitis; Ramsay-Hunt syndrome (types I and II); Rasmussen's encephalitis; Reflex sympathetic dystrophy syndrome; Refsum disease; Repetitive movement disorder; Repetitive stress injury; Restless legs syndrome; Retrovirus-associated myelopathy; Rett syndrome; Reye's syndrome; Saint Vitus dance; Sandhoff disease; Schilder's disease; Schizophrenia; Opto-dysplasia; Shaken baby syndrome; Shingles; Shy-Drager syndrome; Sjögren's syndrome syndrome; sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumor; spinal muscular atrophy; Stiff-Person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; Sydenham chorea; syncope; syringomyelia; tardive dyskinesia;

[1359] Tay-Sachs disease; temporal arteritis; tethered cord syndrome; Thomsen disease; thoracic outlet syndrome; Tic Douloureux; Todd's paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathy; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paresis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; von Hippel-Lindau disease; Wallenberg's syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wildon's disease disease); amyotrophic lateral sclerosis and Zelweger syndrome.

[1360] In some embodiments, the condition, disease or disorder is a condition associated with STING, for example, type I interferon disease (e.g., STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutières Syndrome (AGS), inherited forms of lupus and inflammation-related diseases, such as systemic lupus erythematosus and rheumatoid arthritis. In some embodiments, the condition, disease or disorder is an autoimmune disease (e.g., an autoinflammatory disease triggered by cytoplasmic DNA). Non-limiting examples include: rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC), which are chronic inflammatory diseases with polygenic susceptibility. In some embodiments, the disorder is inflammatory bowel disease. In some embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by adoptive cell therapy treatment, colitis associated with one or more alloimmune diseases (e.g., graft versus host disease, such as acute graft versus host disease and chronic graft versus host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In some of these embodiments, the condition is an alloimmune disease (e.g., graft versus host disease, such as acute graft versus host disease and chronic graft versus host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis, or intestinal mucositis).

[1361] In some embodiments, regulation of the immune system by STING provides treatment of diseases, including diseases caused by exogenous factors. Exemplary infections of exogenous factors that can be treated and / or prevented by the methods of the present invention include: bacterial (e.g., Gram-positive or Gram-negative bacteria) infections, fungal infections, parasitic infections, and viral infections. In one embodiment of the present invention, the infection is a bacterial infection (e.g., Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Salmonella spp., Staphylococcus aureus, Streptococcus or vancomycin-resistant enterococci) or sepsis. In another embodiment, the infection is a fungal infection (e.g., mold, yeast or higher fungal infection). In another embodiment, the infection is a parasitic infection (e.g., an infection caused by a unicellular or multicellular parasite, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondiz). In yet another embodiment, the infection is a viral infection (e.g., a viral infection 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).

[1362] In some embodiments, the disorder, disease or condition is hepatitis B (see, e.g., WO 2015 / 061294).

[1363] In some embodiments, the condition, disease or disorder is selected from cardiovascular disease (including, for example, myocardial infarction).

[1364] In some embodiments, the condition, disease or disorder is age-related macular degeneration.

[1365] In some embodiments, the condition, disease or disorder is mucositis, also known as stomatitis, which can occur as a result of chemotherapy or radiation therapy, used alone or in combination, as well as damage caused by exposure to radiation outside the context of radiation therapy.

[1366] In some embodiments, the condition, disease, or disorder is uveitis, which is an inflammation of the uvea (e.g., anterior uveitis, such as iridocyclitis or iritis; intermediate uveitis (also known as parsplanitis); posterior uveitis; or chorioretinitis, such as pan-uveitis).

[1367] In some embodiments, the condition, disease or disorder is selected from the group consisting of cancer, a neurological disease, an autoimmune disease, hepatitis B, uveitis, cardiovascular disease, age-related macular degeneration, and mucositis.

[1368] Other examples may include those indications discussed herein and below in contemplated combination treatment regimens.

[1369] Combination therapy

[1370] The present disclosure encompasses monotherapy regimens as well as combination therapy regimens.

[1371] In some embodiments, the methods described herein can further comprise administering one or more additional therapies (eg, one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the compounds described herein.

[1372] In some embodiments, the methods described herein can further comprise administering one or more additional cancer therapies.

[1373] One or more additional cancer therapies may include, but are not limited to, surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, hepatitis B vaccine, Oncophage, Provenge) and gene therapy, and combinations thereof. Immunotherapy, including but not limited to adoptive cell therapy, derivation of stem cells and / or dendritic cells, transfusion, lavage and / or other therapies, including but not limited to freezing of tumors.

[1374] In some embodiments, the one or more additional cancer therapies is chemotherapy, which may include the administration of one or more additional chemotherapeutic agents.

[1375] In some embodiments, the other chemotherapeutic agent is an immunomodulatory molecule, such as an immune checkpoint inhibitor. In some of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1–PD-L1, PD-1–PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9–TIM3, phosphatidylserine–TIM3, lymphocyte activation gene 3 protein (LAG3), MHC Class II – LAG3, 4-1BB – 4-1BB ligand, OX40 – OX40 ligand, GITR, GITR ligand – GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25 – TL1A, CD40L, CD40 – CD40 ligand, HVEM – LIGHT – LTA, HVEM, HVEM – BTLA, HVEM – 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, HHLA 2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, 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.

[1376] In some of these embodiments, the immune checkpoint inhibitor is selected from: Urelumab, PF-05082566, MEDI6469, TRX518, Varlilumab, CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), Atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-L1), Avelu mab) (PD-L1), PDR001 (PD1), BMS-986016, MGA271, Lirilumab, IPH2201, Emactuzumab, INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavituximab, CC-90002, Bevacizumab, MNRP1685A, and MGA271.

[1377] In some embodiments, other chemotherapeutic agents are alkylating agents. Alkylating agents are so named because they are able to alkylate many nucleophilic functional groups under conditions present in cells, including but not limited to cancer cells. In another embodiment, alkylating agents include but are not limited to: cisplatin, carboplatin, methylethylamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin. In one embodiment, alkylating agents may act by disrupting cellular function by forming covalent bonds with amino, carboxyl, sulfhydryl and phosphate groups in biologically important molecules, or they may act by modifying the DNA of the cell. In another embodiment, the alkylating agent is synthetic, semisynthetic or a derivative.

[1378] In some embodiments, other chemotherapeutic agents are antimetabolites. Antimetabolites disguise themselves as purines or pyrimidines, which are the basic components of DNA, and usually prevent these substances from incorporating into DNA during the "S" phase (cell cycle), thereby preventing normal development and division. Antimetabolites also affect RNA synthesis. In one embodiment, antimetabolites include but are not limited to: azathioprine and / or mercaptopurine. In another embodiment, antimetabolites are synthetic, semisynthetic or derivatives.

[1379] In some embodiments, other chemotherapeutic agents are plant alkaloids and / or terpenes. These alkaloids are usually derived from plants and prevent cell division by preventing microtubule function. In one embodiment, plant alkaloids and / or terpenoids are vinca alkaloids, podophyllotoxins and / or taxanes. Typically, vinca alkaloids bind to specific sites on tubulin, usually in the M phase of the cell cycle, inhibiting tubulin from assembling into microtubules. In one embodiment, vinca alkaloids are not limited to: Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). In one embodiment, vinca alkaloids include but are not limited to: vincristine, vinblastine, vinorelbine and / or vindesine. In one embodiment, taxanes include but are not limited to: Taxol, paclitaxel and / or docetaxel. In another embodiment, plant alkaloids or terpenoids are synthetic, semi-synthetic or derivatives. In another embodiment, podophyllotoxins are but are not limited to etoposide and / or teniposide. In one embodiment, the taxane is but not limited to docetaxel and / or octataxel.

[021] In one embodiment, the cancer therapeutic agent is a topoisomerase. Topoisomerase is an essential enzyme for maintaining the topological structure of DNA. The inhibition of type I or type II topoisomerase interferes with the transcription and replication of DNA by destroying the appropriate DNA supercoil. In another embodiment, the topoisomerase is but not limited to a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, a type I topoisomerase inhibitor is but not limited to camptothecin. In another embodiment, camptothecin is but not limited to exatecan, irinotecan, rutotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and / or ST1481. In one embodiment, a type II topoisomerase inhibitor is but not limited to epipodophyllotoxin. In another embodiment, an epipodophyllotoxin is but not limited to amsacrine, etoposide, etoposide phosphate and / or teniposide. In another embodiment, the topoisomerase is synthetic, semisynthetic or a derivative, including those found in nature, such as but not limited to epipodophyllotoxin, which is a substance naturally present in the root of the American Mayapple (Podophyllum peltatum).

[1380] In some embodiments, the other chemotherapeutic agent is a stilbenes. In further embodiments, stilbenes include, but are not limited to, Resveratrol, Piceatannol, Pinosylvin, Pterostilbene, Alpha-Viniferin, Ampelopsin A, Ampelopsin E, Diptoindonesin C, Diptoindonesin F, Epsilon-Vinferin, Flexuosol A, Gnetinins D, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid and Diptoindonesin A. In another embodiment, the stilbenes are synthetic, semi-synthetic or derivatives.

[1381] In some embodiments, other chemotherapeutic agents are cytotoxic antibiotics. In one embodiment, cytotoxic antibiotics are but are not limited to: actinomycin, anthracenedione, anthracyclines, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose and / or chlofazimine. In one embodiment, actinomycin is but is not limited to: actinomycin D, bacitracin, colistin (polymyxin E) and / or polymyxin B. In another embodiment, anthraquinones are but are not limited to mitoxantrone and / or pixantrone. In another embodiment, anthracyclines are but are not limited to bleomycin, doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, promycin and / or valfloxacin. In another embodiment, cytotoxic antibiotics are synthetic, semisynthetic or derivatives.

[1382] In some embodiments, the additional chemotherapeutic agent is selected from the group consisting of endostatin, angiopoietin, angiostatin, chemokine, angioarrestin, angiostatin (plasminogen fragment), basement membrane collagen-derived anti-angiogenic factors (tumstatin, canstatin or arrestin), anti-angiogenic antithrombin III, signal transduction inhibitors, cartilage-derived inhibitor (CDI), CD59 complement fragment, fibronectin fragment, gro-β, heparinase, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon α / β / γ, interferon-induced protein (IP-10), interleukin 12, kringle 5 (plasminogen fragment), metalloproteinase inhibitor (TIMP), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4), prolactin 16kD fragment, proliferation protein-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin 1 (TSP-1), transforming growth factor-β (TGF-β), vasculostatin, vasostatin (calreticulin fragment), etc.

[1383] In some embodiments, the other chemotherapeutic agent is selected from the group consisting of abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-1-L proline-tert-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norv in-caleukoblastine, docetaxel, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), actinomycin, daunorubicin, decitabine, dolastatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyureaamine taxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, alachlor (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, paclitaxel, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

[1384] In some 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, folinate, methotrexate, gemcitabine, taxanes, folinic acid, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide, and doxorubicin. Other agents include mTOR (mammalian target of rapamycin) inhibitors, including but not limited to rapamycin, everolimus, temsirolimus, and deforolimus.

[1385] In other embodiments, the additional chemotherapeutic agent may be selected from those described in US Pat. No. 7,927,613, which is incorporated herein by reference in its entirety.

[1386] In some embodiments, the additional therapeutic agent and / or regimen can be used to treat other STING-associated disorders, such as type I interferonopathies, e.g., STING-associated vasculopathy of infancy (SAVI), cardio-Menty syndrome (AGS), inherited forms of lupus, inflammation-associated disorders, such as systemic lupus erythematosus, and rheumatoid arthritis, among others.

[1387] Non-limiting examples of additional therapeutic agents and / or treatment regimens for the treatment of 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), Leflunomide Hydroxychloroquine (Plaquenil), PF-06650833, iguratimod, tofacitinib ABBV-599, evobrutinib and sulfasalazine and biologics (eg, abatacept Adalimumab Anakinra Certolizumab Etanercept Golimumab infliximab Rituximab Tocilizumab Vobarilizumab, sarilumab secukinumab, ABP501, CHS-0214, ABC-3373, and tocilizumab ).

[1388] Non-limiting examples of additional therapeutic agents and / or treatment regimens for the treatment of lupus include: steroids, topical immunomodulators (e.g., tacrolimus ointment and pimecrolimus cream ), thalidomide Nonsteroidal anti-inflammatory drugs (NSAIDs; for example, ibuprofen and naproxen), antimalarial drugs (for example, hydroxychloroquine (Plaquenil)), corticosteroids (for example, prednisone), immunomodulators (for example, evobrutinib, iberdomide, voclosporin, cenerimod, azathioprine) Cyclophosphamide Cyclosporine (Neoral, ), mycophenolate mofetil), baricitinib, iguratimod, filogotinib, GS-9876, rapamycin, and PF-06650833), biologics (eg, belimumab anifrolumab, prezalumab, MEDI0700, obinutuzumab, vobarilizumab, lulizumab, atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin Dapirolizumab, edratide, IFN-α-kinoid, OMS721, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab For example, non-limiting treatments for systemic lupus erythematosus include: nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarials (e.g., hydroxychloroquine (Plaquenil)), corticosteroids (e.g., prednisone), and immunomodulators (e.g., iberdomide, voclosporin, azathioprine Cyclophosphamide and cyclosporine (Neoral, ), and mycophenolate mofetil, baricitinib, filogotinib, and PF-06650833), as well as biologics (eg, belimumab anifrolumab, prezalumab, MEDI0700, vobarilizumab, lulizumab, atacicept, PF-06823859, lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin Dapirolizumab, edratide, IFN-α-kinoid, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab As another example, non-limiting examples of treatments for cutaneous lupus include: steroids, immunomodulators (e.g., tacrolimus ointment and pimecrolimus cream ), GS-9876, filogotinib, and thalidomide Agents and regimens for the treatment of drug-induced and / or neonatal lupus may also be administered.

[1389] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating STING-associated vasculopathy of infancy (SAVI) include JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[1390] Non-limiting examples of additional therapeutic agents and / or treatment regimens for the treatment of AGS include: physical therapy, treatment of respiratory complications, anticonvulsant therapy for seizures, tube feeding, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine (e.g., ), tenofovir (e.g. ), emtricitabine / tenofovir (e.g. ), zidovudine, lamivudine, and abacavir), and JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).

[1391] Non-limiting examples of additional therapeutic agents and / or treatment 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 cobitolimod, corticosteroids (e.g., prednisone, methylprednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbiota transplantation, figlotinib, fingolimod, firategrast (SB-683699) (formerly known as T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, HMPL-004 (Andrographis paniculata), paniculata extract), IMU-838, infliximab, interleukin-2 (IL-2), Janus kinase (JAK) inhibitors, laquinimod, masitinib (AB1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mirikizumab (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peficitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab (MK 3222), TJ301, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, vatelizumab, VB-201, vedolizumab, and vidofludimus.

[1392] Non-limiting examples of other therapeutic agents and / or treatment regimens for treating irritable bowel syndrome include: alosetron, bile acid sequestrants (e.g., cholestyramine, celestipol, 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 tanpanor.

[1393] Non-limiting examples of additional therapeutic agents and / or treatment regimens for the treatment of scleroderma include: nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), immunomodulators (e.g., azathioprine, methotrexate), Cyclophosphamide and cyclosporine Antithymocyte globulin, mycophenolate mofetil, intravenous immune globulin, 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, prostaglandins, and tyrosine kinase inhibitors (e.g., imatinib, nilotinib, and dasatinib).

[1394] Non-limiting examples of additional therapeutic agents and / or treatment regimens for the treatment of Crohn's disease (CD) include: adalimumab, autologous CD34-selected peripheral blood stem cell transplantation, 6-mercaptopurine, azathioprine, certolizumab pegol Corticosteroids (e.g., prednisone), etrolizumab, E6011, fecal microbiota transplantation, figlotinib, 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.

[1395] Non-limiting examples of additional therapeutic agents and / or treatment regimens for the treatment of UC include: AbGn-168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, belimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol CP-690,550, corticosteroids (e.g., multimax budesonide, methylprednisolone), cyclosporine, E6007, ertuximod, etrolizumab, fecal microbiota transplantation, filotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mesalamine, mirikizumab (LY3074828), RPC1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tofacitinib, tofacitinib, ustekinumab, UTTR1147A, and vedolizumab.

[1396] Non-limiting examples of other therapeutic agents and / or treatment regimens for treating autoimmune colitis include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), benhydrasol / atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[1397] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating iatrogenic autoimmune colitis include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), benhydrasol / atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[1398] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating colitis induced by one or more chemotherapeutic agents include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), benhydrasol / atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[1399] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating colitis caused by adoptive cell therapy include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), benhydrasol / atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848) and vedolizumab.

[1400] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating colitis associated with one or more alloimmune diseases include: corticosteroids (eg, budesonide, prednisone, prednisolone, beclomethasone dipropionate), sulfasalazine, and eicosapentaenoic acid.

[1401] Non-limiting examples of additional therapeutic agents and / or treatment 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.

[1402] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating collagenous colitis include: 6-mercaptopurine, azathaioprine, bismuth subsalicate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), mesalamine, methotrexate, probiotics, and sulfasalazine.

[1403] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating lymphocytic colitis include: 6-mercaptopurine, azathaioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), mesalamine, methotrexate, and sulfasalazine.

[1404] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating microbial colitis include: 6-mercaptopurine, azathioprine, bismuth subsalicate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), fecal microbiota transplantation, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.

[1405] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating alloimmune diseases include: intrauterine platelet transfusion, intravenous immunoglobulin, maternal steroids, abatacept, alemtuzumab, alpha 1-antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin-toxin conjugates, diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[1406] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating multiple sclerosis (MS) include: alemtuzumab ALKS 8700, amiloride, ATX-MS-1467, azathioprine, baclofen beta interferons (eg, IFN-beta-1a, IFN-beta-1b), cladribine, corticosteroids (eg, methylprednisolone), daclizumab, dimethyl fumarate Fingolimod Fluoxetine, glatiramer acetate Hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab NeuroVax TM , ocrelizumab, ofatumumab, pioglitazone, and RPC1063.

[1407] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating graft-versus-host disease include: abatacept, alemtuzumab, alpha 1-antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin-toxin conjugates, and / or sirolimus. diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[1408] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating acute graft-versus-host disease include: alemtuzumab, alpha 1-antitrypsin, antithymocyte globulin, basiliximab, brentuximab, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, photohemolysis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.

[1409] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating chronic graft-versus-host disease include: abatacept, alemtuzumab, AMG592, anti-thymocyte globulin, basiliximab, bortezomib, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, denileukin-toxin conjugates, diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photohemolysis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[1410] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating celiac disease include: AMG 714, AMY01, Aspergillus niger prolyl endoproteinase, BL-7010, CALY-002, GBR 830, Hu-Mik-Beta-1, IMGX003, KumaMax, Larazotide Acetate, Pancreatic lipase, TIMP-GLIA, vedolizumab, and ZED 1227.

[1411] 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 ), local P-3073, local LEO 90100 Betamethasone dipropionate topical Betasol Propionate Vitamin D analogs (eg, calcipotriene Calcitriol ), anthralin (e.g., and ), topical retinoids (e.g., tazarotene) (e.g., and )), calcineurin inhibitors (eg, tacrolimus and pimecrolimus ), salicylic acid, coal tar, moisturizers, light therapy (eg, exposure to sunlight, UVB light therapy, narrow-band UVB light therapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), retinoids (eg, acitretin Methotrexate Apo805K1, baricitinib, FP187, KD025, prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (servopitant), upadacitinib (ABT-494), aprmilast, tofacitinib, cyclosporine Biologics (eg, etanercept Etanercept-szzs Infliximab Adalimumab Adalimumab-adbm Ustekinumab Golimumab Apremilast Secukinumab peg-cetuximab, secukinumab, tildrakizumab-ASMN, infliximab-dyyb, abatacept, ixekizumab ABP 710, BCD-057, BI695501, bimekizumab (UCB4940), CHS-1420, GP2017, guselkumab (CNTO1959), HD203, M923, MSB11022, mirikizumab (LY3074828), PF-06410293, PF-06438179, risankizumab (BI655066), SB2, SB4, SB5, siliq (brodalumab), namilumab (MT203, tildrakizumab (MK-3222), and ixekizumab ), thioguanine, and hydroxyurea (e.g., and ).

[1412] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating cutaneous T-cell lymphoma include: phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow-band UVB phototherapy, Gokman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photopheresis, radiation therapy (e.g., spot radiation and whole-body electron beam therapy), stem cell transplantation, corticosteroids, imiquimod, bexarotene gel, topical bischloroethyl-nitrosourea, methoxyethylamine gel, vorinostat, Romidepsin Pralatrexate Biologics (eg, alemtuzumab) brentuximab vedotin (SGN-35), mogamulizumab and IPH4102).

[1413] Non-limiting examples of additional therapeutic agents and / or regimens for the treatment of uveitis include: corticosteroids (e.g., intravitreal triamcinolone acetonide injection), antibiotics, antivirals (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide, and cyclosporine chlorambucil, azathioprine, methotrexate, and mycophenolate mofetil), biologics (eg, infliximab Adalimumab Etanercept Golimumab Certolizumab Rituximab Abatacept Basiliximab Anakinra Canakinumab Gevokixumab (XOMA052), tocilizumab Alemtuzumab Efalizumab LFG316, sirolimus Abatacept, sarilumab and daclizumab ), cytotoxic drugs, surgical implants (eg, fluocinolone inserts), and vitrectomy.

[1414] Non-limiting examples of additional therapeutic agents and / or treatment regimens for treating mucositis include: AG013, SGX942 (dusquetide), amifostine Cryotherapy, cepacol lozenges (lonzenges), mucosal adhesives (e.g., ), oral diphenhydramine (eg, elixirs), oral bioadhesives (eg, polyvinylpyrrolidone-sodium hyaluronate gel ), oral lubricants (eg, Oral ), caphosol, chamomilla recutita mouthwash, edible grape plant exosomes, antiseptic mouthwashes (e.g., chlorhexidine gluconate (e.g., or ), topical analgesics (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and (0.6% phenol), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; ), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble beta-1,3 / 1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, granules containing vaccinium myrtillus extract, macleaya cordata alkaloids and echinacea angustifolia extract (e.g., ), and gastrointestinal mixture (an acid reducing agent such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungal (e.g., nystatin), and analgesic (e.g., hurricane liquid). For example, non-limiting examples of additional therapeutic agents and / or treatment regimens for treating oral mucositis include: AG013, amifostine Cryotherapy, cepacol lozenges (lonzenges), mucosal adhesives (e.g., ), oral diphenhydramine (eg, elixirs), oral bioadhesives (eg, polyvinylpyrrolidone-sodium hyaluronate gel ), oral lubricants (eg, Oral ), caphosol, chamomilla recutita mouthwash, edible grape plant exosomes, antiseptic mouthwashes (e.g., chlorhexidine gluconate (e.g., or ), topical analgesics (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and (0.6% phenol), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; ), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble beta-1,3 / 1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, and a gastrointestinal mixture (an acid reducing agent such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid As another example, non-limiting examples of treatments for esophageal mucositis include: xylenecaine (e.g., gel viscous xylenecaine 2%). As another example, treatments for intestinal mucositis, treatments that alter intestinal mucositis, and treatments for signs and symptoms of intestinal mucositis include: a gastrointestinal mixture (an acid reducing agent such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., Hurricane liquid).

[1415] In some embodiments, the subject is administered a second therapeutic agent or regimen prior to contact with or administration of the chemical entity (e.g., about an hour before, or about 6 hours before, or about 12 hours before, or about 24 hours before, or about 48 hours before, about a week before, or about a month before).

[1416] In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as the contact or administration of the chemical entity. For example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in separate dosage forms.

[1417] In other embodiments, the subject is administered a second therapeutic agent or regimen after contact with or administration of the chemical entity (e.g., after about one hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, about 1 week, or about 1 month).

[1418] Patient selection

[1419] In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of such treatment (e.g., by biopsy, endoscopy, or other conventional methods known in the art). In some embodiments, the STING protein can be used as a biomarker for some types of cancers, such as colon cancer and prostate cancer. In other embodiments, identifying a subject can include analyzing the presence of T cells and / or the presence of exhausted T cells in the tumor microenvironment of a patient (e.g., a patient with one or more cold tumors). Such patients may include patients who are resistant to treatment with checkpoint inhibitors. In some embodiments, such patients can be treated with the chemical entities herein, for example, to recruit T cells into the tumor, and in some cases, for example, once the T cells are exhausted, further treated with one or more checkpoint inhibitors.

[1420] In some embodiments, the chemical entities, methods and compositions described herein can be administered to certain patient populations that are resistant to treatment (e.g., patients who are resistant to checkpoint inhibitors; e.g., patients with one or more cold tumors (e.g., tumors that lack T cells or are T cell-depleted)).

[1421] Compound preparation

[1422] As will be appreciated by those skilled in the art, methods for synthesizing compounds of the formula described herein will be apparent to those of ordinary skill in the art. For example, the compounds described herein can be synthesized. Synthetic chemical transformations and protecting group methods (protection and deprotection) that can be used to synthesize the compounds described herein are known in the art, and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Press (1989); T. W. Greene and R. G. M. Wuts, Protecting Groups in Organic Synthesis, 2nd Edition, John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Organic Synthesis Reagents, John Wiley and Sons (1994); L. Paquette, ed., Encyclopedia of Organic Synthesis Reagents, John Wiley and Sons (1995), and subsequent editions thereof. The raw materials used to prepare the compounds of the present invention are known, can be prepared by known methods, or can be commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein can be interchanged with alternative art-recognized equivalents. For example, in many reactions, triethylamine can be exchanged with other bases, such as non-nucleophilic bases (eg, diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

[1423] The skilled artisan will recognize a variety of analytical methods that can be used to characterize the compounds described herein, including e.g. 1 HNMR, heteronuclear NMR, mass spectroscopy, liquid chromatography and infrared spectroscopy. The foregoing list is a subset of the characterization methods available to one skilled in the art and is not intended to be limiting.

[1424] To further illustrate the foregoing, the following non-limiting exemplary synthetic schemes are included. Variations of these embodiments within the scope of the claims are within the knowledge of those skilled in the art and should be considered to fall within the scope of the invention as described and claimed. The reader will recognize that those skilled in the art will be able to prepare and use the present invention based on this disclosure without the need for detailed examples.

[1425] The following abbreviations have the indicated meanings:

[1426] ACN = acetonitrile

[1427] AcOH = acetic acid

[1428] DCM = dichloromethane

[1429] DMF=N,N-dimethylformamide

[1430] DMSO = dimethyl sulfoxide

[1431] DIEA=N,N-diisopropylethylamine

[1432] TBS = tert-butyldimethylsilyl chloride

[1433] Py = Pyridine

[1434] Et=ethyl

[1435] EtOH = ethanol

[1436] LC-MS = Liquid Chromatography-Mass Spectrometry

[1437] Me = methyl

[1438] MeOH = methanol

[1439] n-Bu=n-butyl

[1440] NMR = Nuclear Magnetic Resonance

[1441] HPLC = High Performance Liquid Chromatography

[1442] TEA = triethylamine

[1443] TFA = trifluoroacetic acid

[1444] THF = Tetrahydrofuran

[1445] RHS = Right Hand Side

[1446] LHS = Left Hand Side

[1447] IPA = Isopropyl Alcohol

[1448] BTC = bis(trichloromethyl) carbonate

[1449] Scheme I illustrates a general method for preparing compounds of formula I:

[1450] Scheme I

[1451]

[1452] Referring to Scheme I, an amine I-1 wherein ring A is as defined in Formula I is reacted with a compound of Formula I-2 wherein ring B is as defined in Formula I, and X L is a leaving group, such as -Cl, to provide the sulfonamide I-3. Compound I-3 is converted to a compound of formula I by activating a sulfonyl=O group (e.g., PPh 3 Cl 2 and NEt), and then the intermediate is reacted with (R N ) 2NH coupling, where each R N As defined in Formula I.

[1453] It is conceivable by those skilled in the art that I-1 and I-2 can be prepared by methods known in the art. For example, I-1 can be obtained by sequential electrophilic aromatic nitration and reduction of an intermediate nitro compound. For example, I-2 can be prepared by lithium-halogen exchange with SO 2 Prepared by capturing an organolithium species and then chlorinating it with an intermediate sulfinate (eg, with NCS).

[1454] Example

[1455] The following example is a method for preparing compound 1. Example 2 disclosed later discloses another method for preparing compound 1.

[1456] Example 1

[1457] N'-(1H-indol-3-yl)-4-(trifluoromethyl)benzenesulfonimidamide Preparation of (Compound 1)

[1458]

[1459] Sulfonamide (1 mmol) and TEA (1 mmol) were dissolved in DCM and cooled to 0°C. Triphenylphosphine dihydrochloride (1 mmol) was added dropwise to the solution over 10 minutes. The resulting mixture was stirred at -78°C for 2 hours, then liquid ammonia in THF (5 M solution, 30 mmol NH 3 ) and stirred the reaction overnight. The solution was concentrated in vacuo; and the crude product was partitioned between water and DCM. The organic layer was concentrated in anhydrous MgSO 4 The crude product was purified by flash chromatography on silica gel using hexane / EtOAc as eluent. LCMS (Method A): 340.1 [M+H] + , retention time 1.77 minutes.

[1460] Method A: Shim-pack XR-ODS, C18, 3x50 mm, 2.5um column, 1.0uL injection, 1.5mL / min flow rate, 90-900amu scan range, 190-400nm UV range, 5-100% (1.1 minutes), 100% (0.6 minutes) gradient of ACN (0.05% TFA) and water (0.05% TFA), total run time 2 minutes.

[1461] The following compounds can also be synthesized from the corresponding sulfonamides by the above method. The methods disclosed subsequently can also be used to prepare one or more of the following compounds.

[1462]

[1463]

[1464]

[1465]

[1466]

[1467] Subsequent disclosures provide further methods for the compounds of formula I.

[1468] Materials and methods

[1469] The progress of the reaction is usually monitored by TLC or LC-MS. Product identification is usually confirmed by LC-MS. LC-MS is recorded using one of the following methods.

[1470] Method A: Titank C18, 50x3 mm, 3um column, 0.3uL injection, 1.5mL / min flow rate, 90-900amu scan range, 254nm UV detection. Mobile phase A: water + 5mM NH 4 HCO 3 and mobile phase: acetonitrile. 10% MPB to 95.0% in 1.39 min, hold at 95% MPB for 0.8 min, 95% MPB to 10% in 0.03 min, then equilibrate at 10% MPB for 0.27 min.

[1471] Method B: EVO-C18, 50x3 mm, 2.6um column, 2.0uL injection, 1.2mL / min flow rate, 90-900amu scan range, 254nm UV detection. Mobile phase A: water + 5mM NH 4 HCO 3 and mobile phase B: acetonitrile. 10% MPB to 95.0% in 1.99 min, hold at 95% MPB for 0.6 min, 95% MPB to 10% in 0.20 min, then equilibrate at 10% MPB for 0.25 min.

[1472] Method C: Poroshell HPH-C18, 50*3mm, 2.6um column, 4.0uL injection, 1.2mL / min flow rate, 30-2000amu scan range, 254nm UV detection. Mobile phase A: water / 5mmol NH 4 CO 3and mobile phase B: acetonitrile. 5% MPB to 95% in 1.29 min, hold at 90% MPB for 0.9 min, 95% MPB to 10% in 0.05 min, then equilibrate at 10% MPB for 0.25 min.

[1473] Method D: Poroshell HPH-C18, 50*3mm, 2.6um column, 2.7uL injection, 1.2mL / min flow rate, 90-900amu scan range, 254nm UV detection. Mobile phase A (MPA): water / 0.04% NH4OH and mobile phase B (MPB): acetonitrile. Elute 10% MPB to 95% in 1.99 minutes, hold at 95% MPB for 0.6 minutes, 95% MPB to 10% in 0.03 minutes, then balance at 10% MPB for 0.17 minutes.

[1474] Method E: XBridge Shield RP18, 50*3.0mm, 2.2um column, 5.0uL injection, 1.5mL / min flow rate, 90-900amu scan range, 254nm UV detection. Mobile phase A (MPA): water / 0.04% NH4OH and mobile phase B (MPB): acetonitrile. Elute 10% MPB to 95% in 2 minutes, hold at 95% MPB for 0.79 minutes, 95% MPB to 10% in 0.05 minutes, then balance at 10% MPB for 0.16 minutes.

[1475] Method F: CORTECS C18+MVK, 50*2.1mm, 2.0uL injection, 1.0mL / min flow rate, 90-900amu scan range, 210nm UV detection. Mobile phase A: water + 0.1% FA; Mobile phase B: acetonitrile + 0.05% FA 10.0% MPB to 100.0% in 2.0 minutes, hold at 100.0% MPB for 0.75 minutes, 100.0% MPB to 10.0% in 0.02 minutes, and then equilibrate at 10.0% MPB for 0.23 minutes.

[1476] Method J: Kinetex@2.7um XB-C18 100A, 50*3.0mm, 1.5uL injection, 1.0mL / min flow rate, 90-900amu scan range, 210nm UV detection. Mobile phase A: water (0.05% TFA) and mobile phase B: MeCN. .5% MPB to 100% in 1.5 minutes, hold at 100% MPB for 0.8 minutes, 100% MPB to 5% in 0.03 minutes, then equilibrate at 10% MPB for 0.17 minutes.

[1477] Method K: Shim-pack XR-ODS, 50*3.0mm, 50*3.0mm, 2.2um column, 2.2μL injection, 1.2mL / min flow rate, method Kte, 90-900amu scan range, 254nm UV detection. Mobile phase A (MPA):: water / 0.05% TFA and mobile phase B (MPB): acetonitrile. Elute 5% MPB to 95% in 2 minutes, hold at 95% MPB for 0.7 minutes, 95% MPB to 10% in 0.05 minutes, then balance at 5% MPB for 0.25 minutes.

[1478] The final target product was purified by Prep-HPLC. Preparative HPLC was performed using the following method.

[1479] Method G: Pre-HPLC: Column: XBridge preparative C18 OBD column 19*150 mm, 5 μm; Mobile phase: water (10 mM NH 4 HCO 3 +0.1% NH 3 ·H 2 O) and ACN, UV detection 254 / 210 nm.

[1480] Method H: Pre-HPLC: Column: XBridge preparative C18 OBD column 19*150 mm, 5 μm; Mobile phase: water (10 mM NH 4 HCO 3 ) and ACN, UV detection 254 / 210nm.

[1481] Method I: Pre-HPLC: Column: YMC-Actus Triart C18 column 30*250 mm, 5 μm; Mobile phase: water (10 MMOL / L NH 4 HCO 3 +0.1% NH 3 .H 2 O) and ACN, UV detection 254 / 210 nm.

[1482] On BRUKER NMR 300.03Mz, DUL-CH, ULTRASHIELD TM 300,AVANCE II 300B-ACS TM 120 or BRUKER NMR 400.13Mz, BBFO, ULTRASHIELD TM 400,AVANCE III 400,B-ACS TM NMR was recorded at 120°C.

[1483] Schemes for the Preparation of Exemplary Intermediates: The following schemes illustrate the preparation of the remaining exemplified key intermediates.

[1484] Scheme 1: Synthesis of Intermediate 1 (N'-(tert-butyldimethylsilyl)-4-ethylbenzenesulfonimide amide)

[1485]

[1486] Step 1: N-(tert-Butyldimethylsilyl)-4-ethylbenzenesulfonamide

[1487]

[1488] 4-Ethylbenzenesulfonamide (5.0 g, 26.9 mmol, 1.0 eq) was dissolved in THF (30.0 mL) and DIEA (13.97 mL, 81.0 mmol, 3.0 eq) ...

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt or tautomer thereof: in: A is selected from the following group: (i) a heteroaryl group containing 5-6 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O, S and S(O)2, and wherein 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 and CR 3 , provided that at least one ring atom is R 1 Replacement; and (ii) a heteroaryl group containing 7 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 3-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 and C(R 3 )2; B and each occurrence of R N according to (A) and (B) definition: (A) B is: (a)C 1-15 Alkyl, which is optionally substituted by 1 to 6 R a replace; (b)C 3-20 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace; (c) phenyl, which is substituted by 1 to 4 R c replace; (d)C 8-20 Aryl, which is optionally substituted by 1 to 4 R c replace; (e) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl ring is optionally replaced by 1-4 independently selected R c replace; or (f) a heterocyclic group containing 3 to 16 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace; Each R N Independently for: (i) H, (ii)C 1-6 Alkyl, optionally with 1-3 R a replace, (iii)C 3-6 Cycloalkyl, optionally substituted with 1 to 3 R a replace, (iv)-C(O)(C 1-4 alkyl), and (v) -C(O)O(C 1-4 alkyl), (B) B and an R N Together with the atoms to which they are attached, they form a ring containing 5-20 ring atoms, wherein the ring contains: (a) 0 to 4 ring heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 (remove (a) 2 to 17 ring carbon atoms, each of which is optionally substituted by 1 to 2 substituents independently selected from the following: (i) H; (ii) oxo; (iii) halogen; (iv) hydroxyl group; (v)C 1-6 alkyl; (vi)C 1-6 Haloalkyl; (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c replace; (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace; (ix) a heterocyclic group containing 3 to 16 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b Replacement; and (x)C 3-20 Cycloalkyl, which is optionally substituted by 1 to 4 R b Replacement; and The remaining R N Is H or C 1-6 alkyl; W is O, NH or N(R d ); R 1 yes: (i)-(U 1 ) q -U 2 , in which: q is 0 or 1; ●U 1 It is C 1-6 Alkylene, which is optionally substituted by 1 to 6 R a Replacement; and ●U 2 yes: (a)C 3-12 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace, (b)C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace; (c) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl ring is optionally replaced by 1-4 independently selected R c Replace, or (d) a heterocyclic group containing 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace, or, (ii)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace; Each occurrence of R 2 Independently selected from the following group: (i)C 1-6 Alkyl, which is optionally substituted by 1-4 independently selected R a replace; (ii)C 3-6 Cycloalkyl; (iii) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 ; (iv)-C(O)(C 1-4 alkyl); (v) -C(O)O(C 1-4 alkyl); (vi) -CON(R')(R'); (vii)-S(O) 1-2 (NR'R”); (viii)-S(O) 1-2 (C 1-4 alkyl); (ix) -OH; and (x)C 1-4 Alkoxy; Each occurrence of R 3 independently selected from the group consisting of halogen, cyano, optionally substituted by 1-2 R a Substituted C 1-6 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, oxo, -S(O) 1-2 (NR'R"), -C 1-4 Thioalkoxy, -NO2, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R"); Each occurrence of R a Independently selected from the group consisting of: -OH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); cyano; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution; Each occurrence of R b Independently selected from the group consisting of 1-6 independently selected R a Substituted C 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 1-4 alkyl); -C(=O)O(C 1-4 -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 ; Each occurrence of R c Independently selected from the group consisting of: (a) halogen; (b) cyano; (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace; (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 1-4 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 ; R d Select from the following group: C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy; Each occurrence of R e and R f Independently selected from: H; C 1-6 Alkyl; C 1-6 Haloalkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy; or R e and R f Together with the nitrogen atom to which they are attached, they form a ring containing 3-8 ring atoms, wherein the ring contains: (a) 1-7 ring carbon atoms, each carbon atom being replaced by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms (except R e and R f , each of which is independently selected from the following group: N(R d ), NH, O and S; -L 1 Is a chemical bond or C1 -3 Alkylene; -L 2 is –O-, -N(H)-, -S-, or a bond; R h Selected from: ●C 3-8 Cycloalkyl, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl and C 1-4 haloalkyl (in some embodiments, provided that when R h is optionally 1-4 independently selected C 1-4 Alkyl substituted C 3-6 When cycloalkyl, -L 1 is key, or -L 2 is –O-, -N(H)-, or -S-); ● Heterocyclyl, wherein the heterocyclyl contains 3-16 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 wherein the heterocyclyl ring is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; A heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl and C 1-4 haloalkyl; and ·C 6-10 Aryl, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl or C 1-4 haloalkyl; and Each occurrence of R' and R" is independently selected from the group consisting of H, C 1-4 Alkyl and C 6-10 Aryl, which is optionally selected from halogen, C 1-4 Alkyl and C 1-4 or R' and R" together with the nitrogen atom to which they are attached form a ring containing 3-8 ring atoms, wherein the ring contains: (a) 1-7 ring carbon atoms, each of which is independently selected from H and C 1-3 alkyl is substituted with 1-2 substituents; and (b) 0-3 ring heteroatoms (excluding the nitrogen atom connected to R' and R "), each of which is independently selected from the following groups: N (H), N (R d ), O and S; The proviso is that the compound is not:

2. The compound according to claim 1, wherein A is: a heteroaryl group containing 7-20 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the following group: N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 3-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 and C(R 3 )2.

3. The compound according to any one of claims 1 to 2, wherein A is: a heteroaryl group containing 8-16 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the following group: N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 4-15 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 and C(R 3 )2.

4. The compound according to any one of claims 1 to 3, wherein A is: a heteroaryl group containing 8-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the following group: N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 4-9 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 and C(R 3 )2.

5. The compound according to any one of claims 1 to 4, wherein A is: a heteroaryl group containing 8-9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the following group: N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 4-8 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 and C(R 3 )2.

6. The compound according to any one of claims 1 to 5, wherein A is (A-1): in, Z is selected from the following group: key, CH, CR 1 , CR 3 、N、NH、N(R 1 ) and N(R 2 ); Y 1 , Y 2 and Y 3 Each independently selected from the following group: O, S, CH, CR 1 , CR 3 、N、NH、N(R 1 ) and NR 2 ; Y 4 is C or N; X 1 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ; X 2 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ;and each are independently single bonds or double bonds, provided that Y 4 , X 1 and X 2 The five-membered ring is a heteroaryl group; and contains Z, Y 1 , Y 2 , Y 3 and Y 4 The ring is aromatic (ie, an aromatic carbocyclic or heterocyclic ring).

7. The compound according to claim 6, wherein Z is independently selected from the group consisting of: CH, CR 1 , CR 3 , N and N(R 2 ).

8. The compound according to any one of claims 6 to 7, wherein Z is selected from the following group: CH, CR 1 , CR 3 and N.

9. The compound according to any one of claims 6 to 8, wherein Z is selected from the following group: CH, CR 1 and CR 3 (eg, Z is CH).

10. The compound according to any one of claims 6 to 9, wherein Y 1 , Y 2 and Y 3 Each independently selected from the following group: CH, CR 1 , CR 3 and N.

11. The compound according to any one of claims 6 to 10, wherein Y 1 , Y 2 and Y 3 Each independently selected from the following group: CH, CR 1 and CR 3 .

12. The compound according to any one of claims 6 to 11, in, Said Part is wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (eg, m1=0 or 1; and m3=0, 1 or 2).

13. The compound according to any one of claims 6 to 10, wherein 1-2 Y 1 , Y 2 and Y 3 Independently is N.

14. The compound according to any one of claims 6 to 10 and 13, wherein A Y 1 , Y 2 and Y 3 Independently is N.

15. The compound according to claim 14, wherein The remaining Y 1 , Y 2 and Y 3 Each independently selected from the following group: CH, CR 1 and CR 3 , the condition is one or more Y 1 , Y 2 and Y 3 independently CH.

16. The compound according to any one of claims 6-10 and 13-15, wherein Said Part is in: Asterisk indicates the same as Y 4 Connect the dots; and m3=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

17. The compound according to any one of claims 6-10 and 13-15, wherein Said Part is in: Asterisk indicates the same as Y 4 Connect the dots; and m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

18. The compound according to any one of claims 6 to 10 and 13, wherein 2 Y 1 , Y 2 and Y 3 Independently is N.

19. The compound according to claim 18, wherein The remaining Y 1 , Y 2 and Y 3 independently CH or CR 1 .

20. The compound according to any one of claims 6 to 8, wherein Z is N.

21. A compound as described in any one of claims 6 to 8 and 20, wherein Y 1 , Y 2 and Y 3 Each independently selected from the following group: CH, CR 1 , CR 3 and N.

22. The compound of any one of claims 6-8 and 20-21, wherein A Y 1 , Y 2 and Y 3 are independently N; wherein the remaining Y 1 , Y 2 and Y 3 Each independently is CH, CR 1 , CR 3 and N.

23. The compound of claim 22, wherein The remaining Y 1 , Y 2 and Y 3 Each independently is CH, CR 1 and CR 3 .

24. The compound according to any one of claims 6-8 and 20-23, wherein Said Part is in: Asterisk indicates the same as Y 4 Connect the dots; and m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m=0 or 1; and m3=0 or 1).

25. The compound of claim 6, wherein Z is the key.

26. A compound according to any one of claims 6 and 25, wherein Y 1 , Y 2 and Y 3 Each independently selected from the following group: O, S, CH, CR 1 , CR 3 , N, NH and NR 2 .

27. A compound as described in any one of claims 6 and 25-26, wherein 1-2 Y 1 , Y 2 and Y 3 Independently selected from the group consisting of O, S, N, NH and NR 2 (e.g., S, N, and NR 2 ).

28. A compound as described in any one of claims 6 and 25-27, wherein Said Part is in: Asterisk indicates the same as Y 4 Connected points; and m1=0 or 1; and m3=0, 1 or 2.

29. A compound as described in any one of claims 6 and 25-27, wherein Said Part is (For example, ), The asterisk indicates 4 Connect the dots.

30. A compound according to any one of claims 6 to 29, wherein Y 4 It is C.

31. A compound as described in any one of claims 6 to 30, wherein X 1 Selected from the group consisting of O, S, NH, NR 1 and NR 2 .

32. A compound as described in any one of claims 6 to 31, wherein X 1 Selected from the following group: NH, NR 1 and NR 2 (For example, X 1 It can be NH).

33. A compound as described in any one of claims 6 to 32, wherein X 2 Selected from the group consisting of N, CH, CR 1 and CR 3 .

34. A compound as described in any one of claims 6 to 33, wherein X 2 Selected from the following group: N, C(C 1-3 Alkyl) and CH.

35. A compound as described in any one of claims 6 to 34, wherein X 2 It is CH.

36. The compound of any one of claims 6 to 35, X 1 and X 2 Together is in, Asterisk indicates the same as Y 4 Connect the dots.

37. A compound as described in any one of claims 1-12 and 30-36, wherein A is: (For example, ), wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (eg, m1=0 or 1; and m3=0, 1 or 2).

38. A compound as described in any one of claims 1-10, 13-16 and 30-36, wherein A is: wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

39. A compound as described in any one of claims 1-10, 13-15, 17 and 30-36, wherein A is: wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

40. The compound of any one of claims 1-8, 20-24 and 30-36, wherein A is: Wherein m1=0, 1 or 2; and m3=0, 1 or 2.

41. A compound as described in any one of claims 1-6, 25-27 and 30-36, wherein A is: Wherein m1=0 or 1; and m3=0, 1 or 2.

42. A compound as described in any one of claims 1-6, 25-27 and 30-36, wherein A is: (For example, ).

43. The compound of claim 1, wherein A is a heteroaryl group containing 8-20 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 4-19 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 and C(R 3 )2.

44. A compound as described in any one of claims 1 and 43, wherein A is a heteroaryl group containing 10-16 ring atoms (e.g., a tricyclic heteroaryl group), wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and wherein 6-15 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 and C(R 3 )2.

45. A compound as described in any one of claims 1 and 43-44, wherein A is (A-2): Z is selected from the following group: bond, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 , C(R 3 )2, O, N, NH, N(R 1 ) and N(R 2 ); Y 1 and Y 2 Each is independently selected from the following group: O, S, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 , C(R 3 )2, N, NH, N(R 1 ) and NR 2 ; Q 1 and Q 2 One of the does not exist, and Q 1 and Q 2 The other one is C 2-5 Alkylene, which is optionally interrupted by a heteroatom selected from: -NH-, -N(R 1 )-、-N(R 2 )- and –O-; and each is independently a single bond or a double bond.

46. ​​The compound of claim 45, wherein Z is selected from: CH, CR 1 , CR 3 and N.

47. The compound of claim 46, wherein Z is selected from: CH and N (eg, Z is CH).

48. A compound as described in any one of claims 45 to 47, wherein Y 1 and Y 2 Each independently selected from the following group: CH, CR 1 , CR 3 and N.

49. A compound as described in any one of claims 45 to 48, wherein Y 1 and Y 2 Each independently selected from the following group: CH, CR 1 and CR 3 .

50. A compound as described in any one of claims 45-49, wherein Q 1 It is C 2-5 Alkylene, which is optionally interrupted by a heteroatom selected from: -NH-, -N(R 1 )-、-N(R 2 )- and –O-; and Q 2 Does not exist.

51. A compound as described in any one of claims 45-50, wherein Q 1 It is C 2-3 Alkylene (e.g., C2).

52. A compound as described in any one of claims 45 to 49, wherein Q 2 It is C 2-5 Alkylene, which is optionally interrupted by a heteroatom selected from: -NH-, -N(R 1 )-、-N(R 2 )- and –O-; and Q 1 Does not exist.

53. A compound as described in any one of claims 45-49 and 52, wherein Q 2 It is C 3-4 Alkylene (e.g., C3).

54. A compound as described in any one of claims 45-51, wherein A is: wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (eg, m1=0; and m3=0).

55. A compound as described in any one of claims 45-49 and 52-53, wherein A is: wherein m1=0, 1, 2 or 3; and m3=0, 1, 2 or 3 (eg, m1=0; and m3=0).

56. The compound of any one of claims 1 and 43, wherein A is (A-3): in, Ring A 3A is a monocyclic or bicyclic ring containing 5-12 ring atoms, wherein 0-2 ring atoms are cumulatively selected for Y 4 wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and 2-12 are ring carbon atoms, each independently selected from: C, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 and C(R 3 )2, the condition is that ring A 3A is non-aromatic; X 1 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ; X 2 Selected from the following group: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ; The condition is to contain Y 4 , X 1 and X 2 The ring of is heteroaromatic; and Y 4 Selected from: N or C.

57. The compound of claim 56, wherein Y 4 It is C.

58. A compound as described in any one of claims 56-57, wherein Ring A 3A is a monocyclic ring containing 5-8 ring atoms, of which 0-2 ring atoms are cumulative and selected for Y 4 wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and 2-8 rings are carbon atoms, each independently selected from: C, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 and C(R 3 )2, the condition is that ring A 3A It is non-aromatic.

59. A compound as described in any one of claims 56-57, wherein Ring A 3A is a monocyclic ring containing 5-6 ring atoms, wherein 0-2 (e.g., 0 or 1, e.g., 0) ring atoms are cumulatively selected for Y 4 wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and 2-6 are ring carbon atoms, each independently selected from: C, CH2, CHR 1 , C(R 1 2. CHR 3 and C(R 3 )2, the condition is that ring A 3A It is non-aromatic.

60. A compound as described in any one of claims 56-59, wherein A is: wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

61. A compound as described in any one of claims 56-57, wherein Ring A 3A is a bicyclic ring (eg, a spirobicyclic ring) containing 7-12 ring atoms, wherein 0-2 (eg, 0 or 1, eg, 1) ring atoms are cumulatively selected for Y 4 wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and 4-12 are ring carbon atoms, each independently selected from: C, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 and C(R 3 )2, the condition is that ring A 3A It is non-aromatic.

62. A compound as described in any one of claims 56-57, wherein Ring A 3A is a bicyclic ring (eg, a spirobicyclic ring) containing 7-9 (eg, 8) ring atoms, wherein 0-2 (eg, 0 or 1, eg, 1) ring atoms are cumulatively selected for Y 4 wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S(O) 0-2 , and 4-9 are ring carbon atoms, each independently selected from: C, CH, CH2, CR 1 , CHR 1 , C(R 1 2.CR 3 , CHR 3 and C(R 3 )2, the condition is that ring A 3A It is non-aromatic.

63. A compound as described in any one of claims 56-57, wherein Ring A 3A is a bicyclic ring (eg, a spirobicyclic ring) containing 7-9 (eg, 8) ring atoms, wherein 0-2 (eg, 0 or 1, eg, 1) ring atoms are cumulatively selected for Y 4 wherein each heteroatom is independently selected from the group consisting of N, N(H), N(R d ) and O, and 4-9 are ring carbon atoms, each independently selected from: C, CH2, CHR 1 , C(R 1 2. CHR 3 and C(R 3 )2, the condition is that ring A 3A It is non-aromatic.

64. A compound as described in any one of claims 56-57 and 61-63, wherein A is: wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

65. A compound as described in any one of claims 56 to 64, wherein X 1 Selected from: NH, N(R 2 ), O and S.

66. A compound as described in any one of claims 56 to 65, wherein X 1 It's NH.

67. A compound as described in any one of claims 56 to 66, wherein X 2 Selected from: N, CH and CR 1 .

68. A compound as described in any one of claims 56-67, wherein X 2 It is CH.

69. A compound as described in any one of claims 56-59 and 65-68, wherein A is: wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

70. A compound as described in any one of claims 56-57, 61-64 and 65-68, wherein A is: wherein m1=0, 1 or 2; and m3=0, 1 or 2 (eg, m1=0 or 1; and m3=0 or 1).

71. The compound of claim 1, wherein A is a heteroaryl group containing 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O, S and S(O)2, and wherein 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 and CR 3 , provided that at least one ring atom is R 1 replace.

72. The compound of claim 71, wherein A is a heteroaryl group containing 5 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 )、N(R 2 ), O and S, and wherein 1-4 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 and CR 3. , provided that at least one ring atom is R 1 replace.

73. A compound as described in any one of claims 71-72, wherein A is a heteroaryl group containing 5 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R 1 ),N(R 2 ), O and S, and wherein 1-4 ring atoms are carbon atoms, each independently selected from the group consisting of C, CH, CR 1 and CR 3 , provided that a ring atom is occupied by 1-2 (e.g., 1) R 1 replace.

74. A compound as described in any one of claims 1 and 71-73, wherein A is (A-4): in: Z 2 Selected from: CH, R 2 and N; X 3 Selected from: O, S, N, NH, NR 1 NR 2 , CH, CR 1 and CR 3 ; Y 5 and Y 6 Each independently selected from O, S, CH, CR 1 , CR 3 NR 1 NR 2 , NH and N; and Each are independently single bonds or double bonds, provided that Y 5 , Y 6 , X 3 and Z 2 The five-membered ring of is a heteroaryl group.

75. The compound of claim 74, wherein: When X 3 YesNR 1 or CR 1 When Y 5 and Y 6 Each independently selected from O, S, CH, CR 1 , CR 3 NR 1 NR 2 , NH and N; and When X 3 Selected from O, S, N, NH, NR 2 , CH and CR 3 When Y 5 and Y 6 One of them is CR 1 or NR 1 (In some embodiments, Y 5 and Y 6 The other one is selected from O, S, CH, CR 3 NR 2 , NH and N).

76. A compound as described in any one of claims 74-75, wherein Z 2 is selected from CH and N.

77. A compound as described in any one of claims 74-76, wherein Z 2 It is CH.

78. A compound as described in any one of claims 74-77, wherein Y 6 Selected from: N, CH and CR 3 .

79. A compound as described in any one of claims 74-78, wherein Y 6 It is N.

80. A compound as described in any one of claims 74-79, wherein Y 5 Yes CR 1 ..

81. A compound as described in any one of claims 74-80, wherein X 3 Selected from: S, O, NH and N(R 2 ).

82. A compound as described in any one of claims 74-81, wherein A is selected from:

83. The compound of claim 82, wherein A is 84. The compound of claim 82, wherein A is 85. A compound as described in any one of claims 74-76, wherein Z 2 It is N.

86. A compound as described in any one of claims 74-76 and 85, wherein Y 6 Selected from: N, CH and CR 3 .

87. A compound as described in any one of claims 74-76 and 85-56, wherein Y 6 is CH.

88. A compound as described in any one of claims 74-76 and 85-87, wherein Y 5 Yes CR 1 .

89. A compound as described in any one of claims 74-76 and 85-88, wherein X 3 Selected from: O, S, NH and NR 2 .

90. A compound as described in any one of claims 74-76 and 85-89, wherein A is selected from:

91. The compound of claim 90, wherein A is 92. A compound as described in any one of claims 1 to 91, wherein Each occurrence of R 1 Independently selected from: (i)-(U 1 ) q -U 2 , in which: q is 0 or 1; ●U 1 It is C 1-6 Alkylene, which is optionally substituted by 1 to 6 R a Replacement; and ●U 2 yes: (a)C 3-10 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace, (b)C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace; (c) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl ring is optionally replaced by 1-4 independently selected R c Replace, or (d) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace, and (ii)C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

93. A compound as described in any one of claims 1 to 92, wherein R 1 Yes-(U 1 ) q -U 2 .

94. A compound as described in any one of claims 1 to 93, wherein q is 0.

95. A compound as described in any one of claims 1 to 94, wherein U 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace.

96. The compound of any one of claims 1 to 95, wherein U 2 It is C 6-10 Aryl, which is optionally substituted by 1-2 R c replace.

97. A compound as described in any one of claims 1 to 96, wherein U 4 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c replace.

98. A compound as described in any one of claims 1 to 94, wherein U 2 is a heteroaryl group containing 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring is optionally replaced by 1-4 independently selected R c replace.

99. A compound as described in any one of claims 1-94 and 98, wherein U 2 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c replace.

100. The compound of any one of claims 1-94 and 98-99, wherein U 2 is a heteroaryl group containing 6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c replace.

101. The compound of claim 100, wherein U 4 is pyridinyl (eg, 2-pyridinyl) or pyrimidinyl (2-pyrimidinyl), each of which is optionally substituted by 1-2 independently selected R c (e.g., unsubstituted) substituted.

102. A compound as described in any one of claims 95-101, wherein Every time U appears 2 R c The substituents are selected from: (a) halogen (e.g., Cl, F); (b) cyano; (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace; (f)C 1-4 Haloalkyl; (g)C 1-4 Alkoxy; (h)C 1-4 haloalkoxy; and (m)-C 1-4 Thioalkoxy.

103. A compound as described in any one of claims 95-102, wherein Every time U appears 2 R c The substituents are selected from: halogen (e.g., Cl, F; e.g., F), cyano, C 1-6 Alkyl and C 1-4 Halogenated alkyl.

104. A compound as described in any one of claims 95-103, wherein Every time U appears 2 R c The substituents are selected from halogen (eg, Cl, F; eg, F).

105. A compound as described in any one of claims 1 to 94, wherein U 2 is a heterocyclic group containing 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace.

106. A compound as described in any one of claims 1-94 and 105, wherein U 2 is a heterocyclic group containing 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace.

107. A compound as described in any one of claims 1-94 and 105-106, wherein U 2 is a heterocyclic group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b replace.

108. A compound as described in any one of claims 1-94 and 105-107, wherein U 2 is a heterocyclic group containing 5 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by an independently selected R b (For example, U 2 is tetrahydrofuranyl).

109. A compound as described in any one of claims 93-97, wherein R 1 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c replace.

110. The compound of claim 109, wherein Each R c As defined in any one of claims 102-104.

111. A compound as described in any one of claims 93-94 and 98-99, wherein R 1 is a heteroaryl group containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally substituted by 1-2 independently selected R c (For example, R 1 is substituted with pyridyl, such as 2-pyridyl, or pyrimidinyl, such as 2-pyrimidinyl).

112. The compound of claim 96, wherein Each R c As defined in any one of claims 102-104.

113. A compound as described in any one of claims 1 to 92, wherein R 1 It is C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

114. A compound as described in any one of claims 1-92 and 113, wherein R 1 It is C 1-6 Alkyl, which is optionally substituted by 1-4 independently selected R a replace.

115. A compound as described in any one of claims 1-92 and 113-114, wherein R 1 It is C 1-3 Alkyl, which is optionally substituted by 1-4 independently selected R a replace.

116. A compound as described in any one of claims 1-92 and 113-115, wherein R 1 It is C 1-3 Alkyl, which is optionally substituted with 1-3 (e.g., 1, 2 or 3) independently selected R a replace.

117. A compound as described in any one of claims 1-92 and 113-116, wherein Each occurrence of R 1 R a The substituents are independently selected from: -OH; -F; -Cl; -NR e R f ; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); cyano; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution.

118. A compound as described in any one of claims 1-92 and 113-117, wherein Each occurrence of R 1 R a The substituents are independently selected from: -OH; -F; -Cl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)OH, and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution.

119. A compound as described in any one of claims 1-92 and 113-118, wherein Each occurrence of R 1 R a The substituents are independently selected from: -F and -C(=O)OH.

120. The compound of any one of claims 113-119, wherein R 1 It is CF3 or CH2CO2H.

121. A compound as described in any one of claims 1 to 120, wherein Each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, 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, -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

122. A compound as described in any one of claims 1 to 121, wherein Each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -S(O) 1-2 (C 1-4 Alkyl), -S(O) 1-2 (NR'R"), -C(=O)(C 1-4 alkyl), -C(=O)O(C 1-4 alkyl), -C(=O)OH and -C(=O)N(R')(R").

123. A compound as described in any one of claims 1 to 122, wherein Each occurrence of R 3 Independently selected from the group consisting of halogen, cyano, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

124. A compound as described in any one of claims 1 to 123, wherein Each occurrence of R 2 Independently selected from: (i)C 1-6 Alkyl (e.g., methyl); (ii)C 3-6 Cycloalkyl; (iv)-C(O)(C 1-4 alkyl) (e.g., C(O)Me); (v) -C(O)O(C 1-4 alkyl); (vi) -CON(R')(R'); (vii)-S(O) 1-2 (NR'R"); and (viii)-S(O) 1-2 (C 1-4 alkyl) (e.g., S(O)2Me).

125. A compound as described in any one of claims 12, 16, 17 and 24, wherein m1＝1。 126. The compound of claim 125, wherein m3＝0。 127. A compound as described in any one of claims 125-126, wherein R 1 As defined in any one of claims 93-104 and 109-112.

128. A compound as described in any one of claims 125-126, wherein R 1 As defined in any one of claims 93-94 and 105-108.

129. A compound as described in any one of claims 125-126, wherein R 1 As defined in any one of claims 113 to 120.

130. A compound as described in any one of claims 12, 16, 17 and 24, wherein m1=0; and m3=0.

131. The compound of claim 28, wherein m1=1; and m3=0.

132. A compound as described in any one of claims 28-29 and 131, wherein R 1 As defined in any one of claims 93-104 and 109-112.

133. A compound as described in any one of claims 28-29 and 131, wherein R 1 As defined in any one of claims 93-94 and 105-108.

134. A compound as described in any one of claims 28-29 and 131, wherein R 1 As defined in any one of claims 113 to 120.

135. A compound as described in any one of claims 37-41, wherein m1＝1。 136. The compound of claim 135, wherein m3=0.

137. A compound as described in any one of claims 135-136, wherein R 1 As defined in any one of claims 93-104 and 109-112.

138. A compound as described in any one of claims 135-136, wherein R 1 As defined in any one of claims 93-104 and 105-108.

139. The compound of any one of claims 135-136, wherein R 1 As defined in any one of claims 113 to 120.

140. The compound of any one of claims 37-41, wherein m1=0; and m3=0.

141. A compound as described in any one of claims 60, 64 and 69-70, wherein m1＝1。 142. A compound as described in any one of claims 60, 64, 69-70 and 141, wherein R 1 As defined in any one of claims 93-104 and 109-112.

143. A compound as described in any one of claims 60, 64, 69-70 and 141, wherein R 1 As defined in any one of claims 93-94 and 105-108.

144. A compound as described in any one of claims 60, 64, 69-70 and 141, wherein R 1 As defined in any one of claims 113 to 120.

145. A compound as described in any one of claims 60, 64 and 69-70, wherein m1=0; and m3=0.

146. A compound as described in any one of claims 82-84 and 90-91, wherein R 1 As defined in any one of claims 93-104 and 109-112.

147. A compound as described in any one of claims 82-84 and 90-91, wherein R 1 As defined in any one of claims 93-94 and 105-108.

148. A compound as described in any one of claims 82-84 and 90-91, wherein R 1 As defined in any one of claims 113 to 120.

149. A compound as described in any one of claims 12, 16, 17, 24 and 37-41, wherein m3=1 or 2.

150. The compound of claim 149, wherein m1 = 0.

151. A compound as described in any one of claims 149-150, wherein Each occurrence of R 3 Independently as defined in any one of claims 121-123.

152. A compound as described in any one of claims 54-55, wherein m1＝0。 153. The compound of claim 152, wherein m3=0 or 1 (eg, 0).

154. A compound as described in any one of claims 1 to 153, wherein B and each occurrence of R N According to (A) definition.

155. A compound as described in any one of claims 1-154, wherein B is c Substituted phenyl.

156. A compound as described in any one of claims 1 to 155, wherein B is 1-2 R c Substituted phenyl, 1-2 R c In formula I, -S(O)(=N(R N )2)-part of the ring carbon at the para or meta position (e.g., an R c The ring carbon is located in the para position).

157. A compound as described in any one of claims 1 to 154, wherein B is a heteroaryl group containing 5-20 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring is optionally replaced by 1-4 independently selected R c replace.

158. A compound as described in any one of claims 1-154 and 157, wherein B is a heteroaryl group containing 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally substituted by 1-3 independently selected R c replace.

159. A compound as described in any one of claims 1-154 and 157-158, wherein B is a heteroaryl group containing 5 ring atoms, wherein 1-3 (e.g., 2) of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally substituted by 1-3 independently selected R c replace.

160. The compound of any one of claims 1-154 and 157-159, wherein B is pyrazolyl or imidazolyl, each of which is optionally substituted with 1-2 independently selected R c replace.

161. A compound as described in any one of claims 1-154 and 157-158, wherein B is a heteroaryl group containing 6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c replace.

162. A compound as described in any one of claims 1-154, 157-158 and 161, wherein B is pyridyl (eg, 2-pyridyl, 3-pyridyl, and 4-pyridyl), optionally substituted with 1-2 independently selected R c replace.

163. A compound as described in any one of claims 1-154 and 157, wherein B is a heteroaryl group containing 9-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring is optionally replaced by 1-3 independently selected R c replace.

164. A compound as described in any one of claims 1-154, 157 and 163, wherein B is a tricyclic heteroaryl group containing 12-15 (e.g., 13) ring atoms, wherein 1-3 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring is optionally replaced by 1-3 independently selected R c replace.

165. A compound as described in any one of claims 1-154, 157 and 163-164, wherein B is which is optionally replaced by 1-2 independently selected R c replace.

166. A compound as described in any one of claims 155-165, wherein Each occurrence of R on B c The substituents are selected from: (a) halogen; (b) cyano; (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace; (g)C 1-4 Alkoxy; (h)C 1-4 Haloalkoxy; (i)-S(O) 1-2 (C 1-4 alkyl); (m)-C 1-4 Thioalkoxy; (o)-C(=O)(C 1-4 alkyl); (p)-C(=O)O(C 1-4 alkyl); (r)-C(═O)N(R′)(R″); and (s)-L 1 -L 2 -R h 。 167. A compound as described in any one of claims 155-166, wherein Each occurrence of R on B c The substituents are selected from: (a) halogen; (b) cyano; (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace; (g)C 1-4 Alkoxy; (h)C 1-4 haloalkoxy; and (s)-L 1 -L 2 -R h 。 168. A compound as described in any one of claims 155-167, wherein Each occurrence of R on B c The substituents are selected from: (a) halogen; (c)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a Replacement; and (s)-L 1 -L 2 -R h 。 169. A compound as described in any one of claims 155-168, wherein One occurrence of R c It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

170. The compound of any one of claims 155-169, wherein One occurrence of R c It is C 1-3 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

171. The compound of claims 169-170, wherein Each occurrence of R a Independently selected from: -F; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy.

172. A compound as described in any one of claims 169-171, wherein R c CF3 or (For example, R c Can be CF3).

173. The compound of claim 169, wherein R c is unsubstituted C 1-10 (For example, unsubstituted C 1-6 (For example, C 1-3 )alkyl.

174. A compound as described in any one of claims 155-168, wherein one occurrence of R c Yes-L 1 -L 2 -R h .

175. The compound of claim 174, wherein -L 1 is the key.

176. The compound of claim 174, wherein -L 1 It is C 1-3 Alkylene.

177. A compound as described in any one of claims 174-176, wherein -L 2 is the key.

178. A compound as described in any one of claims 174-176, wherein -L 2 It's –O-.

179. The compound of claim 174, wherein -L 1 is the key; and –L 2 is the key.

180. The compound of claim 174, wherein -L 1 is the key; and –L 2 It's –O-.

181. The compound of claim 174, wherein -L 1 It is C 1-3 Alkylene; and –L 2 It's –O-.

182. A compound as described in any one of claims 174-181, wherein R h Selected from: C 3-8 Cycloalkyl, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl and C 1-4 haloalkyl, provided that when R h is optionally 1-4 independently selected C 1-4 Alkyl substituted C 3-6 When cycloalkyl, -L 1 is key, or -L 2 is –O-, -N(H)-, or -S-; and C 6-10 Aryl, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

183. A compound as described in any one of claims 174-182, wherein R h Selected from: C 6-8 Cycloalkyl, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl and C 1-4 haloalkyl, provided that when R h is optionally 1-4 independently selected C 1-4 Alkyl substituted C 3-6 When cycloalkyl, -L 1 is key, or -L 2 is –O-, -N(H)-, or -S-; and Phenyl, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

184. A compound as described in any one of claims 174-183, wherein One occurrence of R c Selected from:

185. A compound as described in any one of claims 155-168, wherein One occurrence of R c is unsubstituted C 1-3 alkyl.

186. A compound as described in any one of claims 155-168, wherein One occurrence of R c is a halogen (eg, -F or -Cl).

187. A compound as described in any one of claims 169-186, wherein The second occurrence of R c When present is independently halogen.

188. A compound as described in any one of claims 1 to 154, wherein B is C 3-20 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace.

189. The compound of any one of claims 1-154 and 188, wherein B is C 3-12 Cycloalkyl, which is optionally substituted by 1-2 R b replace.

190. A compound as described in any one of claims 1-154 and 188-188, wherein B is C 6-12 Cycloalkyl, which is optionally substituted by 1-2 R b replace.

191. A compound as described in any one of claims 1-154 and 188-190, wherein B is C 6-12 Cycloalkyl (for example, B can be ).

192. A compound as described in any one of claims 1 to 154, wherein B is a heterocyclic group containing 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace.

193. A compound as described in any one of claims 1-154 and 192, wherein B is a heterocyclic group containing 3-12 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b replace.

194. A compound as described in any one of claims 1-154 and 192-193, wherein U 2 is a heterocyclic group containing 3-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b Substitution (for example, B can be It is further optionally represented by 1 R b replace).

195. A compound as described in any one of claims 1-154 and 192-193, wherein B is a heterocyclic group containing 7-12 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b Substitution (for example, B can be Each of which is further optionally represented by 1 R b replace).

196. A compound as described in any one of claims 188-195, wherein Each occurrence of R b Independently selected from the following group: C 1-10 Alkyl; C 1-4 Haloalkyl; –OH; oxo; -F; -Cl; –NR e R f ; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)(C 1-4 alkyl); -C(=O)O(C 1-4 Alkyl); -S(O) 1-2 (C 1-4 alkyl); cyano; and -L 1 -L 2 -R h .

197. A compound as described in any one of claims 188-196, wherein Each occurrence of R b Independently selected from: C 1-10 Alkyl; C 1-4 Haloalkyl; -F; C 1-4 Alkoxy; C 1-4 Haloalkoxy; and -L 1 -L 2 -R h .

198. A compound as described in any one of claims 188-197, wherein Each occurrence of R b Independently selected from the following group: C 1-10 Alkyl; C 1-4 haloalkyl; -F; and -L 1 -L 2 -R h .

199. A compound as described in any one of claims 188-198, wherein Each occurrence of R b Independently -L 1 -L 2 -R h .

200. The compound of claim 199, wherein -L 1 is the key; and –L 2 is the key.

201. A compound as described in any one of claims 199-200, wherein R h It is C 6-10 Aryl, which is optionally substituted by 1-4 (eg, 1-2, eg, 1) substituents independently selected from the group consisting of halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

202. A compound as described in any one of claims 1-154, wherein B is in: n1 = 0 or 1; and R cA and R cB Each is independently selected R c .

203. The compound of claim 202, wherein R cB is R as defined in any one of claims 169 to 172 c (For example, R cA Can be CF3).

204. The compound of claim 202, wherein R cB is R as defined in any one of claims 174 to 184 c .

205. The compound of claim 202, wherein R cB is unsubstituted C 1-10 Alkyl (e.g., C 1-3 alkyl).

206. The compound of claim 202, wherein R cB It's a halogen.

207. A compound as described in any one of claims 202-206, wherein n1 is 0.

208. A compound as described in any one of claims 202-207, wherein n1 is 1; and R cA It's a halogen.

209. The compound of any one of claims 1-154, wherein B is a heteroaryl group containing 6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c Replacement; and R c As defined in any one of claims 169-173 (e.g., R c Can be CF3).

210. The compound of any one of claims 1 to 154, wherein B is a heteroaryl group containing 6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c Replacement; and R c As defined in any one of claims 174 to 184.

211. A compound as described in any one of claims 1 to 154, wherein B is a heteroaryl group containing 5 ring atoms, wherein 1-3 (e.g., 2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c Replacement; and R c As defined in any one of claims 174 to 184.

212. The compound of claim 211, wherein B is pyrazolyl or imidazolyl, each of which is optionally substituted with 1-2 independently selected R c replace.

213. A compound as described in any one of claims 211-212, wherein one occurrence of R c Yes-L 1 -L 2 -R h ; where -L 1 is a key; and / or –L 2 is the key.

214. A compound as described in any one of claims 1 to 213, wherein Each R N Independently selected from: (i) H, (ii)C 1-6 Alkyl, optionally with 1-3 R a replace, (iii)C 3-6 Cycloalkyl, optionally substituted with 1-2 R a replace, (iv)-C(O)(C 1-4 alkyl), and (v) -C(O)O(C 1-4 alkyl).

215. A compound as described in any one of claims 1 to 214, wherein One occurrence of R N It's H.

216. The compound of claim 215, wherein The second occurrence of R N It's H.

217. The compound of claim 215, wherein The second occurrence of R N Selected from: (ii)C 1-6 Alkyl, optionally with 1-3 R a replace, (iii)C 3-6 Cycloalkyl, optionally substituted with 1-2 R a replace, (iv)-C(O)(C 1-4 alkyl), and (v) -C(O)O(C 1-4 alkyl).

218. The compound of claim 217, wherein The second occurrence of R N It is C 1-6 Alkyl, optionally with 1-3 R a (e.g., 1-2, e.g., 1) substitutions.

219. The compound of claim 218, wherein Each occurrence of R a Selected from C 1-4 Alkoxy, C 3-6 Cycloalkyl and hydroxy.

220. The compound of claim 217, wherein The second occurrence of R N Yes -C(O)O(C 1-4 alkyl) (e.g., -C(O)Me).

221. The compound of claim 217, wherein The second occurrence of R N is unsubstituted C 1-6 alkyl.

222. The compound of any one of claims 1 to 214, wherein One occurrence of R N It is C 1-6 alkyl.

223. The compound of claim 222, wherein The second occurrence of R N Select from the following group: (ii)C 1-6 Alkyl, optionally with 1-3 R a replace, (iii)C 3-6 Cycloalkyl, optionally substituted with 1-2 R a replace, (iv)-C(O)(C 1-4 alkyl), and (v) -C(O)O(C 1-4 alkyl).

224. A compound as described in any one of claims 222-223, wherein The second occurrence of R N It is C 1-6 alkyl.

225. The compound of any one of claims 222-224, wherein The second occurrence of R N It is C 1-3 alkyl.

226. The compound of any one of claims 1 to 154, wherein B and each occurrence of R N According to (B) definition.

227. The compound of any one of claims 1-154 and 226, wherein B and an R N Together with the atoms to which they are attached, they form a ring containing 5-15 ring atoms, wherein the ring contains: (a) 0-4 ring heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 (Except for the above (a) 2 to 12 ring carbon atoms, each of which is optionally substituted with 1 to 2 substituents independently selected from the following: (i) H; (ii) oxo; (iii) halogen; (iv) hydroxyl group; (v)C 1-6 alkyl; (vi)C 1-6 Haloalkyl; (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c replace; (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace; (ix) a heterocyclic group containing 3 to 16 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-4 independently selected R b Replacement; and (x)C 3-20 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace.

228. A compound as described in any one of claims 1-154 and 226-227, wherein B and an R N Together with the atoms to which they are attached, they form a ring containing 5-15 ring atoms, wherein the ring contains: (a) 0-4 ring heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 (Except for the moiety) and (b) 2 to 12 ring carbon atoms, each of which is optionally substituted with 1 to 2 substituents independently selected from the following: (i) H; (ii) oxo; (iii) halogen; (iv) hydroxyl group; (v)C 1-6 alkyl; (vi)C 1-6 Haloalkyl; (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c Replacement; and (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

229. A compound as described in any one of claims 1-154 and 226-228, wherein B and an R N Together with the atoms to which they are attached, they form a ring containing 8-15 ring atoms, wherein the ring contains: (a) 0-4 ring heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 (Except for the above (a) 2 to 12 ring carbon atoms, each of which is optionally substituted with 1 to 2 substituents independently selected from the following: (i) H; (ii) oxo; (iii) halogen; (iv) hydroxyl group; (v)C 1-6 Alkyl; and (vi)C 1-6 Halogenated alkyl.

230. The compound of any one of claims 1-154 and 226-229, wherein B and an R N Together with the atoms they are connected to form: It is optionally substituted with 1 to 3 substituents independently selected from the following: (ii) oxo; (iii) halogen; (iv) hydroxyl group; (v)C 1-6 Alkyl; and (vi)C 1-6 Halogenated alkyl.

231. The compound of claim 230, wherein B and an R N Together with the atoms they are connected to form: It is further optionally substituted by 1-2 substituents independently selected from the following: (ii) oxo; (v)C 1-6 Alkyl; and (vi)C 1-6 Halogenated alkyl.

232. A compound as described in any one of claims 1-154 and 226-227, wherein B and an R N Together with the atoms to which they are attached, they form a ring containing 5-7 ring atoms, wherein the ring contains: (a) 0-4 ring heteroatoms, each independently selected from N, N(H), N(R d ), O and S(O) 0-2 (Except for the above (a) 2 to 3 ring carbon atoms, each of which is optionally substituted by 1 to 2 substituents independently selected from the following: (i) H; (ii) oxo; (iii) halogen; (iv) hydroxyl group; (v)C 1-6 alkyl; (vi)C 1-6 Haloalkyl; (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c Replacement; and (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

233. A compound as described in any one of claims 1-154, 226-227 and 232, wherein B and an R N Together with the atoms they are connected to form: It is optionally substituted by 1 to 3 substituents independently selected from the following: (ii) oxo; (iii) halogen; (iv) hydroxyl; and (v) C 1-6 alkyl; Among them, Ar N Selected from: (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c Replacement; and (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c Substitution (e.g., Ar N It is C 6-10 Aryl, optionally substituted with 1-2 R c Substitution (e.g., R c It can be a halogenated alkyl group, such as CF3)).

234. A compound as described in any one of claims 226-233, wherein The second occurrence of R N It's hydrogen.

235. The compound of any one of claims 1 to 234, wherein W is O.

236. The compound of claim 1, wherein The compound has formula (I-1): Where n1 = 0 or 1; and R cA and R cB Each is independently selected R c .

237. The compound of claim 236, wherein A is (A-1) as defined in claim 6.

238. A compound as described in any one of claims 236-237, wherein A As defined in claim 37.

239. The compound of any one of claims 236-237, wherein A is defined in any one of claims 38-39.

240. The compound of any one of claims 236-237, wherein A is as defined in claim 40.

241. A compound as described in any one of claims 236-237, wherein A is defined in any one of claims 41-42.

242. The compound of claim 236, wherein A is (A-2) as defined in claim 45.

243. A compound as described in any one of claims 236 and 242, wherein A is defined in any one of claims 54-55.

244. The compound of claim 236, wherein A is (A-3) as defined in claim 56.

245. The compound of any one of claims 236 and 244, wherein A is defined in any one of claims 60, 64 and 69-70.

246. The compound of claim 236, wherein A is (A-4) as defined in claim 74.

247. The compound of any one of claims 236 and 244, wherein A is defined in any one of claims 82-84.

248. The compound of any one of claims 236 and 244, wherein A is defined in any one of claims 90-91.

249. A compound as described in any one of claims 236-248, wherein Each R 1 As defined in any one of claims 92 to 120.

250. The compound of any one of claims 236-249, wherein Each R 3 As defined in any one of claims 121 to 123.

251. A compound as described in any one of claims 236-250, wherein R cB is R as defined in any one of claims 169 to 172 c (For example, R cB Can be CF3).

252. A compound as described in any one of claims 236-250, wherein R cB is R as defined in any one of claims 174 to 184 c .

253. A compound as described in any one of claims 236-250, wherein R cB YesR c is unsubstituted C 1-6 Alkyl (e.g., C 1-3 alkyl).

254. A compound as described in any one of claims 236-250, wherein R cB It's a halogen.

255. A compound as described in any one of claims 236-254, wherein n1＝0。 256. A compound as described in any one of claims 236-255, wherein Each R N As defined in any of claims 214-225.

257. A compound as described in any one of claims 236-255, wherein R N It's H.

258. The compound of claim 1, wherein The compound has formula (I-2): Wherein B2 is selected from: a) a heteroaryl group containing from 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl ring is optionally substituted by 1-2 independently selected R c Replacement; and b) a heteroaryl group containing from 5 ring atoms, wherein 1 to 3 (e.g., 2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and wherein the heteroaryl ring is optionally substituted by 1-2 independently selected R c replace.

259. The compound of claim 258, wherein B 2 is a heteroaryl group containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c Replacement; and R c As defined in any one of claims 147-150 (e.g., R c Can be CF3).

260. The compound of claim 258, wherein B 2 is a heteroaryl group (e.g., pyrazolyl or imidazolyl) containing 5 ring atoms, wherein 1-3 (e.g., 2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S, and wherein the heteroaryl ring is optionally replaced by 1-2 independently selected R c Replacement; and R c As defined in any one of claims 151 to 161.

261. A compound as described in any one of claims 258-260, wherein A is (A-1) as defined in claim 6.

262. A compound as described in any one of claims 258-261, wherein A As defined in claim 37.

263. A compound as described in any one of claims 258-261, wherein A is defined in any one of claims 38-39.

264. A compound as described in any one of claims 258-261, wherein A is as defined in claim 40.

265. A compound as described in any one of claims 258-261, wherein A is defined in any one of claims 41-42.

266. A compound as described in any one of claims 258-265, wherein Each R 1 As defined in any one of claims 92 to 120.

267. A compound as described in any one of claims 258-266, wherein Each R 3 As defined in any one of claims 121 to 123.

268. A compound as described in any one of claims 258-267, wherein Each R N As defined in any of claims 214-225.

269. A compound as described in any one of claims 258-267, wherein R N It's H.

270. The compound of claim 1, wherein The compound has formula (I-3): Among them B 3 Selected from: a)C 6-12 Cycloalkyl, which is optionally substituted by 1-2 R b replace; b) a heterocyclic group containing 3 to 6 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b Replacement; and c) a heterocyclic group containing 7 to 12 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b replace.

271. The compound of claim 270, wherein B 3 It is C 6-12 Cycloalkyl, which is optionally substituted with one R b replace.

272. The compound of claim 270, wherein B 3 is a heterocyclic group containing 3-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b Replace; one occurrence of R b As defined in claims 196-201.

273. The compound of claim 270, wherein B 3 is a heterocyclic group containing 7-12 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl ring is optionally replaced by 1-2 independently selected R b replace.

274. The compound of any one of claims 273, wherein B 3 is unsubstituted.

275. The compound of any one of claims 270-274, wherein A is (A-1) as defined in claim 6.

276. The compound of any one of claims 270-275, wherein A As defined in claim 37.

277. The compound of any one of claims 270-275, wherein A is defined in any one of claims 38-39.

278. The compound of any one of claims 270-275, wherein A is as defined in claim 40.

279. The compound of any one of claims 270-275, wherein A is defined in any one of claims 41-42.

280. The compound of any one of claims 270-274, wherein A is (A-4) as defined in claim 74.

281. A compound as described in any one of claims 270-274 and 280, wherein A is as defined in claims 82-84.

282. A compound as described in any one of claims 270-274 and 280-281, wherein A is as defined in claims 90-91.

283. A compound as described in any one of claims 270-282, wherein Each R 1 As defined in any one of claims 92 to 120.

284. A compound as described in any one of claims 270-283, wherein Each R 3 As defined in any one of claims 121 to 123.

285. A compound as described in any one of claims 270-284, wherein Each R N As defined in any of claims 214-225.

286. A compound as described in any one of claims 270-285, wherein R N It's H.

287. The compound of claim 1, wherein A is (A-1) as defined in claim 6; and B is (B) as defined in claim 1.

288. The compound of claim 287, wherein A is as defined in claim 37.

289. The compound of claim 287, wherein A is defined in any one of claims 38-39.

290. The compound of claim 287, wherein A is as defined in claim 40.

291. The compound of claim 287, wherein A is defined in any one of claims 41-42.

292. A compound as described in any one of claims 287-291, wherein B and an R N Together with the atoms they are connected to form: It is optionally substituted with 1 to 3 substituents independently selected from the following: (ii) oxo; (iii) halogen; (iv) hydroxyl group; (v)C 1-6 Alkyl; and (vi)C 1-6 Halogenated alkyl.

293. A compound as described in any one of claims 287-291, wherein B and an R N Together with the atoms they are connected to form: It is optionally substituted by 1 to 3 substituents independently selected from the following: (ii) oxo; (iii) halogen; (iv) hydroxyl; and (v) C 1-6 alkyl; Among them, Ar N Selected from: (vii)C 6-10 Aryl, which is optionally substituted by 1 to 3 R c Replacement; and (viii) a heteroaryl group containing 5 to 20 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

294. A compound as described in any one of claims 287-293, wherein Each R1 is as defined in any one of claims 92-120.

295. A compound as described in any one of claims 287-294, wherein Each R3 is defined as in any one of claims 121-123.

296. The compound of claim 1, wherein The compound is selected from the group consisting of the compounds and pharmaceutically acceptable salts thereof described in the following table:

297. The compound of any one of claims 1 to 296, wherein Said (R N The sulfur atom in the )2NS(O)(=N)- moiety has a (S) stereochemistry.

298. A compound as described in any one of claims 1 to 296, wherein Said (R N The sulfur atom in the )2NS(O)(=N)- moiety has a (R) stereochemistry.

299. A pharmaceutical composition comprising a compound as described in any one of claims 1-296 and one or more pharmaceutically acceptable excipients.

300. A method of inhibiting STING activity, the method comprising contacting STING with a compound as described in any one of claims 1-298 or a pharmaceutical composition as described in claim 299.

301. The method of claim 300, wherein: The inhibition comprises antagonizing STING.

302. The method of any one of claims 300-301, wherein the method is performed in vitro.

303. The method of claim 302, wherein: The method comprises contacting a sample comprising one or more cells containing STING with the compound.

304. The method of claim 303, wherein: The one or more cells are one or more cancer cells.

305. The method of claim 303 or 304, wherein: The sample also comprises one or more cancer cells (e.g., the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma).

306. The method of claim 300, wherein the method is performed in vivo.

307. The method of claim 306, wherein: The methods include administering the compound to a subject having a disease in which increased (eg, excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease.

308. The method of claim 307, wherein: The subject is a human being.

309. The method of claim 307, wherein the disease is cancer.

310. The method of claim 309, wherein: The cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor or hepatocellular carcinoma.

311. The method of claim 309 or 310, wherein: The cancer is a refractory cancer.

312. The method of claim 307, wherein: The compounds are administered in combination with one or more additional cancer therapies.

313. The method of claim 312, wherein: The one or more additional cancer therapies include: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

314. The method of claim 313, wherein: The chemotherapy includes the administration of one or more other chemotherapeutic agents.

315. The method of claim 314, wherein: The one or more other chemotherapeutic agents are selected from: alkylating agents (e.g., cisplatin, carboplatin, nitrogen mustard, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); antimetabolites (e.g., azathioprine and / or mercaptopurine); terpenoids (e.g., vinca alkaloids and / or taxanes; e.g., vincristine, vinblastine, vinorelbine and / or vindesine, taxol, paclitaxel and / or docetaxel); topoisomerases (e.g., type I topoisomerases and / or type 2 topoisomerases; e.g., camptothecins, e.g., irinotecan and / or topotecan; amazon oxazolidinone, etoposide, etoposide phosphate and / or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); hormones (e.g., luteinizing hormone-releasing hormone agonists; e.g., leuprolide, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, alizumab, basiliximab, belimumab, bevacizumab, monoclonal antibody, brentuximab, canakinumab, cetuximab, becerolizumab, daclizumab, denosumab, eculizumab, efavirenz, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofavumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agent; cytokine; thrombotic agent; growth inhibitor; anti-creep agent insecticide; and immune checkpoint inhibitors targeting immune checkpoint receptors selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1–PD-L1, PD-1–PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T-cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB–4-1BB ligand, OX40–OX40 ligand, GITR, GITR ligand–GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25–TL1A, CD40L, CD40–CD40 ligand, HVEM–LIGHT–LTA, HVEM, HVEM–BTLA, HVEM–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, butyrophilin, including BTN L2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86–CD28, CD86–CTLA, CD80–CD28, CD39, CD73 adenosine–CD39–CD73, CXCR4–CXCL12, phosphatidylserine, TIM3, phosphatidylserine–TIM3, SIRPA–CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

316. The method of any one of claims 307-315, wherein: The compound is administered intratumorally.

317. A method of treating cancer comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1-298 or a pharmaceutical composition according to claim 299.

318. The method of claim 317, wherein: The cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor or hepatocellular carcinoma.

319. The method of claim 317 or 318, wherein: The cancer is a refractory cancer.

320. The method of claim 317, wherein: The compounds are administered in combination with one or more additional cancer therapies.

321. The method of claim 320, wherein: The one or more additional cancer therapies include: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

322. The method of claim 321, wherein: The chemotherapy includes the administration of one or more other chemotherapeutic agents.

323. The method of claim 322, wherein: The one or more other chemotherapeutic agents are selected from: alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); antimetabolites (e.g., azathioprine and / or mercaptopurine); terpenoids (e.g., vinca alkaloids and / or taxanes; e.g., vincristine, vinblastine, vinorelbine and / or vindesine, taxol, paclitaxel and / or docetaxel); topoisomerases (e.g., type I topoisomerases and / or type 2 topoisomerases; e.g., camptothecins, e.g., irinotecan and / or topotecan; amsacrine, etoposide, etoposide phosphate and / or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); hormones ( For example, luteinizing hormone-releasing hormone agonists; e.g., leuprolide, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, alizumab, basiliximab, belimumab, bevacizumab, brentuximab, canakinumab, cetuximab, beceretuzumab, daclizumab, denosumab, eculizumab); monoclonal antibody, efaizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofavumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agent; cytokine; thrombogenic agent; growth inhibitor; anthelmintic agent;and immune checkpoint inhibitors targeting immune checkpoint receptors selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1–PD-L1, PD-1–PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC Class II – LAG3, 4-1BB – 4-1BB ligand, OX40 – OX40 ligand, GITR, GITR ligand – GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25 – TL1A, CD40L, CD40 – CD40 ligand, HVEM – LIGHT – LTA, HVEM, HVEM – BTLA, HVEM – CD160, HVEM – LIGHT, HVEM – BTLA – CD160, CD80, CD80 – PDL-1, PDL2 – CD80, CD244, C D48–CD244, CD244, ICOS, ICOS–ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2–TMIGD2, butyrophilin including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86–CD28, CD86–CTLA, CD80–CD28, CD39, CD73 adenosine–CD39–CD73,; CXCR4–CXCL12, phosphatidylserine, TIM3, phosphatidylserine–TIM3, SIRPA–CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

324. The method of any one of claims 317-323, wherein: The compound is administered intratumorally.

325. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-298 or a pharmaceutical composition according to claim 299.

326. The method of claim 325, wherein: The subject suffers from cancer.

327. The method of claim 326, wherein: The subject has undergone and / or is undergoing and / or will undergo one or more cancer therapies.

328. The method of claim 326, wherein: The cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor or hepatocellular carcinoma.

329. The method of claim 328, wherein the cancer is a refractory cancer.

330. The method of claim 325, wherein: The immune response is an innate immune response.

331. The method of claim 327, wherein: The at least one or more additional cancer therapies include: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

332. The method of claim 331, wherein: The chemotherapy includes the administration of one or more other chemotherapeutic agents.

333. The method of claim 332, wherein: The one or more other chemotherapeutic agents are selected from: alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); antimetabolites (e.g., azathioprine and / or mercaptopurine); terpenoids (e.g., vinca alkaloids and / or taxanes; e.g., vincristine, vinblastine, vinorelbine and / or vindesine, taxol, paclitaxel and / or docetaxel); topoisomerases (e.g., type I topoisomerases and / or type 2 topoisomerases; e.g., camptothecins, e.g., irinotecan and / or topotecan; amsacrine, etoposide, etoposide phosphate and / or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); hormones ( For example, luteinizing hormone-releasing hormone agonists; e.g., leuprolide, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, alizumab, basiliximab, belimumab, bevacizumab, brentuximab, canakinumab, cetuximab, beceretuzumab, daclizumab, denosumab, eculizumab); monoclonal antibody, efaizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofavumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agent; cytokine; thrombogenic agent; growth inhibitor; anthelmintic agent;and immune checkpoint inhibitors targeting immune checkpoint receptors selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1–PD-L1, PD-1–PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC Class II – LAG3, 4-1BB – 4-1BB ligand, OX40 – OX40 ligand, GITR, GITR ligand – GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25 – TL1A, CD40L, CD40 – CD40 ligand, HVEM – LIGHT – LTA, HVEM, HVEM – BTLA, HVEM – CD160, HVEM – LIGHT, HVEM – BTLA – CD160, CD80, CD80 – PDL-1, PDL2 – CD80, CD244, C D48–CD244, CD244, ICOS, ICOS–ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2–TMIGD2, butyrophilin including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86–CD28, CD86–CTLA, CD80–CD28, CD39, CD73 adenosine–CD39–CD73,; CXCR4–CXCL12, phosphatidylserine, TIM3, phosphatidylserine–TIM3, SIRPA–CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

334. A method of treating a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease, the method comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1-298 or a pharmaceutical composition according to claim 299.

335. A method of treatment comprising administering to a subject having a disease in which increased (e.g., excessive) STING signaling leads to pathology and / or symptoms and / or progression of the disease an effective amount of a compound according to any one of claims 1-298 or a pharmaceutical composition according to claim 299.

336. A method of treatment comprising administering to a subject a compound according to any one of claims 1-298 or a pharmaceutical composition according to claim 299, wherein: The compound or composition is administered in an amount effective to treat a disease in which increased (eg, excessive) STING signaling contributes to the pathology and / or symptoms and / or progression of the disease, thereby treating the disease.

337. The method of any one of claims 334-336, wherein the disease is cancer.

338. The method of claim 337, wherein: The cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor or hepatocellular carcinoma.

339. The method of claim 337 or 338, wherein: The cancer is a refractory cancer.

340. The method of any one of claims 337-339, wherein: The compounds are administered in combination with one or more additional cancer therapies.

341. The method of claim 340, wherein: The one or more additional cancer therapies include: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

342. The method of claim 341, wherein: The chemotherapy includes the administration of one or more other chemotherapeutic agents.

343. The method of claim 342, wherein: The one or more other chemotherapeutic agents are selected from: alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and / or oxaliplatin); antimetabolites (e.g., azathioprine and / or mercaptopurine); terpenoids (e.g., vinca alkaloids and / or taxanes; e.g., vincristine, vinblastine, vinorelbine and / or vindesine, taxol, paclitaxel and / or docetaxel); topoisomerases (e.g., type I topoisomerases and / or type 2 topoisomerases; e.g., camptothecins, e.g., irinotecan and / or topotecan; amsacrine, etoposide, etoposide phosphate and / or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and / or mitomycin); hormones ( For example, luteinizing hormone-releasing hormone agonists; e.g., leuprolide, goserelin, triptorelin, histrelin, bicalutamide, flutamide and / or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, alizumab, basiliximab, belimumab, bevacizumab, brentuximab, canakinumab, cetuximab, beceretuzumab, daclizumab, denosumab, eculizumab); monoclonal antibody, efaizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofavumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab, tositumomab and / or trastuzumab); antiangiogenic agent; cytokine; thrombogenic agent; growth inhibitor; anthelmintic agent;and immune checkpoint inhibitors targeting immune checkpoint receptors selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1–PD-L1, PD-1–PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC Class II – LAG3, 4-1BB – 4-1BB ligand, OX40 – OX40 ligand, GITR, GITR ligand – GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25 – TL1A, CD40L, CD40 – CD40 ligand, HVEM – LIGHT – LTA, HVEM, HVEM – BTLA, HVEM – CD160, HVEM – LIGHT, HVEM – BTLA – CD160, CD80, CD80 – PDL-1, PDL2 – CD80, CD244, C D48–CD244, CD244, ICOS, ICOS–ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2–TMIGD2, butyrophilin including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86–CD28, CD86–CTLA, CD80–CD28, CD39, CD73 adenosine–CD39–CD73,; CXCR4–CXCL12, phosphatidylserine, TIM3, phosphatidylserine–TIM3, SIRPA–CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

344. The method of any one of claims 334-343, wherein: The compound is administered intratumorally.

345. A method of treating a disease, disorder or condition associated with STING, comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1-298 or a pharmaceutical composition according to claim 299.

346. The method of claim 345, wherein the disease, disorder or condition is selected from the group consisting of: type I interferonopathy, Acardi-Gutiérrez syndrome (AGS), hereditary forms of lupus, inflammation-related disorders, and rheumatoid arthritis.

347. The method of claim 346, wherein the disease, disorder or condition is a type I interferonopathy (eg, STING-associated vasculopathy of infancy (SAVI)).

348. The method of claim 347, wherein the Type I interferonopathy is STING-associated vasculopathy of infancy (SAVI).

349. The method of claim 346, wherein: The disease, disorder or condition is Aicardi-Gutiérrez syndrome.

350. The method of claim 346, wherein the disease, disorder or condition is a genetic form of lupus.

351. The method of claim 346, wherein: The disease, disorder or condition is an inflammation-related disorder.

352. The method of claim 351, wherein: The inflammation-related disorder is systemic lupus erythematosus.

353. The method of any one of claims 300-352, wherein the method further comprises identifying an object.

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