Compounds and compositions for treating conditions associated with sting activity

Abstract

To provide chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and / or hydrate, and / or cocrystal, and / or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING).SOLUTION: The chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., enhanced) STING activation (e.g., STING signaling) contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the chemical entities as well as methods of using and making the chemical entities.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 861,714, filed June 14, 2019, and U.S. Provisional Patent Application No. 62 / 861,714, filed December 14, 2019. This application claims the benefit of U.S. Provisional Patent Application No. 62 / 955,924, filed on January 31, 2002, and the related provisional applications. each of which is incorporated herein by reference in its entirety.

[0002] Technical Field The present disclosure relates to a method for inhibiting (e.g., antagonizing) STING (Stimulator of Interferon Gene). ) a chemical entity (a compound or a pharmaceutically acceptable salt and / or hydrate of said compound) The chemical entities are characterized by, e.g., For example, the pathology and function of a condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). and / or increased STING activation (e.g., STING signaling) in symptoms and / or progression The present invention is useful for treating conditions, diseases, or disorders in which (e.g., hyperactivity) of the IL-1 receptor agonist contributes. The disclosure also provides compositions containing the chemical entities, as well as methods for using and making the chemical entities. The method is characterized. [Background technology]

[0003] background STING, also known as transmembrane protein 173 (TMEM173) and MPYS / MITA / ERIS, is a human STING is a protein encoded by the TMEM173 gene in the mouse. STING has been shown to play a role in the regulation of immune responses by cells against viruses, mycobacteria, and Infection with intracellular pathogens such as leukemia and intracellular parasites induces type I interferon production. STING-mediated type I interferons are autocrine and paracrine. In an in vivo system, it protects infected cells and nearby cells from local infection.

[0004] The STING pathway is pivotal in mediating the recognition of cytosolic DNA. STING, a transmembrane protein localized to the endoplasmic reticulum (ER), is produced by cGAS after dsDNA binding. It acts as a second messenger receptor for 2',3' cyclic GMP-AMP (hereafter referred to as cGAMP), which is In addition, STING also binds bacterial cyclic dinucleotides (CDNs) and small molecule agonists. They can function as the primary pattern recognition receptors for endogenous or prokaryotic CDN recognition proceeds through the carboxy-terminal domain of STING, which is expressed in the cytosol. It faces the STING receptor, creating a V-shaped binding pocket formed by the STING homodimer. Ligand-induced activation of G triggers its relocalization to the Golgi, which mediates STING's interaction with TBK1. This protein complex then interacts with transcription factors, a process essential for promoting transcription. It signals through its receptor IRF-3 and mediates type I interferon (IFN) and other co-regulated In addition, STING induces the activation of NF-κB and MAP kinases. After the initiation of signaling, STING is rapidly degraded, which is a key factor in the inflammatory response. This is a step that is considered important in completing the answer.

[0005] Hyperactivation of STING is associated with a subset of monogenic autoinflammatory conditions, so-called type I interferon. Examples of these diseases include the TMEM173 gene (the name of the STING gene) A new disease called STING-associated vasculitis in infancy (SAVI) is caused by a gain-of-function mutation in Furthermore, STING is known to be involved in Aicardi-Goutières syndrome (AGS). In contrast to SAVI, AGS is involved in the pathogenesis of idiopathic lupus erythematosus (S) and hereditary forms of lupus. The basis for continuous innate immune activation is dysregulation of nucleic acid metabolism. Apart from harm, emerging evidence suggests that inflammatory bowel disease may also be a contributing factor in a wide range of inflammation-related disorders, e.g., systemic lupus erythematosus, This points to a more general pathogenic role for STING in rheumatoid arthritis and cancer. Therefore, small molecule-based pharmacological intervention in the STING signaling pathway has potential for the treatment of a wide range of diseases. holds significant potential for Summary of the Invention

[0006] overview The present disclosure relates to a method for inhibiting (e.g., antagonizing) STING (Stimulator of Interferon Gene). ) a chemical entity (a compound or a pharmaceutically acceptable salt and / or hydrate of said compound) The chemical entities are characterized by, e.g., For example, the pathology and function of a condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). and / or increased STING activation (e.g., STING signaling) in symptoms and / or progression The present invention is useful for treating conditions, diseases, or disorders in which (e.g., hyperactivity) of the IL-1 receptor agonist contributes. The disclosure also provides compositions containing the chemical entities, as well as methods for using and making the chemical entities. The method is characterized.

[0007] An "antagonist" of STING is an agent that inhibits, e.g., inhibits, agonist-mediated, or inhibits the activity of STING. The protein is then reduced by blocking or attenuating the sexual response, altering distribution, or otherwise. These include compounds that directly bind to or modify STING at the protein level. STING antagonists interfere with or inhibit STING signaling. , chemical entities.

[0008] In one aspect, a compound of formula (I): TIFF2025037981000001.tif25128, or a pharmaceutically acceptable salt thereof, wherein: 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 6 , W, and A may be as defined anywhere herein. .

[0009] In one aspect, the chemical entities described herein (e.g., those generically or specifically described herein) or a pharmaceutically acceptable salt thereof, or a composition containing the same) and one or more pharmaceutically acceptable excipients.

[0010] In one aspect, STING can be administered as a chemical entity described herein (e.g., as collectively referred to herein). or a compound specifically described, or a pharmaceutically acceptable salt thereof, or a compound containing the same and a method for inhibiting (e.g., antagonizing) STING activity, comprising contacting the antibody with a composition. The method is characterized by an in vitro method, e.g., a method for detecting one or more STING-containing genes. A number of cells (e.g., innate immune cells, e.g., mast cells, macrophages, dendritic cells (DCs) In vitro methods of contacting a sample containing cells (e.g., erythrocytes, leukocytes, and natural killer cells) with a chemical entity. The method includes an in vivo method, e.g., a method for treating a disease condition and / or symptom and / or The present invention relates to a subject having a disease in which increased (e.g., hyperactivity) of STING signaling contributes to the progression of the disease (e.g., The method can further include in vivo methods of administering the chemical entity to a subject (e.g., a human).

[0011] In one aspect, a condition, disease, or disorder that is ameliorated by antagonizing STING. Methods for treating harm, e.g., a condition, disease, or disorder (e.g., a rheumatoid arthritis) in a subject (e.g., a human) STING activation (e.g., STING ) is involved in the pathology and / or symptoms and / or progression of cancer. A method for treating a condition, disease, or disorder in which increased (e.g., enhanced) signal transduction contributes. The method comprises administering to a subject in need of such treatment an effective amount of any of the compounds described herein. The chemical entities described above (e.g., compounds or compounds described generically or specifically herein) or a pharmaceutically acceptable salt thereof, or a composition containing same).

[0012] In another aspect, a subject in need of such treatment is administered an effective amount of a chemical compound described herein. An entity (e.g., a compound generically or specifically described herein or its pharmaceutical a therapeutically acceptable salt thereof or a composition containing the same) The law is characterized.

[0013] In a further aspect, other STING-associated conditions, such as type I interferonopathy (e.g., breast cancer) are also treated with steroids. STING-associated vasculitis in children (SAVI), Aicardi-Goutières syndrome (AGS), hereditary lupus, as well as inflammation-related disorders such as systemic lupus erythematosus and rheumatoid arthritis The method includes administering to a subject in need of such treatment an effective amount of the compound of formula (I). Chemical entities described herein (e.g., chemicals described generically or specifically herein) or a pharmaceutically acceptable salt thereof, or a composition containing the same. nothing.

[0014] In another aspect, a subject in need thereof is administered an effective amount of a chemical entity described herein (e.g., , a compound generically or specifically described herein or a pharmaceutically acceptable salt thereof and administering to a subject a STING-dependent type I inflammatory cytokine, a soluble form of ... Methods for suppressing interferon production are featured.

[0015] In a further aspect, STING activation ( For example, methods for treating diseases in which increased (e.g., enhanced) STING signaling contributes The method comprises administering to a subject in need of such treatment an effective amount of a compound described herein. Chemical entities (e.g., compounds described generically or specifically herein or The method includes administering a pharmaceutically acceptable salt thereof or a composition containing the same.

[0016] In another aspect, a subject is administered an effective amount of a chemical entity described herein (e.g., The compounds generically or specifically described or pharmaceutically acceptable salts thereof or and administering to the subject a composition containing the compound (composition containing the compound), wherein the subject is treated with the compound for the treatment of the disease pathology and / or symptoms and / or or increased (e.g., hyper) STING activation (e.g., STING signaling) contributes to progression The present invention features methods of treatment for those who have (or are predisposed to have) a disease associated with the condition.

[0017] In a further aspect, the method of treatment involves administering to a subject a chemical entity described herein (e.g., A compound generically or specifically described in the document or a pharmaceutically acceptable salt thereof, or and administering to the subject a compound (composition containing the compound) in a manner that the chemical entity is effective in treating the disease pathology and / or , the symptoms and / or progression may be related to increased STING activation (e.g., STING signaling) (e.g., The compound is administered in an amount effective to treat a disease in which the compound contributes to the disease, thereby treating the disease. will be done.

[0018] Embodiments can include one or more of the following features.

[0019] The chemical entity may be administered in combination with one or more additional therapeutic agents and / or regimens. For example, the method may include one or more (e.g., 2, 3, 4, 5, 6, or The method can further comprise administering an additional agent (or more).

[0020] The chemical entity may also be involved in other STING-associated conditions, such as type I interferonopathy (e.g., infantile onset). STING-associated vasculitis (SAVI), Aicardi-Goutières syndrome (AGS), and hereditary Treats inflammatory disorders such as lupus, systemic lupus erythematosus, and rheumatoid arthritis and administering the compound in combination with one or more additional therapeutic agents and / or regimens useful for preventing or treating the It can be given.

[0021] The chemical entity may be administered in combination with one or more additional cancer therapies (e.g., surgery, radiation therapy, chemotherapy). therapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof, e.g. For example, one or more (e.g., 2, 3, 4, 5, 6, or more) additional chemotherapeutic agents may be administered. The compound may be administered in combination with chemotherapy, including administering an additional chemotherapeutic agent. Non-limiting examples include alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin anti-metabolites (e.g., azathioprine and / or mercaptopurine), lupenoids (e.g., vinca alkaloids and / or taxanes, e.g., vincris vinblastine, vinorelbine, and / or vindesine Taxol, Paclitaxel Taxel, and / or docetaxel), topoisomerases (e.g., type I topoisomerase topoisomerase and / or type 2 topoisomerase, e.g., irinotecan and / or topoisomerase camptothecins, amsacrine, etoposide, etoposide phosphate, and / or teniposide), cytotoxic antibiotics (e.g., actinomycin, anthracycline, Clin, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin , bleomycin, plicamycin, and / or mitomycin), hormones (e.g. For example, luteinizing hormone-releasing hormone agonists, such as leuprolidine ), goserelin, triptorelin, histrelin, bicalutamide, flutamide, and / or nilutamide), antibodies (e.g., abciximab, adalimumab, alemtuzumab, Atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, Canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, excreta Ibritumomab, efalizumab, gemtuzumab, golimumab, ibritumomab Uxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, offer Tutumab, omalizumab, palivizumab, panitumab, ranibizumab, rituximab, tocilizumab, tositumomab, and / or trastuzumab), antiangiogenic agents, anti-inflammatory drugs, anti-thrombotic agents, growth inhibitors, anti-helminthic agents, and immune checkpoint receptors. an immune checkpoint inhibitor selected from those that target the immune checkpoint receptor; These include CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), and Indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor- β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-T IM3, 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, T MIGD2, HHLA2-TMIGD2, butyrophilins including BTNL2, Siglec family, TIGIT and and PVR family members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD 244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD39-CD73, CXCR 4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEG F, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L 1).

[0022] The subject can have cancer, e.g., the subject has received one or more cancer therapies. have been and / or are undergoing and / or are about to be undergoing.

[0023] 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 Cancer, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma ( hepatocellular cancer), malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms tumor, or hepatocellular carcinoma In certain embodiments, the cancer is a refractory cancer. It could be.

[0024] The chemical entity may be administered intratumorally.

[0025] The method can further include identifying the subject.

[0026] Other aspects include those described in the detailed description and / or claims.

[0027] Additional definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the organic compounds described herein are Laboratory procedures in biology, medicinal chemistry, and pharmacology are well known and commonly used in the art. Unless otherwise defined, all terms used herein are used interchangeably. Technical and scientific terms are generally those commonly understood by one of ordinary skill in the art to which this disclosure belongs. Patents, applications, and publications referred to throughout this specification and attachments have the same meaning as those in the accompanying documents. Each of the application publications, and other publications, is incorporated herein by reference in its entirety.

[0028] As used herein, the term "STING" refers to a nucleic acid, polynucleotide, , oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, pairs peptides, polypeptides, proteins, homologous and / or orthologous STING molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles The term "antibody" is meant to include, but is not limited to, different species, as well as active fragments thereof. isn't it.

[0029] The term "acceptable" in reference to a formulation, composition, or component is used herein to mean When used in a therapeutically effective manner, it should have no lasting adverse effects on the general health of the subject being treated. This means that

[0030] "API" refers to the active pharmaceutical ingredient.

[0031] The terms "effective amount" or "therapeutically effective amount" as used herein mean a therapeutically effective amount. alleviate to some extent one or more of the symptoms of the disease or condition being treated Refers to a sufficient amount of a chemical entity being administered. A result is the appearance of signs, symptoms, or causes of a disease. reduction and / or amelioration of, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is an amount that provides a clinically significant reduction in disease symptoms. is the amount of a composition comprising a compound as disclosed herein required to An appropriate "effective" amount in any individual case may be determined using any suitable technique, such as a dose escalation study. is determined.

[0032] The term "excipient" or "pharmaceutically acceptable excipient" refers to a liquid or solid filler. pharmaceutically acceptable materials, compositions, such as agents, diluents, carriers, solvents, or encapsulating materials; means a vehicle. In one aspect, each component is compatible with the other components of the pharmaceutical formulation, and a reasonable benefit / risk ratio without excessive toxicity, irritation, allergic response, or immunosuppressive effects. It can be brought into contact with human and animal tissues or organs without causing any toxic or other problems or complications. "Pharmaceutically acceptable" means suitable for use in a pharmaceutical composition. See, for example, Remington: The Science and Practice of Pharmacy,21st ed.;Lippincott Williams&Wilkins:Philad elphia,PA,2005;Handbook of Pharmaceutical Excipients,6th ed.;Rowe et al.,Eds.;Th e Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company:2 007;Pharmaceutical Preformulation and Formulation,2nd ed.;Gibson Ed.;CRC Press L See LC: Boca Raton, FL, 2009.

[0033] The term "pharmaceutically acceptable salt" means a compound that does not cause significant irritation to an organism to which it is administered. refers to a formulation of a compound that does not cause side effects and does not interfere with the compound's biological activity and properties. In certain cases, pharmaceutically acceptable salts are prepared by converting the compounds described herein into hydrochloride, hydrobromide, or other salts. Acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. A compound having an acidic group as described herein may be reacted with a base to form a salt, e.g. For example, ammonium salts, alkali metal salts such as sodium or potassium salts, alkali metal salts such as ... potassium earth metal salts, e.g., calcium or magnesium salts; organic bases, e.g., di- cyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine and salts with amino acids such as arginine and lysine. or by other methods previously determined. There is no particular limitation as long as it can be used in medicine. Examples of salts that may be formed include those formed with inorganic bases such as sodium, potassium, magnesium, calcium, and its salts with aluminum; organic bases, e.g., methylamine, ethylamine; its salts with amine and ethanolamine; basic amino acids, e.g., lysine and olni; The salts may be acid addition salts, and may be ammonium salts. This includes mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, Organic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid , maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid acid addition salts with sulfonic acid, acidic amino acids, e.g., aspartic acid and glutamic acid This is particularly exemplified by:

[0034] The term "pharmaceutical composition" refers to a pharmaceutical composition containing a pharmaceutical agent containing other chemical components (collectively referred to herein as "excipients"). (also referred to as "anti-inflammatory agents"), such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or enhancers. A pharmaceutical composition refers to a mixture of a compound described herein with a viscosity agent. Several techniques exist in the art for administering compounds, including rectal, oral, including, but not limited to, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration This is not the case.

[0035] The term "subject" refers to an animal, including primates (e.g., humans), monkeys, Examples include cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used to refer to, for example, but not limited to, Used interchangeably herein in reference to a mammalian subject, such as a human.

[0036] "Treat" in the context of treating a disease or disorder and "treatment" refers to the treatment of a disorder, disease, or condition, or Alleviating or preventing one or more of the symptoms associated with a disease or condition or a disease, disorder, or condition or one or more of these symptoms "Cure of cancer" is meant to include slowing the progression, spread, or worsening of the condition. "Treatment" refers to one or more of the following effects: (1) (i) slowing down and (ii) complete success. (2) inhibition of tumor growth to some degree, including cessation of tumor growth; (3) reduction of tumor cell numbers; (4) maintain tumor size; (5) (i) decrease, (ii) slow down, or (iii) ) inhibition of tumor cell invasion into peripheral organs, including complete prevention; (6) (i) reduction; (ii) slowing; or (iii) inhibition of metastasis, including complete prevention; (7) (i) maintenance of tumor size; (ii) (iii) a reduction in tumor size; (iv) a slowing of tumor growth; or (v) a reduction or slowing of tumor invasion; or (8) enhancing anti-tumor immune responses, which may result in prevention, and / or Any reduction in the severity or number of one or more associated symptoms.

[0037] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I)

[0038] The term "alkyl" refers to an alkyl group having a designated number of carbon atoms, which may be straight or branched. refers to a hydrocarbon chain containing atoms, e.g., C 1~10 The number of groups is 1 to 10 (number of both ends) Non-limiting examples include methyl, Examples include ethyl, isopropyl, tert-butyl, and n-hexyl.

[0039] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halogen atoms. It refers to alkyl substituted with b.

[0040] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0041] The term "alkylene" refers to a divalent alkyl (eg, --CH.sub.2--).

[0042] The term "alkenyl" refers to a straight-chain or It refers to a hydrocarbon chain that may be branched. The alkenyl moiety has the indicated number of carbon atoms. For example, C 2~6 means that the group has 2 to 6 carbon atoms (inclusive) This indicates that the user may have

[0043] The term "alkynyl" refers to a straight-chain or It refers to a hydrocarbon chain that may be branched. The alkynyl moiety has the indicated number of carbon atoms. For example, C 2~6 means that the group has 2 to 6 carbon atoms (inclusive) This indicates that the user may have

[0044] The term "aryl" refers to a system in which at least one ring is aromatic (e.g., a 6-carbon ring). monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring systems), and 0, 1, 2, 3 of each ring or a monocyclic or bicyclic ring of 6 to 20 carbon atoms, 4 of which may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, and and tetrahydronaphthyl.

[0045] The term "cycloalkyl" as used herein means a group of 3 to 20 ring carbon atoms. Preferably, the ring has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms or 3 to 10 carbon atoms. The cycloalkyl group may be substituted or unsubstituted. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl includes, but is not limited to, 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]octanol bicyclo[3.2.1]octane, and bicyclo[2.2.2]octane. Cycloalkyl also includes spirocyclic rings (e.g., two rings joined through only one atom). Non-limiting examples of spirocyclic cycloalkyl include: Examples include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, and spiro[2.2]pentane. Pyro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane , spiro[4.5]decane, spiro[3.6]decane, and spiro[5.5]undecane. Examples include:

[0046] The term "cycloalkenyl" as used herein refers to an alkyl group having 3 to 20 rings. carbon, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons or 3 to 10 ring Contains partially unsaturated cyclic hydrocarbon groups having carbon or 3 to 6 ring carbons, cycloalkanes, The cycloalkenyl group may be substituted. Examples of cycloalkenyl groups include cyclopentenyl and cyclopentenyl. cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl groups may have any degree of saturation, provided that: None of the rings in the ring system are aromatic and the cycloalkenyl group as a whole is not fully saturated. Cycloalkenyl may include multiple fused and / or bridged rings and / or spinels. It may contain a bicyclic ring.

[0047] The term "heteroaryl" as used herein refers to a heteroaryl having 5 to 20 ring atoms. Alternatively, the cyclic array may have 5, 6, 9, 10, or 14 ring atoms and may have 6 shared ring atoms. means a monocyclic, bicyclic, tricyclic, or polycyclic group having 10, 10, or 14 pi electrons At least one ring in the system is aromatic (provided that rings containing heteroatoms, e.g., tetrahydroisoquinolinyl, e.g., but not necessarily tetrahydroquinolyl), and At least one ring in the system is one or more independently selected from the group consisting of N, O, and S. contains multiple heteroatoms. A heteroaryl group can be unsubstituted or It may be substituted with one or more substituents. Examples of heteroaryl include thienoyl, ... Nyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl , triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrazolyl Nyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothiazolyl nyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl aryl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, na Phthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2 ,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo [3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine ...b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[3,4-b]pyridin Lazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4 ]dioxin, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydrofuran doloquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, and In some embodiments, heteroaryl is thienyl, pyridinyl, phenyl ... pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidine It is selected from mizinil.

[0048] The term "heterocyclyl" refers to a ring system having 1 to 3 heteroatoms in monocyclic cases and 1 to 3 heteroatoms in bicyclic cases. 1 to 6 heteroatoms, or 1 to 9 heteroatoms if tricyclic or polycyclic Monocyclic, bicyclic, tricyclic, or polycyclic non-aromatic ring systems having 3 to 16 ring atoms ( For example, a 5-8 membered monocyclic, an 8-12 membered bicyclic, or an 11-14 membered tricyclic ring system), Heteroatoms are selected from O, N, or S (e.g., carbon atoms and monocyclic, bicyclic, or 1 to 3, 1 to 6, or 1 to 9 heteroatoms of N, O, or S, respectively, if tricyclic; ), and 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. Examples of aryl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and Heterocyclyl includes multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyls 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 San, 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[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[1.1.0]butane Cyclo[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]hexane 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[4.1.0]heptane Oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[4.2.0]octane Examples include 2-oxabicyclo[2.2.2]octane and 3-oxabicyclo[3.2.1]octane. Tetracyclyl also includes spirocyclic rings (e.g., two rings joined through only one atom). Non-limiting examples of spirocyclic heterocyclyls include: These include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, and 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[2.6]nonane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2 -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[3.5]nonane 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, ,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro [5.5]undecane, and 3-oxa-9-azaspiro[5.5]undecane. .

[0049] In addition, the atoms constituting the compounds of this embodiment include all isotopic forms of such atoms. Isotopes, as used herein, are groups having the same atomic number but As a general, non-limiting example, an isotope of hydrogen is thorium. Lithium and deuterium are isotopes of carbon. 13 C and 14 C is one example.

[0050] In addition, the compounds disclosed generically or specifically herein include all tautomeric forms. So, for example, the part: The compound containing TIFF2025037981000002.tif15128 is the moiety: TIFF2025037981000003.tif16128. Similarly, it is described as being optionally substituted with a hydroxyl. The pyridinyl or pyrimidinyl moieties referred to herein include pyridone or pyrimidone tautomers. do.

[0051] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. . DETAILED DESCRIPTION OF THE INVENTION

[0052] Detailed Description The present disclosure relates to a method for inhibiting (e.g., antagonizing) STING (Stimulator of Interferon Gene). ) a chemical entity (a compound or a pharmaceutically acceptable salt and / or hydrate of said compound) The chemical entities are characterized by, e.g., For example, the pathology and function of a condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). and / or increased STING activation (e.g., STING signaling) in symptoms and / or progression The present invention is useful for treating conditions, diseases, or disorders in which (e.g., hyperactivity) of the IL-1 receptor agonist contributes. The disclosure also provides compositions containing the chemical entities, as well as methods for using and making the chemical entities. The method is characterized.

[0053] Compounds of Formula I In one aspect, provided herein are compounds of formula I: TIFF2025037981000004.tif33128 or a pharmaceutically acceptable salt or tautomer thereof, In formula (I), Y 1 , Y2 , Y 3 , Y 4 , and Y 5 Each of N and CR 1 Independently selected from the group consisting of , WA is defined in accordance with (A) or (B) below: (A) W is (a)*C(=O)NR N , *C(=S)NR N , *C(=NR N )NR N (For example, *C(=NCN)NR N ), *C(=CNO2)NR N , (b)*S(O) 1~2 NR N , (c) TIFF2025037981000005.tif21128, (d) TIFF2025037981000006.tif18128, and (e)*Q 1 -Q 2 selected from the group consisting of Asterisk means NR 6 represents the point of attachment to Q 1 teeth, (a) 1 to 2 independently selected R q1 phenylene optionally substituted with and (b) Heteroarylene containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroaryls. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 A group consisting of and the heteroarylene ring is a heteroaryl ring having 1 to 4 independently selected R q1 in Optionally substituted heteroarylene selected from the group consisting of Q 2 is a bond, NR N , -S(O) 0~2 -, -O-, and -C(=O)- , A is, (i)-Y A1 -Y A2 And, Y A1 is a bond, or Y A1 but, ○R a , ○ 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~1 0 aryl, and Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroaryls. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 A group consisting of and the heteroaryl ring is selected from 1 to 4 independently selected C 1~4 a heteroaryl, optionally substituted with alkyl; and optionally substituted with 1 to 6 substituents independently selected from the group consisting of: C 1~6 Alkylene or Y A1 But, Y A3 -Y connected to W via A3 -Y A4 -Y A5 where: ○Y A3 is one to two independently selected R a C optionally substituted with 1~3 Al It is Kiren, ○Y A4 is -O-, -NH-, or -S-, and ○Y A5is a bond or one to two independently selected R a Replaced with C 1~3 alkylene, and Y A2 but, (a) 1 to 4 R b C optionally substituted with 3~20 cycloalkyl, (b) 1 to 4 R c C optionally substituted with 6~20 aryl, (c) Heteroaryl containing 5 to 20 ring atoms, wherein 1 to 3 ring atoms are heteroaryls. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Consists of and the heteroaryl ring is selected from 1 to 4 independently selected R c Place optionally substituted heteroaryl, or (d) Heterocyclyl containing 3 to 16 ring atoms, wherein 1 to 3 of the ring atoms are heterocyclic. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Consists of and the heterocyclyl ring is 1 to 4 independently selected R b Place optionally substituted heterocyclyl That is, -Y A1 -Y A2 , or (ii)-Z 1 -Z 2 -Z 3 And, Z 1 However, 1 to 4 R a C optionally substituted with 1~3 is alkylene, Z 2 However, -N(H)-, -N(R d)-, -O-, or -S-, and Z 3 However, 1 to 4 R a C optionally substituted with 2~7 is alkyl, -Z 1 -Z 2 -Z 3 , or (iii) 1 to 6 independently selected R a C optionally substituted with 1~20 Alkyl is; or (B) W is (a) 1 to 4 R c C optionally substituted with 8~20 Bicyclic or Polycyclic Arylene , and (b) a bicyclic or polycyclic heteroarylene containing 8 to 20 ring atoms, ~4 ring atoms are heteroatoms, each heteroatom is N, N(H), N(R d ), O, and S (O) 0~2 and the heteroaryl ring is independently selected from the group consisting of 1 to 4 independent R is selected by c heteroarylene optionally substituted with selected from the group consisting of A is (A) or A is H; R 1 Each occurrence of H, Hello, Cyano, 1-2 R a C optionally substituted with 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 1~4 haloalkyl, C1~4 Alkoxy, C 1~4 haloalkoxy, -S(O) 1~2 (C 1~4 alkyl), -S(O)(=NH)(C 1~4 alkyl), SF5, -NR e R f , -OH, 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, -C(=O)N(R')(R''), and -L 3 -L 4 -L 5 -R i or independently selected from the group consisting of Or, a pair of R on adjacent atoms 1 together with the atoms that connect them , forming a ring (e.g., aromatic or non-aromatic) containing 4 to 15 ring atoms, and 0 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 from and the ring is selected from 1 to 4 independently selected R 2 is replaced by Also, Each R 2 teeth, Hello, Cyano, 1-2 R a C optionally substituted with 1~6Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 1~4 haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy, 1 to 3 independently selected R a -S(O) optionally substituted with 1~2 (C 1~4 Alkyl ), 1 to 3 independently selected R a -S(O)(=NH)(C 1~4 Al kill), SF5, -NR e R f , -OH, Oxo, -S(O) 1~2 (NR'R''), -C 1~4 thioalkoxy, -NO2, 1 to 3 independently selected R a may be substituted with -C(=O)(C 1~4 alkyl) , 1 to 3 independently selected R a may be substituted with -C(=O)O(C 1~4 Alkyl ), ·-C(=O)OH, -C(=O)N(R')(R''), and -L 3 -L 4 -L 5 -R i are independently selected from the group consisting of: R 6 is H;C 1~6 Alkyl; -OH; C 1~4Alkoxy; C(=O)H; C(=O)(C 1~4 alkyl); CN; 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~10 aryl; and heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms. where each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independent from the group consisting of and the heteroaryl ring is selected from 1 to 4 independently selected C 1~4 With alkyl optionally substituted heteroaryl; R q1 Each occurrence of (a) halo, (b) cyano, (c) 1 to 6 independently selected R a It may be replaced by I C 1~10 Alkyl, (d) C 2~6 Alkenyl, (e) C 2~6 Alkynyl, (f) C 3~6 Cycloa Lukil, (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 blood Oraloxy, (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) oxo are independently selected from the group consisting of: R a Each occurrence of is -OH; -F; -Cl; -Br; -NR eR 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'' );-OCON(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano, and 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 3~6 independently selected from the group consisting of: cycloalkyl; R b Each occurrence of a C optionally substituted with 1~10 Alkyl ;C 1~4 Haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haroarco -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-C(=O )N(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano ; and -L 1 -L 2 -R h are independently selected from the group consisting of: R c Each occurrence of (a) halo, (b) cyano, (c) 1 to 6 independently selected R a It may be replaced by I C 1~10 Alkyl, (d) C 2~6 Alkenyl, (e) C 2~6Alkynyl, (g) C 1~4 Alcoki Shi, (h)C 1~4 Haloalkoxy, (i) -S(O) 1~2 (C 1~4 alkyl) or -S(O) 1~2 (C 1~4 haloalkyl), (j)-NR e R f , (k)-OH, (l)-S(O) 1~2 (NR'R''), (m )-C 1~4 Thioalkoxy or -C 1~4 Thiohaloalkoxy, (n)-NO2, (o)-C(=O) (C 1~10 alkyl), (p)-C(=O)O(C 1~4 alkyl), (q)-C(=O)OH, (r)-C (=O)N(R')(R''), (s)-L 1 -L 2 -R h , (t)-SF5, and (u) azide are independently selected from the group consisting of: R d Each occurrence of 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, C 1~4 is selected from the group consisting of alkoxy, and CN; R e and R f Each occurrence of H; halo, CN, C 1~4 Alkoxy, C 1~4 Haloalkoxy, NR'R 1 to 4 substituents independently selected from -OH, - C 1~6 Alkyl; C1~6 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);-S(O)(=NR')(C 1~4 alkyl); -OH; and C 1~4 alkoxy, or R e and R f are respectively Together with the nitrogen atom to which it is attached, it forms a ring containing 3 to 8 ring atoms, and the ring is (a) H and C1 ~3 1 to 7 rings, each substituted with 1 to 2 substituents independently selected from alkyl carbon atoms and (b) N(R d ), NH, O, and S, each independently selected from the group consisting of 0 to 3 ring heteroatoms (R e and R f In addition to the nitrogen atom bonded to -L 1 is a bond or optionally substituted with oxo; 1~3 is alkylene, -L 2 -O-, -N(H)-, -S(O) 0~2 - or a bond, R h teeth, Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Ha C 1~4 Alkoxy; and C 1~4 Independently from the group consisting of haloalkoxy C is optionally substituted with 1 to 4 substituents selected from 3~8Cycloalkyl (however, In certain embodiments, R h is 1 to 4 independently selected C 1~4 substituted with alkyl Good C 3~6 When it is cycloalkyl, -L 1 is a bond or -L 2 However, -O-, -N(H )- or -S-) Heterocyclyl contains 3 to 16 ring atoms, 1 to 3 of which are heteroatoms, and each The heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independently selected from the group consisting of wherein heterocyclyl is halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 Haloalkoxy Heterocyclic rings optionally substituted with 1 to 4 substituents independently selected from the group consisting of Lil, Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independent from the group consisting of and the heteroaryl ring is selected from halo; 1 to 2 independently selected R a is replaced by May be C 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 Ha and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy and methyl. , heteroaryl, and Halo; 1 to 2 independently selected Ra C optionally substituted with 1~4 Alkyl; C 1~4 Ha C 1~4 Alkoxy; and C 1~4 Independently from the group consisting of haloalkoxy C is optionally substituted with 1 to 4 substituents selected from 6~10 Aryl is selected from -L 3 is a bond or optionally substituted with oxo; 1~3 is alkylene, -L 4 is a bond; -O-; -N(R N )-;-S(O) 0~2 -;C(=O);-NR N S(O) 0~2 -;-S(O) 0~2 NR N -;-NR N S(O) 1~2 NR N -;-S(=O)(=NR N );-NR N S(=O)(=NR N );-S(=O)(=NR N ) NR N ;NR N S(=O)(=NR N )NR N ;-NR N C(O)-;-NR N C(O)NR N -;C 3~6 Cycloalkylene; or heterocyclylene containing 3 to 8 ring atoms, in which 1 to 3 ring atoms are heteroatoms; Each heteroatom is N, NH, N(R d ), O, and S(O) 0~2 Independently selected from the group consisting of is a heterocyclylene selected from -L 5 is a bond or C 1~4 is alkylene, Ri teeth, Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Ha C 1~4 Alkoxy; and C 1~4 Independently from the group consisting of haloalkoxy C is optionally substituted with 1 to 4 substituents selected from 3~8 Cycloalkyl (however, In certain embodiments, R i But C 1~4 substituted with 1 to 4 substituents independently selected from alkyl C 3~6 When it is cycloalkyl, -L 1 is a bond or -L 2 but,- -O-, -N(H)-, or -S-), Heterocyclyl contains 3 to 16 ring atoms, 1 to 3 of which are heteroatoms, and each The heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independently selected from the group consisting of wherein heterocyclyl is halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 Haloalkoxy Heterocyclic rings optionally substituted with 1 to 4 substituents independently selected from the group consisting of Lil, Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independent from the group consisting of and the heteroaryl ring is selected from halo; 1 to 2 independently selected R a is replaced by May be C 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 Ha and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy and methyl. , heteroaryl, and Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Ha C 1~4 Alkoxy; and C 1~4 Independently from the group consisting of haloalkoxy C is optionally substituted with 1 to 4 substituents selected from 6~10 Aryl is selected from R N Each occurrence of is independently H or R d and Each occurrence of R' and R'' is H, C 1~4 Alkyl and halo, C 1~4 Alkyl, Call C 1~4 C optionally substituted with 1 to 2 substituents selected from haloalkyl 6~10 a or R' and R'' are each independently selected from the group consisting of a bond; together with the nitrogen atom attached thereto, form a ring containing 3 to 8 ring atoms, the ring being (a) H and C 1~3 1 to 7 alkyl groups each substituted with 1 to 2 substituents independently selected from the group consisting of alkyl ring carbon atoms and (b) N(H), N(C 1~6 alkyl), O, and S. 0 to 3 ring heteroatoms (nitrogen atoms bonded to R' and R'') each independently selected In addition to children) and

[0054] In some embodiments, one or more of the compound definitions herein apply.

[0055] In one aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025037981000007.tif33128 or a pharmaceutically acceptable salt or tautomer thereof, In formula (I), Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 Each of N and CR 1 Independently selected from the group consisting of , WA is defined in accordance with (A) or (B) below: (A) W is (a)*C(=O)NR N , *C(=S)NR N , *C(=NR N )NR N (For example, *C(=NCN)NR N ), *C(=CNO2)NR N , (b)*S(O) 1~2 NR N , (c) TIFF2025037981000008.tif21128, (d) TIFF2025037981000009.tif18128, and (e)*Q 1 -Q 2 selected from the group consisting of Asterisk means NR 6 represents the point of attachment to Q 1 teeth, (a) 1 to 2 independently selected R q1phenylene optionally substituted with, and Beauty (b) Heteroarylene containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroaryls. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 A group consisting of and the heteroarylene ring is a heteroaryl ring having 1 to 4 independently selected R q1 in Optionally substituted heteroarylene selected from the group consisting of Q 2 is a bond, NR N , -S(O) 0~2 -, -O-, and -C(=O)- , A is, (i)-Y A1 -Y A2 And, Y A1 is a bond, or Y A1 but, ○R a , ○ 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~1 0 aryl, and Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroaryls. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 A group consisting of and the heteroaryl ring is selected from 1 to 4 independently selected C 1~4 a heteroaryl, optionally substituted with alkyl; C1 optionally substituted with 1 to 6 substituents independently selected from the group consisting of ~6 alkylene, or Y A1But, Y A3 -Y connected to W via A3 -Y A4 -Y A5 where: ○Y A3 is one to two independently selected R a C optionally substituted with 1~3 Al It is Kiren, ○Y A4 is -O-, -NH-, or -S-, and ○Y A5 is a bond or one to two independently selected R a Replaced with C 1~3 alkylene, and Y A2 but, (a) 1 to 4 R b C optionally substituted with 3~20 cycloalkyl, (b) 1 to 4 R c C optionally substituted with 6~20 aryl, (c) Heteroaryl containing 5 to 20 ring atoms, wherein 1 to 3 ring atoms are heteroaryls. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Consists of and the heteroaryl ring is selected from 1 to 4 independently selected R c Place optionally substituted heteroaryl, or (d) Heterocyclyl containing 3 to 16 ring atoms, of which 1 to 3 ring atoms are heterocyclic. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Consists of and the heterocyclyl ring is selected from 1 to 4 independently selected R b Place optionally substituted heterocyclyl That is, -Y A1 -Y A2 or (ii)-Z 1 -Z 2 -Z 3 And, Z 1 However, 1 to 4 R a C optionally substituted with 1~3 is alkylene, Z 2 However, -N(H)-, -N(R d )-, -O-, or -S-, and Z 3 However, 1 to 4 R a C optionally substituted with 2~7 is alkyl, -Z 1 -Z 2 -Z 3 , or (iii) 1 to 6 independently selected R a C optionally substituted with 1~20 Alkyl That is, or (B) W is (a) 1 to 4 R c C optionally substituted with 8~20 Bicyclic or Polycyclic Arylene , and (b) a bicyclic or polycyclic heteroarylene containing 8 to 20 ring atoms, ~4 ring atoms are heteroatoms, each heteroatom is N, N(H), N(R d ), O, and S (O) 0~2 and the heteroaryl ring is independently selected from the group consisting of 1 to 4 independent R is selected by c heteroarylene optionally substituted with selected from the group consisting of A is (A) or A is H; R 1 Each occurrence of H, Hello, Cyano, 1-2 R a C optionally substituted with 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 1~4 haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy, -S(O) 1~2 (C 1~4 alkyl), -S(O)(=NH)(C 1~4 alkyl), SF5, -NR e R f , -OH, Oxo, -S(O) 1~2 (NR'R''), -C 1~4 thioalkoxy, -NO2, -C(=O)(C 1~4 alkyl), -C(=O)O(C 1~4 alkyl), ·-C(=O)OH, -C(=O)N(R')(R''), and -L 3 -L 4 -L 5 -R i or independently selected from the group consisting of Or, a pair of R on adjacent atoms 1 together with the atoms that connect them , forming a ring (e.g., aromatic or non-aromatic) containing 4 to 15 ring atoms, and 0 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 from and the ring is 2 It is replaced by It is okay to Each R 2 is halo; cyano; 1-2 R a C optionally substituted with 1~6 Alkyl; C 2~6 Arke Nil;C 2~6 Alkynyl; C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 Haloalkoxy; 1-3 independently selected R a -S(O) optionally substituted with 1~2 (C 1~4 alkyl); 1-3 independently selected R a -S(O)(=NH)(C 1~4 alkyl);S F5;-NR e R f ;-OH;oxo;-S(O) 1~2 (NR'R'');-C 1~4 Thioalkoxy; -NO2; 1 to 3 Independently selected R a may be substituted with -C(=O)(C 1~4 alkyl); 1 to 3 independent R selected independently a may be substituted with -C(=O)O(C 1~4 alkyl);-C(=O)OH; -C(=O)N(R')(R''); and -L 3 -L 4 -L 5 -R i are independently selected from the group consisting of: R 6 is H;C 1~6 Alkyl; -OH; C 1~4Alkoxy; C(=O)H; C(=O)(C 1~4 alkyl); CN; 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~10 aryl; and heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms. where each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independent from the group consisting of and the heteroaryl ring is selected from 1 to 4 independently selected C 1~4 With alkyl optionally substituted heteroaryl; R q1 Each occurrence of (a) halo, (b) cyano, (c) 1 to 6 independently selected R a It may be replaced by I C 1~10 Alkyl, (d) C 2~6 Alkenyl, (e) C 2~6 Alkynyl, (f) C 3~6 Cycloa Lukil, (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 blood Oraloxy, (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) oxo are independently selected from the group consisting of: R a Each occurrence of is -OH; -F; -Cl; -Br; -NR eR f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(= O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CON(R')(R'' );-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano; and 1 to 4 independent C is independently selected 1~4 C optionally substituted with alkyl 3~6 The group consisting of cycloalkyl more independently selected, R b Each occurrence of a C optionally substituted with 1~10 Alkyl ;C 1~4 Haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haroarco -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-C(=O )N(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano ; and -L 1 -L 2 -R h are independently selected from the group consisting of: R c Each occurrence of (a) halo, (b) cyano, (c) 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl, (d)C 2~6 alkenyl, (e)C 2~6 Alkynyl, (g)C 1~4 Alkoxy, (h)C 1~4 haloalkoxy, (i)-S(O) 1~2 (C 1~4 alkyl) or -S(O) 1~2 (C 1~4 haloalkyl), (j)-NR e R f , (k)-OH, (l)-S(O) 1~2 (NR'R''), (m)-C 1~4 Thioalkoxy or -C 1~4 thiohaloalkoxy, (n)-NO2, (o)-C(=O)(C 1~10 alkyl), (p)-C(=O)O(C 1~4 alkyl), (q) -C(=O)OH, (r)-C(=O)N(R')(R''), (s)-L 1 -L 2 -R h , and (t)-SF5 are independently selected from the group consisting of: R d Each occurrence of 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, C 1~4 is selected from the group consisting of alkoxy, and CN; R e and R f Each occurrence of H; halo, CN, C1~4 Alkoxy, C 1~4 Haloalkoxy, NR'R 1 to 4 substituents independently selected from -, ... Ru, 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);-S(O)(=NR')(C 1~4 alkyl); -OH; and C 1~4 Arco or R e and R f are each connected together with the nitrogen atom forming a ring containing 3 to 8 ring atoms, the ring being (a) H and C 1~3 Archi and 1 to 7 ring carbon atoms each substituted with 1 to 2 substituents independently selected from , (b) N(R d ), 0 to 3 independently selected from the group consisting of NH, O, and S The ring heteroatom (R e and R f In addition to the nitrogen atom bonded to -L 1 is a bond or optionally substituted with oxo; 1~3 is alkylene, -L 2 -O-, -N(H)-, -S(O) 0~2 - or a bond, R h teeth, Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Ha C 1~4 Alkoxy; and C 1~4 Independently from the group consisting of haloalkoxy C is optionally substituted with 1 to 4 substituents selected from 3~8 Cycloalkyl (however, In certain embodiments, R h is 1 to 4 independently selected C 1~4 substituted with alkyl Good C 3~6 When it is cycloalkyl, -L 1 is a bond or -L 2 However, -O-, -N(H )- or -S-) Heterocyclyl contains 3 to 16 ring atoms, 1 to 3 of which are heteroatoms, and each The heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independently selected from the group consisting of wherein heterocyclyl is halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 Haloalkoxy Heterocyclic rings optionally substituted with 1 to 4 substituents independently selected from the group consisting of Lil, Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independent from the group consisting of and the heteroaryl ring is selected from halo; 1 to 2 independently selected R a is replaced by May be C 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C1~4 Ha and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy and methyl. , heteroaryl, and Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Ha C 1~4 Alkoxy; and C 1~4 Independently from the group consisting of haloalkoxy C is optionally substituted with 1 to 4 substituents selected from 6~10 Aryl is selected from -L 3 is a bond or optionally substituted with oxo; 1~3 is alkylene, -L 4 is -O-, -N(R N )-, -S(O) 0~2 -, C(=O), -NR N S(O) 0~2 -, -S(O) 0~2 NR N -, -NR N S(O) 1~2 NR N -, -S(=O)(=NR N ), -NR N S(=O)(=NR N ), -S(=O)(=N R N )NR N , N.R. N S(=O)(=NR N )NR N , -NR N C(O)-, -NR N C(O)NR N - or a combination , -L 5 is a bond or C 1~4 is alkylene, R i teeth, Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Ha C 1~4 Alkoxy; and C 1~4 Independently from the group consisting of haloalkoxy C is optionally substituted with 1 to 4 substituents selected from 3~8 Cycloalkyl (however, In certain embodiments, R i But C 1~4 substituted with 1 to 4 substituents independently selected from alkyl C 3~6 When it is cycloalkyl, -L 1 is a bond or -L 2 but,- -O-, -N(H)-, or -S-), Heterocyclyl contains 3 to 16 ring atoms, 1 to 3 of which are heteroatoms, and each The heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independently selected from the group consisting of wherein heterocyclyl is halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 Haloalkoxy Heterocyclic rings optionally substituted with 1 to 4 substituents independently selected from the group consisting of Lil, Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independent from the group consisting of and the heteroaryl ring is selected from halo; 1 to 2 independently selected R a is replaced by May be C 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 Ha and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy and methyl. , heteroaryl, and Halo; 1 to 2 independently selected R a C optionally substituted with 1~4 Alkyl; C 1~4 Ha C 1~4 Alkoxy; and C 1~4 Independently from the group consisting of haloalkoxy C is optionally substituted with 1 to 4 substituents selected from 6~10 Aryl is selected from R N Each occurrence of is independently H or R d and and Each occurrence of R' and R'' is H, C 1~4 Alkyl and halo, C 1~4 Alkyl and and C 1~4 C optionally substituted with 1 to 2 substituents selected from haloalkyl 6~10 Ants or R' and R'' are independently selected from the group consisting of together with the nitrogen atom present, form a ring containing 3 to 8 ring atoms, the ring being (a) H and C 1~3 a 1 to 7 alkyl groups, each of which is substituted with 1 to 2 substituents independently selected from the group consisting of alkyl, alkyl, and alkyl. and (b) N(H), N(C 1~6 alkyl), O, and S, respectively 0 to 3 ring heteroatoms (including nitrogen atoms bonded to R' and R'') independently selected from In addition,

[0056] In one aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is TIFF2025037981000010.tif33128 or a pharmaceutically acceptable salt or tautomer thereof, In formula (I), Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 Each of N and CR 1 Independently selected from the group consisting of , WA is defined in accordance with (A) or (B) below: (A) W is (a)*C(=O)NR N , *C(=S)NR N , *C(=NR N )NR N (For example, *C(=NCN) NH), *C(=CNO2)NR N , (b)*S(O) 1~2 NR N , (c) TIFF2025037981000011.tif21128, (d) TIFF2025037981000012.tif18128, and (e)*Q 1 -Q 2 , selected from the group consisting of The asterisk indicates NR. 6 represents the point of attachment to Q 1 teeth, (a) 1 to 2 independently selected R q1 phenylene optionally substituted with and (b) Heteroarylene containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroaryls. Each heteroatom is N, N(H), N(Rd ), O, and S(O) 0~2 A group consisting of and the heteroarylene ring is a heteroaryl ring having 1 to 4 independently selected R q1 in Optionally substituted heteroarylene selected from the group consisting of Q 2 is a bond, NR N , -S(O) 0~2 -, -O-, and -C(=O)- , A is (i)-Y A1 -Y A2 And, Y A1 is a bond, or Y A1 C 1~6 alkylene, C 1~6 The alkylene is R a 1 to 4 independently selected Selected C 1~4 C optionally substituted with alkyl 6~10 Aryl; and 5 to 10 ring atoms wherein 1 to 4 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 and The aryl ring is selected from 1 to 4 independently selected C 1~4 optionally substituted with alkyl, substituted with 1 to 6 substituents each independently selected from the group consisting of heteroaryl; may be present, and Y A2 but, (a) 1 to 4 R b C optionally substituted with 3~20 cycloalkyl, (b) 1 to 4 R c C optionally substituted with 6~20 aryl, (c) Heteroaryl containing 5 to 20 ring atoms, wherein 1 to 3 ring atoms are heteroaryls. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Consists of and the heteroaryl ring is selected from 1 to 4 independently selected R c Place optionally substituted heteroaryl, or (d) Heterocyclyl containing 3 to 16 ring atoms, wherein 1 to 3 of the ring atoms are heterocyclic. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Consists of and the heterocyclyl ring is 1 to 4 independently selected R b Place optionally substituted heterocyclyl That is, -Y A1 -Y A2 , or (ii)-Z 1 -Z 2 -Z 3 And, Z 1 However, 1 to 4 R a C optionally substituted with 1~3 is alkylene, Z 2 However, -N(H)-, -N(R d )-, -O-, or -S-, and Z 3 However, 1 to 4 R a C optionally substituted with 2~7 is alkyl, -Z 1 -Z 2 -Z 3 , or (iii) 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl is; or (B) W is (a) 1 to 4 R c C optionally substituted with 8~20 bicyclic or polycyclic aryl, and (b) a bicyclic or polycyclic heteroaryl containing 8 to 20 ring atoms, ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O ) 0~2 and the heteroaryl ring is selected from the group consisting of 1 to 4 independently selected Selected R c Heteroaryl, optionally substituted with selected from the group consisting of: R 1 Each occurrence of H, Hello, Cyano, 1-2 R a C optionally substituted with 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 1~4 haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy, -S(O) 1~2 (C 1~4 alkyl), -S(O)(=NH)(C 1~4 alkyl), SF5, -NR e R f , -OH, Oxo, -S(O) 1~2 (NR'R''), -C 1~4thioalkoxy, -NO2, -C(=O)(C 1~4 alkyl), -C(=O)O(C 1~4 alkyl), ·-C(=O)OH, -C(=O)N(R')(R''), and -L 3 -L 4 -L 5 -R i or independently selected from the group consisting of Or, a pair of R on adjacent atoms 1 together with the atoms that connect them , forming a ring (e.g., aromatic or non-aromatic) containing 4 to 15 ring atoms, and 0 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 from and the ring is selected from 1 to 4 independently selected R 2 is replaced by Also, Each R 2 teeth, Hello, Cyano, 1-2 R a C optionally substituted with 1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 1~4 haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy, -S(O) 1~2 (C 1~4 alkyl), -S(O)(=NH)(C 1~4 alkyl), SF5, -NR eR 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, -C(=O)N(R')(R''), and -L 3 -L 4 -L 5 -R i are independently selected from the group consisting of: R 6 is H;C 1~6 Alkyl; -OH; C 1~4 Alkoxy; C(=O)H; C(=O)(C 1~4 alkyl); CN; 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 6~10 aryl; and heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms. where each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independent from the group consisting of and the heteroaryl ring is selected from 1 to 4 independently selected C 1~4 With alkyl optionally substituted heteroaryl; R q1 Each occurrence of (a) halo, (b) cyano, (c) 1 to 6 independently selected R a It may be replaced by I C 1~10 Alkyl, (d) C 2~6 Alkenyl, (e) C 2~6 Alkynyl, (f) C3~6 Cycloa Lukil, (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 blood Oraloxy, (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) oxo are independently selected from the group consisting of: R a Each occurrence of is -OH; -F; -Cl; -Br; -NR e R f ;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(= O)O(C 1~4 alkyl);-C(=O)(C 1~4 alkyl);-C(=O)OH;-CON(R')(R'' );-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano, and 1 to 4 Independently selected C 1~4 C optionally substituted with alkyl 3~6 consisting of cycloalkyl independently selected from the group, R b Each occurrence of a C optionally substituted with 1~10 Alkyl ;C 1~4 Haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ;C 1~4 Alkoxy;C1~4 Haroarco -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-C(=O)OH;-C(=O )N(R')(R'');-S(O) 1~2 (NR'R'');-S(O) 1~2 (C 1~4 alkyl); cyano , and -L 1 -L 2 -R h are independently selected from the group consisting of: R c Each occurrence of (a) halo, (b) cyano, (c) 1 to 6 independently selected R a It may be replaced by I C 1~10 Alkyl, (d) C 2~6 Alkenyl, (e) C 2~6 Alkynyl, (g) C 1~4 Alcoki Shi, (h)C 1~4 Haloalkoxy, (i) -S(O) 1~2 (C 1~4 alkyl), (j)-NR e R f , ( k) -OH, (l) -S(O) 1~2 (NR'R''), (m)-C 1~4 Thioalkoxy, (n)-NO2, (o )-C(=O)(C 1~10 alkyl), (p)-C(=O)O(C 1~4 alkyl), (q)-C(=O)O H, (r)-C(=O)N(R')(R''), and (s)-L 1 -L 2 -R h are independently selected from the group consisting of: R d Each occurrence of C 1~6 Alkyl, C 3~6 Cycloalkyl, -C(O)(C 1~4 alkyl), -C (O)O(C1~4 alkyl), -CON(R')(R''), -S(O) 1~2 (NR'R''), -S(O) 1~2 (C 1~4 alkyl), -OH, C 1~4 is selected from the group consisting of alkoxy, and CN; R e and R f Each occurrence of H; halo, CN, C 1~4 Alkoxy, C 1~4 Haloalkoxy, NR'R 1 to 4 substituents independently selected from -OH, - 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);-S(O)(=NR')(C 1~4 alkyl); -OH; and C 1~4 alkoxy, or R e and R f are respectively Together with the nitrogen atom to which it is attached, it forms a ring containing 3 to 8 ring atoms, and the ring is (a) H and C1 ~3 1 to 7 rings, each substituted with 1 to 2 substituents independently selected from alkyl carbon atoms and (b) N(R d ), NH, O, and S, each independently selected from the group consisting of 0 to 3 ring heteroatoms (R e and R f In addition to the nitrogen atom bonded to -L 1is a bond or optionally substituted with oxo; 1~3 is alkylene, -L 2 -O-, -N(H)-, -S(O) 0~2 - or a bond, R h teeth, Halo, C 1~4 Alkyl, and C 1~4 haloalkyl C optionally substituted with 1 to 4 substituents 3~8 Cycloalkyl (provided that in certain embodiments is R h is 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 3~6 Shik If it is -L, then it is -L 1 is a bond or -L 2 is -O-, -N(H)-, or -S- ), Heterocyclyl contains 3 to 16 ring atoms, 1 to 3 of which are heteroatoms, and each Heteroatoms are N, N(H), N(R d ), O, and S(O) 0~2 Independently selected from the group consisting of and heterocyclyl is halo, C 1~4 Alkyl, and C 1~4 The group consisting of haloalkyl heterocyclyl optionally substituted by 1 to 4 substituents independently selected from Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independent from the group consisting of and the heteroaryl ring is selected from halo, C 1~4 Alkyl, and C 1~4 Haloalkyl Heteroaryl may be substituted with 1 to 4 substituents independently selected from the group consisting of Rules, and Halo, C 1~4 Alkyl, and C 1~4 haloalkyl C optionally substituted with 1 to 4 substituents 6~10 Aryl is selected from -L 3 is a bond or optionally substituted with oxo; 1~3 is alkylene, -L 4 is -O-, -N(R N )-, -S(O) 0~2 -, -NR N S(O) 0~2 -, -S(O) 0~2 NR N -, -NR N S( O) 1~2 NR N -, -S(=O)(=NR N ), -NR N S(=O)(=NR N ), -S(=O)(=NR N )NR N , N R N S(=O)(=NR N )NR N , -NR N C(O)-, -NR N C(O)NR N - or a bond, -L 5 is a bond or C 1~4 is alkylene, R i teeth Halo, C 1~4 Alkyl, and C 1~4 haloalkyl C optionally substituted with 1 to 4 substituents 3~8 Cycloalkyl (provided that in certain embodiments is R i But C 1~4and optionally substituted with 1 to 4 substituents independently selected from alkyl. I C 3~6 When it is cycloalkyl, -L 1 is a bond or -L 2 However, -O-, -N(H)-, or -S-), Heterocyclyl contains 3 to 16 ring atoms, 1 to 3 of which are heteroatoms, and each The heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independently selected from the group consisting of and heterocyclyl is halo, C 1~4 Alkyl, and C 1~4 The group consisting of haloalkyl heterocyclyl optionally substituted by 1 to 4 substituents independently selected from Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independent from the group consisting of and the heteroaryl ring is selected from halo, C 1~4 Alkyl, and C 1~4 Haloalkyl Heteroaryl may be substituted with 1 to 4 substituents independently selected from the group consisting of Rules, and Halo, C 1~4 Alkyl, or C 1~4 haloalkyl C optionally substituted with 1 to 4 substituents 6~10 Aryl is selected from R N Each occurrence of is independently H or R d and and Each occurrence of R' and R'' is H, C 1~4 Alkyl and halo, C 1~4 Alkyl, Call C 1~4 C optionally substituted with 1 to 2 substituents selected from haloalkyl 6~10 a or R' and R'' are each independently selected from the group consisting of a bond; together with the nitrogen atom attached thereto, form a ring containing 3 to 8 ring atoms, the ring being (a) H and C 1~3 1 to 7 alkyl groups each substituted with 1 to 2 substituents independently selected from the group consisting of alkyl ring carbon atoms and (b) N(H), N(C 1~6 alkyl), O, and S. 0 to 3 ring heteroatoms (nitrogen atoms bonded to R' and R'') each independently selected In addition to children) and

[0057] Symbol Y 1 ~Y 5 and R 1 In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 2 to 5 of them are independently CR 1 is.

[0058] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing TIFF2025037981000013.tif23128.

[0059] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 Each of the 1 in (i.e., Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing TIFF2025037981000014.tif25128).

[0060] In certain of these embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing TIFF2025037981000015.tif23128.

[0061] In a certain aspect (Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing TIFF2025037981000016.tif25128), Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing TIFF2025037981000017.tif28156, wherein each R 1a are independently selected R 1 is.

[0062] In a certain aspect (Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing TIFF2025037981000018.tif25128), Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing TIFF2025037981000019.tif57128.

[0063] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 One or two of the items (e.g., one or two) independently N and the remaining Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 Each of the CRs is selected independently. 1 is.

[0064] In certain of these embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing .

[0065] As a non-limiting example of the above embodiment, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing the pyridine-2 -Il TIFF2025037981000020.tif28128.

[0066] In a certain aspect (Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 When the ring containing So, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing TIFF2025037981000021.tif23128 TIFF2025037981000022.tif18128.

[0067] In certain embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing pyridin-3-yl TIFF2025037981000023.tif22128 or pyridin-4-yl The file is TIFF2025037981000024.tif27128.

[0068] In certain of these embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing TIFF2025037981000025.tif22128 TIFF2025037981000026.tif19128.

[0069] In a certain aspect (Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing pyridin-3-yl or pyridinyl In the case of benzoyl, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing TIFF2025037981000027.tif27128.

[0070] In certain embodiments, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing pyrimidinyl TIFF2025037981000028.tif23128.

[0071] As a non-limiting example of the above embodiment, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 The ring containing TIFF2025037981000029.tif23128.

[0072] In some embodiments, a pair of R on adjacent atoms 1 together with the atoms that connect them and 4 to 15 (e.g., 5 to 12 (e.g., 5, 6, 7, 8, 9, or 10)) ring atoms. Forms a ring containing 0 to 3 ring atoms, each heteroatom being N, N(H), N( R d ), O, and S(O) 0~2 and the ring is independently selected from the group consisting of 1 to 4 independent R is selected by 2 may be substituted with.

[0073] In certain of these embodiments, a pair of R on adjacent atoms 1 The source that connects them Together with the aryls, they contain 4 to 12 (e.g., 4, 5, 6, 7, 8, 9, or 10) ring atoms. Forms a ring containing 0 to 3 ring atoms, each heteroatom being N, N(H), N(R d ), O, and S(O) 0~2 and the ring is independently selected from the group consisting of 1 to 4 Selected R 2 may be substituted with.

[0074] In certain of these embodiments, a pair of R on adjacent atoms 1 The source that connects them A ring that, taken together with its ring members, contains 5 to 12 (e.g., 5, 6, 7, 8, 9, or 10) ring atoms wherein 0 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~2 and the ring is 1 to 4 independently selected from the group consisting of R 2 may be substituted with.

[0075] In certain embodiments, a pair of R on adjacent atoms 1 along with the atoms that connect them together form a ring containing 5 or 6 ring atoms (e.g., an aromatic ring containing 5 or 6 ring atoms) , 0 to 2 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and and S(O) 0~2 and the ring is selected from the group consisting of 1 to 4 independently selected R 2 may be substituted with.

[0076] In certain of these embodiments, a pair of R on adjacent atoms 1 The source that connects them Together with the alkyl group, they form a ring containing 5 ring atoms, of which 0 to 2 are heteroatoms. and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independent from the group consisting of and the ring is selected from 1 to 4 independently selected R 2 may be substituted with.

[0077] In certain embodiments of the above, a pair of R on adjacent atoms 1 are the atoms connecting them together form an aromatic ring containing 5 ring atoms, and 1 to 2 (e.g., 1 or At least two ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ), O, and S(O) 0~2 and the ring is selected from the group consisting of 1 to 4 independently selected R 2 in It may be substituted.

[0078] In certain embodiments, a pair of R on adjacent atoms 1 along with the atoms that connect them Together, they form one to two independently selected R 2 forming a pyrrolyl ring optionally substituted with do.

[0079] In certain of these embodiments, a pair of R on adjacent atoms 1 The source that connects them Together with the child, TIFF2025037981000030.tif21128 is formed, where each R 2’ are independently H or R 2 is TIFF2025037981000031.tif21128.

[0080] In certain embodiments, a pair of R on adjacent atoms 1 along with the atoms that connect them Together, they form one to two independently selected R 2 a pyrazolyl ring optionally substituted with i It forms a midazolyl or thiazolyl ring.

[0081] In certain of these embodiments, a pair of R on adjacent atoms 1 The source that connects them Together with the child, TIFF2025037981000032.tif23128, where each R 2’ are independently H or R 2 is TIFF2025037981000033.tif20134.

[0082] In certain embodiments, a pair of R on adjacent atoms 1 along with the atoms that connect them Together they form a non-aromatic ring containing 5-6 ring atoms, 0-2 of which are heteroatoms and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independent from the group consisting of and the ring is selected from 1 to 4 independently selected R 2 may be substituted with.

[0083] In certain of these embodiments, a pair of R on adjacent atoms 1 The source that connects them Together with the alkyl group, they form a non-aromatic ring containing five ring atoms, one or two of which are heterocyclic. atoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 A group consisting of and the ring is a ring having 1 to 4 independently selected R 2 may be substituted with.

[0084] In certain of these embodiments, a pair of R on adjacent atoms 1 The source that connects them Together with the alkyl group, they form a non-aromatic ring containing five ring atoms, one or two of which are heterocyclic. atoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 A group consisting of and the ring is substituted with 1 to 2 oxo groups and the ring is substituted with 1 to 2 independent R selected independently 2 It may be further substituted with.

[0085] As a non-limiting example of the embodiment, a pair of R on adjacent atoms 1 is connecting them Together with the atoms, Form TIFF2025037981000034.tif23128.

[0086] In certain embodiments, a pair of R on adjacent atoms 1 along with the atoms that connect them Together they form a non-aromatic ring containing 5 ring atoms, 1 or 2 of which are heteroatoms. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independent from the group consisting of and one ring atom is selected from -O- or S(O) 0~2 and the ring is one to two independently selected RuR 2 may be substituted with (e.g., tetrahydrofuranyl TIFF2025037981000035.tif18128.

[0087] In certain embodiments, a pair of R on adjacent atoms 1 along with the atoms that connect them Together they form a ring containing six ring atoms (e.g., an aromatic ring containing six ring atoms (e.g., a pyridinyl ring) aryl or pyrimidinyl), wherein 0 to 2 ring atoms are heteroatoms, and each heteroatom is , N, N(H), N(R d ), O, and S(O) 0~2 and independently selected from the group consisting of is 1 to 4 independently selected R 2 may be substituted with.

[0088] In certain of these embodiments, a pair of R on adjacent atoms 1 The source that connects them Together with the child, 1 to 3 independently selected R 2Pyridinyl optionally substituted with The resulting product forms a hydroxyl group (including pyridonyl).

[0089] As a non-limiting example of the above embodiment, a pair of R 1 is connecting them Together with the atoms, Form TIFF2025037981000036.tif26128.

[0090] In certain embodiments, a pair of R on adjacent atoms 1 along with the atoms that connect them taken together to form a cycloalkyl ring containing 5 to 6 ring atoms, and the ring is R is selected as 2 may be substituted with.

[0091] In certain of these embodiments, a pair of R on adjacent atoms 1 The source that connects them Together with the child, Form TIFF2025037981000037.tif17128.

[0092] In certain embodiments, a pair of R on adjacent atoms 1 along with the atoms that connect them Together they form a ring containing 7-12 ring atoms, of which 0-2 are heteroatoms , each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independently from the group consisting of and the ring is selected from 1 to 4 independently selected R 2 may be substituted with.

[0093] In certain of these embodiments, a pair of R on adjacent atoms 1 The source that connects them Together with the child, 8-12 (e.g. 8) or 9-12 (e.g. 9, 10, 11, or form a ring containing 12 or 13 ring atoms, 0 to 2 of which are heteroatoms, and each hetero The atoms are N, N(H), N(R d ), O, and S(O) 0~2 are independently selected from the group consisting of: and the ring is selected from 1 to 4 independently selected R 2 may be substituted with.

[0094] In certain embodiments of the above, a pair of R on adjacent atoms 1 are the atoms connecting them Together, 8 to 12 (e.g., 9 to 12 (e.g., 9, 10, 11, or 12)) ring atoms forming a spirocyclic bicyclic ring containing 1 to 2 ring atoms, wherein 0 to 2 ring atoms are heteroatoms, and each heteroatom The children are N, N(H), and N(R d ), O, and S(O) 0~2 are independently selected from the group consisting of The ring is a ring having 1 to 4 independently selected R 2 may be substituted with.

[0095] As a non-limiting example of the embodiment, a pair of R on adjacent atoms 1 is connecting them One to two independently selected R 2 Each is further replaced by It may be Form TIFF2025037981000038.tif26128.

[0096] In some embodiments, the compound has the following formula: TIFF2025037981000039.tif26128, In the formula, ring B is a ring (e.g., a ring having 4 to 15 (e.g., 5 to 12 (e.g., 5 to 10)) ring atoms. monocyclic, bicyclic, or tricyclic ring) in which 0 to 3 ring atoms are heteroatoms; Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independently selected from the group consisting of and the ring is selected from 1 to 4 independently selected R 2 may be substituted with.

[0097] In certain of these embodiments, the compound has the following formula: TIFF2025037981000040.tif54149, where R 2’ is H or R 2 (e.g., R 2’ is H) (in certain embodiments, The compounds have formula (I-a1), and in certain embodiments thereof, R 2’ is H). In certain embodiments, Y 3 is CR 1 and R 1 is other than H, OH, or oxo. For example, Y 3 is C-halo or C-cyano.

[0098] In certain embodiments (e.g., when the compound has formula (I-1) or formula (I-2)), the compound The substance has the following formula: TIFF2025037981000041.tif25128, where R 2’ is H or R 2 is TIFF2025037981000042.tif23128 (e.g. R 2’ is H) (In certain embodiments, the compounds have the formula (I-b1), In certain embodiments, R 2’ is H).

[0099] In certain embodiments (e.g., when the compound has formula (I-1) or formula (I-2)), the compound The substance has the following formula: TIFF2025037981000043.tif22128, wherein B2 is an aromatic ring containing 5 ring atoms, and 1 to 2 (e.g., 2) of the ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O, and S(O) 0~2 Because provided that B2 is other than pyrrolyl and the ring has 1 to 4 independent Selected R 2 may be substituted with.

[0100] In certain of these embodiments, B2 is selected from 1 to 2 independently selected R 2 is replaced by It may also be a pyrazolyl ring, an imidazolyl ring, or a thiazolyl ring.

[0101] As a non-limiting example, B2 is TIFF2025037981000044.tif23128, where each R 2’ are independently H or R 2 is TIFF2025037981000045.tif20128.

[0102] In certain embodiments (e.g., when the compound has formula (I-1) or formula (I-2)), the compound The substance has the following formula: TIFF2025037981000046.tif22128, wherein B3 is a) a non-aromatic ring containing 5 to 6 ring atoms, 0 to 2 of which are heteroatoms, and each The heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independently selected from the group consisting of and the ring is selected from 1 to 4 independently selected R 2 a non-aromatic ring optionally substituted with b) a ring (e.g., a spirocyclic ring) containing 8 to 12 (e.g., 9 to 12) ring atoms, Two ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O ) 0~2 and the ring is selected from the group consisting of 1 to 4 independently selected R 2 Place optionally substituted, is selected from the group consisting of:

[0103] In certain of these embodiments, B3 is a non-aromatic ring containing 5-6 ring atoms and 0-2 The ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O) 0~ 2, and the ring is 2 is replaced by It may be possible.

[0104] In certain embodiments, B3 is a non-aromatic ring containing 5-6 ring atoms, and 0-2 ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O, and S(O) 0~2 Because and the ring is selected from 1 to 4 independently selected R 2 Even if it is replaced by good.

[0105] In certain embodiments, B3 is a non-aromatic ring containing 5 ring atoms, 1-2 of which are hydroxyl groups. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Consists of independently selected from the group consisting of 1 to 2 oxo groups and 1 to 2 substituted rings; are independently selected R 2 may be further substituted with TIFF2025037981000047.tif23128.

[0106] In certain embodiments, B3 is a non-aromatic ring containing 5 ring atoms, 0-1 of which is N , N(H), N(R d ), O, and S(O) 0~2 is a heteroatom selected from the group consisting of The ring is formed by one to two independently selected R 2 may be substituted with TIFF2025037981000048.tif18128.

[0107] In certain embodiments, B3 is a ring (e.g., spin) containing 8 to 12 (e.g., 9 to 12) ring atoms. cyclic ring), in which 0 to 2 ring atoms are heteroatoms, and each heteroatom is N, N(H), N (R d ), O, and S(O) 0~2 and the ring is independently selected from the group consisting of 1 to 4 independent R is selected as 2 may be substituted with.

[0108] In certain of these embodiments, B3 is a spiro group containing 8 to 12 (e.g., 9 to 12) ring atoms. A cyclic bicyclic ring in which 0-2 ring atoms are heteroatoms, each heteroatom being selected from N, N(H), , N(R d ), O, and S(O) 0~2 and the ring is independently selected from the group consisting of 1 to 4 independent R selected independently 2 may be substituted with.

[0109] As a non-limiting example of the above embodiment, B3 is selected from 1 to 2 independently selected R 2 So each one may be substituted with The file is TIFF2025037981000049.tif26128.

[0110] In certain embodiments, the compound has the following formula: TIFF2025037981000050.tif22128, wherein B4 is an aromatic ring containing 6 ring atoms, and 0 to 2 ring atoms are heteroatoms. and each heteroatom is N, N(H), and N(R d ), and The ring is a ring having 1 to 4 independently selected R 2 may be substituted with.

[0111] In certain of these embodiments, B4 is selected from 1 to 3 independently selected R 2 is replaced by It is also possible to use pyridinyl (including pyridonyl) TIFF2025037981000051.tif26128.

[0112] In certain embodiments, the compound has formula (I-1), (I-a1), (I-b1), (I-c1), (I-d1) , or (I-e1), Y 1 , Y 2 , and Y 3 Each of the is selected independently CR 1 and the compound is represented by formula (I-2), (I-a2), (I-b2), (I-c2), (I-d2), or ( I-e2), Y 2 , Y 3 , and Y 4 Each of the CRs is selected independently. 1 Yes do.

[0113] In certain embodiments, the compound has formula (I-1), (I-a1), (I-b1), (I-c1), (I-d1) , or (I-e1), Y 1 , Y 2 , and Y 3 One of the is N and the remaining Rino Y 1 , Y 2, and Y 3 Each of the CRs is selected independently. 1 and The compound is of formula (I-2), (I-a2), (I-b2), (I-c2), (I-d2), or (I-e2). If it is a compound, Y 2 , Y 3 , and Y 4 One of the elements is N and the remaining Y 2 , Y 3 , and Y 4 That Each is selected independently. 1 is.

[0114] In some embodiments, the compound has formula (I-a1-b): TIFF2025037981000052.tif26128, where R 2’ is H or R 2 is.

[0115] In certain of these embodiments, the compound has formula (I-a1-b): TIFF2025037981000053.tif26128 (e.g. R 1 is other than hydrogen (e.g., R 1 is other than hydrogen and A is Y A1 -Y A2 Yes (e.g., Y A2 is an optionally substituted aryl or an optionally substituted heteroaryl. aryl, for example optionally substituted pyridyl as defined herein).

[0116] In certain embodiments, the compound has formula (I-a1-c): I have TIFF2025037981000054.tif25128.

[0117] In certain embodiments, the compound has formula (I-a1-d): I have TIFF2025037981000055.tif20128.

[0118] In certain embodiments, the compound has formula (I-a1-e): TIFF2025037981000056.tif27128 (e.g. R 1 is other than hydrogen (e.g., R 1 is other than hydrogen and A is Y A1 -Y A2 Yes (e.g., Y A2 is an optionally substituted aryl or an optionally substituted heteroaryl. aryl, for example optionally substituted pyridyl as defined herein).

[0119] In some embodiments, the compound has formula (I-b1-a): TIFF2025037981000057.tif24128, where R 2’ is H or R 2 is.

[0120] In certain embodiments, the compound has formula (I-b1-b): I have TIFF2025037981000058.tif21128.

[0121] In certain embodiments, the compound has formula (I-b1-c): I have TIFF2025037981000059.tif23128.

[0122] In certain embodiments, the compound has formula (I-b1-d): I have TIFF2025037981000060.tif21128.

[0123] In some embodiments, R 1 R that does not form a ring together with the atom to which it is attached 1 Each occurrence of H, Hello, Cyano, 1-2 R a C optionally substituted with1~6 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 1~4 haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy, -S(O) 1~2 (C 1~4 alkyl), -NR e R f , -OH, Oxo, -S(O) 1~2 (NR'R''), -C(=O)(C 1~4 alkyl), -C(=O)O(C 1~4 alkyl), ·-C(=O)OH, -C(=O)N(R')(R''), and -L 3 -L 4 -R i are independently selected from the group consisting of:

[0124] In some embodiments, R 1 R that does not form a ring together with the atom to which it is attached 1 Each occurrence of is H.

[0125] In some other embodiments, R 1 does not form a ring together with the atoms to which it is attached I R 1 one to three (e.g., one, two, or three) occurrences of are other than H, and R 1 The atoms that are bonded R that does not join with its children to form a ring 1 Each of the remaining occurrences of is H.

[0126] In certain of these embodiments, R 1 together with the atoms to which they are attached to form a ring Each R 1 is other than H and R 1 together with the atoms to which they are attached to form a ring R that never does 1 Each of the remaining occurrences of is H.

[0127] In some embodiments, R 1 One occurrence of is halo (eg, -F or -Cl).

[0128] In some embodiments, R 1 One occurrence of NR e R f (e.g., NHAc) or C 1~4 Alkoxy (e.g. For example, methoxy.

[0129] In some embodiments, R 1 One occurrence of is one or two R a C optionally substituted with 1~6 Alkyl (e.g., methyl, CH2OH, or CH2CH2OH).

[0130] In some embodiments, R 1 One occurrence of is cyano.

[0131] In some embodiments, R 1 One occurrence of -L 3 -L 4 -R i (e.g., -L 3 is a bond, and -L 4 -O - (e.g., R 1 is phenoxy).

[0132] In certain of these embodiments, -L 3 is a bond, and -L 4 is -O- (e.g., R 1 Is Pheno (It is a kisi).

[0133] In certain other embodiments, -L 3 is a bond, and -L 4 is a bond (e.g., R 1 is pyrazolyl or phenyl).

[0134] In some embodiments, R 1 One occurrence of is C(=O)OH and C(=O)O(C 1~4 alkyl) or is selected from the group consisting of:

[0135] Symbol R 2 In some embodiments, R 2 Each occurrence of Hello, Cyano, 1-2 R a C optionally substituted with 1~6 Alkyl, C 1~4 haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy, -S(O) 1~2 (C 1~4 alkyl), -S(O)(=NH)(C 1~4 alkyl), -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, -C(=O)N(R')(R''), and -L 3 -L 4 -L 5 -R i are independently selected from the group consisting of:

[0136] In some embodiments, R 2 One occurrence of is halo (e.g., F, Cl, or Br (e.g., F or Cl) Or cyano.

[0137] In some embodiments, R 2 One occurrence of is one or two R a C optionally substituted with 1~6 Alkyl In certain of these embodiments, R a Each occurrence of is independently -F, -Cl, -OH, C 1~4 a Lukoxi, C 1~4 Haloalkoxy, and -NR e R f (e.g., R 2 is methyl, CH2OH, or is CH2CH2OH).

[0138] In some embodiments, R 2 One occurrence of is oxo or R 2 One occurrence of is OH.

[0139] In some embodiments, R 2 One occurrence of NR e R f is.

[0140] In certain of these embodiments, R e and R f Each of these is H; halo, OH, C 1~4 Alcoki C 1~4 1 to 2 substituents each independently selected from haloalkoxy, and CN; C optionally substituted with 1~6Alkyl; -C(O)(C 1~4 alkyl);-C(O)O(C 1~4 Al KILL);-CON(R')(R'');-S(O) 1~2 (C 1~4 alkyl); and -S(O)(=NR') (C 1~4 alkyl).

[0141] In certain embodiments of the above, R e and R f is H (e.g., NR e R f NHAc, NHS(O)2M e, NHS(O)(=NH)Me, or NH(CH2CH2OH).

[0142] In some embodiments, R 2 One occurrence of -L 3 -L 4 -L 5 -R i is.

[0143] In certain of these embodiments, R 2 -L 3 is a bond. In certain other embodiments, R 2 of- L 3 is C 1~3 Alkylene (e.g., CH2).

[0144] In certain embodiments, R 2 -L 4 is NR N (e.g., NH).

[0145] In certain embodiments, R 2 -L 4 is a bond.

[0146] In certain embodiments, R 2 -L 4 is -NR N C(O)-, -NR N S(O)0~2 -, or -NR N S(=O )(=NR N ) (e.g. R N is H).

[0147] In certain embodiments, R 2 -L 4 is NR N S(=O)(=NR N )NR N , -NR N S(O) 1~2 NR N -,oh Yobi-NR N C(O)NR N -(e.g. R N is H).

[0148] In certain embodiments, -L 5 is a bond.

[0149] In certain other embodiments, -L 5 is C 1~3 Alkylene (e.g., -CH(CH3)CH2-).

[0150] In certain embodiments, R 2 R i Ha, Halo, C 1~4 Alkyl, and C 1~4 From haloalkyl and optionally substituted with 1 to 4 (for example, 1 to 2) substituents independently selected from the group consisting of C 3~8 (e.g., C)cycloalkyl (provided that in certain embodiments, R h But C 1~4 Al C optionally substituted with 1 to 4 substituents independently selected from alkyl 3~6 Cycloalkane If it is a 1 is a bond or -L 2 is -O-, -N(H)-, or -S-) .

[0151] In certain embodiments, R 2 R i Ha, Halo, C 1~4 Alkyl, and C 1~4 From haloalkyl and optionally substituted with 1 to 4 (for example, 1 to 2) substituents independently selected from the group consisting of C 6~10 (e.g., C6)aryl.

[0152] In certain embodiments, R 2 R i is a heteroaryl containing 5 to 6 ring atoms and 1 to 4 are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O)0 ~2 and the heteroaryl ring is independently selected from the group consisting of halo, C 1~4 Alkyl, and C 1~4 substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; It may be possible.

[0153] As a non-limiting example, R 2 Ga-L 3 -L 4 -L 5 -R i If R 2 teeth It can be TIFF2025037981000061.tif36157.

[0154] As a further non-limiting example, R 2 Ga-L 3 -L 4 -L 5 -R i If R 2 teeth, TIFF2025037981000062.tif40128.

[0155] In some embodiments, R 2 One occurrence of is C(O)OH.

[0156] WA (A) The aspect when defined according to In some embodiments, WA is as defined according to (A).

[0157] Symbol W In some embodiments, W is *C(=O)NR N , *C(=S)NR N , *C(=NR d )NR N , *C(=CNO 2)NR N is selected from the group consisting of:

[0158] In certain embodiments, W is *C(=O)NR N is.

[0159] In certain of these embodiments, W is *C(=O)NH or *C(=O)N(C 1~3 Alkyl )

[0160] As a non-limiting example of said embodiment, W is *C(=O)NH.

[0161] In certain embodiments, W is *S(O) 1~2 NR N In certain of these embodiments, W is *S(O)2NR N (e.g., *S(O)2NH).

[0162] In certain embodiments, W is TIFF2025037981000063.tif19128 (for example, each R N is H).

[0163] In certain embodiments, W is TIFF2025037981000064.tif18128.

[0164] In certain of these embodiments, Q 2 is NR N In certain embodiments, Q 2 is NH or N( C 1~3 alkyl). For example, Q 2 is NH.

[0165] In certain embodiments, W is -Q 1 -Q 2 In certain of these embodiments, -Q 1 5 to 6 pieces wherein 1 to 4 of the ring atoms are heteroatoms, and each hetero The atoms are N, N(H), N(R d ), O, and S, and The arylene ring is a ring having 1 to 4 independently selected R q1 may be substituted with.

[0166] In certain embodiments of the above, Q 1 is a heteroarylene containing 6 ring atoms, 1 to 3 One or two (e.g., one or two) ring atoms are ring nitrogen atoms, and the heteroarylene ring has one or two independent R selected independently q1 may be substituted with.

[0167] In certain embodiments, Q 1 is a heteroarylene containing 6 ring atoms, and 1 to 3 (e.g. For example, 1 to 2) ring atoms are ring nitrogen atoms, and the heteroarylene ring has 1 to 2 independent Selected R q1 may be substituted with.

[0168] In certain embodiments, Q 1 is one to two independently selected R q1 are replaced by and optionally pyridylene or pyrimidinylene.

[0169] As a non-limiting example of said embodiment, Q 1 is one to two independently selected R q1 And each one may be substituted TIFF2025037981000065.tif42128, wherein the asterisk represents Q 2 represents the connection point of TIFF2025037981000066.tif16128.

[0170] In a particular embodiment (W is -Q 1 -Q 2 (if so), then each R q1 is halo; cyano; 1 to 6 independent R is selected by a C optionally substituted with 1~10 Alkyl (e.g., unsubstituted C 1~10 alkyl) ;C 3~6 cycloalkyl; and oxo.

[0171] In a particular embodiment (W is -Q 1 -Q 2 If so, then Q 2 is a bond.

[0172] In a particular embodiment (W is -Q 1 -Q 2 If so, then Q 2 is -O-, -NH-, or -S(O) 0~2 in Yes (for example, Q 2 is -O- or Q 2 is -NH- or Q 2 is -S(O)2-) .

[0173] Symbol A In some embodiments, A is -Y A1 -YA2 is.

[0174] In certain of these embodiments, Y A1 is a bond.

[0175] In certain other embodiments, Y A1 is 1 to 4 R a C optionally substituted with 1~6 Alkylene is.

[0176] In certain embodiments of the above, Y A1 is C 1~6 It is alkylene.

[0177] In certain embodiments, Y A1 is 1 to 2 R a C optionally substituted with 1~6 Alkylene do.

[0178] As a non-limiting example, Y A1 -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CF3)-, -CH2CH (OH)-, TIFF2025037981000067.tif17133 (for example, Y A1 is CH2).

[0179] For example, Y A1 can be -CH2- or -CH2CH2-.

[0180] In certain other embodiments, Y A1 is Y A3 -Y A4 -Y A5 is.

[0181] In certain of these embodiments, Y A3 is C 2~3 alkylene, and / or Y A4 Ha-O-Ma or -S- and / or Y A5is a bond.

[0182] As a non-limiting example of the above embodiment, Y A1 teeth It can be TIFF2025037981000068.tif10128.

[0183] In certain of these embodiments, Y A3 is C 2~3 alkylene, and / or Y A4 Ha-O-Ma or -S- and / or Y A5 is C 1~2 It is alkylene.

[0184] As a non-limiting example, Y A1 teeth It can be TIFF2025037981000069.tif7128.

[0185] Y A1 However, 1 to 4 R a C optionally substituted with 1~6 Non-limiting examples of alkylene As, Y A1 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CF3)-, -CH2CH(OH)-, or TIFF2025037981000070.tif11128 (e.g. CH2).

[0186] In some embodiments, Y A2 is 1 to 3 R c C optionally substituted with 6~10 It is aryl.

[0187] In certain embodiments, Y A2 is a C6 aryl.

[0188] In certain embodiments, Y A2 is 1 to 3 R c is a C6 aryl substituted with

[0189] In certain embodiments, Y A2 is 1 to 3 (e.g. 1 or 2) R c Phenylenium substituted with is one R c is Y A1 It is located on the ring carbon para to the point of attachment to

[0190] In certain embodiments, Y A2 is 1 to 3 (e.g. 1 or 2) R c Phenylenium substituted with and 1 to 2 (e.g., 1) R c is Y A1 Located on a ring carbon meta to the point of attachment to do.

[0191] In certain embodiments, Y A2 is 1 to 3 (e.g. 1 or 2) R c Phenylenium substituted with and 1 to 2 (e.g., 1) R c is Y A1 Located on the ring carbon ortho to the point of attachment to do.

[0192] In certain embodiments, Y A2 is 1 to 3 R c C optionally substituted with 7~10 Bicyclic arylate (e.g., Y A2 is 1 to 3 R c naphthyl, each of which may be substituted with TIFF2025037981000071.tif18128, Indacenyl TIFF2025037981000072.tif23128, or tetrahydronapthyl).

[0193] In some embodiments, Y A2 is a heteroaryl containing 5 to 14 ring atoms, and The atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 mosquito and the heteroaryl ring is selected from 1 to 4 independently selected R c may be substituted with.

[0194] In certain embodiments, Y A2 is a heteroaryl containing 5 ring atoms, and The atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 mosquito and the heteroaryl ring is selected from the group consisting of 1 to 3 independently selected R c may be substituted with.

[0195] In certain of these embodiments, Y A2 is one to two (e.g., one) independently selected R c in Thiazolyl, thiadiazolyl, isoxazolyl, and the like, each of which may be substituted; thiazolyl, or pyrazolyl (e.g., Y A2 is one or two (for example, one) independently selected Selected R c and pyrazolyl, which may be substituted with, for example, Y A2 teeth TIFF2025037981000073.tif15128).

[0196] In certain of these embodiments, Y A2 is one to two (e.g., one) independently selected R c in each of which is optionally substituted thiazolyl, triazolyl, or pyrazolyl; (For example, Y A2 is one to two (e.g., one) independently selected R coptionally substituted with Irazoryl (e.g., Y A2 teeth TIFF2025037981000074.tif15128).

[0197] In certain embodiments, Y A2 is a heteroaryl containing 6 ring atoms (e.g., pyridyl or is pyrimidinyl (e.g., pyridyl) TIFF2025037981000075.tif23128), wherein one to two ring atoms are ring nitrogen atoms, and the heteroaryl ring is R is selected as c may be substituted with.

[0198] In certain of these embodiments, Y A2 is 1 to 3 independently selected R c is replaced by , R c One occurrence of Y A1 It is at the ring carbon atom para to the point of attachment to

[0199] In a certain aspect (Y A2 is a heteroaryl containing 6 ring atoms (e.g., pyridyl or pyridyl); Rimidinyl (e.g., pyridyl TIFF2025037981000076.tif23128), in which 1 to 2 ring atoms are ring nitrogen atoms, and the heteroaryl ring has 1 to 3 independent R is selected by c (optionally substituted with) Y A2 are 1 to 3 independently selected RuR c is substituted with R c One or two occurrences of Y A1 A ring carbon atom meta to the point of attachment to It's in the child.

[0200] In certain embodiments, Y A27-14 (e.g., 9-12 (e.g., 9, 10, 11, or 12) )) is a bicyclic or tricyclic heteroaryl containing ring atoms of atoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 A group consisting of and the heteroaryl ring is a heteroaryl ring having 1 to 4 independently selected R c is replaced by may be used (e.g., Y A2 is one to two independently selected R c Each is replaced by Good TIFF2025037981000077.tif27128).

[0201] WA (B) The aspect when defined according to In some embodiments, WA is as defined according to (B).

[0202] In certain of these embodiments, W is selected from 1 to 4 R c C optionally substituted with 8~10 bicyclic It is an arylene.

[0203] In certain embodiments, when W A is defined according to (B), W contains 8 to 10 ring atoms. Bicyclic heteroarylene, wherein 1 to 4 ring atoms are heteroatoms, and each heteroatom is , N, N(H), N(R d ), O, and S(O) 0~2 and The heteroaryl ring is a ring of 1 to 4 independently selected R c may be substituted with.

[0204] In certain of these embodiments, W is heteroarylene containing 9 to 10 ring atoms; One to two ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S (O) 0~2 and the heteroaryl ring is selected from the group consisting of 1 to 2 independently Selected R c may be substituted with.

[0205] In certain of the above embodiments, W is selected from 1 to 2 independently selected R c Each is replaced by quinolinylene, isoquinolinylene, and quinazolinylene, which may be are selected.

[0206] As a non-limiting example of such an embodiment, W is TIFF2025037981000078.tif15128.

[0207] In certain embodiments, A is H when WA is defined according to (B).

[0208] In certain other embodiments, when WA is defined according to (B), A is defined according to (A). For example, A may be 1 to 6 independently selected R a Even if it is replaced by Good C 1~20 Alkyl (e.g., C 1~3 alkyl).

[0209] Symbol R c In some embodiments, R c Each occurrence of Hello, Cyano, 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 1~4 Alkoxy, C 1~4 haloalkoxy, -S(O) 1~2 (C 1~4 alkyl), -S(O) 1~2 (C 1~4 haloalkyl), -NR e R f , -C 1~4 thioalkoxy, -C 1~4 thiohaloalkoxy, -SF5, -C(=O)(C 1~10 alkyl), -C(=O)(OH), -C(=O)O(C 1~4 alkyl), and -L 1 -L 2 -R h are independently selected from the group consisting of:

[0210] In certain embodiments, R c Each occurrence of Hello, Cyano, 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 1~4 Alkoxy, C 1~4 haloalkoxy, -S(O) 1~2 (C 1~4 alkyl), -NR e R f , -C 1~4 thioalkoxy, -C(=O)(C 1~10 alkyl), -C(=O)(OH), -C(=O)O(C 1~4 alkyl), and -L 1 -L 2 -R h are independently selected from the group consisting of:

[0211] In certain embodiments, R c One occurrence of is a halo.

[0212] In certain embodiments, R c One occurrence of is cyano.

[0213] In certain embodiments, R c Each occurrence of a is replaced by C 1~10 It is alkyl.

[0214] In certain of these embodiments, R c One occurrence of is unsubstituted C 1~10 Alkyl (e.g., C2, C 3, C4, C5, C6, or C 7~10 )

[0215] As a non-limiting example of said embodiment, R c One occurrence of is ethyl, propyl (e.g., n-propyl) butyl), butyl (e.g., n-butyl, iso-butyl, sec-butyl, tert-butyl), pentyl , or octyl (e.g., n-octyl) (e.g., R c is butyl (e.g., n-butyl) be).

[0216] In certain embodiments, R c One occurrence of is unsubstituted C 6~10 Alkyl (e.g., linear C 6~10 a Rukill).

[0217] In certain embodiments, R c Each occurrence of a C replaced with 1~10 It is alkyl.

[0218] In certain of these embodiments, R a Each occurrence of is -F, -Br, -Cl, OH, C 1~4 Alkoxy, N R e R f , C 1~4 haloalkoxy, and 1 to 4 independently selected C 1~4 Alkyl-substituted C 3~6 cycloalkyl. As a non-limiting example, Each R a is -F.

[0219] As a non-limiting example of said embodiment, R c One occurrence of CF3, CHF2, CH2CF3, CH2CH2CF3, C H2CH2CH2OH, CH2CH2OH, CH2OH, CH2CH2OMe, CH2OEt, CH2OCH2CH2CH3, CH(OH)CH2CH3, C H2NMe2, CH2CH2NMe2, and Selected from TIFF2025037981000079.tif11128 (e.g. R c is CF3).

[0220] In certain embodiments, R c One occurrence of is -SF5.

[0221] In certain embodiments, R c One occurrence of is -S(O) 1~2 (NR'R'') The file is TIFF2025037981000080.tif16128.

[0222] In certain embodiments, R cOne occurrence of is S(O) 1~2 (C 1~4 alkyl) or S(O) 1~2 (C 1~4 haloalkyl) (e.g., S(O)CF). In certain embodiments, R c One of the Currently C 1~4 Alkoxy or C 1~4 Haloalkoxy (e.g., OCF3, OCF2H, OCH2CF3, and C such as OCH2CF2H 1~4 haloalkoxy). In certain embodiments, R c One occurrence of C2 ~6 Alkenyl or C 2~6 Alkynyl (e.g., C 2~6 Alkynyl (e.g., acetylenyl) In certain embodiments, R c One occurrence of is -C(=O)(C 1~10 alkyl) (e.g. -C(=O)(C 3~10 alkyl) (e.g., —C(═O)CHCHCHCHCHCHCHCHCH)).

[0223] In certain embodiments, R c One occurrence of -L 1 -L 2 -R h In certain of these embodiments, , L 1 is a bond. In certain other embodiments, L 1 is CH2, CH2CH2, or C(=O) In a certain aspect (R c One occurrence of -L 1 -L 2 -R h In this case, L 2 is a bond. In certain other embodiments, L 2 is -O-. In certain embodiments (R c One occurrence of -L 1 -L 2 -Rh in If there is one, L 1 is a bond and L 2 is a bond. In certain other embodiments, L 1 is a bond and L 2 is -O-.

[0224] In a particular aspect (R c One occurrence of -L 1 -L 2 -R h In this case, R h Ha, Halo, C 1~4 a Lukil, and C 1~4 haloalkyl; Optionally substituted C 3~8 It is cycloalkyl.

[0225] Certain aspects of these (e.g., -L 1 is a bond and -L 2 is a bond), then R h Ha, Halo, C 1~4 Alkyl, and C 1~4 haloalkyl C optionally substituted with 1 to 4 substituents 3~6 cycloalkyl The file is TIFF2025037981000081.tif23128.

[0226] For example, R h teeth TIFF2025037981000082.tif23128.

[0227] In certain embodiments, R h is a heterocyclyl, and the heterocyclyl has 4 to 10 carbon atoms (e.g., 4, 5, or 6) ring atoms, and 1 to 3 (e.g., 1 to 2, e.g., 1) ring atoms are heterocyclic. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Consists of and heterocyclyl is selected from the group consisting of halo; 1 to 2 independently selected R a Place C may be replaced 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; is also good, for example, R h teeth The file is TIFF2025037981000083.tif22128.

[0228] In a particular aspect (R c One occurrence of -L 1 -L 2 -R h In this case, R h Halo, Cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 From Haloalkoxy C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 6~10 With Aryl be.

[0229] In a particular aspect (R c One occurrence of -L 1 -L 2 -R h In this case, R h Ha, Halo, C 1~4 a Lukil, and C 1~4 haloalkyl; Optionally substituted C 6~10 It is aryl.

[0230] In certain embodiments, R h Halo, Cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~ 4 alkoxy, and C 1~4 haloalkoxy, 1 to 2 substituents independently selected from the group consisting of C6 aryl optionally substituted with a substituent (e.g., R h is unsubstituted phenyl or or R h teeth TIFF2025037981000084.tif22128).

[0231] In certain of these embodiments, R h Ha, Halo, C 1~4 Alkyl, and C 1~4 Haloalkyl C6 aryl optionally substituted with 1 to 2 substituents independently selected from the group consisting of (e.g. R h is unsubstituted phenyl, or R h teeth TIFF2025037981000085.tif11128).

[0232] R c In one or more of the foregoing embodiments, the remaining R, when present, c Each of these is independent and halo or R a C optionally substituted with 1~4 It is alkyl.

[0233] In some embodiments, Y A2 is 1 to 4 (e.g. 1 to 2) R b C replaced with 3~6 (For example, C3, C5, or C6) cycloalkyl (e.g., Y A2 is 1 to 2 R b are replaced by optionally cyclopropyl, cyclopentyl, bicyclo[1.1.1]pentyl, or cyclopropyl; cyclohexyl).

[0234] In certain of these embodiments, Y A2 is 1 to 2 R b Optionally substituted cyclohexane It's Sil.

[0235] In certain of these embodiments, R b One occurrence of Y A1 Para to the point of attachment to the ring carbon It is found in elementary atoms.

[0236] In certain embodiments, R b One occurrence of Y A1 On a ring carbon atom meta to the point of attachment to be.

[0237] In certain embodiments, R b One occurrence of Y A1 A ring carbon atom ortho to the point of attachment to is located.

[0238] In certain embodiments, Y A2 is 1 to 4 R b C optionally substituted with 7~10 Cycloalkane (e.g., Y A2 is 1 to 3 R b each of which may be further substituted by a bicyclo Octyl TIFF2025037981000086.tif23128 or spiroundecanyl (e.g., spiro[5,5]undecanyl, e.g. TIFF2025037981000087.tif18128, Spirooctyl TIFF2025037981000088.tif22128).

[0239] In some embodiments, Y A2is a heterocyclyl containing 3 to 12 ring atoms, The atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 mosquito and the heterocyclyl ring is selected from 1 to 4 independently selected R b may be substituted with.

[0240] In certain of these embodiments, Y A2 is a heterocyclic ring containing 5 to 12 (e.g., 5 to 10) ring atoms. is a cyclocyclyl, wherein 1 to 3 (e.g., 1 or 2) ring atoms are heteroatoms, and each hetero The atoms are N, N(H), N(R d ), O, and S(O) 0~2 are independently selected from the group consisting of: and the heterocyclyl ring is selected from 1 to 4 independently selected R b may be substituted with (e.g. Y A2 is one to three independently selected R b Pyril, each of which may be further substituted Jinil TIFF2025037981000089.tif19128, piperidinyl TIFF2025037981000090.tif23128, or tetrahydropyranyl TIFF2025037981000091.tif20128, or TIFF2025037981000092.tif28128).

[0241] In certain embodiments, Y A2 is a heterocyclic ring containing 5 to 6 (e.g., 5 or 6) ring atoms. wherein one to two (e.g., one or two) ring atoms are heteroatoms, and each heteroatom is , N, N(H), N(R d ), O, and S(O) 0~2and The cyclyl ring is a ring having 1 to 4 independently selected R b may be substituted with (e.g., Y A2 is 1~ Three independently selected R b each of which may be further substituted by TIFF2025037981000093.tif18128, piperidinyl TIFF2025037981000094.tif23128).

[0242] As a non-limiting example of the above embodiment, Y A2 is one to three independently selected R b Place it further may be replaced The file is TIFF2025037981000095.tif22128.

[0243] In certain embodiments, Y A2 R b Each occurrence of a substituent is selected from 1 to 6 independently selected R a Place C may be replaced 1~10 Alkyl; C 1~4 Haloalkyl; -F; -Cl; -Br; Cyano; C 1~4 Arco Kishi;C 1~4 Haloalkoxy; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl) ;-S(O) 1~2 (C 1~4 alkyl); oxo; cyano; and -L 1 -L 2 -R h Independent from the group consisting of is selected.

[0244] In certain embodiments, Y A2 R b Each occurrence of a substituent is selected from 1 to 6 independently selected R a in Optionally substituted C 1~10 It is alkyl.

[0245] In certain of these embodiments, Y A2 R b One occurrence of a substituent is an unsubstituted C 1~10 Alkyl (e.g. For example, C 2、 C 3、 C 4、 C 5、 C6, or C 7~10 )

[0246] In certain embodiments of the above, Y A2 R b One occurrence of a substituent may be ethyl, propyl (e.g. n-propyl), butyl (e.g. n-butyl, or sec-butyl, or tert-butyl, or iso-butyl), or octyl (e.g., n-octyl) (e.g., butyl (e.g., n- butyl).

[0247] In certain embodiments, Y A2 R b Each occurrence of a substituent is selected from 1 to 6 independently selected R a in Substituted C 1~10 It is alkyl.

[0248] In certain such embodiments, R a Each occurrence of is -F, -Br, -Cl, OH, C 1~4 Alkoxy, NR e R f , C 1~4 haloalkoxy, and 1 to 4 independently selected C 1~4 Alkyl substituted C 3~6 cycloalkyl.

[0249] In certain embodiments, R b One occurrence of -L 1-L 2 -R h In certain of these embodiments, , L 1 is a bond. In certain embodiments (R b Ga-L 1 -L 2 -R h In this case, L 2 is a bond .

[0250] In a particular aspect (R b Ga-L 1 -L 2 -R h In this case, R h Ha, Halo, C 1~4 Alkyl and and C 1~4 substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; Good C 3~6 It is cycloalkyl.

[0251] In a particular aspect (R b Ga-L 1 -L 2 -R h In this case, R h is heterocyclyl, Tetracyclyl contains 3 to 10 (e.g., 4, 5, 6, 7, 8, 9, or 10) ring atoms and 1 to 3 ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S(O ) 0~2 and heterocyclyl is independently selected from the group consisting of halo, C 1~4 Alkyl, Call C 1~4 substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; It's fine.

[0252] In a particular aspect (R b Ga-L 1 -L 2 -R hIn this case, R h Ha, Halo, C 1~4 Alkyl, also is C 1~4 substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; Good C 6~10 aryl (e.g., C6) (e.g., R h is unsubstituted phenyl).

[0253] In certain embodiments, R b one occurrence of is -Cl or -F (e.g., -F), or R b One occurrence of is oxo or cyano.

[0254] R b In one or more of the foregoing embodiments, R b Each remaining occurrence of is -Cl, -F, -Br, No, C 1~3 Alkyl, and C 1~3 haloalkyl.

[0255] In certain embodiments, Y A2 teeth TIFF2025037981000096.tif14128, n1 is 0, 1, or 2, R cA and R cB Each of R is independently selected c in be.

[0256] In certain embodiments, Y A2 teeth TIFF2025037981000097.tif21128, n1 is 0, 1, or 2, R cA and R cB Each of R is independently selected c in be.

[0257] In certain embodiments, Y A2 teeth TIFF2025037981000098.tif15128, X 1 and X 2 One of them is N and X 1 and X 2 The other of these is CH, and n1 is 0 , 1, or 2, and R cA and R cB Each of R is independently selected c is.

[0258] In certain embodiments, Y A2 teeth, TIFF2025037981000099.tif16128, X 1 、 X 2 , X 3 , and X 4 One of them is N and the other is X 1 、 X 2 , X 3 , and X 4 The remainder of Each of n1 is CH, n1 is 0, 1, or 2, and R cA and R cB Each of these is independent. R is selected by c is.

[0259] In a certain aspect (Y A2 but TIFF2025037981000100.tif23130) in R cA No. 6,239,693, filed on Dec. 1, 2002, which is incorporated herein by reference in its entirety. In any one of claims 124 to 133 of Application No. 62 / 861,714, R c It is defined as It is.

[0260] In a certain aspect (Y A2 but TIFF2025037981000101.tif23129), R cAis any one of paragraphs 153 to 165 (for example, paragraph 153, paragraph 154) , Section 155, Section 156, Section 157, Section 159, Section 160, Section 161, Section 162, Section 163, Section 164. Section 165) c As defined for

[0261] In certain embodiments, R cA is 1 to 6 independently selected R a C replaced with 1~10 Al In certain of these embodiments, each R a -F, -Cl, OH, C 1~4 Alkoxy, NR e R f , C 1~4 haloalkoxy, and 1 to 4 independently selected C 1~4 Alkyl-substituted C 3~6 cycloalkyl (e.g., each R a teeth- F)).

[0262] In certain embodiments, R cA is C substituted with 1 to 3 -F 1~3 alkyl (e.g., R c A is —CF3). In certain embodiments, R cA is unsubstituted C 1~10 Alkyl (e.g., straight chain C2, C3 , C4, C5, C6, or C 7~10 alkyl).

[0263] In certain embodiments, R cA is C 2~6 Alkenyl, C 2~6 Alkynyl, or -C(=O)( C 1~10 alkyl) (e.g., -C(=O)(C 3~10alkyl) (e.g., -C(=O)CH2CH2CH2CH2 CH2CH2CH2).

[0264] In certain embodiments, R cA -SF5;-S(O) 1~2 (NR'R'') TIFF2025037981000102.tif16128;S(O) 1~2 (C 1~4 alkyl); and S(O) 1~2 (C 1~4 haloalkyl) (e.g., S(O) 2CF3).

[0265] In certain embodiments, R cA is C 1~4 Alkoxy or C 1~4 Haloalkoxy (e.g., OCF3 , OCF2H, OCH2CF3, and OCH2CF2H, etc. 1~4 haloalkoxy).

[0266] In a certain aspect (Y A2 but TIFF2025037981000103.tif23132), R cA No. 6,239,693, filed on Dec. 1, 2002, which is incorporated herein by reference in its entirety. In any one of claims 134 to 143 of Application No. 62 / 861,714, R c It is defined as It is.

[0267] In a certain aspect (Y A2 but TIFF2025037981000104.tif23131), R cA is R in any of paragraphs 166 to 177. c is defined in terms of (For example, R c Ha-L 1 -L 2 -R hFor example, R h and R h , Articles 175, 176, or as defined in section 177).

[0268] In certain embodiments, R cA Ha-L 1 -L 2 -R h wherein -L 1 is a bond, CH2, or -CH2CH2 and -L 2 is a bond or -O-.

[0269] In certain of these embodiments, R h Ha, Halo, C 1~4 Alkyl, and C 1~4 Haloalkyl C optionally substituted with 1 to 4 substituents independently selected from the group consisting of 3~6 Cyclo Alkyl The file is TIFF2025037981000105.tif23128.

[0270] In certain embodiments, R h is a heterocyclyl, and the heterocyclyl has 4 to 10 carbon atoms (e.g., 4, 5, or 6) ring atoms, and 1 to 3 (e.g., 1 to 2, e.g., 1) ring atoms are heterocyclic. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Consists of and heterocyclyl is selected from the group consisting of halo; 1 to 2 independently selected R a Place C may be replaced 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; is also good, for example, Rh teeth The file is TIFF2025037981000106.tif22128.

[0271] In certain of these embodiments, R h Halo, Cyano, C 1~4 Alkyl, C 1~4 Hello Aruki Lu, C 1~4 Alkoxy, and C 1~4 1 independently selected from the group consisting of haloalkoxy C6 aryl optionally substituted with up to two substituents (e.g., R h is unsubstituted phenyl or R h teeth TIFF2025037981000107.tif22128).

[0272] In a certain aspect (Y A2 but TIFF2025037981000108.tif23128), n1 is 0.

[0273] In certain other embodiments, n1 is 1 or 2. In certain of these embodiments, each R cB are independently halo or R a C optionally substituted with 1~4 It is alkyl.

[0274] In certain embodiments, Y A2 teeth TIFF2025037981000109.tif15128, n2 is 0, 1, or 2, and R bA and R bB Each of R is independently selected b in be.

[0275] In certain embodiments, Y A2 teeth TIFF2025037981000110.tif19128, n2 is 0, 1, or 2, R bA and R bB Each of R is independently selected b in be.

[0276] In a certain aspect (Y A2 but TIFF2025037981000111.tif21128) in R bA No. 6,239,693, filed on Dec. 1, 2002, which is incorporated herein by reference in its entirety. R in claim 154 of Application No. 62 / 861,714 b As defined for

[0277] In a certain aspect (Y A2 but TIFF2025037981000112.tif20128) in R bA is R in paragraph 189. b As defined for

[0278] In certain embodiments, R bA is 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl; C 1~4 Haloalkyl; -F; -Cl; -Br; Cyano; C 1~4 Alkoxy;C 1~4 Haloal -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-S(O) 1~2 (C 1~ 4 alkyl); oxo; cyano; and -L 1 -L 2 -R h are independently selected from the group consisting of:

[0279] In a certain aspect (Y A2 but TIFF2025037981000113.tif21128), R bA No. 6,239,693, filed on Dec. 1, 2002, which is incorporated herein by reference in its entirety. In any one of claims 155 to 159 of Application No. 62 / 861,714, R b It is defined as It is.

[0280] In a certain aspect (Y A2 but TIFF2025037981000114.tif21128), R bA is any one of paragraphs 190 to 194 (for example, paragraph 190, paragraph 191) , 192, 193, or 194) b As defined for

[0281] In certain embodiments, R bA is 1 to 6 independently selected R a C optionally substituted with 1~10 It is alkyl.

[0282] In certain embodiments, R bA is unsubstituted C 1~10 Alkyl (e.g., straight chain C2, C3, C4, C5, C6, or C 7~10 alkyl).

[0283] In certain embodiments, R bA is 1 to 6 independently selected R a C replaced with 1~10 Al Kill, e.g., -F, -Cl, OH, C 1~4 Alkoxy, NR e R f , C 1~4 Haloalkoxy, and 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 3~6 Cycloal C substituted with 1 to 6 substituents each independently selected from the group consisting of 1~10 a It's Rukiru.

[0284] In a certain aspect (Y A2 but TIFF2025037981000115.tif21128), R bA No. 6,239,693, filed on Dec. 1, 2002, which is incorporated herein by reference in its entirety. In any one of claims 160 to 165 of Application No. 62 / 861,714, R b It is defined as It is.

[0285] In a certain aspect (Y A2 but TIFF2025037981000116.tif20128) in R bA is any one of paragraphs 195 to 200 (for example, paragraph 195, paragraph 196) , 197, 198, 199, or 200) b As defined for be.

[0286] In certain embodiments, R bA Ha-L 1 -L 2 -R h where L 1 is a bond and L 2 is a join or -O-, R h Ha, Halo, C 1~4 Alkyl, and C 1~4 haloalkyl C optionally substituted with 1 to 4 substituents 3~6 is cycloalkyl, or R h Ha, Halo, C 1~4 Alkyl, or C 1~4 haloalkyl C optionally substituted with 1 to 4 substituents 6~10 aryl (e.g., C6) (e.g., R h is unsubstituted phenyl, or R h teeth TIFF2025037981000117.tif22128).

[0287] In a certain aspect (Y A2 but TIFF2025037981000118.tif21128) in R bA No. 6,239,693, filed on Dec. 1, 2002, which is incorporated herein by reference in its entirety. R in claim 166 of Application No. 62 / 861,714 b As defined for

[0288] In certain embodiments, R bA is -Cl or -F (e.g., F).

[0289] In a certain aspect (Y A2 but TIFF2025037981000119.tif21128), n2 is 0.

[0290] In certain other embodiments, n2 is 1 or 2. In certain of these embodiments, R bB teeth , -Cl, -F, C 1~3 Alkyl, and C 1~3 haloalkyl do.

[0291] In some embodiments, A is selected from 1 to 6 independently selected R a C optionally substituted with 1~10 In certain embodiments, A is 1 to 6 independently selected R a is replaced by May be C 2~10(e.g. C2, C3, C4, C5, C6, C7, C8, C9, C 10 ) alkyl. In some embodiments, A is selected from 1 to 6 independently selected R a C optionally substituted with 10~20 a In certain embodiments, A is unsubstituted C 10~20 Alkyl (e.g., C 10~12 , C 13 ~15 , C 16~18 , C 19~20 In certain embodiments, A is an unsubstituted linear C 10~ 20 Alkyl (e.g., linear C 10~12 , C 13~15 , C 16~18 , C 19~20 alkyl).

[0292] Symbol R 6 In some embodiments, R 6 is H. In some embodiments, R 6 is C 1~3 It is alkyl.

[0293] Symbol R N In some embodiments, R N Each occurrence of is independently H or C 1~3 It is alkyl.

[0294] In some embodiments, R N Each occurrence of is independently H.

[0295] Non-limiting combinations In some embodiments, the compound has the following formula: TIFF2025037981000120.tif26128, where n1 is 0, 1, or 2, and R cA and R cB Each of the is selected independently RuR c is.

[0296] In some embodiments, the compound has the following formula: TIFF2025037981000121.tif26128, where n1 is 0, 1, or 2, and R cA and R cB Each of the is selected independently RuR c is.

[0297] In some embodiments, the compound has the following formula: TIFF2025037981000122.tif25128, where X 1 and X 2 One of them is N and X 1 and X 2 The other is CH , n1 is 0, 1, or 2, and R cA and R cB Each of R is independently selected c is.

[0298] In some embodiments, the compound has the following formula: TIFF2025037981000123.tif26128, where X 1 、 X 2 , X 3 , and X 4 One of them is N and the other is X 1 、 X 2 , X 3 , X 4 The remainder of Each of n1 is CH, n1 is 0, 1, or 2, and R cA and R cB Each of these is independent. R is selected by c is.

[0299] In some embodiments, the compound has the following formula: TIFF2025037981000124.tif27128 (e.g. R cA is L 1 -L2 -R h wherein n1 is 0 or 1, and R cA and R cB Noso Each is selected independently. c is.

[0300] In some embodiments, the compound has the following formula: TIFF2025037981000125.tif26143, During the ceremony, n1 is 0, 1, or 2 (e.g., 0 or 1), and R cA and R cB Each of the Selected R c and W is *C(=O)NR N , for example *C(=O)NH, and The TIFF2025037981000126.tif16128 part is TIFF2025037981000127.tif21128, where R 2 ' is H or R 2 is.

[0301] In certain of these aspects, The TIFF2025037981000128.tif16128 part is TIFF2025037981000129.tif24128, e.g., R 1 is other than H (e.g., R 1 is halo or cyano) (a1-b) is.

[0302] In certain embodiments of formulas (I-AA), (I-BB), (I-CC), (I-DD), and (I-EE), R cA No. 62 / 861,714, the entire contents of which are incorporated herein by reference. In any one of claims 124 to 133, R c or as defined for RcA is a claim of U.S. Provisional Application No. 62 / 861,714, which is incorporated herein by reference in its entirety. In any one of items 134 to 143, R c As defined for

[0303] In certain embodiments of formulas (I-AA), (I-BB), (I-CC), (I-DD), and (I-EE), R cA 153 to 165 (e.g., 153, 154, 155, 156, 157, 15 9, 160, 161, 162, 163, 164, or 165) In the term R c or as defined for R cA is any of paragraphs 166 to 177 In any one term, R c as defined for (e.g., R c Ha-L 1 -L 2 -R h and For example, R h and R h is as defined in paragraph 175, 176, or 177 be).

[0304] In certain embodiments of formulas (I-AA), (I-BB), (I-CC), (I-DD), and (I-EE), R cA is C substituted with 1 to 3 -F 1~3 alkyl (e.g., R cA is -CF3).

[0305] In certain embodiments of formulas (I-AA), (I-BB), (I-CC), (I-DD), and (I-EE), R cA is unsubstituted C 1~10 Alkyl (e.g., straight chain C2, C3, C4, C5, C6, or C7~10 alkyl) is.

[0306] In certain embodiments of formulas (I-AA), (I-BB), (I-CC), (I-DD), and (I-EE), R cA is C 2~6 Alkenyl, C 2~6 Alkynyl, or -C(=O)(C 1~10 alkyl) (e.g. Ba-C(=O)(C 3~10 alkyl) (e.g., —C(═O)CHCHCHCHCHCHCHCHCH)).

[0307] In certain embodiments of formulas (I-AA), (I-BB), (I-CC), (I-DD), and (I-EE), R cA -SF5, -S(O) 1~2 (NR'R'') TIFF2025037981000130.tif16128, S(O) 1~2 (C 1~4 alkyl), and S(O) 1~2 (C 1~4 haloalkyl) (e.g., S(O )2CF3).

[0308] In certain embodiments of formulas (I-AA), (I-BB), (I-CC), (I-DD), and (I-EE), R cA is C 1~4 Alkoxy or C 1~4 Haloalkoxy (e.g., OCF3, OCF2H, OCH2CF3, and and C such as OCH2CF2H 1~4 haloalkoxy).

[0309] In certain embodiments of formulas (I-AA), (I-BB), (I-CC), (I-DD), and (I-EE), R cA Ha-L 1 -L 2 -Rh is.

[0310] In certain of these embodiments, -L 1 is a bond. In certain other embodiments, -L 1 is CH2 or -CH2CH2. In certain embodiments, -L 2 is a bond or -O-.

[0311] In certain embodiments, R h Ha, Halo, C 1~4 Alkyl, and C 1~4 consisting of haloalkyl C optionally substituted with 1 to 4 substituents independently selected from the group 3~6 cycloalkyl is TIFF2025037981000131.tif23128.

[0312] In certain embodiments, R h Halo, Cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~ 4 alkoxy, and C 1~4 haloalkoxy, 1 to 2 substituents independently selected from the group consisting of C6 aryl optionally substituted with a substituent (e.g., R h is unsubstituted phenyl or or R h teeth TIFF2025037981000132.tif22128).

[0313] In certain embodiments of formulas (I-AA), (I-BB), (I-CC), (I-DD), and (I-EE), n1 is 0. In certain other embodiments, n1 is 1. In certain of these embodiments, each R cB are independently halo or R a C optionally substituted with 1~4 is alkyl .

[0314] In some embodiments, the compound has the following formula: TIFF2025037981000133.tif25128, where n2 is 0, 1, or 2, and R bA and R bB Each of these is selected independently. R b is.

[0315] In some embodiments, the compound has the following formula: TIFF2025037981000134.tif25128, where n2 is 0, 1, or 2, and R bA and R bB Each of these is selected independently. R b is.

[0316] In some embodiments, the compound has the following formula: TIFF2025037981000135.tif25128, where n2 is 0, 1, or 2, and R bA and R bB Each of these is selected independently. R b is.

[0317] In certain embodiments of formulas (I-FF), (I-GG), and (I-HH), R bA is referred to by reference. Any of claims 155-159 of U.S. Provisional Patent Application No. 62 / 861,714, the entirety of which is incorporated herein. as defined in any one of the preceding claims.

[0318] In certain embodiments of formulas (I-FF), (I-GG), and (I-HH), R bA Articles 190 to 19 In any one of paragraphs 4 (for example, paragraph 190, paragraph 191, paragraph 192, paragraph 193, or paragraph 194), as defined in

[0319] In certain of these embodiments, R bA is unsubstituted C 1~10 Alkyl (e.g., straight chain C2, C3, C4, C 5, C6, or C 7~10 alkyl).

[0320] In certain other embodiments, R bA is 1 to 6 independently selected R a C replaced with 1~10 Alkyl, for example, -F, -Cl, OH, C 1~4 Alkoxy, NR e R f , C 1~4 Haloalkoxy and 1 to 4 independently selected C 1~4 C optionally substituted with alkyl 3~6 Cyclo C substituted with 1 to 6 substituents each independently selected from the group consisting of alkyl 1~ 10 It is alkyl.

[0321] In certain embodiments of formulas (I-FF), (I-GG), and (I-HH), R bA is referred to by reference. Any of claims 160-165 of U.S. Provisional Patent Application No. 62 / 861,714, the entirety of which is incorporated herein by reference. as defined in any one of the preceding claims.

[0322] In certain embodiments of formulas (I-FF), (I-GG), and (I-HH), R bA Articles 195 to 20 0 (e.g., paragraph 195, paragraph 196, paragraph 197, paragraph 198, paragraph 199, or paragraph 20) As defined in Section 0).

[0323] In certain embodiments, R bA Ha-L 1 -L2 -R h where L 1 is a bond and / or L 2 is a bond or -O-, and / or R h Ha, Halo, C 1~4 Alkyl, and C 1~4 haloalkyl C optionally substituted with 1 to 4 substituents 3~6 is cycloalkyl, and / or R h Ha, Halo, C 1~4 Alkyl or C 1~4 Independently selected from the group consisting of haloalkyl C optionally substituted with 1 to 4 substituents 6~10 Aryl (e.g., C6) BaR h is unsubstituted phenyl, or R h teeth TIFF2025037981000136.tif22128).

[0324] In certain embodiments of formulas (I-FF), (I-GG), and (I-HH), R bA is referred to by reference. Claim 166 of U.S. Provisional Patent Application No. 62 / 861,714, the entirety of which is incorporated herein by reference. As defined.

[0325] In certain embodiments of formulas (I-FF), (I-GG), and (I-HH), R b is 1 to 6 independent R is selected by a C optionally substituted with 1~10 Alkyl; C 1~4 Haloalkyl; -F; -Cl; -Br; Cyano;C 1~4 Alkoxy;C 1~4 Haloalkoxy; -C(=O)(C 1~10 alkyl);-C(=O) O(C1~4 alkyl);-S(O) 1~2 (C 1~4 alkyl); oxo; cyano; and -L 1 -L 2 -R h mosquito are independently selected from the group consisting of:

[0326] In certain embodiments of formulas (I-FF), (I-GG), and (I-HH), n2 is 0.

[0327] In certain other embodiments, n2 is 1 or 2. In certain of these embodiments, each R bB are independently -F, -Cl, or C 1~3 It is alkyl.

[0328] In some embodiments, the compound has the following formula: TIFF2025037981000137.tif20128, wherein ring E1 is a group selected from the group consisting of 1 to 4 R b C optionally substituted with 7~10 Cycloalkyl (For example, Y A2 is 1 to 3 R b each of which may be further substituted by TIFF2025037981000138.tif23128 or spiroundecanyl (e.g. TIFF2025037981000139.tif18128) is a spiro[5,5]undecanyl.

[0329] In certain of these embodiments, R b is incorporated herein by reference in its entirety. As defined in claim 154 of U.S. Provisional Application No. 62 / 861,714.

[0330] In certain embodiments of Formula (I-II), R b is as defined in paragraph 189.

[0331] In certain embodiments of Formula (I-II), R of ring E1 b The substituents are 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl; C 1~4 Haloalkyl; -F; -Cl; -Br; Cyano; C 1~4 a Alkoxy;C 1~4 Haloalkoxy; -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 Archi Le);-S(O) 1~2 (C 1~4 alkyl); oxo; cyano; and -L 1 -L 2 -R h From the group consisting of are selected independently.

[0332] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH ), and in certain embodiments of (I-II), Y A1 is a bond.

[0333] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH ), and in certain embodiments of (I-II), Y A1 is CH2 or C(=O).

[0334] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH ), and in certain embodiments of (I-II), Y A1 is one to two independently selected R a Place C may be replaced 1~4 Non-limiting examples include Y A1 -CH2-, -CH2C H2-, -CH2CH2CH2-, -CH(CF3)-, -CH2CH(OH)-, TIFF2025037981000140.tif17131 (e.g. Y A1 is CH2).

[0335] In some embodiments, the compound has the following formula: TIFF2025037981000141.tif19128, wherein A 2 is 1 to 6 independently selected R a C optionally substituted with 1~20 Al It's a kill.

[0336] In certain embodiments of formula (I-JJ), A 2 is 1 to 6 independently selected R a is replaced by C 8~20 (e.g. C8, C9, C 10 , C 11~13 , C 14~16 , C 17~19 , or C 20 )Al In certain embodiments, A 2 is unsubstituted C 8~20 (e.g. C8, C9, C 10 , C 11~13 , C1 4~16 , C 17~19 , or C 20 ) alkyl. In certain embodiments, A 2 is unsubstituted C 10~20 (For example, C 10 , C 11~13 , C 14~16 , C 17~19 , or C 20 ) alkyl. For example, A 2 is a linear C 10~20 (For example, C 10 , C 11~13 , C 14~16 , C 17~19 , or C 20 )a It can be Lukil.

[0337] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-JJ), W is *C(=O)NR N Formula (I- AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH), (I- In certain embodiments of II), and (I-JJ), W is *C(=O)NH or *C(=O)N(C 1~ 3 alkyl). Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF) In certain embodiments of (I-GG), (I-HH), (I-II), and (I-JJ), W is *C(=O )NH.

[0338] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-JJ), W is *S(O) 1~2 NR N The formula ( I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH), ( In certain embodiments of (I-II), and (I-JJ), W is *S(O)NR N (e.g., *S(O)2NH) is.

[0339] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-JJ), W is *C(=NR N )NR N (e.g. C( =NCN)NH).

[0340] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-JJ), W is TIFF2025037981000142.tif19128 (for example, each R N is H).

[0341] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-JJ), W is TIFF2025037981000143.tif18128. In certain of these embodiments, Q 2 is NR N As a non-limiting example, Q 2 NH or N(C 1~3 alkyl) (e.g., NH).

[0342] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-JJ), W is -Q 1 -Q 2 (e.g., -Q 1 teeth, Heteroarylene containing six ring atoms, one to three (e.g., one to two) of which are ring nitrogen atoms. and the heteroarylene ring is selected from 1 to 2 independently selected R q1 is replaced by (This is also acceptable.)

[0343] In certain of these embodiments, Q 1 is one to two independently selected R q1 Each one is placed may be replaced TIFF2025037981000144.tif41159, wherein the asterisk represents Q 2 represents the connection point of TIFF2025037981000145.tif16128.

[0344] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH ), (I-II), and (I-JJ) (W is -Q 1 -Q 2 If so, then Q 2 Ha Yui It is a combination.

[0345] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH ), (I-II), and (I-JJ) (W is -Q 1 -Q 2 If so, then Q 2 teeth,- O-, -NH-, or -S(O) 0~2 (For example, Q 2 is -O- or Q 2 is -NH- , or Q 2 is -S(O)2-).

[0346] In some embodiments, the compound has the formula (I-KK): TIFF2025037981000146.tif19128, wherein A is H and W is 1 to 4 R c C optionally substituted with 8~10 Bicyclic ants and heteroarylene containing 8 to 10 ring atoms, wherein 1 to 2 ring atoms are heteroaryls. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 A group consisting of and the heteroaryl ring is selected from 1 to 3 independently selected R c Replace with and heteroarylene, optionally substituted or unsubstituted.

[0347] In certain of these embodiments, W is heteroarylene containing 9 to 10 ring atoms; One to two ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d ), O, and S (O) 0~2 and the heteroaryl ring is selected from the group consisting of 1 to 2 independently Selected R c may be substituted with.

[0348] In certain of these embodiments, W is selected from 1 to 2 independently selected R c are replaced by the group consisting of quinolinylene, isoquinolinylene, and quinazolinylene, optionally is selected from.

[0349] As a non-limiting example, W is It can be TIFF2025037981000147.tif15128.

[0350] In certain embodiments of formula (I-KK), R c Each occurrence of a C replaced with 1~10 It is alkyl (e.g., -CF3).

[0351] In certain embodiments of formula (I-KK), R c One occurrence of is halo (e.g., —Cl or F). .

[0352] In certain embodiments of formula (I-KK), R c One occurrence of -L 1 -L 2 -Rh is.

[0353] In certain of these embodiments, R c One occurrence of is R h and R h Ha, Halo, C 1~4 Alkyl , and C 1~4 substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl; C 3~6 Cycloalkyl TIFF2025037981000148.tif23128.

[0354] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000149.tif16128 part is TIFF2025037981000150.tif25128, In the formula, ring B is a ring (e.g., a ring having 4 to 15 (e.g., 5 to 12 (e.g., 5 to 10)) ring atoms. monocyclic, bicyclic, or tricyclic ring), in which 0 to 3 ring atoms are heteroatoms, and each Heteroatoms are N, N(H), N(R d ), O, and S(O) 0~2 Independently selected from the group consisting of and the ring is selected from 1 to 4 independently selected R 2 may be substituted with.

[0355] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000151.tif16128 part is TIFF2025037981000152.tif26170, where R 2’ is H or R 2 (e.g., R 2’ is H).

[0356] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000153.tif16128 part is TIFF2025037981000154.tif25128, where R 2’ is H or R 2 is TIFF2025037981000155.tif20128 (e.g. R 2’ is H).

[0357] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000156.tif16128 part is TIFF2025037981000157.tif21128, where R 2’ is H or R 2 (e.g., R 2’ is H).

[0358] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000158.tif16128 part is TIFF2025037981000159.tif21128, wherein B2 is an aromatic ring containing 5 ring atoms, and 1 to 2 (e.g., 2) of the ring atoms are heteroatoms, each heteroatom being N, N(H), N(R d ), O, and S(O) 0~2 Because provided that B2 is other than pyrrolyl and the ring has 1 to 4 independent Selected R 2 may be substituted with.

[0359] In certain of these embodiments, B2 is TIFF2025037981000160.tif23128, where each R 2 are independently H or R 2 is TIFF2025037981000161.tif20128.

[0360] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000162.tif16128 part is TIFF2025037981000163.tif21128, wherein B3 is a) a non-aromatic ring containing 5 to 6 ring atoms, 0 to 2 of which are heteroatoms, and each The heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Independently selected from the group consisting of and the ring is selected from 1 to 4 independently selected R 2 a non-aromatic ring optionally substituted with b) a ring (e.g., a spirocyclic ring) containing 8 to 12 (e.g., 9 to 12) ring atoms, Two ring atoms are heteroatoms, and each heteroatom is selected from N, N(H), N(R d), O, and S(O ) 0~2 and the ring is selected from the group consisting of 1 to 4 independently selected R 2 Place optionally substituted, is selected from the group consisting of:

[0361] In certain of these embodiments, B3 is a non-aromatic ring containing 5 ring atoms and 1-2 ring atoms. The atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 and the ring is substituted with 1 to 2 oxo groups, and the ring is one to two independently selected R 2 may be further substituted with TIFF2025037981000164.tif23128.

[0362] In certain embodiments, B3 is a non-aromatic ring containing 5 ring atoms, 0-1 of which is N , N(H), N(R d ), O, and S(O) 0~2 is a heteroatom selected from the group consisting of The ring is formed by one to two independently selected R 2 may be substituted with TIFF2025037981000165.tif18128.

[0363] In certain embodiments, B3 is a ring (e.g., spin) containing 8 to 12 (e.g., 9 to 12) ring atoms. cyclic ring), in which 0 to 2 ring atoms are heteroatoms, and each heteroatom is N, N(H), N (R d ), O, and S(O) 0~2 and the ring is independently selected from the group consisting of 1 to 4 independent R is selected as 2 may be substituted with.

[0364] In certain embodiments, B3 is a spirocyclic bicyclic ring containing 8 to 12 (e.g., 9 to 12) ring atoms. wherein 0 to 2 ring atoms are heteroatoms, and each heteroatom is selected from the group consisting of N, N(H), N(R d ) , O, and S(O) 0~2 and the ring is independently selected from the group consisting of 1 to 4 independently selected rings. Selected R 2 (e.g., B3 is optionally substituted with 1 to 2 independently selected R 2 Desara may be substituted with TIFF2025037981000166.tif26128).

[0365] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000167.tif16128 part is TIFF2025037981000168.tif21128, wherein B4 is an aromatic ring containing 6 ring atoms, and 0 to 2 ring atoms are heteroatoms. and each heteroatom is N, N(H), and N(R d ), and The ring is a ring having 1 to 4 independently selected R 2 may be substituted with.

[0366] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), If the TIFF2025037981000169.tif16128 part is (aa1), (a1), (b1), (c1), (d1), or (e1), then Y 1 , Y 2 , and Y 3 Each of the CRs is selected independently. 1 and If the TIFF2025037981000170.tif16128 part is (aa2), (a2), (b2), (c2), (d2), or (e2), then Y 2 , Y 3 , and Y 4 Each of the CRs is selected independently. 1 is.

[0367] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), If the TIFF2025037981000171.tif16128 part is (aa1), (a1), (b1), (c1), (d1), or (e1), then Y 1 , Y 2 , and Y 3 One of the is N and Y 1 , Y 2 , and Y 3 Each of the remaining Selected CR 1 and If the TIFF2025037981000172.tif16128 part is (aa2), (a2), (b2), (c2), (d2), or (e2), then Y 2 , Y 3 , and Y 4 One of the is N and Y 2 , Y 3 , and Y 4 Each of the remaining Selected CR 1 is.

[0368] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000173.tif16128 part is TIFF2025037981000174.tif84158.

[0369] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000175.tif16128 part is TIFF2025037981000176.tif23128, where R 2’ is H or R 2 is.

[0370] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000177.tif16128 part is TIFF2025037981000178.tif22128.

[0371] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000179.tif16128 part is The file is TIFF2025037981000180.tif23128.

[0372] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000181.tif16128 part is The file is TIFF2025037981000182.tif18128.

[0373] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000183.tif16128 part is TIFF2025037981000184.tif20128, where R 2’ is H or R 2 (e.g., R 2’ is H).

[0374] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000185.tif16128 part is TIFF2025037981000186.tif24128, where R 2’ is H or R 2 is.

[0375] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000187.tif16128 part is TIFF2025037981000188.tif20128.

[0376] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000189.tif16128 part is The file is TIFF2025037981000190.tif22128.

[0377] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), The TIFF2025037981000191.tif16128 part is The file is TIFF2025037981000192.tif18128.

[0378] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), R 1 Each occurrence of H; halo; Cyano; 1 to 2 R a C optionally substituted with 1~6 Alkyl; C 2~6 Alkenyl; C 2~6 Archi Nil;C 1~4 Haloalkyl;C 1~4 Alkoxy;C 1~4 Haloalkoxy;-S(O) 1~2 (C 1~4 a rukiru);-NR e R f ;-OH;oxo;-S(O) 1~2 (NR'R'');-C(=O)(C 1~4 alkyl);- C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); and -L3 -L 4 -R i are independently selected from the group consisting of:

[0379] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), R 1 is referred to by reference Any of claims 59-64 of U.S. Provisional Patent Application No. 62 / 861,714, the entirety of which is incorporated herein. as defined in paragraph (1).

[0380] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), each R 1 is H.

[0381] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), R 1 and the atom to which it is bonded R that do not join together to form a ring 1 One occurrence of is halo, cyano, -C(=O)O (C 1~4 alkyl), -C(=O)OH, and 1 to 2 R a C optionally substituted with 1~6 Al Kill, and R 1 together with the atoms to which they are attached form a ring Each remaining R that does not 1 is H.

[0382] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), R 1 and the atom to which it is bonded R that do not join together to form a ring 1 One occurrence of is -R i and R 1 are combined Each remaining R that does not form a ring with the atoms 1 is H.

[0383] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH ), (I-II), (I-JJ), and (I-KK) The TIFF2025037981000193.tif16128 part is TIFF2025037981000194.tif85159), each R 1 is other than H.

[0384] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), R 2 Each occurrence of Claims 66-85 of U.S. Provisional Patent Application No. 62 / 861,714, which is hereby incorporated by reference in its entirety. as defined in any one of the preceding paragraphs.

[0385] Formulas (I-AA), (I-BB), (I-CC), (I-DD), (I-EE), (I-FF), (I-GG), (I-HH In certain embodiments of (I-II), (I-JJ), and (I-KK), R 2 Each occurrence of Cyano, -C(=O)O(C 1~4 alkyl), -C(=O)OH, and 1 to 2 R a It is replaced by Good C 1~6 alkyl.

[0386] In some embodiments, the compound has formula (I-LL): TIFF2025037981000195.tif26128, where R 2’ is H or R 2 and n3 is 0 or 1.

[0387] In certain of these embodiments, n3=0. In certain other embodiments, n3=1. In certain embodiments, R 2’ is H.

[0388] In certain embodiments of formula (I-LL), R 1 is H. In certain other embodiments, R 1 is other than H In certain of these embodiments, R 1 is halo, cyano, -C(=O)O(C 1~4 Archi -C(=O)OH, and 1-2 R a C optionally substituted with 1~6 alkyl is selected from.

[0389] In certain embodiments, R 1 is other than H, n3 is 0, and R 2 ' is H. In your opinion, R 1 is other than H, n3 is 1, and R 2 is H.

[0390] In certain embodiments of formula (I-LL), R 2 is halo, cyano, -C(=O)O(C 1~4 Alkyl ), -C(=O)OH, and 1 to 2 R a C optionally substituted with 1~6 A group consisting of alkyl are selected independently.

[0391] In certain embodiments of formula (I-LL), W is *C(=O)NR N Certain aspects of these So, W is *C(=O)NH.

[0392] In certain embodiments of formula (I-LL), Y A1 is a bond.

[0393] In certain other embodiments, Y A1 is 1 to 2 R a C optionally substituted with 1~6 Alkylene For example, Y A1 -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CF3)-, -CH2CH(OH)- , TIFF2025037981000196.tif17134 (e.g. Y A1 is CH2).

[0394] In certain embodiments of formula (I-LL), Y A2 teeth TIFF2025037981000197.tif14128, n1 is 0, 1, or 2, R cA and R cB Each of R is independently selected c in be.

[0395] In certain embodiments of formula (I-LL), Y A2 teeth TIFF2025037981000198.tif21128, n1 is 0, 1, or 2, and R cA and R cB Each of R is independently selected c in be.

[0396] In certain embodiments of formula (I-LL), Y A2 teeth TIFF2025037981000199.tif15128, X 1 and X 2 One of them is N and X 1 and X 2 The other of these is CH, and n1 is 0 , 1, or 2, and R cA and R cB Each of R is independently selected c (e.g., X 2 is N).

[0397] In certain embodiments of formula (I-LL), Y A2 teeth, TIFF2025037981000200.tif16128, X 1 、 X 2 , X 3 , and X 4 One of them is N and the other is X 1 、 X 2 , X 3 , and X 4 The remainder of Each of n1 is CH, n1 is 0, 1, or 2, and R cA and R cB Each of these is independent. R is selected by c (e.g., X 2 is N).

[0398] In certain embodiments of formula (I-LL), R cA is C substituted with 1 to 3 -F 1~3 It is alkyl (e.g. R cA is -CF3).

[0399] In certain embodiments of formula (I-LL), R cA is unsubstituted C1~10 Alkyl (e.g., straight chain C2, C3, C 4, C5, C6, or C 7~10 alkyl).

[0400] In certain embodiments of formula (I-LL), R cA is C 2~6 Alkenyl, C 2~6 Alkynyl, also is -C(=O)(C 1~10 alkyl) (e.g., -C(=O)(C 3~10 alkyl) (e.g. -C(=O )CH2CH2CH2CH2CH2CH2CH2)).

[0401] In certain embodiments of formula (I-LL), R cA -SF 5、 -S(O) 1~2 (NR'R'') TIFF2025037981000201.tif16128, S(O) 1~2 (C 1~4 alkyl), and S(O) 1~2 (C 1~4 haloalkyl) (e.g., S(O )2CF3).

[0402] In certain embodiments of formula (I-LL), R cA is C 1~4 Alkoxy or C 1~4 Haloalkoxy (e.g., OCF3, OCF2H, OCH2CF3, and OCH2CF2H) 1~4 haloalkoxy).

[0403] In certain embodiments of formula (I-LL), R cA Ha-L 1 -L 2 -R h is.

[0404] In certain of these embodiments, -L 1 is a bond. In certain other embodiments, -L 1is CH2 or -CH2CH2. In certain embodiments, -L 2 is a bond or -O-.

[0405] In certain embodiments, R h Ha, Halo, C 1~4 Alkyl, and C 1~4 consisting of haloalkyl C optionally substituted with 1 to 4 substituents independently selected from the group 3~6 cycloalkyl is TIFF2025037981000202.tif23128.

[0406] In certain embodiments, R h is a heterocyclyl, and the heterocyclyl has 4 to 10 carbon atoms (e.g., 4, 5, or 6) ring atoms, and 1 to 3 (e.g., 1 to 2, e.g., 1) ring atoms are heterocyclic. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0~2 Consists of and heterocyclyl is selected from the group consisting of halo; 1 to 2 independently selected R a Place C may be replaced 1~4 Alkyl; C 1~4 Haloalkyl;Cyano;C 1~4 Alkoxy; and C 1~4 substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxy; is also good, for example, R h teeth The file is TIFF2025037981000203.tif22128.

[0407] In certain embodiments, R h Halo, Cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~ 4 alkoxy, and C 1~4haloalkoxy, 1 to 2 substituents independently selected from the group consisting of C6 aryl optionally substituted with a substituent (e.g., R h is unsubstituted phenyl or or R h teeth TIFF2025037981000204.tif22128).

[0408] In certain embodiments of formula (I-LL), n1 is 0. In certain other embodiments, n1 is 1. In certain of these embodiments, each R cB are independently halo or R a Replace with C 1~4 It is alkyl.

[0409] In certain embodiments of formula (I-LL), R 6 is H.

[0410] In some embodiments, the compound has the formula (I-MM): TIFF2025037981000205.tif26128, where R 2’ is H or R 2 and n3 is 0 or 1.

[0411] In certain of these embodiments, n3=0. In certain other embodiments, n3=1. In certain embodiments, R 2’ is H.

[0412] In certain embodiments of formula (I-MM), each R 1 is H. In certain other embodiments, two R 1 is H and the remaining R 1 is other than H. In certain of these embodiments, one R 1 Ha, hello, Cyano, -C(=O)O(C 1~4 alkyl), -C(=O)OH, and 1 to 2 R aIt is replaced by Good C 1~6 alkyl.

[0413] In certain embodiments of formula (I-MM), R 2 is halo, cyano, -C(=O)O(C 1~4 Alkyl ), -C(=O)OH, and 1 to 2 R a C optionally substituted with 1~6 A group consisting of alkyl are selected independently.

[0414] In certain embodiments of formula (I-MM), W is *C(=O)NR N Certain aspects of these So, W is *C(=O)NH.

[0415] In certain embodiments of formula (I-MM), Y A1 is a bond.

[0416] In certain other embodiments, Y A1 is 1 to 2 R a C optionally substituted with 1~6 Alkylene For example, Y A1 -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CF3)-, -CH2CH(OH)- , TIFF2025037981000206.tif17134 (e.g. Y A1 is CH2).

[0417] In certain embodiments of formula (I-MM), Y A2 teeth TIFF2025037981000207.tif14128, n1 is 0, 1, or 2, R cA and R cB Each of R is independently selected c in be.

[0418] In certain embodiments of formula (I-MM), Y A2 teeth TIFF2025037981000208.tif21128, n1 is 0, 1, or 2, and R cA and R cB Each of R is independently selected c in be.

[0419] In certain embodiments of formula (I-MM), Y A2 teeth TIFF2025037981000209.tif15128, X 1 and X 2 One of them is N and X 1 and X 2 The other of these is CH, and n1 is 0 , 1, or 2, and R cA and R cB Each of R is independently selected c is.

[0420] In certain embodiments of formula (I-MM), Y A2 teeth, TIFF2025037981000210.tif16128, X 1 、 X 2 , X 3 , and X 4 One of them is N and the other is X 1 、 X 2 , X 3 , and X 4 The remainder of Each of n1 is CH, n1 is 0, 1, or 2, and R cA and R cB Each of these is independent. R is selected by c is.

[0421] In certain embodiments of formula (I-MM), R cA is C substituted with 1 to 3 -F 1~3 It is alkyl (e.g. R cA is -CF3).

[0422] In certain embodiments of formula (I-MM), R cA is unsubstituted C 1~10 Alkyl (e.g., straight chain C2, C3, C 4, C5, C6, or C 7~10 alkyl).

[0423] In certain embodiments of formula (I-MM), R cA is C 2~6 Alkenyl, C 2~6 Alkynyl, also is -C(=O)(C 1~10 alkyl) (e.g., -C(=O)(C 3~10 alkyl) (e.g. -C(=O )CH2CH2CH2CH2CH2CH2CH2)).

[0424] In certain embodiments of formula (I-MM), R cA -SF 5、 -S(O) 1~2 (NR'R'') TIFF2025037981000211.tif16128, S(O) 1~2 (C 1~4 alkyl), and S(O) 1~2 (C 1~4 haloalkyl) (e.g., S(O )2CF3).

[0425] In certain embodiments of formula (I-MM), R cA is C 1~4 Alkoxy or C 1~4 Haloalkoxy (e.g., OCF3, OCF2H, OCH2CF3, and OCH2CF2H) 1~4 haloalkoxy).

[0426] In certain embodiments of formula (I-MM), R cA Ha-L 1 -L 2 -R his.

[0427] In certain of these embodiments, -L 1 is a bond. In certain other embodiments, -L 1 is CH2 or -CH2CH2. In certain embodiments, -L 2 is a bond or -O-.

[0428] In certain embodiments, R h Ha, Halo, C 1~4 Alkyl, and C 1~4 consisting of haloalkyl C optionally substituted with 1 to 4 substituents independently selected from the group 3~6 cycloalkyl is TIFF2025037981000212.tif23128.

[0429] In certain embodiments, R h Halo, Cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~ 4 alkoxy, and C 1~4 haloalkoxy, 1 to 2 substituents independently selected from the group consisting of C6 aryl optionally substituted with a substituent (e.g., R h is unsubstituted phenyl or or R h teeth TIFF2025037981000213.tif22128).

[0430] In certain embodiments of Formula (I-MM), n1 is 0. In certain other embodiments, n1 is 1. In certain of these embodiments, each R cB are independently halo or R a Replace with C 1~4 It is alkyl.

[0431] In certain embodiments of formula (I-MM), R 6 is H.

[0432] At the end of this detailed description, there are provided certain additional information regarding the compounds, compositions, methods, and other subject matter described herein. Here are 383 numbered items for further explanation. For ease of browsing, certain entries may be omitted. For the avoidance of doubt, the definition of a number refers to one or more uniquely numbered items. To specify this, for example, "R b each occurrence of is as defined in paragraph 189 Which words are used? Y A2 R b Each occurrence of a substituent is selected from 1 to 6 independently selected R a C1 optionally substituted with ~10 Alkyl; C 1~4 Haloalkyl; -F; -Cl; -Br; Cyano; C 1~4 Alkoxy;C 1~4 Haroarco -C(=O)(C 1~10 alkyl);-C(=O)O(C 1~4 alkyl);-S(O) 1~2 (C 1~4 alkyl); oxo; cyano, and -L 1 -L 2 -R h Independently selected from the group consisting of This means that:

[0433] Compound regulations In some embodiments, the compound has the formula (I-a1), wherein R 2’ is H or R 2 And WA is ( A) and W is *C(O)NR N (e.g., *C(O)NH-), the following rule applies: One, two, three, four, or five of the following rules apply: TIFF2025037981000214.tif24128(i)Y 1 and Y 2 Each of the is CH and Y 3 is CR 1 and R 1 However, CO2Me, CO2Et, CN, or Cl (e.g., R 2 ' is H), and R 2 does not exist (i.e. C2 and C3 is replaced by H), or Y 1 and Y 2 Each of the following is N, and Y 3 OH or is oxo, A is optionally substituted C 1~6 Alkyl, e.g., methyl and bromine butyl, 1,1,3,3-tetramethylbutyl, and optionally substituted C3 and C6 cycloaliphatic alkyl (e.g., C1 optionally substituted with COH, isocyanate, and substituted amino) ~6 alkyl and C and C cycloalkyl), (ii) Y 1 and Y 2 Each of the following is N, and Y 3 is CR 1 If If WA is benzyl, R 1 cannot be frilly, and ·R 2’ is methyl, or WA is independently selected from -Cl, -F, -Br, and CF3; When R is phenyl substituted with 1 to 2 substituents selected from the group consisting of phenyl and phenyl, R 1 is a substituted N-linked aniline and cannot be chloro, (iii) Y 1 , Y 2 , and Y 3 Each of the is CH and R 2’ is H and R 2 exists and A is bonded to the C3 position of the dole ring, and A is phenyl, tolyl, optionally substituted kyne nazolinyl, optionally substituted pyrazolyl, optionally substituted indolyl, substituted optionally substituted naphthyl, or optionally substituted morpholinyl-phenyl (mor opholinyl-phenyl), R 2 is oxazolyl, pyridyl, C-linked 2-pyridyl cannot be ethyl, phenyl, cyano, or C(O)NH2; (iv) Y 1 and Y 3 Each of the is CH and Y 2 is CH or CMe, and R 2’ is H, or TsuR 2 If does not exist, ·R h cannot be a fused tricyclic ring, Y A2 is an optionally substituted cyclohexyl, cyclohexenyl, imidazo[1,2 -a][1,4]benzodiazepin-4-yl, indenyl, naphthyl, and tetrahydronaphthyl Unable to be chill, Y A1 cannot be alkylene substituted with phenyl; Y A1 When Y is alkylene, A2 It can be phenyl or one of the following substituted phenyl groups: The aryl ring can be 4-Br, 2,4-(Cl)2, 3-propenyl, 2,3-(OMe)2, and 4-CF3. Damage, and Y A1 If does not exist, Y A2 may be a phenyl or one of the following substituted phenyl rings: 3-N O2, 4-Br, 2,4-(Cl)2, 2,3-(OMe)2, 4-CF3, 4-CO2Et, 3-CF3-4-Cl, 2-Cl-4 CF3, 2-O Et, 2-OMe-4-NO2, 3,4-(OMe)2, 2,4-(Me)2, 3,4-(Cl)2, 2,4-(F)2, 2-Et, 2-F, 2-Me, 2-Br, 2-Cl-4-Br, 2-CF3, 2,4-(OMe)2, 2,3-(Me)2, 3,5-(Cl)2, 3-CF3-4-F , 4-isopropyl, 4-OMe, 4-Cl, 3-F-4-Me, 3-CF3, 2,5-(OMe)2, 2-Me-3-Cl, 2,3-( Me)2, 2,3-(Cl)2, 4-Bu, 3-OMe, 3-Cl, 4-Me-2-Cl, 3-SMe, 2-CO2Me, 4-Me-3-Cl, 3,4 -(Me)2, 4-sec-butyl, 2-OMe, 2-Cl, 2,4-(OMe)2-5-Cl, 4-OEt, 4-acetyl, 2-OMe -5-Me, 2-Me-5-Cl, 3,5-(Me)2, 3,5-(Cl)2, 4-NO2, 4-Br, 4-F, 4-Me, 4-Et, 3-F, 3 -Me, 3-acetyl, and 2-Me-5-Cl; and (v) The compound Any file other than TIFF2025037981000215.tif77130.

[0434] In some embodiments, the compound has formula (I-a1): TIFF2025037981000216.tif24128, where R 2’ is H or R 2 where WA is defined according to (A) and W is -*C(O)NH- If Y 3 is CR other than CH 1 For example, Y 3 is C-cyano or C-halo (e.g., C-Cl or C -F).

[0435] Non-limiting exemplary compounds In certain embodiments, the compound is a compound depicted in Table C1 (below) or a pharmaceutically acceptable salt thereof. The salt is selected from the group consisting of:

[0436] (Table C1) TIFF2025037981000217.tif134170TIFF2025037981000218.tif217170TIFF2025037981000219.tif188170TIFF2025037981000220.tif186170TIFF2025037981000221.tif192170TIFF2025037981000222.tif217170TIFF2025037981000223.tif188170TIFF2025037981000224.tif189170TIFF2025037981000225.tif215170TIFF2025037981000226.tif214170TIFF2025037981000227.tif189170TIFF2025037981000228.tif206170TIFF2025037981000229.tif199170TIFF2025037981000230.tif208170TIFF2025037981000231.tif208170TIFF2025037981000232.tif210170TIFF2025037981000233.tif217170TIFF2025037981000234.tif198170TIFF2025037981000235.tif206170TIFF2025037981000236.tif218170TIFF2025037981000237.tif207170TIFF2025037981000238.tif217170TIFF2025037981000239.tif209170TIFF2025037981000240.tif220170TIFF2025037981000241.tif217170TIFF2025037981000242.tif224170TIFF2025037981000243.tif217170TIFF2025037981000244.tif223170TIFF2025037981000245.tif225170TIFF2025037981000246.tif224170TIFF2025037981000247.tif207170TIFF2025037981000248.tif218170TIFF2025037981000249.tif200170TIFF2025037981000250.tif198170TIFF2025037981000251.tif200170TIFF2025037981000252.tif224170TIFF202503798100 0253.tif187170TIFF2025037981000254.tif183170TIFF2025037981000255.tif216170TIFF2025037981000256.tif206170TIFF2025037 981000257.tif205170TIFF2025037981000258.tif223170TIFF2025037981000259.tif181170TIFF2025037981000260.tif219170TIFF20 25037981000261.tif217170TIFF2025037981000262.tif201170TIFF2025037981000263.tif213170TIFF2025037981000264.tif110170.

[0437] Pharmaceutical Compositions and Administration overview In some embodiments, a chemical entity (e.g., a compound that inhibits (e.g., antagonizes) STING) is used. the compound, or a pharmaceutically acceptable salt and / or hydrate thereof, and / or a co-formulation thereof A drug product (drug product, crystal, and / or combination drug) is a compound consisting of a chemical entity and one or more pharmaceutically acceptable salts. and optionally one or more additional therapeutic agents as described herein. The compound is administered as a pharmaceutical composition comprising:

[0438] In some embodiments, the chemical entity is in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include ion exchangers, alumina, Aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), e.g. Pharmaceutical dosage forms such as d-α-tocopherol succinate polyethylene glycol 1000, Tween, etc. surfactants, poloxamers or other similar polymeric delivery matrices used in ricins, serum proteins, e.g., human serum albumin, buffer substances, e.g., phosphate , Tris, glycine, sorbic acid, potassium sorbate, partial glycerides of saturated vegetable fatty acids Lid mixture, water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, Potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate Polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, carbohydrates Sodium hydroxymethylcellulose, polyacrylate, wax, polyethylene-polio Polypropylene block polymers, and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or 2- and and hydroxyalkyl cyclodextrins, including 3-hydroxypropyl-β-cyclodextrin Chemically modified derivatives such as stringins, or other solubilized derivatives, are also described herein. It can be used to enhance the delivery of the compound of the present invention in the range of 0.005% to 100%. A dosage form containing a chemical entity as described in the specification, the remainder of the dosage form being composed of non-toxic excipients. Forms or compositions may be prepared. Contemplated compositions include those containing 0.001% to 100%, in one embodiment. In another embodiment, the content is 0.1 to 95%, in another embodiment, 75 to 85%, and in a further embodiment, 20 to 80%. The actual methods for preparing such dosage forms are well known in the art. and is well known or obvious to those skilled in the art, for example, Remington: The Science and Practice of Pharmacology macy,22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0439] Route of Administration and Composition Components In some aspects, the chemical entities or pharmaceutical compositions thereof described herein may be administered in accordance with any approved The compound can be administered to a subject in need thereof by any of the accepted routes of administration. These include buccal, cutaneous, intracervical, endosinusial, endotracheal, enteral, epidural, and interstitial. Substance, intraabdominal, intraarterial, intrabronchial, intrasynovial, intracerebral, intracistern, intracoronary, intradermal, intraductal, duodenal In the intestine, in the dura mater, in the epidermis, in the esophagus, in the stomach, in the gums, in the ileum, in the lymph, in the marrow, in the meninges, in the muscle Intraperitoneal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasintrasinal, intraspinal, intrasynovial, intratesticular , intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal, nasogastric, oral, parenteral, transdermal (percutaneous), peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal ( transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal In certain embodiments, the preferred route of administration is parenteral (e.g., intratumoral). do.

[0440] The composition can be formulated for parenteral administration, e.g., intravenously, intramuscularly, subcutaneously, or intravenously. or even formulated for injection via the intraperitoneal route. Such compositions may be prepared as injectables, either as liquid solutions or suspensions. and a solid form suitable for use in preparing a solution or suspension by addition of a liquid prior to injection. The preparation may also be emulsified. known to those skilled in the art in light of the present disclosure.

[0441] Suitable pharmaceutical forms for injectable use include sterile aqueous solutions or dispersions, sesame formulations containing oil, peanut oil, or aqueous propylene glycol, and sterile injectable and sterile powders for the extemporaneous preparation of solutions or dispersions. In all cases the forms are sterile. It must be fluid enough to be easily squirted. It should be stable under the conditions of production and storage and should be resistant to the contaminating action of microorganisms such as bacteria and fungi. must be protected against

[0442] Carriers can also be, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, glycol, and liquid polyethylene glycol), suitable mixtures thereof, and The solvent or dispersion medium may be, for example, a solvent containing a vegetable oil. The use of a coating such as lecithin helps maintain the required particle size in the case of dispersions. Prevention of microbial action can be achieved by the use of surfactants and by the maintenance of a protective effect against microbial attack. , various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, This can be achieved by isotonic agents such as benzoyl perfusate and thimerosal. For example, it may be preferable to include sugars or sodium chloride. Contains agents that delay absorption, for example, aluminum monostearate and gelatin. This can be achieved by use in products.

[0443] Sterile injectable solutions may be prepared by appropriate addition of various other ingredients as listed above, as required. The active compound is prepared by incorporating the required amount in a suitable solvent, followed by sterilization by filtration. Generally, dispersions are prepared by combining the basic dispersion medium and the required components from those listed above. Prepared by incorporating various sterilized active ingredients into a sterile vehicle containing other ingredients. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is vacuum drying. drying and freeze-drying technology, which combines the active ingredient with its previously sterile-filtered solution. Bring the powder with any additional desired ingredients from the liquid.

[0444] Intratumoral injection is discussed, for example, in Lammers, et al., "Effect of Intratumoral Injection on Tumor Growth and Development," Tratumoral Injection on the Biodistribution and the Therapeutic Potential of HPM A Copolymer-Based Drug Delivery System”Neoplasia. 2006,10,788-795.

[0445] Pharmacologically available in rectal compositions as gels, creams, enemas, or rectal suppositories Acceptable excipients include cocoa butter glycerides, synthetic polymers such as polyvinyl alcohol, Ibuprofen, PEG (PEG ointment, etc.), glycerin, glycerin gelatin, hydrogenated vegetable oil, poly Loxamer, polyethylene glycols of various molecular weights and polyethylene glycol lipids Mixture of fatty acid esters, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate , menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla Parabens in essential oils, aerosol, phenoxyethanol, sodium methyl p-hydroxybenzoate ammonium, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbomer methyloxybenzoate, macrogol cetearyl ether, cocoyl caprylyl Rocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, Gum, Carboxy-Metabisulfite, Disodium Edetate, Sodium Benzoate, Potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM) , lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate Examples of compounds that can be used include, but are not limited to, any one or more of:

[0446] In certain embodiments, the suppository comprises a chemical entity described herein in a solid form at ambient temperature. but liquid at body temperature, and therefore melt in the rectum to release the active compound. Suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or In another embodiment, the suppository for rectal administration can be prepared by mixing with a suppository wax. The composition is in the form of an enema.

[0447] In other aspects, the compounds described herein or pharmaceutical compositions thereof are administered orally. Suitable for local delivery to the digestive or GI tract (e.g., solid or liquid dosage forms) .

[0448] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity may contain one or more pharmaceutically acceptable salts. acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or or a) fillers or extenders, such as starch, lactose, sucrose, glucose, b) a binder, such as carboxymethylcellulose, mannitol, and silicic acid; , alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, etc. c) humectants, such as glycerol; d) disintegrants, such as agar-agar, calcium carbonate; cereals, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retardants such as paraffin, f) absorption enhancers such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glutaric acid monostearate glycerol, h) absorbents, e.g., kaolin and bentonite clay, and i) lubricants. Lubricants, such as talc, calcium stearate, magnesium stearate, solid poly It is mixed with ethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid compositions of the type also contain high molecular weight polymers in addition to excipients such as lactose or milk sugar. Ethylene glycol and other similar compounds are used as fillers in soft and hard-filled gelatin capsules. It can be used as such.

[0449] In one aspect, the composition is in the form of a unit dosage form such as a pill or tablet, so that The compositions may comprise a chemical entity provided herein together with a diluent, e.g., lactose. , sucrose, or dicalcium phosphate; lubricants, e.g., magnesium stearate; and binders, such as starch, acacia gum, polyvinylpyrrolidine, The solid dosage form may contain cellulose, cellulose, or a cellulose derivative. In powder, marume, solution or suspension (e.g., propylene carbonate, plant oil, PEG, poloxamer 124 or triglycerides) in a capsule (gelatin or cellulose) The compound is encapsulated in a base capsule. unit dosage forms in which the active substances or additional active agents are physically separated, e.g., Capsules with granules (or tablets in capsules), bilayer tablets, two-compartment gel capsules Enteric coated or delayed release oral dosage forms are also contemplated. will be done.

[0450] Other physiologically acceptable compounds may be used as wetting agents, emulsifying agents, dispersing agents, or microbial inhibitors. Preservatives that are specifically useful for preventing the growth or action of various preservatives include: These are well known and include, for example, phenol and ascorbic acid.

[0451] In certain embodiments, the excipients are sterile and generally free of undesirable matter. These compositions may be sterilized by conventional, well known sterilization techniques. Sterility is not required for excipients in various oral dosage forms, such as cereals. is usually sufficient.

[0452] In certain embodiments, the solid oral dosage form is administered to the stomach or lower GI, e.g., the ascending colon and and / or delivery of chemical entities to the transverse colon and / or distal colon and / or small intestine. and one or more ingredients that provide the composition with a chemical and / or structural predisposition for Exemplary formulation techniques can be found in, for example, Filipski, KJ, et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-80 2.

[0453] Examples include upper GI targeting technologies, e.g., Accordion Pill (Intec Pharma); These include floating capsules and materials that can adhere to the mucosal wall.

[0454] Another example is lower GI targeting technology, which targets different regions of the intestinal tract. Several enteric / pH-sensitive coatings and excipients are available to These materials are typically formulated to deliver a specific pH that is selected based on the GI region of the desired drug release. These materials are also polymers that are designed to dissolve or erode in areas where they are , to protect acid-labile drugs from gastric juices or to prevent the active ingredient from being irritating to the upper GI Acts to limit exposure when possible (e.g., hydroxypropyl phthalate) Methylcellulose series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate , hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylate-methylcellulose Other techniques include topical administration in the GI tract. These include dosage forms that respond to local flora, pressure-controlled colonic delivery capsules, and Pulsincap. It can be obtained.

[0455] The ophthalmic composition may contain viscogen (e.g., carboxymethylcellulose, glycerin, polyethylene glycol, polyethylene glycol diglyceride ... vinylpyrrolidone, polyethylene glycol), stabilizers (e.g., Pluronic block copolymer), cyclodextrin), preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride, Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex, Allergan, Inc.) It may include, but is not limited to, one or more of any of the following:

[0456] Topical compositions can include ointments and creams. Ointments are typically It is a semi-solid preparation based on petrolatum or other petroleum derivatives. It contains the selected active agent. Creams are typically viscous liquids or emulsions, often either oil-in-water or water-in-oil. is a semi-solid emulsion. Cream bases are typically water-washable and contain an oil phase, emulsifiers, and an aqueous phase. The oil phase, sometimes called the "internal" phase, is generally made up of petrolatum and and a fatty alcohol, such as cetyl or stearyl alcohol, and the aqueous phase It usually, but not necessarily, exceeds the oil phase in volume and generally contains a humectant. Emulsifiers in emulsion formulations are generally nonionic, anionic, cationic or amphoteric interfacial agents. Like other carriers or vehicles, ointment bases are inert, stable, non-irritating, and It should be non-sensitizing and non-irritating.

[0457] In any of the above embodiments, the pharmaceutical compositions described herein may comprise a lipid, an interbilayer crosslinker, Lamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA ]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particles The membrane may comprise one or more of a membrane-supported lipid bilayer.

[0458] Dosage Dosage will depend on the requirements of the patient, the severity of the condition being treated and the particular Determination of the proper dosage for a particular situation is within the skill of the medical arts. The total daily dosage can be divided into portions throughout the day and can be determined by one skilled in the art. may be administered in divided doses or by any means that provides continuous delivery.

[0459] In some embodiments, the compounds described herein are administered in a dose of about 0.001 mg / Kg to about 500 mg / Kg (e.g., about 0.001mg / Kg ~ approx. 200mg / Kg, approx. 0.01mg / Kg ~ approx. 200mg / Kg, approx. 0.01mg / Kg ~ approx. 150mg / Kg, approx. 0.01 mg / Kg ~ approx. 100 mg / Kg, approx. 0.01 mg / Kg ~ approx. 50 mg / Kg, approx. 0.01 mg / Kg ~ approx. 10 mg / Kg, approx. 0.01 mg / Kg ~ Approx. 5mg / Kg, approx. 0.01mg / Kg ~ approx. 1mg / Kg, approx. 0.01mg / Kg ~ approx. 0.5mg / Kg, approx. 0.01mg / Kg ~ approx. 0.1mg / K g, 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 0.1 mg / Kg ~ approx. 50 mg / Kg, approx. 0.1 mg / Kg ~ approx. 10 mg / Kg, approx. 0.1 mg / Kg ~ approx. 5 mg / Kg, approx. 0.1 mg / Kg ~ approx. 1 mg / Kg, about 0.1 mg / Kg to about 0.5 mg / Kg).

[0460] Regimen The dosages may be administered on a daily basis (e.g., as a single dose or in two or more doses). as divided doses or more) or not on a daily basis (e.g., every other day, every 2 days, every 3 days, It can be administered once a week, twice a week, once every two weeks, or once a month.

[0461] In some embodiments, the duration of administration of the compounds described herein is 1 day, 2 days, 3 days, 4 days, 5 days, or , 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 3rd week, 4th week, 5th week, 6th week, 7th week, 8th week , 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months In a further embodiment, the period of cessation of administration is 1 day, 2 months, 3 months, 4 months, or longer. , 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 3rd week, 4th week , 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In one embodiment, the therapeutic compound In another aspect, the therapeutic compound is administered to an individual at a time period, followed by a separate time period. during a first period and during a second period after the first period during which administration is discontinued during the second period, followed by During a third period of time when administration of the therapeutic compound is initiated, and then during a fourth period after the third period of time when administration is discontinued. In one aspect of this embodiment, the period of administration of the therapeutic compound is The withdrawal period may be repeated for a determined or undetermined period of time. So, 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. Day, 13th, 14th, 3rd week, 4th week, 5th week, 6th week, 7th week, 8th week, 9th week, 10th week, 11th week, 12th week, 4th month, 5th month months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, the period of time during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9th, 10th, 11th, 12th, 13th, 14th, 3rd week, 4th week, 5th week, 6th week, 7th week, 8th week, 9th week, 10th week, 11th week , 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or It's more than that.

[0462] Treatment methods In some embodiments, the pathology and / or the pathology of a condition, disease, or disorder (e.g., immune disorder, cancer) or symptoms and / or progression are associated with increased STING activity (e.g., STING signaling) Methods for treating a subject having a condition, disease, or disorder in which hyperactivity (e.g., hyperactivity) contributes is provided.

[0463] Indications In some embodiments, the condition, disease, or disorder is cancer. Non-limiting examples of cancer include: , melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies More specific examples of such cancers include breast cancer, colon cancer, rectal cancer, Colorectal cancer, kidney or renal cancer, clear cell carcinoma, small cell lung cancer , non-small cell lung cancer, lung cancer including adenocarcinoma of the lung and squamous cell carcinoma of the lung (e.g. , epithelial squamous cell carcinoma), cervical cancer, ovarian cancer, prostate cancer, prostate neoplasms, liver cancer, Gastric or stomach cancer, including bladder cancer, peritoneal cancer, hepatocellular carcinoma, and gastrointestinal cancer ) cancer, gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, capsule Cell tumor, allenoblastoma, hepatoma, non-Hodgkin's lymphoma (NHL), multiple myeloma , myelodysplastic disorders, myeloproliferative disorders, chronic myeloid leukemia, and acute hematological malignancies Hematological malignancies, including endometrial or uterine cancer, endometriosis, endometrial stromal sarcoma, adenocarcinoma Fibrosarcoma, choriocarcinoma, salivary gland cancer, vulvar cancer, thyroid cancer, esophageal cancer , liver cancer, anal cancer, penile cancer, nasopharyngeal cancer, laryngeal cancer, Kaposi's sarcoma, mast cell sarcoma, ovarian cancer Focal sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin cancer, schwannoma, oligodendroglioma, neuroblastoma, Neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, Ewing's sarcoma, peripheral undifferentiated tumor Neuroectodermal tumors, urinary tract cancer, thyroid carcinoma, Wilms' tumor Other causes include abnormal vascular proliferation associated with nevus syndrome, edema (e.g., associated with brain tumors), In some cases, the cancer is melanoma.

[0464] In some embodiments, the condition, disease, or disorder is a neurological disorder, including a central nervous system disorder. (brain, brainstem, and cerebellum), the peripheral nervous system (including the cranial nerves), and the autonomic nervous system (parts of which Non-limiting examples of cancer include disorders involving the nervous system (neuropathies) and the nervous system (neuropathies located in both the central and peripheral nervous systems). Acquired epileptic aphasia, acute powder-induced encephalomyelitis, adrenoleukodystrophy, and Age-related macular degeneration, hypoplasia of the corpus callosum, agnosia, Aicardi syndrome, Alexander disease, Alzheimer's disease Pars disease, alternating hemiplegia, Alzheimer's disease, vascular dementia, amyotrophic lateral sclerosis, anencephaly syndrome, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cyst, arachnoid Anronl - Chiari malformation, arteriovenous malformation, Asperger's syndrome, telangiectasia Ataxia telegiectasia, attention deficit hyperactivity disorder, autism, autonomic dysfunction , back pain, Batten disease, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal (be nign focal), muscle atrophy, benign intracranial hypertension, Binswanger's disease, blepharospasm, Bloch-Sa Rutsberger syndrome, brachial plexus injury, brain abscess, brain injury, brain tumor (including glioblastoma multiforme), Spinal cord tumors, Brown-Séquard syndrome, Canavan disease, carpal tunnel syndrome, burning pain, central pain syndrome, central pontine myelinolysis, head injury, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, brain Paralysis, Charcot-Marie-Tooth disease, chemotherapy-induced neuropathy and neuropathic Pain, Chiari malformation, chorea, chronic inflammatory demyelinating polyneuropathy, chronic pain, chronic focal Pain syndrome, Coffin-Lowry syndrome, coma including persistent vegetative state, congenital facial diplegia , corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob syndrome disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion disease, cytomegalovirus infection , Dancing Eyes-Dancing Feet Syndrome, Dandy-Walker Syndrome, Do Son's disease, Domorsia syndrome, Degerine-Klumke palsy, dementia, dermatomyositis , diabetic neuropathy, diffuse sclerosis, autonomic dysfunction, dysgraphia, dyslexia, dysphagia tonia, early infantile epileptic encephalopathy, empty sella syndrome, encephalitis, encephalocele, cerebral trigeminal Neurogenic angiomatosis, epilepsy, Erb's palsy, essential tremor, Fabry disease, Fahr's syndrome, syncope , familial spastic paralysis, febrile seizures, Fisher syndrome, Friedreich's ataxia, frontal Cerebral dementia and other "tauopathies", Gaucher disease, Gerstmann's syndrome, giant cell ataxia Phlebitis, giant cell inclusion disease, globoid cell leukodystrophy, Guillain-Barré syndrome, HT LV-1-associated myelopathy, Hallervorden-Spatz disease, head injury, headache, hemifacial spasm, hereditary Spastic paraplegia, polyneuropathy-type hereditary ataxia, shingles, herpes zoster, Hirayama syndrome, HIV-related Dementia and neuropathy (also neurological symptoms of AIDS), holoprosencephaly, Huntington's disease Meningitis and other polyglutamine repeat diseases, hydrocephalus anencephaly, hydrocephalus, hypercortisolism, Hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile leukemia Fusam's disease, infantile spasms, inflammatory myopathy, intracranial cysts, intracranial hypertension, Joubert's disease syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbone syndrome, Klippel-Farber syndrome Ille syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Burt-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medulla (Wallenberg syndrome) Leigh syndrome, learning disabilities, Leigh disease, Lennox-Gustaut syndrome, Schneider-Nyhan syndrome, leukodystrophy, dementia with Lewy bodies, lissencephaly, entrapment syndrome syndrome, Lou Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis) , lumbar discopathy, Lyme disease - neurological sequelae, Machado-Joseph disease, encephalopathy aly), megalencephaly, Melkersson-Rosenthal syndrome, Meniere's disease (Menieres disease), meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, hemicephaly pain, Miller-Fisher syndrome, minor stroke, mitochondrial myopathy, Moebius syndrome , single limb muscular atrophy, motor neuron disease, moyamoya disease, mucopolysaccharidosis, multi-infarct (milti-infa RCT) Dementia, multifocal motor neuropathy, multiple sclerosis and other demyelinating disorders, orthostatic Multiple system atrophy with hypotension, p muscular dystrophy dystrophy, myasthenia gravis, myelinoclastic diffuse sclerosis, infantile myelinopathy Oclonus encephalopathy, myoclonus, myopathy, congenital myotonia, narcolepsy, Neurofibromatosis, neuroleptic malignant syndrome, neurological symptoms of AIDS, neurological sequelae of lupus , neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorder, Niemann-Pick O'Sullivan-McLeod syndrome, occult spinal dysraphism, occult spinal dysraphism al dysraphism sequence), Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus- Myoclonus, optic neuritis, orthostatic hypotension, overuse syndrome, paresthesia, Parkinson's disease, Paramyotonia congenita, paraneoplastic disease, seizures, Paley Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralysis, peripheral neuropathy -, painful neuropathy and neuropathic pain, persistent vegetative state, pervasive developmental disorder, photosensitivity Sneeze reflex, phytanic acid storage disease, Pick's disease, pinched nerve, pituitary tumor , polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia, post-infectious encephalomyelitis, orthostasis Hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion disease, progressive hemifacial atrophy progressive sclerosing poliodystrophy, progressive supranuclear palsy, pseudocerebri Tumors, Ramsay-Hunt syndrome (types I and II), Rasmussen's encephalitis, reflex sympathetic Dystrophic syndrome, Refsum's disease, repetitive movement disorder, repetitive stress injury, restlessness Legg syndrome, retroviral-associated myelopathy, Rett syndrome, Reye syndrome, chorea, Sand Hoff's disease, Schilder's disease, schizencephaly, septo-optic dysplasia, shaken baby syndrome, varicella zoster rash, Shy-Drager syndrome, Sjogren's syndrome, sleep apnea, Sotos syndrome, convulsions spinal cord atrophy, spina bifida, spinal cord injury, spinal tumor, spinal muscular atrophy, stiff-person syndrome, stroke , Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, Sydenham Chorea, syncope, syringomyelia, tardive dyskinesia, Tay-Sachs disease, temporal arteritis, spinal cord Tethered syndrome, Thomsen's disease, thoracic outlet syndrome, trigeminal neuralgia, Todd's palsy, Tourette's syndrome , transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia , tropical spastic paraplegia, tuberous sclerosis, vascular dementia (multi-infarct dementia), and temporal arteritis. Vasculitis, von Hippel-Lindau disease, Wallenberg syndrome, Werdnig-Hoffmann syndrome disease, West syndrome, whiplash injury, Williams syndrome, Wildon's disease se), amyotrophic lateral sclerosis, and Zellweger syndrome. do.

[0465] In some embodiments, the condition, disease, or disorder is a STING-associated condition, e.g., a type I interface disorder. Vasculitis (e.g., STING-associated vasculitis in infancy (SAVI)), Aicardi-Goutière disease Syndrome (AGS), hereditary forms of lupus, as well as systemic lupus erythematosus and rheumatoid arthritis In certain aspects, the condition, disease, or disorder is an inflammation-related disorder such as an autoimmune Diseases (e.g., cytosolic DNA-induced autoinflammatory diseases). Non-limiting examples include: Rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, chronic inflammation with polygenic susceptibility Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are common conditions. In certain embodiments, the condition is inflammatory bowel disease. Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, or The colitis induced by multiple chemotherapy agents, the colitis induced by treatment with adoptive cell therapy, colitis, one or more alloimmune diseases (e.g., graft-versus-host disease, e.g., acute transplant Colitis, radiation enteritis, collagen-related colitis associated with graft-versus-host disease and chronic graft-versus-host disease These include colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain embodiments, the condition is an alloimmune disease (e.g., graft-versus-host disease, e.g., acute graft Host-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 nasal mucositis, esophageal mucositis or intestinal mucositis).

[0466] In some embodiments, STING-mediated modulation of the immune system is mediated by exogenous factors. The present invention provides treatment for diseases, including diseases that can be treated and / or prevented by the methods of the present invention. Exemplary infections caused by foreign agents that may occur include bacterial (e.g., gram-positive or gram-negative) negative bacterial infections, fungal infections, parasitic infections, and viruses In one aspect of the present invention, the infection is a bacterial infection (e.g., Escherichia coli). (E. coli), Klebsiella pneumoniae, Pseudomonas Pseudomonas aeruginosa, Salmonella spp., Staphylococcus aureus, Streptococcus spp. (S streptococcus spp., or vancomycin-resistant enterococcus In another embodiment, the infection is a fungal infection (e.g., a mold infection), or sepsis. In yet another embodiment, the infection is a parasitic infection. bacterial infections (e.g., Giardia duodenalis, Cryptosporidium Cryptosporidium parvum, Cyclospora cayetanensis ( Cyclospora cayetanensis, and Toxoplasma gondiz In yet another aspect, the infection is an infection caused by a single-celled or multicellular parasite, including Viral infections (e.g., AIDS, bird flu, chickenpox, cold sores, stomach flu, Enteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and viruses associated with lower or upper respiratory tract infections (e.g., respiratory syncytial virus) infectious disease).

[0467] In some embodiments, the condition, disease, or disorder is hepatitis B (e.g., See WO 2015 / 061294).

[0468] In some embodiments, the condition, disease, or disorder is cardiovascular disease (including, e.g., myocardial infarction). is selected from.

[0469] In some embodiments, the condition, disease, or disorder is age-related macular degeneration.

[0470] In some aspects, the condition, disease, or disorder is treated with chemotherapy, either alone or in combination. caused by exposure to radiation outside of radiation therapy, in addition to radiation therapy or radiotherapy Mucositis, also known as stomatitis, can occur as a result of injury. do.

[0471] In some embodiments, the condition, disease, or disorder is uveitis, which is inflammation of the uvea (e.g., Anterior uveitis, e.g., iridocyclitis or iritis, intermediate uveitis (ciliary ulcers) pars planitis), posterior uveitis, or chorioretinitis (e.g., panuveitis) is.

[0472] In some embodiments, the condition, disease, or disorder is cancer, a neurological disorder, an autoimmune disease, B Hepatitis, uvetitis, cardiovascular disease, age-related macular degeneration, and mucositis The compound is selected from the group consisting of:

[0473] Further examples include those discussed below in this specification and contemplated combination therapy regimens. The indications discussed include:

[0474] Combination therapy The present disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[0475] In some aspects, the methods described herein are combined with the administration of a compound described herein. in combination with one or more additional therapies (e.g., one or more additional therapeutic agents and / or The method can further comprise administering one or more therapeutic regimens.

[0476] In certain embodiments, the methods described herein may be used in combination with the administration of one or more additional cancer therapies. The method may further include the step of administering.

[0477] One or more additional cancer therapies include surgery, radiation therapy, chemotherapy, toxin therapy, Immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, Hepatitis B vaccine, Oncophag e, Provenge), and gene therapy, as well as combinations thereof. Immunotherapies include, but are not limited to, adoptive cell therapy, stem cell and / or including, but not limited to, dendritic cell induction, transfusion, lavage, and / or tumor freezing. Other treatments that are not included include, but are not limited to:

[0478] In some embodiments, the one or more additional cancer therapies is chemotherapy, which may comprise one or more It may involve administering multiple additional chemotherapeutic agents.

[0479] In certain embodiments, the additional chemotherapeutic agent is an immunomodulatory moiety, e.g., an immune checkpoint inhibitor. In certain of these aspects, the immune checkpoint inhibitor is an immune checkpoint inhibitor. It targets immune checkpoint receptors, including CTLA-4 and 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 cells Immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylinositol Lucerin-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, TNFR SF25, 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, CD4 8-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIG D2, butyrophilins including BTNL2, Siglec family, TIGIT and PVR family members members, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-C D28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD39-CD73, CXCR4-CXCL12, phosphatase Phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropil CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1). See, e.g., Postow, MJ Clin. Oncol. 2015, 33, 1.

[0480] In certain of these embodiments, the immune checkpoint inhibitor is urelumab, PF-050 82566, MEDI6469, TRX518, valirumab, CP-870893, pembrolizumab (PD1), nibor Mab (PD1), Atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-L1), Abel Mab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, lirilumab, IPH2201, Emactu Izumob, INCB024360, galunisertib, urocupulumab, BKT140, bavituximab, CC-9 0002, bevacizumab, and MNRP1685A, and MGA271.

[0481] In certain embodiments, the additional chemotherapeutic agent is an alkylating agent. Many nucleophiles react under conditions present in cells, including but not limited to cells. It is so named because of its ability to alkylate functional groups. The alkylating agents are cisplatin, carboplatin, mechlorethamine, cyclophosphamide, including, but not limited to, fluticasone, fluoxetine ... In one aspect, the alkylating agent is an alkylating agent that is capable of converting alkyl groups into alkyl groups in biologically important molecules. by forming covalent bonds with amino, carboxyl, sulfhydryl, and phosphate groups They can function by impairing cellular function, or they can damage the cell's DNA. In a further aspect, the alkylating agent can be a synthetic, semi-synthetic It is a compound or derivative.

[0482] In certain embodiments, the additional chemotherapeutic agent is an antimetabolite. An antimetabolite acts on the bilayer of DNA. They disguise themselves as building blocks, purines or pyrimidines, and generally ) prevents these materials from being incorporated into DNA during the "S" phase, preventing normal development and differentiation Antimetabolites can also affect RNA synthesis. Anti-inflammatory drugs include, but are not limited to, azathioprine and / or mercaptopurine. In a further aspect, the antimetabolite is synthetic, semi-synthetic, or a derivative.

[0483] In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and / or a terpenoid. These alkaloids are derived from plants and generally have been shown to prevent microtubule function. In one embodiment, the plant alkaloids and / or terpenoids , vinca alkaloids, podophyllotoxins and / or taxanes. Kaloids generally bind to specific sites on tubulin and are generally expressed during the M phase of the cell cycle. In one embodiment, the vinca alkaloids inhibit the assembly of tubulin into microtubules. The id is Madagascar periwinkle, Catharanthus robur Zeus (Catharanthus roseus) (formerly known as Vinca rosea) In one aspect, the vinca alkaloids are derived from, but not limited to, vinca. including, but not limited to, cristine, vinblastine, vinorelbine and / or vindesine In one embodiment, the taxane is selected from the group consisting of taxol, paclitaxel, and and / or docetaxel. In a further embodiment, Alkaloids or terpenoids are synthetic, semi-synthetic or derivatives. In a further embodiment, the podophyllotoxin is etoposide and / or teniposide In one embodiment, the taxane is docetaxel and / or ophthalmidine. In one embodiment, the cancer therapeutic agent is, but is not limited to, rutataxel. Topoisomerases are essential enzymes that maintain DNA topology. Inhibition of type I or type II topoisomerases disrupts proper DNA supercoiling. Disruption of the topoisomers interferes with both transcription and replication of DNA. Somerase is either a type I topoisomerase inhibitor or a type II topoisomerase inhibitor In one embodiment, the type I topoisomerase inhibitor is a compound selected from the group consisting of cyclohexyl 1-hydroxybenzoates, ... In another embodiment, the camptothecin is, but is not limited to, Xatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67(AR 67) and / or ST 1481. In one embodiment, type II T cells are Polyisomerase inhibitors include, but are not limited to, epipodophyllotoxins. In a further embodiment, the epipodophyllotoxin is selected from the group consisting of amsacrine, etoposide, id), etoposide phosphate, and / or teniposide In a further aspect, the topoisomerase is synthetic, semi-synthetic, or a derivative. This includes the American mayapple (Podophyllum peltatum) )) roots, including, but not limited to, epipodophyllotoxin, a substance naturally occurring in the roots of These include naturally occurring compounds that are not necessarily soluble in water.

[0484] In certain embodiments, the additional chemotherapeutic agent is a stilbenoid. Stilbenoids include resveratrol, piceatannol, pinosylvin, and pterocarboxamide. Stilbene, α-viniferin, ampelopsin A, ampelopsin E, diptoindoline Diptoindonesin C, Diptoindonesin F, Epsilon-Vinferin, Flex Flexuosol A, Gnetin H, Hemsleyanol D, Hopeaphenol, Tran Examples include diptoindonesin B, astringin, piceid, and diptoindonesin A. In a further aspect, the stilbenoid may be a synthetic, It is semi-synthetic or a derivative.

[0485] In certain embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. Cytotoxic antibiotics include actinomycin, anthracenediones, anthracyclines, and saprophylactics. Lidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and / or clofa In one embodiment, actinosides are used, but are not limited to, chlorofazimine. Mycins include actinomycin D, bacitracin, colistin (polymyxin E) and / or or polymyxin B. In another embodiment, anthracycline Antracenedione is mitoxantrone and / or pixantrone In a further aspect, the anthracycline is an anthracycline that inhibits bleomycin, but is not limited to bleomycin, Isin, doxorubicin (adriamycin), daunorubicin (daunomycin), Pirubicin, idarubicin, mitomycin, plicamycin, and / or valrubicin In a further aspect, the cytotoxic antibiotic is , synthetic, semi-synthetic or derivative.

[0486] In certain embodiments, the additional chemotherapeutic agent is endostatin, angiogenin, angiogenesis inhibitor, or thrombin inhibitor. angiostatin, chemokine, angioarrestin, angiostatin (plasminogen cleavage) fragment), basement membrane collagen-derived anti-angiogenic factors (tumstatin, canstatin, or allele antithrombin III, signal transduction inhibitor, cartilage-derived inhibitor CD59 complement fragments, fibronectin fragments, gro-β, heparinase, heparin hexa Sugar fragments, human chorionic gonadotropin (hCG), interferon α / β / γ, interferon Ion-inducible protein (IP-10), interleukin-12, kringle 5 (plasminogen activator) fragments), TIMPs, 2-methoxyestradiol, placenta Ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4 ), prolactin 16kD fragment, proliferin-related protein (PRP), various retinoids , tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transformin Transforming growth factor-β (TGF-β), vasculostatin, and vasostatin (calreticulin fragments) are selected.

[0487] In certain embodiments, the additional chemotherapeutic agent is abiraterone acetate, altretamine, anthracycline, or thiazolinone. Hydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2, 3,4,5,6-Pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide , bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl (pro ly)-1-L-proline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclo Phosphamide, 3',4'-didehydro-4'-deoxy-8'-norvin-caleukoblastine, docetaxel Taxol, doxetaxel, cyclophosphamide, carboplatin, Lumustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacaine Rubadin (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, dolastatin Xorubicin (Adriamycin), etoposide, 5-fluorouracil, finasteride , flutamide, hydroxyurea and hydroxyureataxanes ), ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, meconium Loretamine (nitrogen mustard), melphalan, mibobulin isethionate, Zoxin, sertenef, streptozocin, mitomycin, methotrexate acetaminophen, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, Rocarbazine, RPR109881, stramustine phosphate, tamoxifen Fen, Tasonermin, Taxol, Tretinoin, Vinblastine, Vincristine, It is selected from vindesine sulfate, and vinflunine.

[0488] In certain embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, or ophthalmic solution. Xaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, Etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan amsacrine, etoposide, etoposide phosphate, teniposide, 5-fluorouracil Sil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mycobacterium tomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, Additional agents include ifosfamide and doxorubicin. These include inhibitors of the mammalian target of leukemia, including rapamycin, everolimus, and temsirolimus. Examples of anticoagulants include, but are not limited to, limus and dehololimus.

[0489] In yet another aspect, the additional chemotherapeutic agent is a chemotherapeutic agent, the entirety of which is incorporated herein by reference. They can be selected from those described in detail in US Pat. No. 7,927,613.

[0490] In some embodiments, the additional therapeutic agent and / or regimen is directed to treating other STING-associated conditions, e.g. , type I interferonopathy (e.g., STING-associated vasculitis in infancy (SAVI)), Ecardi - Gouthieres syndrome (AGS), hereditary forms of lupus, and systemic lupus erythematosus and It can be used to treat inflammation-related disorders such as rheumatoid arthritis and rheumatoid arthritis.

[0491] Non-limiting examples of additional therapeutic agents and / or regimens for treating rheumatoid arthritis Nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen and naproxen) ), corticosteroids (e.g., prednisone), disease-modifying antirheumatic drugs (DMARDs, For example, methotrexate (Trexall®, Otrexup®, Rasuvo®) Trademark), Rheumatrex®), leflunomide (Arava®), hydroxybenzoates Chloroquine (Plaquenil), PF-06650833, iguratimod, tofacitinib (Xeljanz ABBV-599, evobrutinib, and sulfasalazine (Azulfidine (Registered Trademark) and biologics (e.g., abatacept (Orencia®), adalimumab, Mab (Humira®), anakinra (Kineret®), certolizumab (C ibzia®), etanercept (Enbrel®), golimumab (Simponi®), infliximab (Remicade®), rituximab (Rituxan®), Registered trademark), tocilizumab (Actemra®), bovalilizumab, sarilumab (K evzara®), secukinumab, ABP 501, CHS-0214, ABC-3373, and tocilizumab Mab (ACTEMRA®)).

[0492] Non-limiting examples of additional therapeutic agents and / or regimens for treating lupus include: topical immunomodulators (e.g., tacrolimus ointment (Protopic®)) and pimecrolimus cream (Elidel®), thalidomide (Thalomid®), nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen and naproxen) antimalarials (e.g., hydroxychloroquine (Plaquenil)), corticosteroids steroids (e.g., prednisone) and immunomodulatory agents (e.g., evobrutinib, iverdrin) cyclophosphamide, voclosporin, cenerimod, azathioprine (Imuran®), cyclophosphamide Sufamide (Cytoxan®, Neosar®, Endoxan®), and and cyclosporine (Neoral, Sandimmune®, Gengraf®), and and mycophenolate mofetil) baricitinib, iguratimod, filgo filogotinib, GS-9876, rapamycin, and PF-06650833), and biologics agents (e.g., belimumab (Benlysta®), anifrolumab, prezalumab (pr ezalumab), MEDI0700, obinutuzumab, bovalilizumab, lulizumab, Atacicept, PF-06823859, and lupizor, rituximab, BT063, BI6 55064, BIIB059, Aldesleukin (Proleukin®), Dapirolizumab, Ed Ratide, IFN-α-kinoid, OMS721, RC18, RSLV-132, celalizumab, XmAb5871, and For example, ustekinumab (Stelara®) is used to treat systemic lupus erythematosus. Non-limiting treatments for rheumatoid arthritis include nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen ... profen and naproxen), antimalarials (e.g., hydroxychloroquine (Plaq uenil), corticosteroids (e.g., prednisone) and immunomodulators (e.g., Ibeldomide, voclosporin, azathioprine (Imuran®), cyclophosphamide amides (Cytoxan®, Neosar®, Endoxan®), and Iclosporins (Neoral, Sandimmune®, Gengraf®), and mycophenolate cophenolate mofetil, baricitinib, filgotinib, and PF-06650833), and and biologics (e.g., belimumab (Benlysta®), anifrolumab, preza Lumab, MEDI0700, bovalilizumab, lulizumab, atacicept, PF-06823859, lupzo rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin (registered) trademark), dapirolizumab, edoratide, IFN-α-kinoid, RC18, RSLV-132, Seraliz mab, XmAb5871, and ustekinumab (Stelara®). For example, non-limiting examples of treatments for cutaneous lupus include steroids, immunomodulators, (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream ( Elidel®), GS-9876, filgotinib, and thalidomide (Thalomid for treating drug-induced and / or neonatal lupus Agents and regimens can also be administered.

[0493] Additional therapeutic agents and / or regimens for treating infantile-onset STING-associated vasculitis (SAVI) Non-limiting examples of agents include JAK inhibitors (e.g., tofacitinib, ruxolitinib, , filgotinib, and baricitinib).

[0494] an additional therapeutic agent for treating Aicardi-Goutières syndrome (AGS) and / or Non-limiting examples of regimens include physical therapy, treatment for respiratory complications, and treatment for seizures. Anticonvulsant therapy, tube feeding, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine For example, Emtriva®), tenofovir (e.g., Viread®), Emt Licitabine / tenofovir (e.g., Truvada®), zidovudine, lamivudine, and and abacavir), and JAK inhibitors (e.g., tofacitinib, ruxolitinib, fulvovir irgotinib, and baricitinib).

[0495] Non-limiting examples of additional therapeutic agents and / or regimens for treating IBD include 6- Mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforce NDC, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34 selection Peripheral blood stem cell transplantation, azathioprine, bertilimumab, BI 655066, BMS-936557, Cert Lizumab pegol (Cimzia®), cobitolimod, corticosteroids (e.g., Prednisone, methylprednisolone, prednisone), CP-690,550, CT-P13, Cyclo Sporin, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbial transplantation, Filgotinib, fingolimod, filategrast (SB-683699) (formerly Name T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, H MPL-004 (Andrographis paniculata extract), IM U-838, infliximab, interleukin-2 (IL-2), Janus kinase (JAK) inhibitor Quality, laquinimod, masitinib (AB1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mirikisma (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, Ficitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB -104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab (MK 3222), TJ301, TNF-Kinoid (registered trademark) ), tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTT R1147A, V565, vatelizumab, VB-201, vedolizumab, and bidofur Examples include Vidofludimus.

[0496] Non-Limiting Examples of Additional Therapeutic Agents and / or Regimens for Treating Irritable Bowel Syndrome Examples include alosetron, bile acid sequesterants (e.g., colestibular lamins, colestipol, colesevelam), chloride channel activators (e.g., rubin Prostone), coated peppermint oil capsules, desipramine, dicyclomine, Ebastine, eluxadoline, farnesoid X receptor agonists (e.g., obetiko guanylate), fecal microbiota transplant, fluoxetine, gabapentin, guanylate Enzyme-C agonists (e.g., linaclotide, plecanatide), ibodutant ant), imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, Andansetron, opioids, paroxetine, pinaverium, polyethylene glycol, Pregabalin, probiotics, ramosetron, rifaximin, and tenapano Examples include tanpanor.

[0497] Non-limiting examples of additional therapeutic agents and / or regimens for treating scleroderma include: , nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen and naproxen), steroids (e.g., prednisone), immunomodulators (e.g., azathioprine, Thotrexate (Trexall®, Otrexup®, Rasuvo®, Rh eumatrex®), cyclophosphamide (Cytoxan®, Neosar® (Trademark), Endoxan®), and cyclosporine (Neoral®, Sandimm une (registered trademark), Gengraf (registered trademark), antithymocyte globulin, mycophenolate monophosphate fetil, intravenous immunoglobulin, rituximab, sirolimus, and alefacept) , calcium channel blockers (e.g., nifedipine), alpha blockers, serotonin receptor antagonists antagonists, angiotensin II receptor blockers, statins, topical nitrates, iloporus phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan, tetracycline Cyclin antibiotics, endothelin receptor antagonists, prostanoids, and thyrotropins kinase inhibitors (e.g., imatinib, nilotinib, and dasatinib). do.

[0498] Non-limiting examples of additional therapeutic agents and / or regimens for treating Crohn's disease (CD) include: Examples include adalimumab, autologous CD34-selected peripheral blood stem cell transplantation, 6-mercaptopurine, and azathioprine. Thiopurines, certolizumab pegol (Cimzia®), corticosteroids (e.g. (e.g., prednisone), etrolizumab, E6011, fecal microbial transplant, filgotinib, Rucumab, infliximab, IL-2, JAK inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, Talizumab, ozanimod, RHB-104, rifaximin, risankizumab, SHP647, sulfonamide, These include asalazine, thalidomide, upadacitinib, V565, and vedolizumab.

[0499] Non-limiting examples of additional therapeutic agents and / or regimens for treating UC include AbG n-168H, ABT-494, ABX464, Apremilast, PF-00547659, PF-06687234, 6-mercapto Purine, adalimumab, azathioprine, bertilimumab, brazikumab (MEDI2070), Cobitolimod, certolizumab pegol (Cimzia®), CP-690,550, Corticos steroids (e.g., multimax budesonide, methylprednisolone) Nisolone), cyclosporine, E6007, etrasimod, etrolizumab, fecal microbial transfer Implantation, filgotinib, 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), tofasi These include rituximab, tofacitinib, ustekinumab, UTTR1147A, and vedolizumab. do.

[0500] Non-limiting examples of additional therapeutic agents and / or regimens for treating autoimmune colitis include: Examples include corticosteroids (e.g., budesonide, prednisone, prednisolone) , beclomethasone dipropionate), diphenoxylate / atropine, infliximab benzodiazepines, loperamide, mesalamine, TIP60 inhibitors (e.g., U.S. Patent Application Publication No. 2012 / 020284 See Issue 8), and vedolizumab.

[0501] Non-limiting examples of additional therapeutic agents and / or regimens for treating iatrogenic autoimmune colitis Typical examples include corticosteroids (e.g., budesonide, prednisone, Zolone, beclomethasone dipropionate), diphenoxylate / atropine, infliximab Ximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012 / 0202848) ), and vedolizumab.

[0502] Additional therapeutic agents and methods for treating colitis induced by one or more chemotherapeutic agents Non-limiting examples of drugs and / or regimens include corticosteroids (e.g., budesonide) prednisone, prednisolone, beclomethasone dipropionate), diphenoxyethanol acetaminophen / atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (e.g. , see U.S. Patent Application Publication No. 2012 / 0202848), and vedolizumab.

[0503] Additional therapeutic agents and methods for treating treatment-induced colitis using adoptive cell therapy Non-limiting examples of medications and / or regimens include corticosteroids (e.g., budesonide) , prednisone, prednisolone, beclomethasone dipropionate), diphenoxyethanol atropine, infliximab, loperamide, TIP60 inhibitors (e.g., U.S. Patent Application Publication No. See Publication No. 2012 / 0202848), and vedolizumab.

[0504] an additional therapeutic agent for treating colitis associated with one or more alloimmune diseases and / or Non-limiting examples of alternative regimens include corticosteroids (e.g., budesonide, promethazine, benzodiazepine ... Rednisone, prednisolone, beclomethasone dipropionate), sulfasalazine, and eicosapentaenoic acid.

[0505] an additional therapeutic agent for treating radiation enteritis and / or Non-limiting examples of regimens include teduglutide, amifostine, angiotensin converting ACE inhibitors (e.g., benazepril, captopril, enalapril, rhinoplasty) Pril, lisinopril, moexipril, perindopril, quinapril, ramipril, and and trandolapril), probiotics, selenium supplementation, statins (e.g., azathioprine, Torvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, These include fluticasone, fluoxetine ... can be.

[0506] Non-limiting examples of additional therapeutic agents and / or regimens for treating collagenous colitis Examples include 6-mercaptopurine, azathioprine, and bismuth subsalicylate. Bismuth subsalicate, Boswellia serrata extract, Restyramine, colestipol, corticosteroids (e.g., budesonide, prednisolone) methadone, prednisolone, beclomethasone dipropionate), loperamide, mesalamine, These include trexate, probiotics, and sulfasalazine.

[0507] Additional therapeutic agents and / or regimens for treating lymphocytic colitis Non-limiting examples of benzodiazepines include 6-mercaptopurine, azathioprine, bismuth subsalicylate, and benzodiazepines. cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisolone, Donisone, prednisolone, beclomethasone dipropionate), loperamide, mesalamine , methotrexate, and sulfasalazine.

[0508] Non-Limiting Examples of Additional Therapeutic Agents and / or Regimens for Treating Microscopic Colitis Examples include 6-mercaptopurine, azathioprine, bismuth subsalicylate, and boswellia. Serrata extract, cholestyramine, colestipol, corticosteroids (e.g., bromide, Desonide, prednisone, prednisolone, beclomethasone dipropionate), fecal microorganisms Implants, loperamide, mesalamine, methotrexate, probiotics, and sulfonamide Fasalazine is an example.

[0509] Non-limiting examples of additional therapeutic agents and / or regimens for treating alloimmune diseases These include intrauterine platelet transfusions, intravenous immunoglobulin, and maternal Steroids, abatacept, alemtuzumab, α1-antitrypsin, AMG592, antithymocyte globulin, baricitinib, basiliximab, bortezomib, Brent ximab, cannabidiol, corticosteroids (e.g., methylprednisolone (me thylprednisone, prednisone, cyclosporine, daclizumab, Defibrotide, denileukin diftitox, glasdegib, ibruci Nib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolic acid Mofetil, natalizumab, nemolizumab (neihulizumab), pentostatin, pevonezi Stat, photobiomodulation, photopheresis, ruxolitinib, sirolimus These include limus, sonidegib, tacrolimus, tocilizumab, and vismodegib.

[0510] Non-limiting examples of additional therapeutic agents and / or regimens for treating multiple sclerosis (MS) include: Notable examples include alemtuzumab (Lemtrada®), ALKS 8700, amiloride, A TX-MS-1467, azathioprine, baclofen (Lioresal®), beta-interferon rons (e.g., IFN-β-1a, IFN-β-1b), cladribine, corticosteroids (e.g., methylprednisolone), daclizumab, dimethyl fumarate (Tecfidera®) , fingolimod (Gilenya®), fluoxetine, glatiramer acetate (Cop axone®), hydroxychloroquine, ibudilast, idebenone, laquinimod , lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montel Kast, natalizumab (Tysabri®), NeuroVax™, ocrelizumab, These include ofatumumab, pioglitazone, and RPC1063.

[0511] Non-Limiting Examples of Additional Therapeutic Agents and / or Regimens for Treating Graft-Versus-Host Disease These include abatacept, alemtuzumab, alpha-1 antitrypsin, AMG592, and antithymocytes. Globulin, baricitinib, basiliximab, bortezomib, brentuximab, cannabinoids Visiol, corticosteroids (e.g., methylprednisolone, prednisone), Iclosporin, daclizumab, defibrotide, denileukin diftitox, glasde Gibberellinib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, Raviroc, mycophenolate mofetil, natalizumab, nemolizumab, pentostatin , Pevonedistat, Photobiomodulation, Photopheresis, Ruxolitic These include nivolumab, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib. It can be obtained.

[0512] Non-limiting examples of additional therapeutic agents and / or regimens for treating acute graft-versus-host disease include: Notable examples include alemtuzumab, alpha-1 antitrypsin, antithymocyte globulin, and basilisk. ximab, brentuximab, corticosteroids (e.g., methylprednisolone, prothrombin) Rednisone), cyclosporine, daclizumab, defibrotide, denileukin difenstitium Tox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate monophosphate Fetil, natalizumab, nemolizumab, pentostatin, photopheresis, ruxo These include ritinib, sirolimus, tacrolimus, and tocilizumab.

[0513] Non-limiting examples of additional therapeutic agents and / or regimens for treating chronic graft-versus-host disease include: Notable examples include abatacept, alemtuzumab, AMG592, antithymocyte globulin, and basilar. ximab, bortezomib, corticosteroids (e.g., methylprednisolone, prednisolone) Nisone), cyclosporine, daclizumab, denileukin diftitox, glasdegib , ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, Pentostatin, photobiomodulation, photopheresis, ruxolitinib , sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib. can be.

[0514] Non-limiting examples of additional therapeutic agents and / or regimens for treating celiac disease AMG 714, AMY01, Aspergillus niger prolylene Doprotease, BL-7010, CALY-002, GBR 830, Hu-Mik-Beta-1, IMGX003, KumaMax, vinegar Larazotide, Nexvan2®, pancrelipase, TIMP-GLIA, vedolizumab, and and ZED1227.

[0515] 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 calcitonin Potriene and betamethasone dipropionate (e.g., MC2-01 cream and Taclonex (Registered Trademark), topical P-3073, topical LEO 90100 (Enstilar®), topical dipropionate Betamethasone dipropriate (Sernivo®), propionate halobetasol phosphate (Ultravate®), vitamin D analogs (e.g., calcitonin), Triene (Dovonex®) and calcitriol (Vectical®) , anthralin (e.g., Dritho-scalp® and Dritho-creme®) topical retinoids (e.g., tazarotene (e.g., Tazorac® and Avage®) calcineurin inhibitors (e.g., tacrolimus (Prograf®)), )) and pimecrolimus (Elidel®)), salicylic acid, coal tar, moisturizing phototherapy (e.g., sun exposure, UVB phototherapy, narrowband UVB phototherapy, get Kelman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), retinoids (e.g., acitretin (Soriatane®)), methotrexate (Trexall®), Registered Trademark), Otrexup®, Rasuvo®, Rheumatrex®), A po805K1, baricitinib, FP187, KD025, prurisol, VTP-43742, XP23829 , ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (serlopitant), Upada Citinib (ABT-494), Apremilast, Tofacitinib , cyclosporine (Neoral®, Sandimmune®, Gengraf®) biologics (e.g., etanercept (Enbrel®), etanercept-s zzs (entanercept-szzs) (Elrezi®), infliximab (Remicade®), trademark), adalimumab (Humira®), adalimumab-adbm (Cyltezo® ustekinumab (Stelara®), golimumab (Simponi®) , apremilast (Otezla®), secukinumab (Cosentyx®), secukinumab Certolixumab pegol, secukinumab, tildrakizumab-asmn, Influenza Riximab-dyyb, abatacept, ixekizumab (Taltz®), ABP 710, BCD -057, BI695501, bimekizumab (UCB4940), CHS-1420, GP2017, guselkumab (CNTO 19 59), HD203, M923, MSB11022, mirikizumab (LY3074828), PF-06410293, PF-06438179 , risankizumab (BI655066), SB2, SB4, SB5, siliq (brodalumab), Mirumab (MT203), tildrakizumab (MK-3222), and ixekizumab (Taltz) thioguanine, and hydroxyurea (e.g., Droxia® and and Hydrea®).

[0516] Non-limiting examples of additional therapeutic agents and / or regimens for treating cutaneous T-cell lymphoma include: Examples include phototherapy (e.g., sunlight exposure, UVB phototherapy, narrowband UVB phototherapy) method, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser). Extracorporeal photopheresis, radiation therapy (e.g., spot radiation and whole-body skin electron beam therapy) method), stem cell transplant, corticosteroids, imiquimod, bexarotene gel, topical viscose Bis-chloroethyl-nitrourea, mechlorethamine gel, borino Stats (Zolinza®), romidepsin (Istodax®), Pralatre Folotyn® biologics (e.g., alemtuzumab (Campath®) These include brentuximab vedotin (SGN-35), mogamulizumab, and IPH4102. It can be obtained.

[0517] Non-limiting examples of additional therapeutic agents and / or regimens for treating uveitis include: corticosteroids (e.g., intravitreal triamcinolone acetonide injectable suspension) fluid), antibiotics, antivirals (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide (Cytoxan®), eosar®, Endoxan®), and cyclosporine (Neoral®) (trademark), Sandimmune®, Gengraf®), chlorambucil, azathioprine phosphate, methotrexate, and mycophenolate mofetil), biologics (e.g., ibuprofen, infliximab (Remicade®), adalimumab (Humira®), ethambutol Nercept (Enbrel®), golimumab (Simponi®), Certoliz Mab (Cimzia®), rituximab (Rituxan®), abatacept (O rencia®), basiliximab (Simulect®), anakinra (Kinere®), t(R), canakinumab (Ilaris(R)), gevokixumab (XOMA052), tocilizumab (Actemra®), alemtuzumab (Campath®), efalizumab (Raptiva®), LFG316, sirolimus (Santen®), (Registered Trademark), abatacept, sarilumab (Kevzara®), and daclizumab (Zenapax®), cytotoxic drugs, surgical implants (e.g., fluoxetine, Nolon inserts), and vitrectomy.

[0518] Non-limiting examples of additional therapeutic agents and / or regimens for treating mucositis include: , AG013, SGX942 (dusquetide), amifostine (Ethyol® ), cryotherapy, cepacol lozenges, capsaicin lozenges, mucous membranes Adhesives (e.g., MuGard®) Oral diphenhydramine (e.g., Benadry®) Elixirs), oral bioadherents (e.g., polyvinylpyrrolidone Lidone-sodium hyaluronate gel (Gelclair®), oral lubricants (e.g. , Oral Balance®), caphosol, chamomilla recutita (ch amomilla recutita) mouthwash, edible grape plant exosomes, disinfectant mouthwash Wash (e.g., chlorhexidine gluconate (e.g., Peridex® or topical pain relievers (e.g., lidocaine, benzocaine, dimethicone, etc.), Clonin hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease ( (Phenol) (0.6% phenol), corticosteroids (e.g., prednisone), Inhalers (e.g., ibuprofen, naproxen, acetaminophen, and opioids) oid), GC4419, Palifermin (keratinocyte growth factor, Kepivance®) ), ATL-104, clonidine lauriad, IZN-6N4, SGX942, Levami Pido, Nepidermin, Soluble β-1,3 / 1,6 Glucan, P276, LP-0004-09, CR-3294, ALD-518 , IZN-6N4, quercetin, vaccinium myrtillus extract Granules containing macleaya cordata alkaloids and echinacea Echinacea angustifolia extract (e.g., SAMITAL (registered trademark) (e.g., aluminum hydroxide and magnesium hydroxide), and gastrointestinal cocktails (acid reducers, e.g., aluminum hydroxide and magnesium hydroxide) Antifungals (e.g., nystatin), and painkillers (e.g., Examples of non-limiting examples of treatment for oral mucositis include: Examples include AG013, amifostine (Ethyol®), cryotherapy, and Cepacor Rose. oral diphenhydramine (e.g., Be nadry® elixir), oral bioadhesives (e.g., polyvinylpyrrolidone-Hear sodium selenite gel (Gelclair®), oral lubricants (e.g., Oral Balan ce(R)), Kafosol, Chamomilla Recutita Mouthwash, Table Grapes Plant exosomes, antiseptic mouthwashes (e.g., chlorhexidine gluconate ( Peridex® or Periodont®), topical pain relievers (e.g. , lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2% phenol), and Ulcerease® (0.6% phenol), corticosteroids drugs (e.g., prednisone), painkillers (e.g., ibuprofen, naproxen, Acetaminophen, and opioids), GC4419, Palifermin (keratinocyte proliferation) Growth factors, Kepivance®, ATL-104, clonidine lauriad, IZN-6N4, SGX942 , rebamipide, nepidermin, soluble β-1,3 / 1,6 glucan, P276, LP-0004-09, CR-3294 , ALD-518, IZN-6N4, quercetin, and a gastrointestinal cocktail (acid reducers, e.g., ammonium hydroxide) aluminum and magnesium hydroxide (e.g., Maalox), antifungals (e.g., nystatin Other examples include esophageal ulcers, esophageal ulcers, and analgesics (e.g., hurricane liquid). Non-limiting examples of treatments for mucositis include xylocaine (e.g., gel viscous xylocaine) Another example is the treatment of intestinal mucositis, the use of anti-intestinal mucositis drugs to modify intestinal mucositis. Treatment for intestinal mucositis and for the signs and symptoms of intestinal mucositis includes a gastrointestinal cocktail (acid reducing agents, such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), anti antifungal agents (e.g., nystatin), and analgesics (e.g., hurricane liquid) can be done.

[0519] In certain embodiments, the second therapeutic agent or regimen is contacted with or comprises a chemical entity. before administration (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours). The antibody is administered to the subject about 1 hour before, or about 48 hours before, or about 1 week before, or about 1 month before.

[0520] In other embodiments, the second therapeutic agent or regimen is contacted with or administered by a chemical entity. For example, the second therapeutic agent or The dimen and chemical entity are provided to the subject simultaneously in the same dosage form. The second therapeutic agent or regimen and the chemical entity are provided to the subject concurrently in separate dosage forms. It is served.

[0521] In yet other embodiments, the second therapeutic agent or regimen is contacted with or administered to a subject. after administration thereof (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours later, or about 48 hours later, or about 1 week later, or about 1 month later) do.

[0522] Patient Selection In some aspects, the methods described herein are directed to a subject in need of such treatment (e.g., , patient) (e.g., by biopsy, endoscopy, or other conventional methods known in the art) In certain embodiments, the STING protein is identified by a specific It may serve as a biomarker for certain types of cancer, e.g., colon cancer and prostate cancer. In other embodiments, the step of identifying the subject can be performed by determining whether the subject has absent and / or exhausted T cells. The tumor microenvironment of a patient for the presence of T cells, e.g., a patient with one or more cold tumors Such patients may include those with checkpoint inhibitors. In certain embodiments, such patients may be resistant to treatment with harmful substances. Such patients may, for example, be administered the chemical agents described herein to recruit T cells to tumors. It can be treated with the body, and in some cases, for example, when T cells become exhausted, one or more can be further treated with multiple checkpoint inhibitors.

[0523] In some aspects, the chemical entities, methods, and compositions described herein are directed to certain therapeutic Treatment-resistant patient populations (e.g., patients resistant to checkpoint inhibitors, e.g., or multiple cold tumors, e.g., patients with tumors lacking T cells or exhausted T cells can be administered.

[0524] compound preparation As can be appreciated by those skilled in the art, methods for synthesizing compounds of the formulae herein are readily apparent to those of skill in the art. Synthetic Chemistry Transformations and Protections Useful in the Synthesis of the Compounds Described Herein Group methodologies (protection and deprotection) are known in the art, see, for example, R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and RG M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991 );L. Fieser and M. Fieser,Fieser and Fieser's Reagents for Organic Synthesis,Jo Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organizations anic Synthesis, John Wiley and Sons (1995), and its subsequent editions. The starting materials used in the preparation of the compounds of the present invention are known. These may be prepared by known methods or may be commercially available. The conditions and reagents described herein are interchangeable with art-recognized alternative equivalents. Recognize that triethylamine can be exchanged. For example, in many reactions, triethylamine is a non-nucleophilic a neutral base (e.g., diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di- Interchange with other bases such as tert-butylpyridine, or tetrabutylphosphazene It is possible.

[0525] Those skilled in the art will appreciate that various methods can be used to characterize the compounds described herein. Recognize analytical methods, including e.g. 1 H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography The above list is intended to provide a comprehensive list of techniques available to those skilled in the art. This is a subset of signature methods and is not intended to be limiting.

[0526] To further illustrate the foregoing, the following non-limiting, exemplary synthetic schemes are included: Variations of these examples that fall within the scope of the claims are within the skill of the art. It is believed to fall within the scope of the invention as described and claimed in this application. and those skilled in the art will be able to prepare and use the present invention without the need for exhaustive examples. The reader knows that it can be used. [Example]

[0527] Compounds 101-152 are synthesized using methods known to those skilled in the art.

[0528] As a non-limiting example, compound 101 can be prepared as shown below. TIFF2025037981000265.tif57128

[0529] Int1 is treated with a urea coupling agent under basic conditions. The resulting intermediate is reacted with Int2 to give compound 101.

[0530] Alternatively, compound 101 can be obtained by treating isocyanate Int3 with Int2.

[0531] Compound numbers 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 15 4, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 13 0, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 14 6, 147, 148, 149, 150, 151, 152, 153, and 154 were prepared using the same method as above. It is possible.

[0532] Preparation example Chemical abbreviations TIFF2025037981000266.tif162163

[0533] material and method Reaction progress was frequently monitored by TLC or LC-MS. LC-MS was recorded using one of the following methods:

[0534] LCMS method AA: EVO C18, 50 x 3.0 mm, injection volume 0.1 μL, flow rate 1.2 mL / min, scan range 90-900 amu, UV detection 254 nm. Mobile phase A (MPA): water / 5 mM NH4HCO3 and mobile phase B (MPB): acetonitrile. Elution: 1.9 From 20% MPB to 70% in 9 minutes, from 70% MPB to 95% in 0.30 minutes, hold at 95% MPB for 0.4 minutes, and then 95% in 0.3 minutes. %MPB to 10%, then equilibrate at 10%MPB for 0.2 min.

[0535] LCMS method AB: Luna Omega, 50 x 3 mm, injection volume 3.0 μL, flow rate 1.5 mL / min, scan range 90-900 amu, UV detection Emission 254 nm. Mobile phase A (MPA): water / 0.09% FA and mobile phase B (MPB): acetonitrile / 0.1% FA. Elution: 5% MPB to 100% in 1.29 min, hold at 100% MPB for 0.9 min, 100% MPB to 5% in 0.05 min, Then equilibrate with 5% MPB for 0.25 min.

[0536] LCMS method AC: Shim-pack XR-ODS, 50 x 3 mm, injection volume 2.2 μL, flow rate 1.2 mL / min, scan range 100-900 amu , UV detection 254 nm. Mobile phase A (MPA): water / 0.05% TFA and mobile phase B (MPB): acetonitrile / 0. 05% TFA. Elution: 50% MPB to 95% in 2.99 min, held at 95% MPB for 0.6 min, 95% MPB to 5% in 0.1 min. %, then equilibrated to 5% MPB for 0.25 min.

[0537] LCMS Method BA Instrumentation: Agilent LCMS system equipped with DAD and ELSD detectors. Ion mode: positive. Column: Waters X-Bridge C18, 50 x 2.1 mm x 5 μm or equivalent. Mobile phase: A: H2O (0.04% TFA); B: CH3CN (0.02% TFA). Gradient: 4.5 min gradient method, actual method depends on the clogP of the compound. Flow rate: 0.6 mL / min or 0.8 mL / min. Column temperature: 40°C or 50°C. UV: 220nm.

[0538] LCMS method BB Instrumentation: Agilent LCMS system equipped with DAD and ELSD detectors. Ion mode: positive. Column: Waters X-Bridge ShieldRP18, 50 x 2.1 mm x 5 μm or equivalent. Mobile phase: A:H2O(0.05%NH 3. HO or 10 mM ammonium bicarbonate );B:CH3CN. Gradient: 4.5 min gradient method, actual method depends on the clogP of the compound. Flow rate: 0.6 mL / min or 0.8 mL / min. Column temperature: 40°C. UV: 220nm.

[0539] CMS Method CA: Kinetex EVO C18 100A, 30 x 3 mm, injection volume 0.5 μL, flow rate 1.2 mL / min, scan Range 90-900 amu, UV detection 254 nm. Mobile phase A (MPA): Water / 5 mM NH4HCO3 and mobile phase B (MPB): Acetonitrile. Elution: 10% MPB to 95% in 2.0 min, hold at 95% MPB for 0.3 min, 95% MPB in 0.1 min B to 10%.

[0540] CMS method CB: Xselect CSH C18, 50 x 3 mm, injection volume 1.0 μL, flow rate 1.2 mL / min, scan range 90 ~900 amu, UV detection 254 nm. Mobile phase A (MPA): water / 0.1% FA and mobile phase B (MPB): acetonitrile Elution: 5% MPB to 100% in 2.00 min, hold at 100% MPB for 0.7 min, 100% in 0.05 min MPB to 5%, then equilibrate at 5% MPB for 0.15 min.

[0541] CMS method CC: XBridge Shield RP18, 50 × 4.6 mm, injection volume 0.5 μL, flow rate 1.2 mL / min, scan Range: 90-900 amu, UV detection: 254 nm. Mobile phase A (MPA): water / 0.04% NH3.H2O and mobile phase B (MPB) Elution: acetonitrile. Elution: 10% MPB to 95% in 2.00 min, held at 95% MPB for 0.79 min, held at 95% MPB for 0.06 min. %MPB to 10%, then equilibrate at 10%MPB for 0.15 min.

[0542] CMS method CD: HALO C18, 30 x 3 mm, injection volume 0.8 μL, flow rate 1.2 mL / min, scan range 90-900 am u, UV detection 254 nm. Mobile phase A (MPA): water / 0.1% FA and mobile phase B (MPB): acetonitrile / 0.0 5% FA. Elution: 10% MPB to 100% in 1.30 min, hold at 100% MPB for 0.50 min, and then return to 100% MPB in 0.03 min. to 10%, then equilibrated at 10% MPB for 0.17 min.

[0543] CMS method CE: Shim-pack XR-ODS, 50 x 3 mm, injection volume 0.3 μL, flow rate 1.2 mL / min, scan range 3 0-2000 amu, UV detection 254 nm. Mobile phase A (MPA): water / 0.05 TFA and mobile phase B (MPB): acetonitrile Trimethylsilyl / 0.05% TFA. Elution: 5% MPB to 100% in 1.10 min, hold at 100% MPB for 0.60 min, and then 0.05 min. Equilibrate from 100% MPB to 5%, then 5% MPB for 0.25 min.

[0544] CMS method CF: YMC-Triart C18, 30 x 2 mm, injection volume 1.0 μL, flow rate 1.2 mL / min, scan range 30 ~2000 amu, UV detection 254 nm. Mobile phase A (MPA): water / 0.05 TFA and mobile phase B (MPB): acetonitrile Trimethylsilyl / 0.05% TFA. Elution: 5% MPB to 95% in 1.00 min, hold at 95% MPB for 0.70 min, 95% MPB for 0.05 min. %MPB to 5%, then equilibrate at 5%MPB for 0.45 min.

[0545] CMS method CG: Kinetex 2.6um EVO C18 100A, 50 × 3mm, injection volume 0.6μL, flow rate 1.2mL / min, step Scan range 30-2000 amu, UV detection 254 nm. Mobile phase A (MPA): water / 5 mM NH4HCO3 and mobile phase B ( MPB): Acetonitrile. Elution: 10% MPB to 95% in 1.20 min, hold at 95% MPB for 0.50 min, 0.05 From 95% MPB to 10% in 10 min, then equilibrate at 10% MPB for 0.10 min.

[0546] CMS method CH: Kinetex 2.6um EVO C18 100A, 50 × 3mm, injection volume 0.6μL, flow rate 1.2mL / min, step Scan range 30-2000 amu, UV detection 254 nm. Mobile phase A (MPA): water / 5 mM NH4HCO3 and mobile phase B ( MPB): Acetonitrile. Elution: 10% MPB to 95% in 1.20 min, hold at 95% MPB for 0.50 min, 0.05 From 95% MPB to 10% in 10 min, then equilibrate at 10% MPB for 0.10 min.

[0547] CMS method CI: EVO C18, 50 x 3 mm, injection volume 0.1 μL, flow rate 1.2 mL / min, scan range 30-2000 am u, UV detection 254 nm. Mobile phase A (MPA): water / 5 mM NH4HCO3 and mobile phase B (MPB): acetonitrile Elution: 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.60 min, 95% MPB to 10% in 0.15 min , then equilibrated in 10% MPB for 0.25 min.

[0548] CMS method CJ: Shim-pack Scepter C18, 50 × 3 mm, injection volume 0.8 μL, flow rate 1.5 mL / min, scan Range: 30-2000 amu, UV detection: 254 nm. Mobile phase A (MPA): water / 0.04% NH3.H2O and mobile phase B (MPB) ): Acetonitrile. Elution: 10% MPB to 95% in 1.00 min, hold at 95% MPB for 0.60 min, and then 0.03 min. Equilibrate from 95% MPB to 10%, then 10% MPB for 0.17 min.

[0549] CMS method CK: Titank C18, 50 x 3 mm, injection volume 0.5 μL, flow rate 1.5 mL / min, scan range 30-200 0 amu, UV detection 254 nm. Mobile phase A (MPA): water / 5 mM NH4HCO3 and mobile phase B (MPB): acetonite Elution: 10% MPB to 95% in 1.80 min, hold at 95% MPB for 0.80 min, 95% MPB to 10% in 0.15 min %, then equilibrated to 10% MPB for 0.25 min.

[0550] CMS method CL: XBridge BEH C18, 50 x 3 mm, injection volume 4.0 μL, flow rate 1.2 mL / min, scan range 30 ~2000 amu, UV detection 254 nm. Mobile phase A (MPA): water / 5 mM NH4HCO3 and mobile phase B (MPB): acetone. Nitrile. Elution: 5% MPB to 95% in 2.00 min, hold at 95% MPB for 0.70 min, then 95% MPB to 0.05 min. to 5%, then equilibrate at 5% MPB for 0.25 min.

[0551] NMR: NMR was performed using BRUKER NMR 300.03 Mz, DUL-CH, ULTRASHIELD™ 300, and AVANCE II 300. B-ACS™ 120 or BRUKER NMR 400.13 Mz, BBFO, ULTRASHIELD™ 400, AVANCE III 400, recorded on a B-ACS™ 120.

[0552] Preparative HPLC conditions device: 1. GILSON 281 and Shimadzu LCMS 2010A 2. GILSON 215 and Shimadzu LC-20AP 3. GILSON 215

[0553] Mobile phase: A: NH4OH / H2O = 0.05% v / v; B: ACN A: FA / HO = 0.225% v / v; B: ACN

[0554] column Xtimate C18 150×25mm×5μm. Flow rate: 25 mL / min or 30 mL / min. Monitor wavelengths: 220 and 254 nm. Slope: The actual method depends on the clogP of the compound. Detector: MS trigger or UV.

[0555] Preparation of synthetic intermediates: Synthesis of Intermediate A1 (1-(5-amino-3-methylpyridin-2-yl)azetidin-3-ol) TIFF2025037981000267.tif23146Step 1: 1-(3-methyl-5-nitropyridin-2-yl)azetidin-3-ol

[0556] 2-Chloro-3-methyl-5-nitropyridine (600.0 mg, 3.5 mmol, 1.0 equiv) in DMF (30.0 mL) CsCO (4531.3 mg, 13.9 mmol, 4.0 equiv.) and azetidin-3-ol hydrochloride ( The reaction mixture was stirred at 60°C for 6 hours, and then water was added. The resulting solution was extracted with ethyl acetate and brine. The resulting solution was washed with 1-(3-methyl-5-methyl-2 ... (-nitropyridin-2-yl)azetidin-3-ol (500 mg, 68.7%) was obtained as a yellow solid. LCMS method CC: [MH] - =208.

[0557] Step 2: 1-(5-amino-3-methylpyridin-2-yl)azetidin-3-ol 1-(3-methyl-5-nitropyridin-2-yl)azetidin-3-ol (450.0 mg, 2.2 mmol, 1 Dissolve the 10.0 mg (10% wt., 0.1 mmol, 0.05 equiv.) in MeOH (30.0 mL) and add Pd / C (90.0 mg, 10% wt., 0.1 mmol, 0.05 equiv.). The resulting mixture was evacuated and refilled with hydrogen three times before being placed in a hydrogen atmosphere. The mixture was stirred at room temperature under atmosphere for 3 hours. The solid was filtered off and the resulting mixture was concentrated in vacuo. By concentrating under reduced pressure, 1-(5-amino-3-methylpyridin-2-yl)azetidin-3-ol was obtained. The product (243.7 mg, 63.1%) was obtained as a brown solid. LCMS Method CD: [M+H] + =180.

[0558] Using the same method as described for Intermediate A1, the intermediates in the table below were prepared. TIFF2025037981000268.tif223170

[0559] Synthesis of Intermediate A9 (6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-amine) TIFF2025037981000269.tif79162

[0560] Step 1: tert-Butyl 3,3-difluorocyclobutane-1-carboxylate 3,3-Difluorocyclobutanecarboxylic acid (1.0 g, 7.3 mmol, 1.0 equiv) in DCM (10.0 mL) N,N-dimethylpyridin-4-amine (92.0 mg, 0.7 mmol, 0.1 equiv.), 2-methylpropional propan-2-ol (1.1 g, 14.7 mmol, 2.0 equiv.) and N,N'-dicyclohexylcarbodiimide The reaction mixture was warmed to room temperature and stirred for 18 hours. The solids were removed by filtration, and the filtrate was diluted with 2N HCl aqueous solution, saturated NaHCO3 aqueous solution, brine, and HCl. The crude 3,3-difluorocyclohexane was obtained by washing with toluene, drying over anhydrous Na2SO4, and concentrating under vacuum. tert-Butyl lobutane-1-carboxylate (896.1 mg, 63.1%) was obtained as a colorless oil. TIFF2025037981000270.tif5128

[0561] Step 2: 3,3-difluoro-1-(3-fluoropyridin-2-yl)cyclobutane-1-carboxylic acid tert- t-butyl 2,3-Difluoropyridine (1.2 g, 10.4 mmol, 1.0 equiv.) and 3,3-difluorocyclobutane tert-Butyl ethane-1-carboxylate (2.0 g, 10.4 mmol, 1.0 equiv.) was dissolved in toluene (60.0 mL). Next, 10 ml of NaHMDS (2 M in THF, 6.2 ml, 12.4 mmol, 1.2 equiv.) was added to the solution with stirring at 0°C. The resulting solution was stirred at 0 °C for 2 h, then added dropwise with saturated aqueous NH4Cl. The resulting solution was extracted with ethyl acetate and The mixture was dried over aqueous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Purification was performed by column chromatography eluting with ethyl acetate / petroleum ether (1:5). and 3,3-difluoro-1-(3-fluoropyridin-2-yl)cyclobutane-1-carboxylic acid tert-butyl ester. t-Butyl ester (1.6 g, 53.4%) was obtained as a colorless oil. LCMS Method CD: [M+H] + =288.

[0562] Step 3: 2-(3,3-difluorocyclobutyl)-3-fluoropyridine 3,3-Difluoro-1-(3-fluoropyridin-2-yl)cyclobutane-1-carboxylic acid tert-butyl Dissolve chiral (1.5 g, 5.2 mmol, 1.0 equiv) in DCM (30.0 mL) and add TFA (3.1 mL, 41.6 mmol, 8.0 equiv). The resulting solution was stirred at ambient temperature for 10 hours and then cooled under vacuum. The residue was dissolved in toluene (30.0 mL) and stirred at 90° C. for 18 hours. After cooling and quenching by adding water, the pH value of the solution was adjusted to 7.5 with saturated aqueous Na2CO3 solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give ethyl acetate. Elution with ethyl acetate / petroleum ether (1:7) gave 2-(3,3-difluorocyclobutyl)-3- The fluoropyridine (700 mg, 71.6%) was obtained as a colorless oil. LCMS Method CD: TIFF2025037981000271.tif12154

[0563] Step 4: 2-(3,3-difluorocyclobutyl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)pyridine 2-(3,3-difluorocyclobutyl)-3-fluoropyridine (700.0 mg, 3.7 mmol, 1.0 equiv.) ) was dissolved in heptane (30.0 mL) and bis(pinacolato)diboron (1.1 g, 4.4 mmol, 1.2 equivalents) was added. amount), 4,4-di-tert-butyl-2,2-dipyridyl (1.0 g, 3.7 mmol, 1.0 equiv.) and di-methano Latodiiridium (Ir-Ir)-cycloocta-1,5-diene (1:2) (495.8 mg, 0.7 mmol, 0.2 (equivalent) was added under a nitrogen atmosphere. The resulting solution was stirred at ambient temperature for 18 hours. The reaction mixture was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate. The residue was extracted with hexane, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purify by column chromatography and elute with ethyl acetate / petroleum ether (1:5). By doing so, 2-(3,3-difluorocyclobutyl)-3-fluoro-5-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl)pyridine (300 mg, 25.6%) was obtained as a white solid. LCMS method CD: [M+H] + =314.

[0564] Step 5: 6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-ol 2-(3,3-difluorocyclobutyl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-di (Oxaborolan-2-yl)pyridine (300.0 mg, 0.9 mmol, 1.0 equiv) in MeOH (10.0 mL) and The mixture was dissolved in HO (3.0 mL). HO (30%, 0.14 mL, 1.4 mmol, 1.5 equiv.) was then added. The resulting solution was stirred at ambient temperature for 30 min, followed by the addition of saturated aqueous Na2S2O3 solution. The resulting solution was extracted with ethyl acetate and anhydrous sodium sulfate. The residue was purified by flash column chromatography on silica gel. 6-( 3,3-Difluorocyclobutyl)-5-fluoropyridin-3-ol (160 mg, 82.2%) white Obtained as a solid. LCMS Method CD: TIFF2025037981000272.tif12128

[0565] Step 6: 6-(3,3-difluorocyclobutyl)-5-fluoropyridinium trifluoromethanesulfonate Lysine-3-yl 6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-ol (160.0 mg, 0.7 mmol) , 1.0 equiv.) was dissolved in DCM (20.0 mL) and treated with TEA (0.1 mL, 0.9 mmol, 1.2 equiv.) and 1,1,1-trimethylisothiazolinone (1.0 equiv.). Trifluoro-N-phenyl-N-trifluoromethanesulfonyl methanesulfonamide (309.4m g, 0.8 mmol, 1.1 equiv.) was added. The resulting solution was stirred at ambient temperature for 30 min. The mixture was then quenched by the addition of water. The solution was extracted with ethyl acetate and The residue was purified by flash column chromatography on silica gel. The product was purified by chromatography and eluted with ethyl acetate / petroleum ether (1:8). 6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-yl fluoromethanesulfonic acid The product (220 mg, 83.3%) was obtained as a white solid. LCMS Method CD: [M+H] + =336.

[0566] Step 7: (6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-yl)carbamic acid tert-butyl 6-(3,3-difluorocyclobutyl)-5-fluoropyridinyl trifluoromethanesulfonate Benzyl-3-yl (220.0 mg, 0.6 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (30.0 mL). , NH2Boc (230.3 mg, 1.9 mmol, 3.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethyl Thixanthene (75.8 mg, 0.1 mmol, 0.2 equiv.) and Pd2(dba)3 (120.1 mg, 0.1 mmol, 0 0.2 equiv.) was added under nitrogen. The resulting solution was heated under nitrogen at 90°C for 3 hours. After stirring, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Purification by chromatography and elution with ethyl acetate / petroleum ether (1:9) gave (6-( tert-Butyl 3,3-difluorocyclobutyl-5-fluoropyridin-3-ylcarbamate (120 mg, 60.4%) was obtained as a white solid. LCMS Method CD: [M+H] + =303.

[0567] Step 8: 6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-amine N-[6-(3,3-difluorocyclobutyl)-5-fluoropyridin-3-yl]carbamic acid te rt-Butyl ether (120.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in DCM (10.0 mL) and TFA (2.0 mL) was added. The resulting solution was stirred at ambient temperature for 30 minutes and then diluted with water. The pH of the solution was adjusted to 7.5 with saturated aqueous Na2CO3 solution, and the solution was extracted with ethyl acetate. The residue was purified by flash column chromatography on silica gel. 6-( 3,3-Difluorocyclobutyl)-5-fluoropyridin-3-amine (60 mg, 74.7%) was obtained as a white solid LCMS Method CD: [M+H] + =203.

[0568] Synthesis of Intermediate A10 (2-(2-(trifluoromethyl)phenoxy)ethan-1-amine) TIFF2025037981000273.tif20149

[0569] Step 1: tert-Butyl (2-(2-(trifluoromethyl)phenoxy)ethyl)carbamate 2-(trifluoromethyl)phenol (2.0 g, 12.3 mmol, 1.0 equiv) in DMF (20.0 mL) Dissolve CsCO (8.0 g, 24.7 mmol, 2.0 equiv.), NaI (5.6 g, 0.1 mmol, 3 equiv.) and N-( tert-Butyl (2-bromoethyl)carbamate (11.1 g, 49.3 mmol, 4.0 equivalents) was added. The resulting solution was stirred at 80° C. for 10 h and then concentrated in vacuo. Purification by flash column chromatography on silica gel with ethyl acetate / petroleum ethanol Elution with 2-(2-(trifluoromethyl)phenoxy)ethyl ether (1:1) tert-Butyl (methyl)carbamate (1.5 g, 39.8%) was obtained as a yellow oil. LCMS Method CI: M+H] + =306.

[0570] Step 2: 2-(2-(trifluoromethyl)phenoxy)ethan-1-amine tert-Butyl [2-[2-(trifluoromethyl)phenoxy]ethyl]carbamate (1.0 g, 3.3 mol, 1.0 equiv) was dissolved in DCM (10.0 mL) and then TFA (2.0 mL) was added. The resulting solution was stirred at ambient temperature for 30 minutes and then diluted with water. The pH of the solution was adjusted to 100 with saturated NaCl. The mixture was adjusted to 7.5 with an aqueous solution of 03 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. and concentrated under vacuum to give 2-[2-(trifluoromethyl)phenoxy]ethaneamine. The compound (500 mg, 74.4%) was obtained as a yellow oil. LCMS Method CD: [M+H] + =206.

[0571] Using the same method as described for Intermediate A10, the intermediates in the table below were prepared. TIFF2025037981000274.tif37152

[0572] Synthesis of intermediate A12 (spiro[5.5]undecane-3-amine) TIFF2025037981000275.tif49142

[0573] Step 1: Spiro[5.5]undecane-3-ol Spiro[5.5]undecan-3-one (1.0 g, 6.0 mmol, 1.0 equiv) was dissolved in EtOH (20.0 mL). Then NaBH4 (682.6 mg, 18.0 mmol, 3.0 equiv) was added portionwise. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and then quenched by the addition of water. The aqueous layer was extracted with ethyl acetate, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was evaporated on silica gel. Purification by flash column chromatography in ethyl acetate / petroleum ether Spiro[5.5]undecan-3-ol (1.1 g, 82.6%) was obtained by elution with 2,4-dichloro-2,4-dichloro-1,4-dichloro-2 ... LCMS Method CD: [M+H] + =169.

[0574] Step 2: 2-(spiro[5.5]undecan-3-yl)isoindoline-1,3-dione Spiro[5.5]undecan-3-ol (1.0 g, 5.9 mmol, 1.0 equiv.) and phthalimide ( Dissolve PPh3 (1.3 g, 8.9 mmol, 1.5 equiv.) in THF (20.0 mL) and add PPh3 (3.1 g, 11.9 mmol, 2.0 equiv.) Then, DIAD (1.2 g, 5.9 mmol, 1.0 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at room temperature under nitrogen for 8 hours and then cooled by the addition of ice water. The resulting solution was extracted with ethyl acetate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give ethyl acetate. Elution with ethyl acetate / petroleum ether (1:6) gave 2-[spiro[5.5]undecan-3-yl] Isoindole-1,3-dione (998 mg, 45.7%) was obtained as an off-white solid. LCMS Method CF: [M+H] + =298.

[0575] Step 3: Spiro[5.5]undecane-3-amine 2-[spiro[5.5]undecan-3-yl]isoindole-1,3-dione (748.0 mg, 2.5 mmol) Dissolve NH 2 .HO (251.8 mg, 5.0 mmol, 2.0 equiv.) in EtOH (25.0 mL) and add N 2 H 4 .HO (251.8 mg, 5.0 mmol, 2.0 equiv.) to the chamber. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 5 hours. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give crude spiro- [5.5]Undecane-3-amine (797 mg) was obtained as a yellow oil. LCMS Method CF: [M+H] + =168.

[0576] Synthesis of intermediate A13 (4-(3,3-difluorocyclobutyl)-3-fluoroaniline) TIFF2025037981000276.tif64133

[0577] Step 1: 4-Bromo-1-(3,3-difluorocyclobutyl)-2-fluorobenzene 3-(4-bromo-2-fluorophenyl)cyclobutan-1-one (1.3 g, 5.3 mmol, 1.0 equiv.) was dissolved in DAST (30.0 mL) under a nitrogen atmosphere at 0° C. The resulting mixture The mixture was stirred at room temperature overnight and then quenched at 0° C. by adding aqueous NaHCO 3 solution. The resulting mixture was extracted with DCM, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel to give ethyl acetate. 4-Bromo-1-(3,3-difluorocyclohexane)-2-(4-bromo-1-(3,3-difluorocyclohexane)-2-(2-methyl-2-propanol)-1-yl ether (1:2) was used for elution. (ethyl)-2-fluorobenzene (1.1 g) was obtained as a yellow oil. TIFF2025037981000277.tif20154

[0578] Step 2: (4-(3,3-difluorocyclobutyl)-3-fluorophenyl)carbamic acid tert-butyl Chill 4-Bromo-1-(3,3-difluorocyclobutyl)-2-fluorobenzene (1.1 g, 4.2 mmol, 1 0.0 equiv.) and BocNH2 (2.4 g, 20.7 mmol, 5.0 equiv.) were dissolved in toluene (11.0 mL). d2(dba)3 (0.4g, 0.4mmol, 0.1eq), XPhos (0.4g, 0.8mmol, 0.2eq) and t-BuO K (2.3 g, 20.7 mmol, 5.0 equiv.) was added at room temperature under nitrogen. The resulting mixture The mixture was stirred at 100° C. overnight and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purify by flash column chromatography on silica gel, ethyl acetate / silica gel Elution with oil ether (1:8) yielded [4-(3,3-difluorocyclobutyl)-3-fluoro- tert-Butyl [chlorophenyl]carbamate (1.0 g, 80.0%) was obtained as a white solid. LCMS Method CA: [M+H] + =302.

[0579] Step 3: 4-(3,3-difluorocyclobutyl)-3-fluoroaniline tert-Butyl [4-(3,3-difluorocyclobutyl)-3-fluorophenyl]carbamate (1.2 g, 4.0 mmol, 1.0 equiv) was dissolved in DCM (12.0 mL) and TFA (3.0 mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The solution was washed with saturated aqueous NaHCO3 and brine, and anhydrous sodium sulfate was added. and concentrated in vacuo to give crude 4-(3,3-difluorocyclobutyl)-3-fluoro- Oloaniline (800 mg) was obtained as a red oil. LCMS Method CA: [M+H] + =202.

[0580] Synthesis of intermediate A14 (cyclopentyl 6-amino-1H-indole-4-carboxylate) TIFF2025037981000278.tif64149

[0581] Step 1: methyl 6-((tert-butoxycarbonyl)amino)-1H-indole-4-carboxylate Methyl 6-amino-1H-indole-4-carboxylate (5.0 g, 26.3 mmol, 1.0 equiv.) was dissolved in THF (100 0.0 mL) / NaOH aqueous solution (4 M, 25.0 mL), and BocO (8.6 g, 39.4 mmol, 1.5 equiv.) was added. The resulting solution was stirred at room temperature for 3 hours. The mixture was extracted with ethyl acetate. The residue was purified by flash column chromatography on silica gel. Purify by chromatography, eluting with acetate / petroleum ether (1:4) , 6-((tert-butoxycarbonyl)amino)-1H-indole-4-carboxylate methyl (4. 1 g, 53.9%) as a white solid. LCMS Method CA: [M+H] + =291.

[0582] Step 2: 6-((tert-butoxycarbonyl)amino)-1H-indole-4-carboxylic acid 6-((tert-butoxycarbonyl)amino)-1H-indole-4-carboxylic acid methyl ester (1.0 g , 3.4 mmol, 1.0 equiv) was dissolved in MeOH / water (10.0 mL / 10.0 mL) and NaOH (0.7 g, 17.2 mmol, 5. 0 equiv.) was added. The reaction mixture was stirred at room temperature for 4 hours. The pH value of the solution was adjusted to 6 with aqueous HCl (2M). After adjusting the temperature to 50°C, the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. By concentrating with 6-((tert-butoxycarbonyl)amino)-1H-indole-4-carboxylate, The carboxylic acid (520 mg, 54.6%) was obtained as a white solid. LCMS Method CC: [MH] - =275.

[0583] Step 3: 6-((tert-butoxycarbonyl)amino)-1H-indole-4-carboxylic acid cyclopentadiene Ntil 6-[(tert-butoxycarbonyl)amino]-1H-indole-4-carboxylic acid (480.0 mg, 1 0.7 mmol, 1.0 equiv) and cyclopentanol (299.2 mg, 3.5 mmol, 2.0 equiv) in DCM (8.0 Dissolved in 1 mL of water and 100 mL of DMAP (106.1 mg, 0.9 mmol, 0.5 equiv.) and DCC (716.9 mg, 3.5 mmol, 2.0 equiv.). (equivalent) was added. The solution was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was added to silica gel. Purification was performed by flash column chromatography on gel and ethyl acetate / petroleum ether. Elution with ethanol (1:1) afforded 6-[(tert-butoxycarbonyl)amino]-1H-indoline. The resulting product was cyclopentyl-4-carboxylate (240 mg, 40.1%) as an off-white solid. LCMS method CJ:[M+H] + =345.

[0584] Step 4: 6-amino-1H-indole-4-carboxylic acid cyclopentyl 6-[(tert-butoxycarbonyl)amino]-1H-indole-4-carboxylic acid cyclopentyl The resulting HCl (240.0 mg, 0.7 mmol, 1.0 equiv.) was dissolved in DCM / TFA (3 mL / 1 mL). The resulting mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was purified by column chromatography on silica gel. Purification was carried out by flash column chromatography eluting with DCM / MeOH (10:1). 6-amino-1H-indole-4-cyclopentyl carboxylate (200 mg) was added to an off-white Obtained as a solid. LCMS Method CJ: [M+H] + =245.

[0585] Intermediate A15 (4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole-6 -amine) TIFF2025037981000279.tif62152

[0586] Step 1: (Z)-4-(2-ethoxyvinyl)-6-nitro-1H-indole 4-Bromo-6-nitro-1H-indole (3.0 g, 12.4 mmol, 1.0 equiv.) was dissolved in dioxane / water (150 Dissolved in (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2- Dioxaborolane (3.7 g, 18.7 mmol, 1.5 equiv.), KCO (3440.2 mg, 24.9 mmol, 2.0 equiv.) ) and Pd(dppf)Cl2 (910.7 mg, 1.2 mmol, 0.1 equiv.) were added under nitrogen. The mixture was stirred at 90° C. under a nitrogen atmosphere for 6 hours, and then concentrated in vacuo. The residue was purified by silica gel chromatography. The product was purified by flash column chromatography in ethyl acetate / petroleum ether (1:3 ) to obtain (Z)-4-(2-ethoxyvinyl)-6-nitro-1H-indole (3.0 g ) was obtained as an orange solid. LCMS Method CD: [M+H] +=233.

[0587] Step 2 / 3: 2-(6-nitro-1H-indol-4-yl)ethan-1-ol 4-[(Z)-2-ethoxyethenyl]-6-nitro-1H-indole (2.0 g, 8.6 mmol, 1.0 equiv.) ) was dissolved in DCM / TFA (200.0 mL / 20 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. Condensation gave crude 2-(6-nitro-1H-indol-4-yl)acetaldehyde. The residue was dissolved in MeOH (10.0 mL) and NaBH4 (741.2 mg, 19.6 mmol, 2.0 equiv.) was added portionwise. The reaction mixture was stirred at room temperature for an additional 2 hours and then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give DC Elution with M / MeOH (10:1) afforded 2-(6-nitro-1H-indol-4-yl)ethan-1-ol. The product (600 mg, 29.7%) was obtained as a brown oil. LCMS Method CD: [M+H] + =207.

[0588] Step 4: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-nitro-1H-indole L 2-(6-nitro-1H-indol-4-yl)ethan-1-ol (600.0 mg, 2.9 mmol, 1.0 equiv. ) was dissolved in THF (30.0 mL), and NaH (in mineral oil, 60% wt, 232.8 mg, 5.8 mmol, 2.0 equiv.) was added to the After stirring for 30 min, TBSCl (657.9 mg, 4.4 mmol, 1.5 equiv) was added. The reaction mixture was stirred for 2 h and then quenched by adding 10 mL of MeOH. The resulting mixture was concentrated in vacuo and the residue was subjected to flash column chromatography on silica gel. Purification by column chromatography eluting with DCM / MeOH (10:1) gave 4-(2-( (tert-Butyldimethylsilyl)oxy)ethyl)-6-nitro-1H-indole (560 mg, 60 1%) as a yellow oil. LCMS Method CC: [M+H] + =321.

[0589] Step 5: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole-6-amine hmm 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-nitro-1H-indole ( Dissolve Pd / C (500.0 mg, 1.6 mmol, 1.0 equiv.) in MeOH (30.0 mL) and The resulting mixture was evacuated and refilled with hydrogen three times. The mixture was then stirred under a hydrogen atmosphere for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. By this, crude 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indo 450 mg of methyl-6-amine was obtained as an off-white solid. LCMS Method CD: [M+H] + =2 91.

[0590] Synthesis of Intermediate A16 (4-(2-Methoxyethyl)-1H-indol-6-amine) TIFF2025037981000280.tif31149

[0591] Step 1 / 2: 4-(2-Methoxyethyl)-6-nitro-1H-indole 2-(6-nitro-1H-indol-4-yl)ethanol (300.0 mg, 1.5 mmol, 1.0 equiv.) and Dissolve TEA (441.6 mg, 4.4 mmol, 3.0 equiv.) in THF (10.0 mL) and MsCl (249.9 mg, 2.2 mmol). l, 1.5 equiv.) was added dropwise under nitrogen atmosphere at 0° C. The resulting mixture was cooled to room temperature. After stirring at RT for 5 min, MeONa / MeOH (30% wt, 10.0 mL) was added dropwise to the above mixture at 0°C. The resulting mixture was further stirred at room temperature overnight and concentrated in vacuo. The resulting mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel. 4- was purified by chromatography and eluted with ethyl acetate / petroleum ether (1:2). (2-Methoxyethyl)-6-nitro-1H-indole (101 mg, 31.5%) was obtained as a brown solid. LCMS Method CC: [M+H] + =221.

[0592] Step 3: 4-(2-methoxyethyl)-1H-indol-6-amine 4-(2-Methoxyethyl)-6-nitro-1H-indole (100.0 mg, 0.5 mmol, 1.0 equiv.) was dissolved in TH The resulting mixture was dissolved in 4.0 mL of HCl and Pd / C (48.3 mg, 0.5 mmol, 1.0 equiv.) was added. The resulting mixture was degassed and refilled with hydrogen three times, then stirred under a hydrogen atmosphere at room temperature for 3 hours. The resulting mixture was filtered through Celite and the filtrate was concentrated in vacuo. 4-(2-Methoxyethyl)-1H-indol-6-amine (67 mg, 72.2%) was obtained as a crude orange solid. LCMS method CI obtained as: [M+H] + =191.

[0593] Synthesis of Intermediate A17 (2-(6-amino-1H-indol-4-yl)ethyl methylcarbamate) TIFF2025037981000281.tif40146

[0594] Step 1: 2-(6-nitro-1H-indol-4-yl)ethyl methylcarbamate 2-(6-nitro-1H-indol-4-yl)ethanol (190.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in TH Dissolved in F (10.0 mL), TEA (0.3 mL, 1.8 mmol, 2.0 equiv.), DMAP (225.1 mg, 1.8 mmol, 2.0 equiv.) eq.) and N-methylcarbamoyl chloride (103.4 mg, 1.1 mmol, 1.2 eq.) were added. The resulting solution was stirred at room temperature for 12 hours and then concentrated in vacuo. The resulting mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel. The compound was purified by chromatography and eluted with ethyl acetate / petroleum ether (1:10). 2-(6-nitro-1H-indol-4-yl)ethyl thicarbamate (130 mg, 53.6%) yellow Obtained as an oil. LCMS Method CD: [M+H] + =264.

[0595] Step 2: 2-(6-amino-1H-indol-4-yl)ethyl methylcarbamate 2-(6-nitro-1H-indol-4-yl)ethyl methylcarbamate (120.0 mg, 0.5 mmol) , 1.0 equiv.) and Ni(AcO)2 (156.8 mg, 0.9 mmol, 2.0 equiv.) were dissolved in MeOH (10.0 mL). Then, NaBH4 (69.0 mg, 1.8 mmol, 4.0 equiv.) was added at 0°C. The resulting solution was The mixture was stirred at 0° C. for 1 hour and then quenched by the addition of water. The extract was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The resulting mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel. The N-methyl group was purified by chromatography and eluted with ethyl acetate / petroleum ether (1:8). 2-(6-amino-1H-indol-4-yl)ethyl ethylcarbamate (40 mg, 37.6%) yellow Obtained as an oil. LCMS Method CD: TIFF2025037981000282.tif19154

[0596] Synthesis of intermediate A18 (4-(2-(dimethylamino)ethyl)-1H-indol-6-amine) TIFF2025037981000283.tif35140

[0597] Step 1: N,N-dimethyl-2-(6-nitro-1H-indol-4-yl)ethan-1-amine 2-(6-nitro-1H-indol-4-yl)acetaldehyde (340.0 mg, 1.7 mmol, 1.0 equiv. ) in MeOH (5.0 mL) and dimethylamine (2 M in THF, 1.0 mL, 2.0 mmol, 1.2 equiv.) Then, NaBH4 (111.2 mg, 3.0 mmol, 2.0 equiv.) was added in small portions to the reaction mixture. The mixture was stirred at room temperature for 2 hours and then quenched by the addition of water. After concentration, the residue was Purification by flash column chromatography on gel with ethyl acetate / petroleum ether Elution with ether (1:1) afforded N,N-dimethyl-2-(6-nitro-1H-indol-4-yl) Ethan-1-amine (220 mg, 64.2%) was obtained as a brown oil. LCMS Method CC: [M+H] + =2 34.

[0598] Step 2: 4-(2-(dimethylamino)ethyl)-1H-indol-6-amine N,N-dimethyl-2-(6-nitro-1H-indol-4-yl)ethan-1-amine (200.0 mg, 0.9 m mol, 1.0 equiv.) was dissolved in MeOH (40.0 mL), and then Pd / C (10.0 mg, 0.1 mmol, 0.1 equiv.) was added. The reaction mixture was degassed and refilled with hydrogen three times, then stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give 4-(2-(dichloromethane)-4-(2-dichloromethane). (Methylamino)ethyl)-1H-indol-6-amine (150 mg, 86.1%) was obtained as a colorless oil. LCMS Method CC: [M+H] + =204.

[0599] Synthesis of Intermediate A19 (6-Amino-N-methyl-1H-indole-3-sulfonamide) TIFF2025037981000284.tif54152

[0600] Step 1: 6-nitro-1H-indole-3-sulfonyl chloride To a mixture of HSO3Cl (9 mL) and DCM (90 mL) was added Na2SO4 (2.1 g, 14.8 mmol, 1.0 equiv.). Next, a solution of 6-nitro-1H-indole (2.4 g, 14.8 mmol, 1.0 equiv) in DCM (40.0 mL) was added. The resulting solution was stirred at room temperature for 30 minutes and decanted. The colored oil was treated slowly with water / ice and filtered to give a thick brown oil. The precipitate was collected and dried to give 6-nitro-1H-indole-3-sulfonyl chloride (1.7 g, crude). The product was obtained as a brown solid.

[0601] Step 2: N-methyl-6-nitro-1H-indole-3-sulfonamide 6-Nitro-1H-indole-3-sulfonyl chloride (1.7 g, 6.5 mmol, 1.0 equiv.) was dissolved in THF (10.0 mL ), and methylamine in THF (2 M, 16 mL, 8.0 mmol, 1.2 equiv.) was added, resulting in The resulting solution was stirred at room temperature for 14 hours. After concentration in vacuo, the residue was purified by silica gel chromatography. The mixture was purified by flash column chromatography in ethyl acetate / petroleum ether (1:2 ) to obtain N-methyl-6-nitro-1H-indole-3-sulfonamide (500 mg) was obtained as a yellow oil. LCMS Method CA: [MH] - =254.

[0602] Step 3: 6-amino-N-methyl-1H-indole-3-sulfonamide N-methyl-6-nitro-1H-indole-3-sulfonamide (500.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in MeOH / THF (10 / 5 mL), and Pd / C (10% wt, 176.0 mg, 0.2 mmol, 0.1 equiv.) was added. The reaction mixture was degassed and refilled with hydrogen three times and then stirred under a hydrogen atmosphere for 10 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by filtration on silica gel. Purification was performed by rush column chromatography using dichloromethane / methanol (10:1 ) to obtain 6-amino-N-methyl-1H-indole-3-sulfonamide (450 mg) was obtained as a yellow oil. LCMS Method CA: [MH] - =224.

[0603] Synthesis of Intermediate 20 (6-Amino-N-methyl-1H-indole-3-sulfonamide) TIFF2025037981000285.tif52148

[0604] Step 1: tert-butyl (7-methyl-1H-indol-6-yl)carbamate 6-Bromo-7-methyl-1H-indole (200.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in dioxane (20.0 1 mL) and BrettPhos Pd G3 (86.3 mg, 0.1 mmol, 0.1 equiv.), BrettPhos (51.1 m g, 0.1 mmol, 0.1 equiv.) and Cs2CO3 (620.4 mg, 1.9 mmol, 2.0 equiv.) were heated under nitrogen at room temperature. The resulting mixture was stirred at 105°C under nitrogen for 8 hours and then evaporated under vacuum. The residue was purified by flash column chromatography on silica gel. , and elution with dichloromethane / methanol (10:1) gave (7-methyl-1H-indole- 6-yl) tert-butylcarbamate (200 mg, 85.0%) was obtained as an off-white solid. . LCMS method CI:[M+H] + =247. TIFF2025037981000286.tif12142

[0605] Step 2: 7-methyl-1H-indol-6-amine tert-Butyl (7-methyl-1H-indol-6-yl)carbamate (200.0 mg, 0.8 mmol, 1. 0 equiv.) was dissolved in DCM / TFA (30 mL / 5 mL) at room temperature. The resulting mixture was The mixture was stirred at rt for 5 min and quenched by adding water. The pH of the solution was adjusted to 8 with saturated aqueous NaHCO3. The resulting solution was extracted with ethyl acetate and concentrated under vacuum to give This gave crude 7-methyl-1H-indol-6-amine (110 mg) as a yellow oil. LCMS Method CC: [M+H] + =147.

[0606] Step 3: 6-amino-7-methyl-1H-indole-3-carbonitrile 7-methyl-1H-indol-6-amine (100.0 mg, 0.7 mmol, 1.0 equiv.) and CSI (116.6 mg , 0.8 mmol, 1.2 equiv.) in ACN (15.0 mL) and DMF (0.4 mg, 4.8 mmol, 7.0 equiv.) The resulting mixture was stirred under a nitrogen atmosphere at 0° C. for 2.5 hours. The resulting mixture was then quenched with ethyl acetate. Extraction, washing with brine, drying over anhydrous Na2SO4, and concentration in vacuo afforded the 6-amino 1H-indole-3-carbonitrile (90.0 mg, 76.8%) was obtained as a brown solid. LCMS Method CC: [M+H] + =172.

[0607] Using the same method as described for intermediate A20, the intermediates in the following table were prepared. TIFF2025037981000287.tif46152

[0608] Intermediate A22 (6-amino-1-(2-methylpyridin-3-yl)-1H-indole-3-carbonitrile ) synthesis TIFF2025037981000288.tif62147

[0609] Step 1: 1-(2-methylpyridin-3-yl)-6-nitroindole 6-Nitro-1H-indole (1.5 g, 9.3 mmol, 1.0 equiv.) and 3-iodo-2-methylpyridin Dissolve ethanol (4.1 g, 18.5 mmol, 2.0 equiv.) in DMSO (36.0 mL) and add K2CO3 (2.6 g, 18.5 mmol, 2. 0 equiv.), 8-hydroxyquinoline (268.6 mg, 1.9 mmol, 0.2 equiv.) and CuI (352.4 mg, 1. 9 mmol, 0.2 eq) was added under nitrogen. The resulting mixture was stirred at 110° C. overnight. The mixture was then quenched by the addition of water. The solution was extracted with ethyl acetate and washed with brine. The residue was purified by flash column chromatography on silica gel. Purify by column chromatography, eluting with ethyl acetate / petroleum ether (1:4) 1-(2-methylpyridin-3-yl)-6-nitroindole (990 mg, 42.3%) was obtained as a yellow Obtained as an oil. LCMS Method CD: [M+H] + =254.

[0610] Step 2: 1-(2-methylpyridin-3-yl)-6-nitroindole-3-carbonitrile 1-(2-methylpyridin-3-yl)-6-nitroindole (330.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in ACN (6.0 mL), and CSI (184.4 mg, 1.3 mmol, 1.0 equiv.) was added to the solution at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 2 hours, and then the above mixture was added at 0° C. DMF (0.7 mL, 9.4 mmol, 7.2 equiv.) was added at room temperature. The mixture was stirred for an additional 1.5 hours and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography under the following conditions: Purification was performed by chromatography: column, C18 silica gel, mobile phase, NH4HCO3 in water, 30 min. 0% → 80% MeCN; detector, UV 254 nm. This gave 1-(2-methylpyridin-3-yl)-6-nitrilo Indole-3-carbonitrile (228 mg, 62.9%) was obtained as a yellow oil. LCMS Method CI :[M+H] + =279.

[0611] Step 3: 6-amino-1-(2-methylpyridin-3-yl)indole-3-carbonitrile 1-(2-methylpyridin-3-yl)-6-nitroindole-3-carbonitrile (220.0 mg, 0. 8 mmol, 1.0 equiv.) was dissolved in MeOH (5.0 mL), and Pd / C (16.8 mg, 0.2 mmol, 0.2 equiv.) was added. The resulting mixture was evacuated and refilled with hydrogen three times before being placed under a hydrogen atmosphere. The reaction mixture was stirred under air at room temperature for 1 hour, filtered through Celite, and the filtrate was concentrated in vacuo. By this, 6-amino-1-(2-methylpyridin-3-yl)indole-3-carbonitrile (190 mg, 96.8%) was obtained as a yellow oil. LCMS Method CJ: [M+H] + =279.

[0612] Synthesis of intermediate A23 (1-acetyl-6-amino-1H-indole-3-carbonitrile) TIFF2025037981000289.tif54157

[0613] Step 1: tert-butyl (3-cyano-1H-indol-6-yl)carbamate 6-Nitro-1H-indole-3-carbonitrile (500.0 mg, 2.7 mmol, 1.0 equiv.) was dissolved in THF (10. 0 mL) and NiCl2.6HO (71.4 mg, 0.3 mmol, 0.1 equiv.) and Boc2O (1.2 g, 5.4 mmol) , 2.0 equiv.) was added to the mixture, followed by the addition of NaBH4 (123.1 mg, 3.2 mmol, 1.2 equiv.) at 0 °C. The resulting solution was stirred at room temperature for 8 hours and concentrated in vacuo. The residue was collected on silica gel. Purification was performed by flash column chromatography on gel and ethyl acetate / petroleum ether. Elution with ethanol (1:4) afforded tert-(3-cyano-1H-indol-6-yl)carbamic acid. Butyl (210 mg, 30.6%) was obtained as an off-white solid. LCMS Method CD: [M+H] + = 258.

[0614] Step 2: tert-butyl (1-acetyl-3-cyano-1H-indol-6-yl)carbamate tert-Butyl (3-cyano-1H-indol-6-yl)carbamate (210 mg, 0.8 mmol, 1.0 (equivalent) and TEA (0.2 mL, 1.6 mmol, 2.0 equiv.) were dissolved in THF (5.0 mL), and AC2O (326.4 mg , 3.2 mmol, 4.0 equiv.) was added at 0° C. The reaction mixture was stirred at room temperature for 2 hours and then cooled to room temperature by the addition of water. The resulting solution was extracted with ethyl acetate and washed with brine. , dried over anhydrous Na2SO4, and concentrated under vacuum to give (1-acetyl-3-cyano-1H-isothiazolinone). tert-Butyl (6-(4-hydroxypropyl-2-methyl-2-yl)carbamate (210 mg, 85.9%) was obtained as a yellow oil. CMS method CD: [M+H] + =300.

[0615] Step 3: 1-acetyl-6-amino-1H-indole-3-carbonitrile tert-Butyl (1-acetyl-3-cyano-1H-indol-6-yl)carbamate (200 mg, 0. 7 mmol, 1.0 equiv.) was dissolved in HCl / dioxane (4 M, 5.0 mL). The reaction solution was stirred at room temperature for 2 hours. The mixture was stirred and quenched by adding water. The pH value of the solution was adjusted to 9 with saturated aqueous Na2CO3 solution. The 1-acetylacetone was extracted with ethyl acetate, dried over anhydrous Na2SO4, and concentrated under vacuum. 1H-indole-3-carbonitrile (104 mg, 78.1%) was obtained as a brown solid. LCMS method CD: [M+H] +=200.

[0616] Synthesis of intermediate A24 (6-amino-4-methyl-1H-indole-3-carbonitrile) TIFF2025037981000290.tif26140

[0617] Step 1: 4-methyl-6-nitro-1H-indole-3-carbonitrile 4-Methyl-6-nitro-1H-indole (500.0 mg, 2.8 mmol, 1.0 equiv) in ACN (20.0 mL) The resulting mixture was dissolved and CSI (482.0 mg, 3.4 mmol, 1.2 equiv.) was added at 0°C. The mixture was stirred at 0 °C for 2 h, and then the above mixture was added with DMF (0.4 mL, 5.7 mmol, 2.0 equiv.) at 0 °C. The resulting mixture was stirred at 0°C for a further 2 hours and then diluted with water. The resulting mixture was extracted with ethyl acetate and washed with brine. 4-methyl-6-nitro-1H-indomethyl ... 420 mg (73.56%) of benzoyl-3-carbonitrile was obtained as a yellow oil. LCMS Method CI: [M+H ] + =202.

[0618] Step 2: 6-amino-4-methyl-1H-indole-3-carbonitrile 4-Methyl-6-nitro-1H-indole-3-carbonitrile (400.0 mg, 2.0 mmol, 1.0 equiv.) was dissolved in MeOH (10.0 mL) and Pd / C (105.8 mg, 1.0 mmol, 0.5 equiv.) was added to the reaction mixture. The mixture was degassed and refilled with hydrogen three times, and then stirred under a hydrogen atmosphere at room temperature for 2 hours. The resulting mixture was then concentrated under vacuum to give 6-amino-4-methyl The resulting product was 1H-indole-3-carbonitrile (280 mg, 82.3%) as a yellow oil. Method CI: [M+H] + =172.

[0619] Synthesis of Intermediate A25 (6-amino-4-methyl-1H-indole-3-carbonitrile) TIFF2025037981000291.tif59154

[0620] Step 1: 2-(6-nitro-1H-indol-3-yl)acetic acid 2-(6-nitro-1H-indol-3-yl)acetate (500.0 mg, 2.0 mmol, 1.0 equiv.) was dissolved in Me The solution was dissolved in LiOH / water (5.0 mL / 1.0 mL) and LiOH.HO (422.6 mg, 10.1 mmol, 5.0 equiv.) was added. The resulting solution was stirred at room temperature for 3 h. The pH value of the solution was adjusted to 6 with aqueous HCl (4 M). The resulting mixture was extracted with ethyl acetate, washed with brine, and Water, dried over Na2SO4, and concentrated in vacuo to give (6-nitro-1H-indol-3-yl) Acetic acid (300 mg, 67.6%) was obtained as an off-white solid. LCMS Method CJ: [MH] - =219 .

[0621] Step 2: N-methyl-2-(6-nitro-1H-indol-3-yl)acetamide (6-Nitro-1H-indol-3-yl)acetic acid (500.0 mg, 2.3 mmol, 1.0 equiv.) was dissolved in THF (5.0 mL ) and dissolved in CH3NH 2. HCl (184.1mg, 2.7mmol, 1.2eq), T3P (2167.6mg, 6.8mmol, 3.0 eq.) and TEA (0.6 mL, 4.5 mmol, 2.0 eq.) were added. The resulting solution was The mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. The product was purified by chromatography eluting with ethyl acetate / petroleum ether (1:1) to give N-methyl-2-(6-nitro-1H-indol-3-yl)acetamide (400 mg, 75.5%) Obtained as a white solid. LCMS Method CC: [M+H] + =234.

[0622] Step 3: 2-(6-amino-1H-indol-3-yl)-N-methylacetamide N-methyl-2-(6-nitro-1H-indol-3-yl)acetamide (500.0 mg, 2.1 mmol, 1. 0 equiv.) was dissolved in MeOH (10.0 mL) and Pd / C (222.8 mg, 2.1 mmol, 1.0 equiv.) was added. The mixture was degassed and refilled with hydrogen, then stirred under a hydrogen atmosphere at room temperature for 10 minutes. After filtration and concentration, the residue was purified by flash column chromatography on silica gel. and eluted with ethyl acetate / petroleum ether (1:1) to give 2-(6-amino-1H-isopropyl)- (350 mg, 90.0%) as an off-white solid LCMS Method CC: [M+H] + =204.

[0623] Synthesis of Intermediate A26 (6-amino-4-methyl-1H-indole-3-carbonitrile) TIFF2025037981000292.tif29152

[0624] Step 1: N-methyl-6-nitro-1H-indole-3-carboxamide 6-Nitro-1H-indole-3-carboxylic acid (300.0 mg, 1.5 mmol, 1.0 equiv.) and methyl amine Dissolve amine hydrochloride (110.0 mg, 1.6 mmol, 1.1 equiv.) in THF (20.0 mL) and add HATU (553.3 mg , 1.5 mmol, 1.0 equiv.), DIEA (0.5 mL, 2.9 mmol, 2.0 equiv.) were added. The resulting mixture was stirred at room temperature for 4 hours and concentrated in vacuo. The residue was purified by flushing with silica gel. Purification by column chromatography eluting with DCM / MeOH (10:1) gave N-Methyl-6-nitro-1H-indole-3-carboxamide (240mg, 75.2%) off-white LCMS Method CC: [M+H] + =220.

[0625] Step 2: 6-amino-N-methyl-1H-indole-3-carboxamide N-methyl-6-nitro-1H-indole-3-carboxamide (200.0 mg, 0.9 mmol, 1.0 equiv.) The reaction mixture was dissolved in MeOH (0 mL) and Pd / C (10 wt%, 100 mg, 0.1 mmol, 0.1 equiv.) was added. The mixture was degassed and refilled with hydrogen, then stirred under a hydrogen atmosphere at room temperature for 2 hours. After filtration, the filtrate was concentrated in vacuo to give crude 6-amino-N-methyl-1H-indole-3-carboxylate. Ruboxamide (187 mg) was obtained as a white solid. LCMS Method CC: [M+H] + =190.

[0626] Synthesis of Intermediate A27 (6-Amino-N-methyl-1H-indole-4-carboxamide) TIFF2025037981000293.tif31128

[0627] Methyl 6-amino-1H-indole-4-carboxylate (250.0 mg, 1.3 mmol, 1.0 equiv.) was dissolved in MeOH ( 5.0 mL) and a CH3NH2 / THF solution (5.0 mL, 1 M, 5.0 mmol, 4.0 equivalents) was added at room temperature. The resulting mixture was stirred at 130° C. overnight and then concentrated in vacuo. Purification was carried out by flash column chromatography on silica gel and distillation with DCM / MeOH (10:1) Elution with 6-amino-N-methyl-1H-indole-4-carboxamide (150 mg, 60. 3%) as an orange solid. LCMS Method CF: [M+H] + =190.

[0628] Intermediate A28 (6-amino-1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carbonyl Synthesis of tolyl TIFF2025037981000294.tif62153

[0629] Step 1: 1-(1-methyl-1H-pyrazol-4-yl)-6-nitro-1H-indole 6-nitro-1H-indole (1.0 g, 6.2 mmol, 1.0 equiv.) and 4-iodo-1-methyl-1H-pi Dissolve benzol (2.6 g, 12.5 mmol, 2.0 equiv.) in DMSO (20.0 mL) and add KCO (1.7 g, 12.3 mmol). ol, 2.0 equiv.), CuI (233.0 mg, 1.2 mmol, 0.2 equiv.) and quinolin-8-ol (179.0 mg , 1.2 mmol, 0.2 equiv.) was added under air atmosphere. The reaction mixture was stirred at 110° C. for 2 hours and then vacuum The residue was purified by flash column chromatography on silica gel. 1-(1-methyl-1H-pyrazoline)-2-(2 ... (4-amino-4-yl)-6-nitro-1H-indole (916.0 mg, 61.3%) was obtained as an off-white solid. LCMS Method CE: [M+H]+ =243.

[0630] Step 2: (1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-6-yl)carbamic acid te rt-butyl 1-(1-methyl-1H-pyrazol-4-yl)-6-nitro-1H-indole (700.0 mg, 2.9 mmol, (1.0 equiv.) and BocO (812.0 mg, 3.7 mmol, 1.3 equiv.) were dissolved in THF (20.0 mL) and Pd / C ( 10% by weight, 100.00 mg, 0.1 mmol, 0.03 equiv.) was added. The reaction mixture was degassed and recharged with hydrogen. After repeating this process three times, the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After filtration, the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Purification by chromatography and elution with ethyl acetate / petroleum ether (1:1) gave N-[ tert-Butyl 1-(1-methylpyrazol-4-yl)indol-6-yl]carbamate (630.0 mg) was obtained as a brown solid. LCMS Method CJ: [M+H] + =313.

[0631] Step 3: (3-cyano-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-6-yl)carboxamide tert-Butyl bamate tert-Butyl N-[1-(1-methylpyrazol-4-yl)indol-6-yl]carbamate (600.0 mg, 1.9 mmol, 1.0 equiv.) and CSI (273.1 mg, 1.9 mmol, 1.0 equiv.) were dissolved in ACN (20.0 mL After stirring at room temperature for 2 hours, the above mixture was added with DMF (1.0 mL, 13.5 mmol, 7. The solution was stirred at room temperature for another 2 hours, and then added with aqueous NaOH (1 mol / L) The pH value of the solution was adjusted to 6 by dropwise addition of ethyl acetate. The residue was purified by filtration, washed with HCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The product was purified by flash column chromatography and dissolved in ethyl acetate / petroleum ether (1:1). By releasing N-[3-cyano-1-(1-methylpyrazol-4-yl)indol-6-yl] tert-Butyl carbamate (300.0 mg) was obtained as an off-white solid. LCMS Method CI: [M+H] + =338.

[0632] Ste...

Claims

1. Formula I: A compound of the formula: In formula (I), Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 Each of N and CR 1 Independently selected from the group consisting of 、 A WA is defined in accordance with (A) or (B) below: （A） W is (k)*C(=O)NR N ,*C(=S)NR N ,*C(=NR N )NO N (eg*C(=NCN)NO N ),*C(=CNO 2 )NR N 、 (l)*S(O) 1～2 NR N 、 （m） 、 （n） , and (o)*Q 1 -Q 2 、 is selected from the group consisting of Asterisks are NR 6 represents the attachment point to Q 1 teeth (e) 1 to 2 independently selected R q1 phenylene which may be substituted with Beauty (f) Heteroarylene containing 5 to 6 ring atoms, 1 to 4 of which are heteroaryls. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 A group consisting of and the heteroarylene ring is selected from 1 to 4 independently selected R q1 in The optionally substituted heteroarylene is selected from the group consisting of Q 2 is a bond, NR N , -S(O) 0～2 -, -O-, and -C(=O)-; 、 A is, (i)-Y A1 -Y A2 And, ・Y A1 is a bond, or ・Y A1 C 1～6 alkylene, 1～6 The alkylene is ○R a 、 ○ 1 to 4 independently selected C 1～4 C optionally substituted with alkyl 6～1 0 Aryl, and Heteroaryl containing 5 to 10 ring atoms, where 1 to 4 ring atoms are heteroaryls. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 A group consisting of and the heteroaryl ring is selected from 1 to 4 independently selected C 1～4 a the heteroaryl optionally substituted with alkyl; may be substituted with 1 to 6 substituents independently selected from the group consisting of ,or ・Y A1 But, Y A3 -Y connected to W via A3 -Y A4 -Y A5 where: ○Y A3 is one to two independently selected R a C which may be substituted with 1～3 Al Kiren, ○Y A4 is -O-, -NH-, or -S-; and ○Y A5 is a bond or one to two independently selected R a Replaced with C may be 1～3 alkylene, and ・Y A2 but, (a) 1 to 4 R b C which may be substituted with 3～20 Cycloalkyl, (b) 1 to 4 R c C which may be substituted with 6～20 Aryl, (c) Heteroaryl containing 5 to 20 ring atoms, of which 1 to 3 ring atoms are heteroaryl. Each heteroatom is a heteroatom, and each heteroatom is a heteroatom. d ), O, and S(O) 0～2 Consists of and the heteroaryl ring is selected from 1 to 4 independently selected R c Place the heteroaryl, optionally substituted, (d) Heterocyclyl containing 3 to 16 ring atoms, of which 1 to 3 ring atoms are heterocyclic. Each heteroatom is a heteroatom, and each heteroatom is a heteroatom. d ), O, and S(O) 0～2 Consists of and the heterocyclyl ring is selected from 1 to 4 independently selected R b Place The optionally substituted heterocyclyl That is, The -Y A1 -Y A2 , or (ii)-Z 1 -Z 2 -Z 3 And, ・Z 1 But 1 to 4 R a C which may be substituted with 1～3 is alkylene, ・Z 2 However, -N(H)-, -N(R d ) -, -O-, or -S-; and ・Z 3 But 1 to 4 R a C which may be substituted with 2～7 is alkyl, The -Z 1 -Z 2 -Z 3 、 or (iii) 1 to 6 independently selected R a C which may be substituted with 1～20 Alkyl That is, or （B） W is (a) 1 to 4 R c C which may be substituted with 8～20 Bicyclic or Polycyclic Arylenes , and (b) a bicyclic or polycyclic heteroarylene containing 8 to 20 ring atoms, ~ 4 ring atoms are heteroatoms, each heteroatom is N, N(H), N(R d ), O, and S (O) 0～2 and the heteroaryl ring is independently selected from the group consisting of 1 to 4 independent R is selected by c The heteroarylene may be substituted with is selected from the group consisting of A is as defined for (A) or A is H; R 1 Each occurrence of ・H、 ・Halo, ・Cyano, ・1 to 2 R a C which may be substituted with 1～6 Alkyl, ・C 2～6 Alkenyl, ・C 2～6 Alkynyl, ・C 1～4 Haloalkyl, ・C 1～4 Alkoxy, ・C 1～4 Haloalkoxy, -S(O) 1～2 (C 1～4 alkyl), -S(O)(=NH)(C 1～4 alkyl), ・SF 5 、 ・-NR e R f 、 -OH, ・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, -C(=O)N(R')(R''), and ・-L 3 -L 4 -L 5 -R i or Or, a pair of R on adjacent atoms 1 together with the atoms that connect them , forming a ring (e.g., aromatic or non-aromatic) containing 4 to 15 ring atoms, and 0 to 3 ring atoms are heteroatoms, and each heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 from and the ring is selected from 1 to 4 independently selected R 2 It is replaced by It is okay to Each R 2 teeth, ・Halo, ・Cyano, ・1 to 2 R a C which may be substituted with 1～6 Alkyl, ・C 2～6 Alkenyl, ・C 2～6 Alkynyl, ・C 1～4 Haloalkyl, ・C 1～4 Alkoxy, ・C 1～4 Haloalkoxy, ・1 to 3 independently selected R a -S(O) 1～2 (C 1～4 Alkyl ）、 ・1 to 3 independently selected R a -S(O)(=NH)(C 1～4 Al kill), ・SF 5 、 ・-NR e R f 、 -OH, ・Oxo, ・-S(O) 1～2 (NR’R’’)、 -C 1～4 Thioalkoxy, ・-NO 2 、 ・1 to 3 independently selected R a -C(=O) (C 1～4 Alkyl) 、 ・1 to 3 independently selected R a -C(=O)O(C 1～4 Alkyl ）、 -C(=O)OH, -C(=O)N(R')(R''), and ・-L 3 -L 4 -L 5 -R i are independently selected from the group consisting of R 6 is H;C 1～6 Alkyl;-OH;C 1～4 Alkoxy; C(=O)H; C(=O)(C 1～4 alkyl); CN; 1 to 4 independently selected C 1～4 C optionally substituted with alkyl 6～10 Aryl; and heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 are heteroatoms. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 Independent from the group consisting of and the heteroaryl ring is selected from 1 to 4 independently selected C 1～4 With alkyl is selected from the heteroaryl, optionally substituted; R q1 Each occurrence of (a) halo, (b) cyano, (c) 1 to 6 independently selected R a may be replaced by I C 1～10 Alkyl, (d) C 2～6 Alkenyl, (e) C 2～6 Alkynyl, (f) C 3～6 Cycloa Rukyr, (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 blood Oralkoxy, (n)-NO 2 , (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) oxo are independently selected from the group consisting of R a Each occurrence of is -OH; -F; -Cl; -Br; -NR e R f ;C 1～4 Alkoxy;C 1～4 Haloalkoxy; -C(= O)O(C 1～4 alkyl);-C(=O)(C 1～4 alkyl);-C(=O)OH;-CON(R')(R'' );-OCON(R')(R'');-S(O) 1～2 (NR'R'');-S(O) 1～2 (C 1～4 alkyl); cyano, and 1 to 4 independently selected C 1～4 C optionally substituted with alkyl 3～6 cycloalkyl; R b Each occurrence of is selected from 1 to 6 independently selected R a C which may be substituted with 1～10 Alkyl ;C 1～4 Haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ;C 1～4 Alkoxy;C 1～4 Haloarco -C(=O)(C 1～10 alkyl);-C(=O)O(C 1～4 alkyl);-C(=O)OH;-C(=O )N(R')(R'');-S(O) 1～2 (NR'R'');-S(O) 1～2 (C 1～4 Alkyl); Cyano ; and -L 1 -L 2 -R h are independently selected from the group consisting of R c Each occurrence of (a) halo, (b) cyano, (c) 1 to 6 independently selected R a may be replaced by I C 1～10 Alkyl, (d) C 2～6 Alkenyl, (e) C 2～6 Alkynyl, (g) C 1～4 Alcoki Shi, (h) C 1～4 Haloalkoxy, (i) -S(O) 1～2 (C 1～4 Alkyl) or -S(O) 1～2 (C 1～4 haloalkyl), (j)-NR e R f , (k)-OH, (l)-S(O) 1～2 (NR'R''), (m )-C 1～4 Thioalkoxy or -C 1～4 Thiohaloalkoxy, (n)-NO 2 , (o)-C(=O) (C 1～10 alkyl), (p)-C(=O)O(C 1～4 alkyl), (q) -C(=O)OH, (r) -C (=O)N(R')(R''), (s)-L 1 -L 2 -R h , (t)-SF 5 , and (u) azide are independently selected from the group consisting of R d Each occurrence of 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, C 1～4 alkoxy, and CN; R e and R f Each occurrence of H; halo, CN, C 1～4 Alkoxy, C 1～4 Haloalkoxy, NR'R 1 to 4 substituents independently selected from -OH, - Ru, 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);-S(O)(=NR')(C 1～4 alkyl); -OH; and C 1～4 Arco or R e and R f are each bonded together with the nitrogen atom forming a ring containing 3 to 8 ring atoms, the ring being 1～3 Al 1 to 7 ring carbon atoms, each substituted with 1 to 2 substituents independently selected from alkyl and (b) N(R d ), 0 to 3, each independently selected from the group consisting of NH, O, and S; Ring heteroatoms (R e and R f In addition to the nitrogen atom bonded to -L 1 is a bond or C optionally substituted with oxo 1～3 is alkylene, -L 2 -O-, -N(H)-, -S(O) 0～2 - or a bond, R h teeth, Halo; 1 to 2 independently selected R a C which may be substituted with 1～4 Alkyl;C 1～4 Ha arylalkyl;cyano;C 1～4 Alkoxy; and C 1～4 Independently from the group consisting of haloalkoxy C is optionally substituted with 1 to 4 substituents selected from 3～8 Cycloalkyl (but In certain embodiments, R h is 1 to 4 independently selected C 1～4 It is substituted with alkyl Good C 3～6 When it is cycloalkyl, -L 1 is a bond or -L 2 But -O-, -N (H )- or -S-) Heterocyclyl contains 3 to 16 ring atoms, 1 to 3 of which are heteroatoms, and each The heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 Independently selected from the group consisting of and the heterocyclyl is selected from halo; a may be replaced by I C 1～4 Alkyl;C 1～4 Haloalkyl;Cyano;C 1～4 Alkoxy; and C 1～4 Haloalkoki The heterocyclic group may be substituted with 1 to 4 substituents independently selected from the group consisting of Cyclyl, Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 are heteroatoms Each heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 Independently from the group consisting of and the heteroaryl ring is selected from halo; 1 to 2 independently selected R a Replaced by C 1～4 Alkyl;C 1～4 Haloalkyl;Cyano;C 1～4 Alkoxy; and C 1～4 Ha and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy, , the heteroaryl, and Halo; 1 to 2 independently selected R a C which may be substituted with 1～4 Alkyl;C 1～4 Ha arylalkyl;cyano;C 1～4 Alkoxy; and C 1～4 Independently from the group consisting of haloalkoxy C is optionally substituted with 1 to 4 substituents selected from 6～10 Aryl is selected from -L 3 is a bond or C optionally substituted with oxo 1～3 is alkylene, -L 4 is a bond;-O-;-N(R N )-;-S(O) 0～2 -;C(=O);-NR N S (O) 0～2 -;-S(O) 0～2 NR N -;-NR N S (O) 1～2 NR N -;-S(=O)(=NR N );-NR N S (=O) (=NR) N );-S(=O)(=NR N ) NR N ;NR N S(=O)(=NR N )NR N ;-NR N C(O)-;-NR N C(O)NR N -;C 3～6 Cycloalkylene; or heterocyclylene containing 3 to 8 ring atoms, of which 1 to 3 ring atoms are heteroatoms; Each heteroatom is N, NH, or N(R d ), O, and S(O) 0～2 Independently selected from the group consisting of The heterocyclylene is -L 5 is a bond or C 1～4 is alkylene, R i teeth Halo; 1 to 2 independently selected R a C which may be substituted with 1～4 Alkyl;C 1～4 Ha arylalkyl;cyano;C 1～4 Alkoxy; and C 1～4 Independently from the group consisting of haloalkoxy C is optionally substituted with 1 to 4 substituents selected from 3～8 Cycloalkyl (but In certain embodiments, R i But, C 1～4 substituted with 1 to 4 substituents independently selected from alkyl C may be 3～6 When it is cycloalkyl, -L 1 is a bond or -L 2 but,- -O-, -N(H)-, or -S- Heterocyclyl contains 3 to 16 ring atoms, 1 to 3 of which are heteroatoms, and each The heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 Independently selected from the group consisting of and the heterocyclyl is selected from halo; a may be replaced by I C 1～4 Alkyl;C 1～4 Haloalkyl;Cyano;C 1～4 Alkoxy; and C 1～4 Haloalkoki The heterocyclic group may be substituted with 1 to 4 substituents independently selected from the group consisting of Cyclyl, Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 are heteroatoms Each heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 Independently from the group consisting of and the heteroaryl ring is selected from halo; 1 to 2 independently selected R a Replaced by C 1～4 Alkyl;C 1～4 Haloalkyl;Cyano;C 1～4 Alkoxy; and C 1～4 Ha and optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy, , the heteroaryl, and Halo; 1 to 2 independently selected R a C which may be substituted with 1～4 Alkyl;C 1～4 Ha arylalkyl;cyano;C 1～4 Alkoxy; and C 1～4 Independently from the group consisting of haloalkoxy C is optionally substituted with 1 to 4 substituents selected from 6～10 Aryl is selected from R N Each occurrence of is independently H or R d and Each occurrence of R' and R'' is H, C 1～4 Alkyl, and halo, C 1～4 Alkyl, and C 1～4 C, optionally substituted with 1 to 2 substituents selected from haloalkyl 6～10 Ants or R' and R'' are each independently selected from the group consisting of together with the nitrogen atom attached thereto, form a ring containing 3 to 8 ring atoms, the ring being selected from the group consisting of (a) H and C 1～3 1 to 7, each of which is substituted with 1 to 2 substituents independently selected from the group consisting of alkyl ring carbon atoms and (b) N(H), N(C 1～6 alkyl), O, and S; 0 to 3 ring heteroatoms (nitrogen atoms bonded to R' and R'', each independently selected In addition to the atoms provided that the compound has the formula (I-a1), wherein R 2’ is H or R 2 and WA follows (A). W is defined as *C(O)NR N (For example, *C(O)NH), among the following provisions 1, 2, 3, 4, or 5 of the following apply: (i) Y 1 and Y 2 Each of the groups is CH, and Y 3 CR 1 and R 1 But CO 2 Me, CO 2 Et, CN, too or Cl, and R 2 is absent (i.e. C2 and C3 are replaced by H) , or Y 1 and Y 2 Each of is N and Y 3 When is OH or oxo, A is Optionally substituted C 1～6 Alkyl, such as methyl and butyl, 1,1,3,3-tetramethyl butyl, and optionally substituted C 3 and C 6 Cycloalkyl (e.g. CO 2 H, I C optionally substituted with socyanate and substituted amino 1～6 Alkyl and C 3 oh Yobi C 6 cycloalkyl), (ii) Y 1 and Y 2 Each of is N and Y 3 CR 1 If When WA is benzyl, R 1 cannot be frilly, and ・R 2’ is methyl, or WA is -Cl, -F, -Br, and CF 3 Selected independently from When R is phenyl substituted with one or two substituents selected from the group consisting of phenyl and phenyl, R 1 is a substituted N-linked aniline and cannot be chloro; (iii) Y 1 , Y 2 , and Y 3 Each of the groups is CH, and R 2’ is H and R 2 exists and A is bonded to the C3 position of the dole ring and A is phenyl, tolyl, optionally substituted kyne nazolinyl, optionally substituted pyrazolyl, optionally substituted indolyl, substituted naphthyl, optionally substituted, or morpholinyl-phenyl (mor opholinyl-phenyl), R 2 is oxazolyl, pyridyl, C-linked 2-pyridyl Ethyl, phenyl, cyano, and C(O)NH 2 It is not possible to be (iv) Y 1 and Y 3 Each of the groups is CH, and Y 2 is CH or CMe, and R 2’ is H, or R 2 If does not exist, ・R h cannot be a fused tricyclic ring, ・Y A2 is an optionally substituted cyclohexyl, cyclohexenyl, imidazo[1,2 -a][1,4]benzodiazepin-4-yl, indenyl, naphthyl, and tetrahydronaphthalene Unable to be chill, ・Y A1 cannot be an alkylene substituted with phenyl; ・Y A1 When Y is alkylene, A2 It can be phenyl or one of the following substituted phenyls: Nyl ring: 4-Br, 2,4-(Cl) 2 , 3-propenyl, 2,3-(OMe) 2 , and 4-CF 3 It may also be Damage, injury ・Y A1 If does not exist, Y A2 can be phenyl or the following substituted phenyl rings: 3-N O 2 、4-Br、2,4-(Cl) 2 、2,3-(OMe) 2 、4-CF 3 、4-CO 2 Et、3-CF 3 -4-Cl、2-Cl-4 CF 3 、2-O Et、2-OMe-4-NO 2 、3,4-(OMe) 2 、2,4-(Me) 2 、3,4-(Cl) 2 、2,4- (F) 2 ,2-Et,2-F, 2-Me、2-Br、2-Cl-4-Br、2-CF 3 、2,4-(OMe) 2 、2,3-(Me) 2 、3,5-(Cl) 2 、3-CF 3 -4-F , 4-isopropyl, 4-OMe, 4-Cl, 3-F-4-Me, 3-CF 3 , 2,5-(OMe) 2 , 2-Me-3-Cl, 2,3- ( Me) 2 、2,3-(Cl) 2 、4-Bu、3-OMe、3-Cl、4-Me-2-Cl、3-SMe、2-CO 2 Me、4-Me-3-Cl、3,4 - (Me) 2 , 4-sec-Butyl, 2-OMe, 2-Cl, 2,4-(OMe) 2 -5-Cl, 4-OEt, 4-Acetyl, 2-OMe -5-Me、2-Me-5-Cl、3,5-(Me) 2 、3,5-(Cl) 2 、4-NO 2 、4-Br、4-F、4-Me、4-Et、3-F、3 -Me, 3-acetyl, and 2-Me-5-Cl; and (v) the compound is Other than that, The compound, or a pharma- ceutically acceptable salt thereof, or a tautomer thereof.

2. A pair of R on adjacent atoms 1 together with the atoms connecting them, form five Form an aromatic ring containing ring atoms, and one or two (e.g., one or two) of the ring atoms are heteroatoms. Each heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 Independently from the group consisting of and the ring is selected from 1 to 4 independently selected R 2 The claim The compound according to item 1.

3. A pair of R on adjacent atoms 1 together with the atoms that connect them, wherein each R 2’ are independently H or R 2 ,for example ,for example 3. The compound of claim 1 or claim 2,

4. The compound has the following formula: for example wherein R 2’ is H or R 2 For example, R 2’ is H, The compound described in item .

5. R 2’ is H or R 2 The formula: ,for example, (For example, R 1 is other than H), Formula (I-a1-c), or (For example, R 1 is other than H) The compound of any one of claims 1 to 4, having the formula:

6. R 1 R that does not form a ring together with the atom to which it is attached 1 Each occurrence of H; B; Cyano; 1 to 2 R a C which may be substituted with 1～6 Alkyl;C 2～6 Alkenyl; C 2～6 a Rukinyl;C 1～4 Haloalkyl;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(=O)(C 1～4 Alkyl );-C(=O)O(C 1～4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); and -L 3 - L 4 -R i Independently selected from the group consisting of, for example, R 1 is halo; cyano; 1-2 R a Replaced with C may be 1～6 Alkyl;C 1～4 Haloalkyl, C 1～4 Alkoxy; or C 1～4 HelloA alkoxy, e.g. R 1 The compound of any one of claims 1 to 5, wherein is halo.

7. The compound according to any one of claims 1 to 6, wherein WA is as defined according to (A). 。

8. W is *C(=O)NR N 8. The compound of claim 7, wherein, for example, *C(=O)NH.

9. The compound according to any one of claims 1 to 6, wherein WA is as defined according to (B). 。

10. W is a bicyclic heteroarylene containing 8 to 10 ring atoms, 1 to 4 of which are heterocyclic. atoms, each heteroatom being N, N(H), N(R d ), O, and S(O) 0～2 A group consisting of and the heteroaryl ring is comprised of 1 to 4 independently selected R c Replaced with and A is H; For example, if W 1 to 2 independently selected R c each of which may be substituted by, quinolinylene, iso Quinolinylene, and Quinazolinylene For example, W is selected from the group consisting of That is, A compound according to any one of claims 1 to 6 and claim 9.

11. A is -Y A1 -Y A2 10. The compound of any one of claims 1 to 9, wherein

12. Y A2 But 1 to 3 R c C which may be substituted with 6～10 aryl, 12. The compound of any one of claims 11.

13. The compound has the following formula: and During the ceremony, n1 is 0, 1, or 2 (e.g., 0 or 1), and R cA and R cB Each of the following is independent: Selected R c and W is *C(=O)NR N , for example *C(=O)NH, and Part where R 2 ' is H or R 2 That is, 2. The compound of claim 1.

14. A portion comprising: , for example, R 1 is other than H (e.g., R 1 is halo or cyano) (a1-b) 14. The compound of claim 13, wherein

15. W is heteroarylene containing 9 to 10 ring atoms, 1 to 2 of which are heteroatoms; Each heteroatom is N, N(H), N(R d ), O, and S(O) 0～2 Independent from the group consisting of and the heteroaryl ring is selected from 1 to 2 independently selected R c It is replaced by For example, W is one to two independently selected R c quinolinylene, each of which may be substituted and quinazolinylene, e.g. W 、 and Part and A is H and optionally R 6 is H, 2. The compound of claim 1.

16. The compound according to claim 1, wherein the compound is selected from the group consisting of the compounds shown in Table C1 or pharma- ceutically acceptable salts thereof. The compound according to claim 1.

17. A compound according to any one of claims 1 to 16 or a pharma- ceutically acceptable salt thereof, and one or more and a plurality of pharma- ceutically acceptable excipients.

18. STING is a compound according to any one of claims 1 to 16 or a pharma- ceutical acceptable salt thereof. or the pharmaceutical composition of claim 17. method.

19. A method of inducing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to the claims. A compound according to any one of claims 1 to 16 or a pharma- ceutically acceptable salt thereof, or claim 17. The method comprises the step of administering the pharmaceutical composition described.

20. STING-related diseases, disorders, or conditions, e.g., ... Diseases in which increased ING signaling contributes to the pathology and / or symptoms and / or progression of the disease A method for treating a disease, disorder, or condition, such as cancer, comprising administering to a subject in need of such treatment An effective amount of a compound according to any one of claims 1 to 16 or a pharma- ceutical acceptable salt thereof is administered to the subject.

20. The method of claim 17, comprising administering a compound comprising the steps of:

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