Nucleoside-diphosphate-heptose compounds for treating conditions related to ALPK1 activity

Abstract

The present invention relates to compounds of formula (X) that modulate, in particular stimulate, alpha kinase 1 (ALPK1), and are useful in treating conditions, diseases or disorders in which decreased or increased ALPK1 activity contributes to the pathology, symptomology or progression thereof, such as cancer, immune or inflammatory related diseases. [C1] TIFF2024538847000319.tif43156

Description

[Technical Field]

[0001] This disclosure features chemical substances (e.g., compounds that modulate (e.g., stimulate) ALPK1, or pharmaceutically acceptable salts and / or hydrates and / or cocrystals and / or tautomers and / or stereoisomers and / or stable isotopes and / or prodrugs and / or compound drugs) that are useful for treating conditions, diseases or disorders (e.g., conditions, diseases or disorders associated with suppressed or impaired ALPK1 signaling; e.g., cancer, or e.g., immune and / or inflammation-related diseases (e.g., IBD)) in subjects (e.g., humans) where a decrease or increase (e.g., decrease) of alpha-kinase 1 (ALPK1) activity contributes to its pathogenesis and / or symptoms and / or progression. This disclosure also features compositions and other methods for using and preparing them. [Background technology]

[0002] Alpha-kinase 1 (ALPK1) has long been recognized as playing a crucial role in the immune system's response to bacterial infections. ALPK1 is a host cytoplasmic protein that functions as a receptor for ADP-heptose, a natural bacterial product, during LPS biosynthesis. When ADP-heptose binds to ALPK1, its kinase activity is activated, inducing phosphorylation of TRAF-interacting protein (TIFA) with a forkhead-binding domain. Finally, the NF-κB pathway is activated, enhancing cytokine transcription and leading to host immune system activity (Gaudet et al., 2015; Milivojevic et al., 2017; Zimmermann et al., 2017; Zhou et al., 2018; Pfannkuch et al., 2019).

[0003] Numerous studies and clinical trials have demonstrated that enhancing the immune response can benefit patients with diseases such as cancer and immune and / or inflammatory disorders. While several immunoactivators are approved for clinical use, there is still a need for new treatment options.

[0004] WO 2019 / 238024, US 2019 / 0367553, WO 2020 / 216327 and WO 2019 / 080898 (each incorporated herein by reference in its entirety) disclose ALPK1 modulators.

SUMMARY OF THE INVENTION

MEANS FOR SOLVING THE PROBLEM

[0005] The present disclosure features a chemical substance (e.g., a compound that modulates (e.g., stimulates) ALPK1, or a pharmaceutically acceptable salt and / or hydrate and / or co-crystal and / or tautomer and / or stereoisomer and / or stable isotope and / or prodrug and / or combination drug of such compound) useful for treating a condition, disease or disorder (e.g., a condition, disease or disorder related to inhibited or impaired ALPK1 signaling; e.g., cancer, or e.g., an immune and / or inflammation-related disease (e.g., IBD)) in a subject (e.g., a human) in which a decrease or increase (e.g., a decrease) in alpha-kinase 1 (ALPK1) activity contributes to its pathology and / or symptoms and / or progression. The present disclosure also features compositions and other methods of using and making the same.

[0006] In one aspect, the present disclosure provides a compound represented by formula (X):

CHEMICAL

[0007] In one embodiment, the pharmaceutical composition is characterized by comprising a chemical substance described herein (for example, a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing the same) and one or more pharmaceutically acceptable additives.

[0008] In one embodiment, the method is characterized by a method for modulating (e.g., stimulating) ALPK1 activity, comprising contacting ALPK1 with a chemical substance described herein (e.g., a compound commonly or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing the same). The method is an in vitro method, for example, comprising contacting a sample containing one or more cells containing ALPK (e.g., innate immune cells, e.g., mast cells, macrophages, dendritic cells (DCs), and natural killer cells) with the chemical substance. The contact may, in some cases, induce an immune response sufficient to kill at least one of one or more cancer cells. The method may also be an in vivo method, for example, administering the chemical substance to a subject (e.g., a human) having a disease (e.g., cancer, e.g., refractory cancer) in which suppressed or impaired ALPK signaling contributes to the pathogenesis and / or symptoms and / or progression of the disease.

[0009] In another embodiment, a method for treating an immune and / or inflammation-related disorder comprises administering an effective amount of a chemical substance described herein (e.g., a compound commonly or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof) to a subject in need of treatment. In some embodiments, the immune and / or inflammation-related disorder is inflammatory bowel disease. In some embodiments, the immune and / or inflammation-related disorder is ulcerative colitis. In some embodiments, the immune and / or inflammation-related disorder is Crohn's disease.

[0010] In further embodiments, a method for treating cancer comprises administering an effective amount of a chemical substance described herein (e.g., a compound commonly or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof) to a subject in need of treatment. In some embodiments, the cancer is selected from the group consisting of brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, hepatocellular carcinoma, prostate cancer, colorectal cancer, hematological cancer, lung cancer, and bone cancer. In certain embodiments, the cancer is selected from the group consisting of small cell lung cancer, non-small cell lung cancer, colorectal cancer, melanoma, renal cell carcinoma, head and neck cancer, Hodgkin lymphoma, and bladder cancer.

[0011] In another embodiment, a method for enhancing the efficacy of a vaccine is characterized by administering an effective amount of a chemical substance described herein (e.g., a compound commonly or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof) to a subject in need of treatment. In some embodiments, the vaccine is a cancer vaccine. In some embodiments, the vaccine is a bacterial vaccine. In some embodiments, the vaccine is a viral vaccine. In some embodiments, the vaccine is a parasitic vaccine. In some embodiments, the chemical substance described herein is an adjuvant.

[0012] In a further embodiment, a method for enhancing innate immunity is characterized by administering an effective amount of a chemical substance described herein (for example, a compound commonly or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof) to a subject in need of treatment.

[0013] In another embodiment, a method for inducing an immune response (e.g., an innate immune response) in a subject of need is characterized by administering to the subject an effective amount of a chemical substance described herein (e.g., a compound commonly or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof).

[0014] In a further embodiment, a method for promoting a systemic immune response in a subject in need is characterized by administering to the subject an effective amount of a chemical substance described herein (e.g., a compound commonly or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof).

[0015] In another embodiment, a method for inducing cytokine production and / or NF-κB pathway activation in a subject of need is characterized by administering to the subject an effective amount of a chemical substance described herein (e.g., a compound commonly or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof).

[0016] In a further embodiment, a method for treating a disease in which suppressed or impaired ALPK1 signaling contributes to its pathogenesis and / or symptoms and / or progression, comprising administering an effective amount of a chemical substance described herein (e.g., a compound described generally or specifically herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof) to a subject in need of treatment.

[0017] In another embodiment, the treatment method is characterized by administering an effective amount of a chemical substance described herein (e.g., a compound commonly or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof) to a subject having a disease in which suppressed or impaired ALPK1 signaling contributes to the pathogenesis and / or symptoms and / or progression thereof.

[0018] In a further embodiment, a therapeutic method comprising administering to a subject a chemical substance described herein (for example, a compound commonly or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof), wherein the chemical substance is administered in an effective amount to treat a disease in which inhibited or impaired ALPK1 signaling contributes to the pathogenesis and / or symptoms and / or progression thereof, thereby treating the disease.

[0019] The embodiments may include one or more of the following features:

[0020] The chemicals disclosed herein can be administered in combination with one or more additional therapeutic agents. For example, the chemicals disclosed herein can be administered together with one or more immunotherapeutic agents. One or more immunotherapeutic agents may include small molecules, antibodies and / or cytokines. In some embodiments, the immunotherapeutic agent is an inhibitor / antagonist of an inhibitory (including co-inhibitory) immune checkpoint. In some embodiments, the immunotherapeutic agent is an antagonist of an inhibitory / co-inhibitory immune checkpoint. In some embodiments, the immunotherapeutic agent is an agonist of an stimulating / co-stimulating receptor.

[0021] Non-limiting examples of immune checkpoints include PD-1 and PD-L1. In some embodiments, the immunotherapy agent is a therapeutic monoclonal antibody. In some embodiments, the antibody is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, semiprimab, camrelizumab, tisrelizumab, BMS-936559, atezolizumab, durvalumab, and avelumab. In some embodiments, the antibody is nivolumab or pembrolizumab. In some embodiments, the immune checkpoint is CTLA-4. In some embodiments, the antibody is ipilimumab. In some embodiments, the immune checkpoint is TIGIT. In some embodiments, the antibody is a TIGIT inhibitory antibody.

[0022] In some embodiments, the immunotherapy agent is an activator / agonist of stimulative (including costimulatory) signals to immune cells (e.g., T cells). Stimulative / costimulatory proteins for the combination therapy of the present invention are described herein. In some embodiments, the stimulative protein may be, but is not limited to, 4-1BB or OX40. In some embodiments, the agonist is a therapeutic monoclonal antibody specific to the activation of 4-1BB or OX40.

[0023] The subject may have cancer. For example, the subject may have received and / or is currently receiving and / or is scheduled to receive treatment for one or more types of cancer.

[0024] Non-limiting examples of cancer include melanoma, cervical cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, adenocarcinoma of the colon, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell tumor, Wilms' tumor, or hepatocellular carcinoma. In certain embodiments, the cancer may be refractory cancer.

[0025] Chemical substances can be administered by means of administration including intramuscular, intraperitoneal, or intravenous administration.

[0026] Chemicals can be administered intratumorally.

[0027] The method may further include identifying the subject.

[0028] Other embodiments include those described in the detailed description and / or claims.

[0029] Additional definitions To aid in understanding the disclosures described herein, some additional terms are defined below. In general, the scientific terms used herein and the experimental procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. For example, the scientific terms can be generated using the software ChemDraw. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Any patents, patent applications, published applications, and other publications referenced throughout this specification and its appendices are incorporated herein by reference in their entirety.

[0030] The terms “including,” “equipped with,” “having,” or “containing” mean “including but not limited to,” or “consisting of,” and for example, a composition “including” X may consist exclusively of X, but may also include additional elements such as X + Y. Furthermore, whenever “including” or another open-ended term is used in one embodiment, it should be understood that the same embodiment may be claimed in a narrower scope using the intermediate term “essentially consisting of,” or the closed term “consisting of.” Where used herein, the articles “one” and “one kind” refer to one or more (e.g., at least one) of the objects of the grammatical articles. The term “or” is used herein to mean the term “and / or” and is used interchangeably with that term unless otherwise specifically indicated in context.

[0031] As used herein, the term “ALPK1 agonist” refers to any compound that can activate the kinase activity of ALPK1, thereby increasing and / or stimulating an immune response. ALPK1 kinase activity is measured by a TIFA (TRAF-interacting protein having a forkhead-binding domain) phosphorylation assay as described herein. Non-limiting examples include UDPS-heptose, ADPS-heptose, or CDPS-heptose. In some embodiments, the compound is selected from the group consisting of a compound of formula (X), a compound of formula (Ih), a compound of formula (Ih-1), a compound of formula (Ih-2), a compound of formula (Ih-3), a compound of formula (Ih-4), a compound of formula (Ih-5), a compound of formula (Ik), a compound of formula (Ik-1), a compound of formula (Ik-2), a compound of formula (Ik-3), a compound of formula (Ik-4), or a compound of formula (Ik-5) (hereinafter referred to as “Formulas Disclosed herein”).

[0032] As used herein, “immunotherapy” or “immunomodulator” refers to a small molecule drug, antibody, or other biological molecule. In some embodiments, the modulator is used to inhibit inhibitory immune receptor signaling to T cells and / or other immune cells (such as dendritic cells). In some embodiments, the modulator is used to enhance and / or stimulate costimulatory immune receptor signaling to T cells and / or other immune cells (such as dendritic cells). In some embodiments, biological immune modulators include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In other embodiments, the monoclonal antibody is humanized.

[0033] In the context of treating a disease, disorder, or condition, the term “treatment” means reducing or suppressing one or more symptoms of the disorder, disorder, or condition, or of symptoms associated therewith, or delaying the progression, expansion, or worsening of the disorder, disorder, or condition, or of one or more symptoms thereof. In many cases, the beneficial effects that a subject may obtain from a therapeutic agent do not result in a complete cure of the disease, disorder, or condition. In some embodiments, the term “treatment” includes virologically curing a viral disorder, disease, or condition; reducing viral RNA levels (e.g., measured by PCR); reducing hospital stays; reducing stays in infectious disease units and / or intensive care units; or delaying (including cessation) the progression / onset of respiratory (or other serious) symptoms.

[0034] "Cancer treatment" means one or more of the following effects: (1) some degree of inhibition of tumor growth (including (i) delay and (ii) complete cessation of growth); (2) reduction of tumor cell count; (3) maintenance of tumor size; (4) reduction of tumor size; (5) inhibition of tumor cell infiltration into peripheral organs (including (i) reduction, (ii) delay or (iii) complete prevention); (6) inhibition of metastasis (including (i) reduction, (ii) delay or (iii) complete prevention); (7) enhancement of anti-tumor immune response (which may result in (i) maintenance of tumor size, (ii) reduction of tumor size, (iii) delay of tumor growth, (iv) reduction, delay or prevention of invasion); and / or (8) some degree of alleviation of the severity or number of one or more symptoms associated with the disorder.

[0035] The term "therapeutic dose" refers to the amount of a drug or other pharmaceutical product (e.g., a compound disclosed herein) that elicits a biological and / or medical response in a tissue, system, animal, or human (e.g., a subject or patient) as determined by a researcher or clinician. Furthermore, the term "therapeutic dose" means any amount sufficient to reduce the rate of progression, prevent the onset, or alleviate to some extent one or more symptoms of the condition or disorder being treated, compared to a corresponding subject (e.g., a patient) that has not received the same amount. The therapeutic dose will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated. In addition, the therapeutic dose may be administered in one or more doses, applications, or dosages and is not intended to be limited to a specific dosage form or route of administration.

[0036] Where used herein, the term “subject or patient” as interchangeably used herein refers to animals including, but not limited to, primates (e.g., humans), monkeys, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. In some embodiments, the subject is a human being treated by the methods and compositions of this disclosure. In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of such treatment (e.g., by biopsy, endoscopy, or other conventional methods known in the art). In some embodiments, the chemicals, methods, and compositions described herein can be administered to a particular patient population with treatment resistance (e.g., patients resistant to checkpoint inhibitors; e.g., patients with one or more cold tumors, e.g., tumors lacking T cells or patients with exhausted T cells).

[0037] The term "vaccine" refers to a biological product administered to a human or animal to induce or enhance a specific immune response and / or protection against one or more antigens in the human or animal. In some embodiments, the vaccine is a cancer vaccine against one or more antigens of cancer cells.

[0038] The term "adjuvant" refers to a secondary therapeutic agent administered (sequentially or simultaneously in any order) with a primary therapeutic agent to obtain certain complementary, synergistic, or other beneficial effects that could not be obtained with the primary therapeutic agent alone. Adjuvants can be used with vaccines, chemotherapy, or some other therapeutic agents. Adjuvants can enhance the effectiveness of the primary therapeutic agent, reduce the toxicity or side effects of the primary therapeutic agent, or provide certain protection to the recipient of the primary therapeutic agent (e.g., improved immune system function, but not limited to these).

[0039] As used herein, the term "cancer" refers to a physiological condition in an object characterized by uncontrolled or dysregulated cell proliferation or cell death. The term "cancer" includes solid tumors and hematological tumors, whether malignant or benign.

[0040] As used herein, the term “acceptable” with respect to a dosage form, composition, or ingredient means that it does not have any lasting or adverse effect on the overall health of the subject being treated.

[0041] "API" refers to the active pharmaceutical ingredient.

[0042] The terms “excipient” or “pharmaceutically acceptable excipient” mean a pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of a pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs, without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit-risk ratio. For example, Remington:The Science and Practice of Pharmacy,21st ed.;Lippincott Williams&Wilkins:Philadelphia,PA,2005;Handbook of Pharmaceutical Excipients,6th ed.;Rowe et al.,Eds.;The Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0043] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not inhibit the biological activity and properties of the compound. In certain cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In some cases, pharmaceutically acceptable salts are obtained by reacting the acidic compounds described herein with bases to form salts with ammonium salts, alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as calcium or magnesium salts), salts with organic bases such as dicyclohexylamine, N-methyl-D-glucamine, and tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine and lysine, or by other methods determined to date. Pharmacologically acceptable salts are not particularly limited insofar as they can be used in pharmaceuticals. Examples of salts formed by using the compounds described herein with bases include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, specifically represented by acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0044] The compounds described herein may have one or more chiral centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers (such as cis and trans isomers), or in the form of a mixture of stereoisomers, including a racemic mixture and a mixture rich in one or more stereoisomers. The isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis.

[0045] In addition, prodrugs are also included in the context of this disclosure. As used herein, the term “prodrug” refers to a compound that is converted in vivo into an active form with medical effects, such as by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are listed in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra, “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

[0046] A prodrug is any covalent carrier that, upon administration to a patient, releases the compound of formula (I) in vivo. Prodrugs are typically prepared by modifying a functional group in a manner that allows for cleavage of the modification in vivo to obtain the parent compound, either by conventional procedures or in a manner that allows for cleavage of the modification in vivo. Examples of prodrugs include compounds disclosed herein in which a hydroxyl group, amine group, or sulfhydryl group is bonded to any group that, upon administration to a patient, can be cleaved to form a hydroxyl group, amine group, or sulfhydryl group. Representative examples of prodrugs include, but are not limited to, acetic acid derivatives, formic acid derivatives, and benzoic acid derivatives of the alcohol, mercapto, and amine functional groups of the compound of formula (I). Furthermore, in the case of a carboxylic acid (-COOH), esters such as methyl esters and ethyl esters can be used. The ester itself may be active and / or hydrolyzable under human conditions. Suitable ester groups that are pharmaceutically acceptable and hydrolyzable in vivo include those that readily decompose in the human body to release a hydrophilic acid or a salt thereof.

[0047] All suitable isotopic derivatives of the compounds disclosed herein are also disclosed herein. An isotopic derivative of a compound disclosed herein is defined as one in which at least one atom is substituted with an atom having the same number of atoms but a different atomic mass than that typically found in nature. Examples of isotopes that may be listed as compounds disclosed herein include hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine isotopes, for example, respectively. 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S and 36 Cl is one example. 3 H and 14Certain isotopic derivatives of the compounds disclosed herein, such as radioactive isotopes of C, are also included and are useful in tissue distribution experiments of drugs and substrates. Tritium (i.e.) 3 H) and carbon-14 (i.e.) 14 C) is easier to prepare and detect and is the first choice as an isotope. In addition, deuterium (i.e. 2 Substitution with isotopes such as H) offers advantages in certain therapeutic approaches due to their good metabolic stability, such as increased in vivo half-life or reduced dosage, and may therefore be preferred in some cases. Isotope derivatives of the compounds disclosed herein can be prepared using appropriate isotope derivatives of appropriate reagents by descriptive methods or conventional procedures such as the preparation methods described in the following examples. The term "stable isotope" refers to one that exists stably in nature.

[0048] The term "pharmaceutical composition" refers to a mixture of the compound described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents and / or thickeners (collectively referred to herein as "excipients"). Pharmaceutical compositions facilitate the administration of the compound to a living organism. Several techniques for administering the compound exist in the art, including, but are not limited to, rectal administration, oral administration, intravenous administration, aerosol administration, parenteral administration, ocular administration, pulmonary administration and topical administration.

[0049] The term "halo" refers to fluoro(F), chloro(Cl), bromo(Br), or iodine(I).

[0050] The term "alkyl" refers to a saturated acyclic hydrocarbon radical, which may be linear or branched, containing the indicated number of carbon atoms. For example, C 1-10This indicates that the group may contain 1 to 10 (inclusive) carbon atoms. Alkyl groups may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. As used in this context, the term “saturated” means that only single bonds exist between the constituent carbon atoms, and other available valencies are occupied by hydrogen and / or other substituents as defined herein.

[0051] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted with independently selected halos.

[0052] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0053] The term "alkylene" refers to a divalent alkyl group (e.g., -CH2-).

[0054] The term "alkenyl" refers to an acyclic hydrocarbon chain, which may be straight or branched, having one or more carbon-carbon double bonds. The alkenyl portion contains the number of carbon atoms indicated. For example, C 2-6 This indicates that the group may contain 2 to 6 (inclusive) carbon atoms. The alkenyl group may be unsubstituted or substituted with one or more substituents. The term "alkenyl" also includes acyclic hydrocarbon chains with cumulative dienes, for example, where there are two adjacent carbon-carbon double bonds and one carbon atom is common to both carbon-carbon double bonds.

[0055] The term "alkynyl" refers to an acyclic hydrocarbon chain, which may be a straight or branched chain, having one or more carbon-carbon triple bonds. The alkynyl portion contains the number of carbon atoms indicated. For example, C 2-6 This indicates that the group may contain 2 to 6 (inclusive) carbon atoms. The alkynyl group may be unsubstituted or substituted with one or more substituents.

[0056] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbon atoms in which at least one ring of the system is aromatic (for example, a monocyclic system of 6 carbon atoms, a bicyclic system of 10 carbon atoms, or a tricyclic system of 14 carbon atoms), and in which 0, 1, 2, 3, or 4 atoms of each ring may be substituted with substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and dihydro-1H-indenyl.

[0057] As used herein, the term "cycloalkyl" refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons, 3 to 10 ring carbons, or 3 to 6 ring carbons, and the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl group may contain multiple fused rings and / or crosslinked rings. Non-limiting examples of complex / crosslinked cycloalkyls include bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, and bicyclo[2.2.2]octanyl. Cycloalkyls also include spiro rings (e.g., spironi rings in which two rings are connected by only one atom). Non-exclusive examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, and spiro[5.5]undecanyl. In this context, the term "saturated" means that only single bonds exist between the constituent carbon atoms.

[0058] As used herein, the term "cycloalkenyl" means a partially unsaturated cyclic hydrocarbon group having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons, 3 to 10 ring carbons, or 3 to 6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As a partially unsaturated cyclic hydrocarbon group, the cycloalkenyl group may have any degree of unsaturation, provided that one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group as a whole is not completely saturated. The cycloalkenyl may include multiple fused rings and / or bridging rings and / or spiro rings.

[0059] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, or alternatively 5, 6, 9, 10, or 14 ring atoms, and having 6, 10, or 14 π electrons shared in a cyclic arrangement, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (however, the ring does not have to contain heteroatoms; for example, tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, thiazolyl, benzothienyl, benzooxadiazolyl, benzofuranil, benzimidazolyl, benzotriazolyl, sinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, prinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyro Examples include ro[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanil, 2,3-dihydrobenzo[b][1,4]dioxynyl, benzo[d][1,3]dioxolyl, benzo[d]thiazolyl, 2,3-dihydrobenzofuran, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathinyl, indolinyl, isoindolinyl, and the like. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0060] The term "heterocyclyl" refers to a saturated ring system of monocyclic, bicyclic, tricyclic, or polycyclic forms having 1 to 3 heteroatoms in the case of a monocyclic, 1 to 6 heteroatoms in the case of a bicyclic, or 1 to 9 heteroatoms in the case of a tricyclic or polycyclic form, wherein the heteroatoms are selected from O, N, or S (for example, 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms and carbon atoms in the case of a monocyclic, bicyclic, or tricyclic form, respectively), and having 3 to 16 ring atoms (for example, a 5 to 8-membered monocyclic system, an 8 to 12-membered bicyclic system, or an 11 to 14-membered tricyclic system), wherein 0, 1, 2, or 3 atoms in each ring may be substituted with substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl. Heterocyclyls may also include multiple fused rings and bridging rings. Non-limiting examples of condensed / crosslinked heterocyclyls include 2-azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]pentanyl, 2-azabicyclo[1.1.1]pentanyl, 3-azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[ Examples include 3.2.1]octanyl, 2-oxabicyclo[1.1.0]butanyl, 2-oxabicyclo[2.1.0]pentanyl, 2-oxabicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[4.2.0]octanyl, 2-oxabicyclo[2.2.2]octanyl, and 3-oxabicyclo[3.2.1]octanyl. Heterocyclines also contain spiro rings (for example, spironi rings in which two rings are connected by only one atom).Non-restrictive examples of spirocyclic heterocyclils include 2-azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, 1-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, 1,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, and 2-oxaspiro[2. Examples include pentanyl, 4-oxaspiro[2.5]octanyl, 1-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonanyl, 1,7-dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, 1-oxaspiro[5.5]undenyl, 3-oxaspiro[5.5]undenyl, and 3-oxa-9-azaspiro[5.5]undenyl. As used in this context, the term “saturated” means that only single bonds exist between the constituent ring atoms, and other available valencies are occupied by hydrogen and / or other substituents as defined herein.

[0061] As used herein, the term "heterocycloalkenyl" refers to a partially unsaturated ring system having 3 to 16 ring atoms (e.g., a 5-8 membered monocyclic system, an 8-12 membered bicyclic system, or an 11-14 membered tricyclic system), wherein 0, 1, 2, or 3 atoms in each ring may be substituted with substituents. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazine, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl. As a partially unsaturated cyclic group, the heterocycloalkenyl group may have any degree of unsaturation, provided that one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and the heterocycloalkenyl group as a whole is not completely saturated. The heterocycloalkenyl may contain multiple fused rings and / or bridging rings and / or spiro rings.

[0062] As used herein, when a ring is described as "aromatic," it means that the ring has a continuous delocalized π-electron system. Typically, the out-of-plane π-electron number corresponds to Hückel's rule (4n+2). Examples of such rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, and isothiazole.

[0063] As used herein, when a ring is described as “partially unsaturated,” it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation inherent in the ring itself; for example, one or more double or triple bonds between the constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, and dihydrothiophene.

[0064] To avoid misunderstanding, unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl and similar as described herein) that contain a sufficient number of ring atoms to form a bicyclic or higher-order cyclic system (e.g., tricyclic, polycyclic), such rings and cyclic groups are defined as having condensation points where (i) adjacent ring atoms (e.g., [xx0] ring systems (where 0 represents zero atomic bridges) (e.g., [ka] )); (ii) A single ring atom (spiro-condensed ring system) (for example, [ka] ); or (iii) a continuous ring atom arrangement (a bridging ring system in which all bridging lengths are greater than 0) (for example, [ka] It is understood that this includes those having a fused ring, including those located at ).

[0065] In addition, the atoms constituting the compounds of this embodiment are intended to include all isotopic forms of such atoms. When used herein, isotopes include these atoms that have the same number of atoms but different mass numbers. As a general example, without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 Includes C.

[0066] In addition, the compounds disclosed herein, generally or specifically, are intended to include all tautomer forms. Therefore, as an example, [ka] Compounds containing: [ka] This includes tautomer forms containing [specific compound names]. Similarly, pyridinyl or pyrimidinyl moieties described as being optionally substituted with hydroxyl include pyridone or pyrimidone tautomer forms. As a further non-limiting example, [ka] Compounds containing: [ka] It includes tautomer forms, including those that are not included in the original form.

[0067] Details of one or more embodiments of this disclosure are described below. Other features and advantages of the present invention will become apparent from this description and the claims. [Modes for carrying out the invention]

[0068] This disclosure features chemical substances (e.g., compounds that modulate (e.g., stimulate) ALPK1, or pharmaceutically acceptable salts and / or hydrates and / or cocrystals and / or tautomers and / or stereoisomers and / or stable isotopes and / or prodrugs and / or compound drugs) that are useful for treating conditions, diseases or disorders (e.g., conditions, diseases or disorders associated with suppressed or impaired ALPK1 signaling; e.g., cancer, or e.g., immune and / or inflammation-related diseases (e.g., IBD)) in subjects (e.g., humans) where a decrease or increase (e.g., decrease) of alpha-kinase 1 (ALPK1) activity contributes to its pathogenesis and / or symptoms and / or progression. This disclosure also features compositions and other methods for using and preparing them.

[0069] The chemicals described herein can promote systemic immune responses and / or cytokine production. In addition, these chemicals can function as vaccine adjuvants, with the promotion of ova (ovalbumin)-specific immunoglobulins (IgG).

[0070] Detailed description of the embodiment In one embodiment, this disclosure relates to formula (X): [ka] We provide compounds represented by, or pharmaceutically acceptable salts, stereoisomers, stable isotopes, prodrugs or tautomers thereof, wherein, R X teeth, (A) Equations (X-Ia), (X-Ib), or (X-Ic): [ka] A part having, in the formula, X 1 However, it is selected from the group consisting of C(=O), C-OH, C=S, C-SH, C-NH2, and C(=NH), X 3 , X 5 and X 6 However, N, NH, N(RXn ), CH, CR Xc , C(=O), C(=S), C(=NH), and C(=NR Xn Each of the groups consisting of ) is independently selected, X 4 However, it is either N or C. R X2 However, -H, R Xn Either or R X2 However, the double bond is NR X2 It does not exist when it is present between adjacent ring atoms. each [ka] These are independently single or double bonds, ●However, formulas (X-Ia), (X-Ib), and (X-Ic) each contain 1 to 2 intraring double bonds. ●However, X 4 If it is C, then the double bond is X 4 It exists between the adjacent ring atom, ●However, if formulas (X-Ia), (X-Ib), and (X-Ic) each contain only one intraring double bond, then X 4 is N and / or X 3 , X 5 and X 6 One or more of these are N, NH, N(R Xn ), C(=O), C(=S), C(=NH), and C(=NR Xn Are they independently selected from the group consisting of )? (B) Each has 1 to 3 R Xc The R is optionally substituted with pyridinyl, pirmidinyl, pyrazinyl, pyridazinyl, or triazinyl, provided that R is ortho or para relative to the ring nitrogen of (B). Xc Are all the groups other than -OH, -SH, or NH2? (C) Formula (X-II): [ka] A part having, in the formula, X7 is C or N, X 8 , X 9 , X 10 and X 11 are each independently selected from the group consisting of CH, C(R Xc ), N, N(H), N(R Xn ), O, S, C(=O), C(=S), C(=NH) and C(=NR Xn ), each

Chemical formula

[0071] Variable element R X In some of the embodiments described above, R X (A) [ka] This is the part that has it.

[0072] In some of the embodiments described above, R X teeth, [ka] That is the case.

[0073] In some of the embodiments described above, (R X When (X-Ia) or equation (I-1), X 1 is C (=O) or C-OH. For example, X 1It can be C (=O).

[0074] In some of the embodiments described above, (R X When (X-Ia) or equation (I-1), X 1 is C (=NH) or C-NH2. For example, X 1 It could be C-NH2.

[0075] In some of the embodiments described above, (R X When (X-Ia) or equation (I-1), X 3 C (=O) is the case.

[0076] In some of the embodiments described above, (R X When (X-Ia) or equation (I-1), X 4 It is N.

[0077] In a particular embodiment of formula (I), (R X When (X-Ia) or equation (I-1), X 3 C (=O) and X 4 It is N.

[0078] In some of the embodiments described above, (R X When (X-Ia) or equation (I-1), R X2 is either -H or does not exist. In certain embodiments of formula (I), (R X When (X-Ia) or equation (I-1), X 1 C (=O) and R X2 is -H. In a particular embodiment, X 1 It is C-NH2, and R X2 It does not exist. In these specific embodiments, X 3 C (=O) and X 4 It is N.

[0079] In some of the embodiments described above, (R X When (X-Ia) or equation (I-1), X 5 and X 6 Each is independently CH or CRXc For example, CH or CR c That is the case.

[0080] In some of the embodiments described above, (R X When (X-Ia) or equation (I-1), R X teeth, [ka] It is selected from the group consisting of the following.

[0081] In these specific embodiments, R X teeth, [ka] It is selected from the group consisting of the following.

[0082] In some of the embodiments described above, (R X When (X-Ia) or equation (I-1), R X teeth, [ka] It is selected from the group consisting of the following.

[0083] In these specific embodiments, R X teeth, [ka] It is selected from the group consisting of the following.

[0084] In some of the embodiments described above, R X (B) Each has 1 to 3 R Xc The R is optionally substituted with pyridinyl, pirmidinyl, pyrazinyl, pyridazinyl, or triazinyl, provided that R is ortho or para relative to the ring nitrogen of (B). Xc The groups are all other than -OH, -SH, or NH2.

[0085] In a particular embodiment, R X teeth, [ka] And in the formula, R Xa teeth, ●-OH, -C 1-4 Alkoxy, -C 1-4 Haloalkoxy, -OR b or -O-(C 1-3 Alkylene)-R b ; ●-NR e R f , -NHR b or -NH-(C 1-3 Alkylene)-R b ; ●-C(O)NR'R”, -C(O)NHR b or -C(O)NH-(C 1-3 Alkylene)-R b ; ●-C(O)OC 1-4 alkyl, -C(O)OH, -C(=O)OR b or -C(=O)O-(C 1-3 Alkylene)-R b ; ●-OC(O)C 1-4 Alkyl, -OC(=O)R b or -OC(=O)-(C 1-3 Alkylene)-R b and ●-NHC(=O)R b or -NHC(=O)-(C 1-3 Alkylene)-R b Selected from the group consisting of, X 2B , X 3B , X 5B and X 6B Each of these is independently N, CH, or CR. Xc However, X 2B , X 3B , X 5B and X 6B 1 to 3 of them are CH, X 2B , X 3B , X 5B and X 6B One or two of them are N, Furthermore, however, X 2B and X 6B If one or both of them are N, then R Xa However, it is not -OH or NH2.

[0086] In some of the embodiments described above, R X teeth, [ka] That is the case.

[0087] In these specific embodiments, X 10 CR Xc That is the case.

[0088] In certain embodiments described above, R X teeth, [ka] And in the formula, X 7 is N or C, and X 8 , X 9 and X 11 Each of them is N, N(H), N(R) Xn ), CH, CR Xc Independently selected from the group consisting of O and S, R Xa teeth, ●-OH, -C 1-4 Alkoxy, -C 1-4 Haloalkoxy, -OR b or -O-(C 1-3 Alkylene)-R b ; ●-NR e R f , -NHR b or -NH-(C 1-3 Alkylene)-R b ; ●-C(O)NR'R”, -C(O)NHR b or -C(O)NH-(C 1-3 Alkylene)-R b ; ●-C(O)OH, -C(O)OC 1-4Alkyl, -C(=O)OR b or -C(=O)O-(C 1-3 Alkylene)-R b ; ●-OC(O)C 1-4 Alkyl, -OC(=O)R b or -OC(=O)-(C 1-3 Alkylene)-R b and ●-NHC(=O)R b or -NHC(=O)-(C 1-3 Alkylene)-R b It is selected from the group consisting of the following.

[0089] In a particular embodiment (R X When (X-II), X 7 It is N.

[0090] In a particular embodiment (R X When (X-II), X 11 It is N or CH.

[0091] In a particular other embodiment (R X When (X-II), X 11 CR Xc X 11 This is other than C-NH2.

[0092] R Xa -C(O)NR'R” and -C(O)NHR b and -C(O)NH-(C 1-3 Alkylene)-R b It is selected from the group consisting of the following.

[0093] In certain embodiments described above, R Xa This is C(O)NR'R'', for example R Xa It is -C(O)NH2.

[0094] As a non-restrictive example (R X When (X-II), R X teeth, [ka] You can choose from the group consisting of these.

[0095] In some of the embodiments described above, R X This is 1 to 4 R Xc C is optionally replaced by 6-10 It is aryl. In these particular embodiments, R X This is 1 to 4 R Xc It is a phenyl compound that is substituted with [a specific compound].

[0096] In certain embodiments described above, R X R Xa It is replaced by and further by 1-2 R c It is a phenyl that is optionally substituted with, in the formula, R Xa teeth, ●-OH, -C 1-4 Alkoxy, -C 1-4 Haloalkoxy, -OR b or -O-(C 1-3 Alkylene)-R b ; ●-NR e R f , -NHR b or -NH-(C 1-3 Alkylene)-R b ; ●-C(O)NR'R”, -C(O)NHR b or -C(O)NH-(C 1-3 Alkylene)-R b ; ●-C(O)OH, -C(O)OC 1-4 Alkyl, -C(=O)OR b or -C(=O)O-(C 1-3 Alkylene)-R b ; ●-OC(O)C 1-4 Alkyl, -OC(=O)R b or -OC(=O)-(C 1-3 Alkylene)-R b and ●-NHC(=O)Rb or -NHC(=O)-(C 1-3 Alkylene)-R b It is selected from the group consisting of the following.

[0097] In a particular embodiment of formula (I), R X teeth, [ka] Therefore, m1 is 0, 1, or 2.

[0098] In a particular embodiment of formula (I), R X teeth, [ka] And in the formula, R Xb is -H, C 1-4 Alkyl, R b or -(C 1-3 Alkylene)-R b Therefore, m1 is 0, 1, or 2.

[0099] In a particular embodiment of formula (I), R X teeth, [ka] And in the formula, R Xb is -H, C 1-4 Alkyl, R b or -(C 1-3 Alkylene)-R b Therefore, m1 is 0, 1, or 2.

[0100] In a particular embodiment of formula (I), R X teeth, [ka] And in the formula, R Xb is -H, C 1-4 Alkyl, R b or -(C 1-3 Alkylene)-R bTherefore, m1 is 0, 1, or 2.

[0101] In a particular embodiment of the formula, R X teeth, [ka] And in the formula, R Xb is -H, C 1-4 Alkyl, R b or -(C 1-3 Alkylene)-R b Therefore, m1 is 0, 1, or 2.

[0102] In some of the embodiments described above, R X This is a bicyclic heteroaryl having 8 to 12 ring atoms, where 1 to 5 ring atoms are N, N(H), N(R) Xn ), O and S(O) 0-2 A heteroatom independently selected from the group consisting of, and one or more ring carbon atoms of the heteroaryl are oxo and R Xc Each substituent is arbitrarily substituted with 1 to 4 substituents independently selected from the group consisting of the above.

[0103] In these specific embodiments, R X This is a bicyclic heteroaryl having 9 to 10 (for example, 9) ring atoms, where 1 to 5 ring atoms are N, N(H), N(R) Xn ), O and S(O) 0-2 A heteroatom independently selected from the group consisting of, and one or more ring carbon atoms of the heteroaryl are oxo and R Xc Each substituent is arbitrarily substituted with 1 to 4 substituents independently selected from the group consisting of the above.

[0104] In some of the embodiments described above, R X teeth, [ka] In the formula, ring B is a heteroaryl having 5 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R) Xn ), a heteroatom independently selected from the group consisting of O and S, and ring B is R Xc It is optionally replaced by R Xn2 is -H or R Xn (For example, -H) R Xc2 is -H or R Xc (For example, -H)

[0105] In these specific embodiments, R Xn2 is -H. In certain embodiments described above, R Xc2 is -H.

[0106] In certain embodiments described above, R X teeth, [ka] It is selected from the group consisting of the following.

[0107] For example, R X teeth, [ka] It is possible.

[0108] In some of the embodiments described above, R X teeth, [ka] Selected from the group consisting of, where ring B is a heteroaryl having 5 ring atoms, and 1 to 2 ring atoms are N, N(H), N(R) Xn ), a heteroatom independently selected from the group consisting of O and S, and ring B is R Xc It is being replaced by an arbitrary choice.

[0109] For example, R X teeth, [ka] You can choose from the group consisting of these.

[0110] In some of the embodiments described above, R X teeth, [ka] Selected from the group consisting of, where ring B is a heteroaryl having 5 ring atoms, and 1 to 2 ring atoms are N, N(H), N(R) Xn ), a heteroatom independently selected from the group consisting of O and S, and ring B is R Xc It is being replaced by an arbitrary choice.

[0111] For example, R X teeth, [ka] You can choose from the group consisting of these.

[0112] R X A non-restrictive example of this is: [ka] These are some examples.

[0113] R X In a particular embodiment, R X teeth, [ka] It is selected from the group consisting of the following.

[0114] R X In another specific embodiment, R X teeth, [ka] It is selected from the group consisting of the following.

[0115] R XIn another specific embodiment, R X teeth, [ka] It is selected from the group consisting of the following.

[0116] R X In another specific embodiment, R X teeth, [ka] It is selected from the group consisting of the following.

[0117] R X In another specific embodiment, R X teeth, [ka] It is selected from the group consisting of the following.

[0118] R X In another specific embodiment, R X teeth, [ka] It is selected from the group consisting of the following.

[0119] R X In another specific embodiment, R X teeth, [ka] Selected from the group consisting of, preferably [ka] That is the case.

[0120] R X In another specific embodiment, R X teeth, [ka] It is selected from the group consisting of the following.

[0121] R X In another specific embodiment, R X teeth, [ka] Selected from the group consisting of, preferably [ka] That is the case.

[0122] R X In another specific embodiment, R X teeth, [ka] That is the case.

[0123] R X In another specific embodiment, R X teeth, [ka] That is the case.

[0124] R X In another specific embodiment, R X teeth, [ka] That is the case.

[0125] Variable element R Y In some of the embodiments described above, R Y is -H. In some of the embodiments described above, R Y is -H, -OH, -SH, -halo, cyano, or azide. In some of the embodiments described above, R Y Each of these has 1 to 6 R a C is optionally replaced by 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 It is a haloalkynyl. In some of the embodiments described above, R Y is a halo. In some of the embodiments described above, R Y C 1-6 Alkyl or C 1-6 It is a haloalkyl. In some of the embodiments described above, R Y is C 1-6 It is alkyl.

[0126] Variable element L 1 , L 2 and L 3 In some of the embodiments described above, L 1 It is -O-.

[0127] In some of the embodiments described above, L 3 It is -O-.

[0128] In some of the embodiments described above, L 2 is -O-. In some of the embodiments described above, L 2 is -S-. In some of the embodiments described above, L 2 -NR L1 - is. In some of the embodiments described above, L 2 is -C(R L2 )(R L2 )-is.

[0129] Variable element Y 0 In some of the embodiments described above, Y 0 It is -SH.

[0130] Variable element Y 1 , Y 2 , Y 3 In some of the embodiments described above, Y 1 , Y 2 is O, Y 3 It is -OH.

[0131] Variable element R4a , R 4b , R 5a and R 5b In some of the embodiments described above, R 4a C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls, R 4b teeth, ●-H, -OH, -SH, -halo, cyano, or azido; ● Each has 1 to 6 R a C is optionally replaced by 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Haloalkynyl; ● Each has 1 to 6 R a C is optionally replaced by 1-4 Alkoxy or C 1-4 Thioalkoxy; ●-OR 9 , -NR e R f ; ●-R b Or -(L b ) b -R b ; ●-OP(=O)(OR')(OR”); and ● 1 to 6 R a -OC(=O)(C) is arbitrarily substituted. 1-6 Alkyl) It is selected from the group consisting of the following.

[0132] In some of the embodiments described above, R 4a C contains 1 to 3 double or triple bonds. 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls.

[0133] In some of the embodiments described above, R 4a C containing cumulative double bonds 2-6 Alkenyl and C 2-6 Selected from the group consisting of haloalkenyls.

[0134] In some of the embodiments described above, R 4a C containing a conjugated double bond 2-6 Alkenyl and C 2-6 Selected from the group consisting of haloalkenyls.

[0135] In some of the embodiments described above, R 4a C contains an independent double bond. 2-6 Alkenyl and C 2-6 Selected from the group consisting of haloalkenyls.

[0136] In some of the embodiments described above, R 4a The compound is selected from the group consisting of ethenyl, propenyl, ethinyl, and propynyl.

[0137] In some of the embodiments described above, R 4a It is selected from the group consisting of ethenyl and ethynyl.

[0138] In some of the embodiments described above, R 4b -H, -OH, -OR 9 -OC(=O)R 9 , -NR e R f The group is selected from the group consisting of and -halo.

[0139] In some of the embodiments described above, R 4b -F, -OH, -OR 9 and -NR e R f It is selected from the group consisting of the following.

[0140] In some of the embodiments described above, R 4bThe group is selected from -F, -OH, -OMe, and -NH2.

[0141] In some of the embodiments described above, R 4b The group is selected from -F, -OH, and -OMe.

[0142] In some of the embodiments described above, R 4a C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls, R 4b -H, -OH, -OR 9 -OC(=O)R 9 , -NR e R f The group is selected from the group consisting of and -halo.

[0143] In some of the embodiments described above, R 4a C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls, R 4b -OH, -OR 9 -OC(=O)R 9 , -NR e R f The group is selected from the group consisting of and -halo.

[0144] In some of the embodiments described above, R 4a C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls, R 4b The group consisting of -OH and -halo is selected.

[0145] In some of the embodiments described above, R 4a C 2-6 Alkenil, C 2-6 Haloalkenil, C2-6 Alkinyl and C 2-6 It is a haloalkynyl, and R 4b The group is selected from the group consisting of -OH and -F.

[0146] In some of the embodiments described above, R 4b -NR e R f -and, R 4a and R 5b teeth, ●-H, -OH, -SH, -halo, cyano, or azido; ● Each has 1 to 6 R a C is optionally replaced by 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Haloalkynyl; ● Each has 1 to 6 R a C is optionally replaced by 1-4 Alkoxy or C 1-4 Thioalkoxy; ●-OR 9 , -NR e R f ; ●-R b or -(L b ) b -R b ; ●-OP(=O)(OR')(OR”); and ● 1 to 6 R a -OC(=O)(C) is arbitrarily substituted. 1-6 Alkyl) It is independently selected from the group consisting of [the specified elements].

[0147] In some of the embodiments described above, R 4b -NR e R f -and, R 4a and R 5b teeth, ●-H, -OH, -SH, -halo, cyano, or azido; ● Each has 1 to 6 R a C is optionally replaced by 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Haloalkynyl; ● Each has 1 to 6 R a C is optionally replaced by 1-4 Alkoxy or C 1-4 Thioalkoxy; ●-OR 9 , -NR e R f ; ● 1 to 6 R a -OC(=O)(C) is arbitrarily substituted. 1-6 Alkyl) It is independently selected from the group consisting of [the specified elements].

[0148] In some of the embodiments described above, R 4b -NR e R f And R 4a is -H, -halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls, R 5b teeth, ●-H, -OH, -SH, -halo, cyano, or azido; ● Each has 1 to 6 R a C is optionally replaced by 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Haloalkynyl; ●-OR 9 , -NRe R f It is independently selected from the group consisting of [the specified elements].

[0149] In some of the embodiments described above, R 4b -NR e R f And R 4a is -H, -halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls, R 5b -OH, -OR 9 , -NR e R f The group is selected from the group consisting of and -halo.

[0150] In some of the embodiments described above, R 4b -NR e R f And R 4a is -H, -halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls, R 5b -OH, -OR 9 and -NR e R f It is selected from the group consisting of the following.

[0151] In some of the embodiments described above, R 4b -NR e R f And R 4a is -H or Me, preferably -H, and R 5b The group is selected from -OH, -NH2, -NHMe, -NMe2, and -NHAc.

[0152] In some of the embodiments described above, R5b -NR e R f And R 4b and R 5a teeth, ●-H, -OH, -SH, -halo, cyano, or azide; ● Each has 1 to 6 R a C is optionally replaced by 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Haloalkynyl; ● Each has 1 to 6 R a C is optionally replaced by 1-4 Alkoxy or C 1-4 Thioalkoxy; ●-OR 9 , -NR e R f ; ●-R b or -(L b ) b -R b ; ●-OP(=O)(OR')(OR”); and ● 1 to 6 R a -OC(=O)(C) is arbitrarily substituted. 1-6 Alkyl) It is independently selected from the group consisting of [the specified elements].

[0153] Variable element R 1 , R 2 , R 3 , R 6 and R 7 In a particular embodiment, R 2 H, D, -halo, -OH, -SH, cyano, -OR 9 -OC(=O)R 9 , -NR e R f , -NR e C(=O)R 9 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 9, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR 8 It is selected from the group consisting of the following.

[0154] In another specific embodiment, R 2 H, D, -halo, -OH, -SH, cyano, -OR 9 -OC(=O)R 9 , -NR e R f , -NR e C(=O)R 9 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 9 , C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls.

[0155] In another specific embodiment, R 2 -HALO, -OH, -OR 9 and -OC(=O)R 9 It is selected from the group consisting of the following.

[0156] In another specific embodiment, R 2 -HALO, -OH, or -OC(=O)R 9 It is selected from the group consisting of the following.

[0157] In another specific embodiment, R 2 This is -OH or -OC(=O)R 9 It is selected from the group consisting of the following.

[0158] In another specific embodiment, R 2 is -OH or -OC(=O)C 1-6 Selected from the group consisting of alkyl groups.

[0159] In another specific embodiment, R 2 The group is selected from the group consisting of -F, -OH, or -OAc.

[0160] In another specific embodiment, R 2The group is selected from the group consisting of -OH and -OAc.

[0161] In another specific embodiment, R 2 These are -OH, -HALO, and -NR e R f It is selected from the group consisting of the following.

[0162] In another specific embodiment, R 2 is -OH or NR e R f That is the case.

[0163] In another specific embodiment, R 2 It is -OH.

[0164] In another specific embodiment, R 3 H, D, -halo, -OH, -SH, cyano, -C(=O)OH, -C(=O)O(C 1-4 Alkyl), -C(=O)NR'R'', -OR 10 -OC(=O)R 10 , -NR e R f , -NR e C(=O)R 10 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 10 , C 1-6 Alkyl, C 1-6 Haloalkyl and -OR 8 It is selected from the group consisting of the following.

[0165] In another specific embodiment, R 3 -OH, -SH, -H, -halo, cyano, -C(=O)OH, -C(=O)O(C 1-4 Alkyl), -C(=O)NR'R”, -OP(=O)(OR')(OR”), C 1-4 Alkoxy, C 1-4 Haloalkoxy, -OR 8 and -NR e R f It is selected from the group consisting of the following.

[0166] In another specific embodiment, R3 These include -OH, halo (e.g., -F), -OP(=O)(OR')(OR") (e.g., -OP(=O)(OH)2), C(=O)OH, and NR. e R f (e.g., NH2), -C(=O)NR'R” and -OR 8 (For example -OC(=O)(C 1-4 Selected from the group consisting of alkyl groups.

[0167] In another specific embodiment, R 3 H, D, -halo, -OH, -SH, cyano, -OR 10 -OC(=O)R 10 , -NR e R f , -NR e C(=O)R 10 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 10 , C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls.

[0168] In another specific embodiment, R 3 -OH, -OR 10 Or -OC(=O)R 10 It is selected from the group consisting of the following.

[0169] In another specific embodiment, R 3 is -OH or -OR 8 That is the case.

[0170] In another specific embodiment, R 3 is -OH or -OC(=O)C 1-20 It is alkyl.

[0171] In another specific embodiment, R 3 It is either -OH or -OAc.

[0172] In another specific embodiment, R 3 It is -OH.

[0173] In another specific embodiment, R 1 , R 6 and R 7 are each independently selected from the group consisting of -OH, -SH, -H, halo, cyano, -NR e R f , C 1-4 alkoxy, C 1-4 haloalkoxy, -OP(=O)(OR’)(OR”), and -OR 8 .

[0174] In another specific embodiment, R 1 , R 6 and R 7 are each independently selected from the group consisting of -OH, -OR 9 and -OC(=O)R 9 .

[0175] In another specific embodiment, R 1 , R 6 and R 7 are each, -OH or -OC(=O)R 9 .

[0176] In another specific embodiment, R 1 , R 6 and R 7 are each, -OH or -OC(=O)C 1-6 alkyl.

[0177] In another specific embodiment, R 1 , R 6 and R 7 are each, -OH or -OAc.

[0178] In another specific embodiment, R 1 , R 6 and R 7 is -OH.

[0179] In an embodiment, the compounds disclosed herein are the compounds described in the examples of this application, such as those in Table 1.

[0180] The compounds of this disclosure can be prepared using the general processes and techniques described in the exemplary embodiments described in Schemes 1 to 11.

[0181] In embodiments, this disclosure provides pharmaceutical compositions comprising compounds described herein and pharmaceutically acceptable carriers.

[0182] In more detailed embodiments, this disclosure relates to the following technical solutions.

[0183] 1.Formula (X): [ka] A compound represented by, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug or tautomer thereof, wherein the formula, R X teeth, (A) Equations (X-Ia), (X-Ib), or (X-Ic): [ka] A part having, in the formula, X 1 However, it is selected from the group consisting of C(=O), C-OH, C=S, C-SH, C-NH2, and C(=NH), X 3 , X 5 and X 6 However, N, NH, N(R Xn ), CH, CR Xc , C(=O), C(=S), C(=NH), and C(=NR Xn Each of the groups consisting of ) is independently selected, X 4 However, it is either N or C. R X2 However, -H, R Xn Either or R X2 However, the double bond is NR X2 It does not exist when it is present between adjacent ring atoms. each [ka] These are independently single or double bonds, ●However, formulas (X-Ia), (X-Ib), and (X-Ic) each contain 1 to 2 intraring double bonds. ●However, X 4 If it is C, then the double bond is X 4 It exists between the adjacent ring atom, ●However, if formulas (X-Ia), (X-Ib), and (X-Ic) each contain only one intraring double bond, then X 4 is N and / or X 3 , X 5 and X 6 One or more of these are N, NH, N(R Xn ), C(=O), C(=S), C(=NH), and C(=NR Xn Are they independently selected from the group consisting of )? (B) Each has 1 to 3 R Xc The R is optionally substituted with pyridinyl, pirmidinyl, pyrazinyl, pyridazinyl, or triazinyl, provided that R is ortho or para relative to the ring nitrogen of (B). Xc Are all the groups other than -OH, -SH, or NH2? (C) Formula (X-II): [ka] A part having, in the formula, X 7 However, it is either C or N, X 8 , X 9 , X 10 and X 11 However, CH, C(R Xc ), N, N(H), N(R Xn ), O, S, C(=O), C(=S), C(=NH), and C(=NR Xn Each of the groups consisting of ) is independently selected, each [ka] is independently a single bond or a double bond, provided that However, one to four of X 7 ~X 11 are independently selected from the group consisting of C, CH, C(R Xc ), C(=O), C(=S), C(=NH) and C(=NR Xn ), and (X-II) is aromatic, or (D) is a C Xc aryl optionally substituted with 1 to 4 R 6-10 s, or (E) is a bicyclic heteroaryl having 8 to 12 ring atoms, wherein 1 to 5 ring atoms are heteroatoms independently selected from the group consisting of N, N(H), N(R Xn ), O and S(=O) 0-2 ), and one or more ring carbon atoms of the heteroaryl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo and R Xc s, each R Xc is independently selected from the group consisting of R c , R b and -(L b ) b -R b , each R Xn is independently selected from the group consisting of R d , R b and -(L b ) b -R b , R Y , R 4a , R 4b , R 5a and R 5b are ● -H, -OH, -SH, -halo, cyano or azide; ● C a alkyl, C 1-6 haloalkyl, C 1-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl or C 2-6 each optionally substituted with 1 to 6 R 2-6Haloalkynyl; ● Each has 1 to 6 R a C is optionally replaced by 1-4 Alkoxy or C 1-4 Thioalkoxy; ●-OR 9 , -NR e R f ; ●-R b or -(L b ) b -R b ; ●-OP(=O)(OR')(OR”); and ● 1 to 6 R a -OC(=O)(C) is arbitrarily substituted. 1-6 Alkyl) They are independently selected from the group consisting of, or L 1 , L 2 , L 3 And A is -O-, -S-, -NR L1 - and -C(R L2 )(R L2 Each of the groups consisting of )- is independently selected, Y 1 and Y 2 These are independently selected from the groups consisting of O and S, Y 0 and Y 3 -OH, -OR 9 -SH and -SR 9 Each is independently selected from the group consisting of, R 1 , R 2 , R 6 and R 7 H, D, -halo, -OH, -SH, cyano, -OR 9 -OC(=O)R 9 , -NR e R f , -NR e C(=O)R 9 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 9 , C 1-6 Alkyl, C 1-6Haloalkyl and -OR 8 Each is independently selected from the group consisting of, R 3 H, D, -halo, -OH, -SH, cyano, -C(=O)OH, -C(=O)O(C 1-4 Alkyl), -C(=O)NR'R'', -OR 10 -OC(=O)R 10 , -NR e R f , -NR e C(=O)R 10 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 10 , C 1-6 Alkyl, C 1-6 Haloalkyl and -OR 8 Selected from the group consisting of, R 3a -OH, -SH, -H, -halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(=O)OH, -C(=O)O(C 1-4 Alkyl), -C(=O)NR'R”, -OP(=O)(OR')(OR”), C 1-4 Alkoxy, C 1-4 Haloalkoxy, -OR 8 and -NR e R f Selected from the group consisting of, Each R 8 teeth, ●R a , R b and -(L b ) b -R b -C(=O)C is arbitrarily substituted with 1 to 10 substituents independently selected from the group consisting of the above. 1-20 alkyl; ●-C(=O)-(R b2 ) m1 -R 8b (In the formula, each R b2 Independently, divalent R b The base is such that m1 is an integer from 1 to 6, and R 8b -H or R c It is; ● [ka] (In the formula, ○m2 is an integer between 1 and 10. ○Each R 8c -H; 1 to 4 R a C is optionally replaced by 1-6 alkyl;-R b ; and -(C 1-6 Alkylene)-R b Independently selected from the group consisting of, ○R 8d These are -H, -OH, and -C 1ー4 Alkoxy and NR e R f Selected from the group consisting of, ○R 8e is -H, C 1-4 Alkyl, C(=O)C 1-4 Alkyl and C(=O)OC 1-4 (Selected from the group consisting of alkyl groups) Independently selected from the group consisting of, Each R 9 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl, C 2-6 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls or 5-10 membered heteroaryls, Each R 10 C 1-20 Alkyl, C 1-20 Haloalkyl, C 2-20 Alkenil, C 2-20 Haloalkenil, C 2-20 Alkinyl, C 2-20 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls or 5-10 membered heteroaryls, Each R L1is -H;NR'R”, -OH, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Independently selected from the group consisting of haloalkynyl and -C(=O)R', Each R L2 -H;-Hallo;-OH;-OR 9 ;NR'R”, -OH, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Independently selected from the group consisting of haloalkynyl and -C(=O)R', Each R a -H, -OH, -halo, -NR e R f , C 1-4 Alkoxy, C 1ー4 Haloalkoxy, -C(=O)O(C 1-4 Alkyl), -C(=O)(C 1-4 Alkyl), -C(=O)OH, -C(=O)NR'R'', -S(=O) 1-2 NR'R”, -S(=O) 1-2 (C 1-4 Independently selected from the group consisting of alkyl and cyano, Each R b teeth, ● Each has 1 to 4 R c C is optionally replaced by 3-10 Cycloalkyl or C 3-10 Cycloalkenyl; ● A heterocyclyl or heterocycloalkenyl having 3 to 10 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R) d ), O and S (=O) 0-2 Each heteroatom is independently selected from the group consisting of the following, and the heterocyclyl or heterocycloalkenyl has 1 to 4 R c A heterocyclyl or heterocycloalkenyl with 3 to 10 ring atoms optionally substituted; ●A heteroaryl with 5 to 10 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R) d ), O and S (=O) 0-2 These are heteroatoms independently selected from the group consisting of, and the heteroaryl has 1 to 4 R c Heteroaryl ring atoms of 5 to 10 atoms that are optionally substituted; ● 1 to 4 R c C is optionally replaced by 6-10 Ariel Independently selected from the group consisting of, Each L b -O-, -NH-, -NR d -S(=O) 0-2 , C (=O) and 1 to 3 R a C is optionally replaced by 1-3 Independently selected from the group consisting of alkylenes, Each b is independently 1, 2, 3, or 4. Each R c This includes halo; cyano; and 1 to 6 independently selected Rs. a C is optionally replaced by 1-10 Alkyl; C 2-6 Alkenil; C 2-6 Alkinyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -S (=O) 1-2 (C 1-4 Alkyl);-NR e R f ;-OH;-SH;-S(=O) 1-2 NR'R”;-C 1-4 Thiokoxy;-NO2;-OC(=O)(C1-4 Alkyl);-OC(=O)H;-C(=O)(C 1-4 Alkyl);-C(=O)H;-C(=O)O(C 1-4 Independently selected from the group consisting of alkyl);-C(=O)OH; and-C(=O)NR'R'', Each R d These are 1 to 3 independently selected R a C is optionally replaced by 1-6 Alkyl;-C(=O)(C 1-4 Alkyl);-C(=O)O(C 1-4 Alkyl);-C(=O)NR'R”;-S(=O) 1-2 NR'R”;-S(=O) 1-2 (C 1-4 Alkyl;-OH;and C 1-4 Independently selected from the group consisting of alkoxys, R e and R f Each of these is -H;NR'R”, -OH, Haro, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl or C 1-6 Haloalkyl;-C(=O)R';-C(=O)OR';-C(=O)NR'R”;C(=NR”)NR'R”;-C(=O)C(=O)R';-S(=O) 1-2 NR'R”;-S(=O) 1-2 R';-OH;and C 1-4 Independently selected from the group consisting of alkoxys, or R e and R f Together with the N atoms connecting them, they form saturated or unsaturated 3-7 member heterocyclines. R' and R'' are each -H; halo, cyano, C 1-4 Alkoxy, C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and -OH. 1-4 Alkyl or C 1-4 It is independently selected from the group consisting of haloalkyls, however, a)R 4a However, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selection from the group consisting of haloalkynyls, b)R 4b NR e R f Being A compound, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug, or tautomer thereof, for which at least one of the following is true.

[0184] 2.R X This is a bicyclic heteroaryl having 8 to 12 ring atoms, where 1 to 5 ring atoms are N, N(H), N(R) Xn ), O and S (=O) 0-2 Each heteroatom is independently selected from the group consisting of the following, and one or more ring carbon atoms of the heteroaryl are oxo and R Xc The compound according to technical solution 1, which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of the above.

[0185] 3.R X This is a bicyclic heteroaryl having 9 to 10 (for example, 9) ring atoms, where 1 to 5 ring atoms are N, N(H), N(R) Xn ), O and S (=O) 0-2 Each heteroatom is independently selected from the group consisting of the following, and one or more ring carbon atoms of the heteroaryl are oxo and R Xc The compound according to any one of technical solutions 1 to 2, which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of the above.

[0186] 4.R X teeth, [ka] In the formula, ring B is a heteroaryl having 5 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R) Xn ), a heteroatom independently selected from the group consisting of O and S, and ring B is R Xc It is optionally replaced in R Xn2 is -H or R Xn (For example, -H) and R Xc2 is -H or R Xc A compound described in any one of technical solutions 1 to 3, which is (for example, -H).

[0187] 5.R Xn2 is -H, preferably R Xc2 A compound described in any one of technical solutions 1 to 4, wherein -H is present.

[0188] 6.R X teeth, [ka] Preferably [ka] A compound selected from the group consisting of, one of the technical solutions 1 to 5.

[0189] 7.R Y The compound is H, as described in any one of technical solutions 1 to 6.

[0190] 8.L 1 The compound is -O- as described in any one of technical solutions 1 to 7.

[0191] 9.L 2 The compound is -O-, as described in any one of technical solutions 1 to 8.

[0192] 10.L 3 The compound is -O-, as described in any one of technical solutions 1 to 9.

[0193] 11.Y 0The compound is -SH, as described in any one of technical solutions 1 to 10.

[0194] 12.R 1 These are -OH, -HALO (e.g., -F), -OP (=O) (OR') (OR") and -OR 8 Selected from the group consisting of -OR, preferably -OR 8 The compound described in any one of the technical solutions 1 to 11.

[0195] 13.R 1 The compound is -OH as described in any one of the technical solutions 1 to 12.

[0196] 14.R 6 and R 7 These are -OH, -SH, -halo (e.g., -F), and -NR. e R f (e.g., NH2), -OP(=O)(OR')(OR”) and -OR 8 Independently selected from the group consisting of, preferably -OR 8 The compound described in any one of the technical solutions 1 to 13.

[0197] 15.R 6 and R 7 The compounds described in any one of technical solutions 1 to 14, wherein each of the groups is -OH.

[0198] 16.R 2 -OH, -HALO (e.g., -F), -OP (=O)(OR')(OR”), -OR 8 or NR e R f And preferably -OR 8 The compound described in any one of technical solutions 1 to 15.

[0199] 17.R 2 The compound is -OH, as described in any one of the technical solutions 1 to 16.

[0200] 18.R 2The carbon atom to which it is bonded has a (S) stereochemical configuration, as described in any one of technical solutions 1 to 17.

[0201] 19.R 3 These include -OH, halo (e.g., -F), -OP(=O)(OR')(OR") (e.g., -OP(=O)(OH)2), C(=O)OH, and NR. e R f (e.g., NH2), -C(=O)NR'R” and -OR 8 (For example -OC(=O)(C 1-4 A compound selected from the group consisting of alkyl compounds, as described in any one of technical solutions 1 to 18.

[0202] 20.R 3 is -OH or -OR 8 And preferably -OR 8 The compound described in any one of the technical solutions 1 to 19.

[0203] 21.R 3 The compound is -OH, as described in any one of the technical solutions 1 to 20.

[0204] twenty two. [ka] teeth, [ka] A compound selected from the group consisting of, one of the technical solutions 1 to 21.

[0205] 23.Y 1 and Y 2 The compound is O, as described in any one of the technical solutions 1 to 22.

[0206] 24.Y 3 The compound is -OH, as described in any one of the technical solutions 1 to 23.

[0207] 25.R 4a C2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls, R 4b -OH, -OR 9 A compound selected from the group consisting of and -halo, as described in any one of technical solutions 1 to 24.

[0208] 26. [ka] teeth, [ka] [ka] [ka] [ka] [ka] A compound described in any one of technical solutions 1 to 25, selected from the group consisting of the following.

[0209] 27. [ka] teeth, [ka] A compound selected from the group consisting of any one of the technical solutions 1 to 26.

[0210] 28.Formula (Ih), (Ih-1), (Ih-2), (Ih-3), (Ih-4) or (Ih-5): [ka] [ka] [ka] [ka] [ka] [ka] A compound represented by, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug or tautomer thereof, wherein the formula, R X teeth, (A) Equations (X-Ia), (X-Ib), or (X-Ic): [ka] A part having, in the formula, X 1 However, it is selected from the group consisting of C(=O), C-OH, C=S, C-SH, C-NH2, and C(=NH), X 3 , X 5 and X 6 However, N, NH, N(R Xn ), CH, CR Xc , C(=O), C(=S), C(=NH), and C(=NR Xn Each of the groups consisting of ) is independently selected, X 4 However, it is either N or C. R X2 However, -H, R Xn Either or R X2 However, the double bond is NR X2 It does not exist when it is present between adjacent ring atoms. each [ka] These are independently single or double bonds, ●However, formulas (X-Ia), (X-Ib), and (X-Ic) each contain 1 to 2 intraring double bonds. ●However, X 4 If it is C, then the double bond is X 4 It exists between the adjacent ring atom, ●However, if formulas (X-Ia), (X-Ib), and (X-Ic) each contain only one intraring double bond, then X 4 is N and / or X 3 , X 5 and X 6 One or more of these are N, NH, N(R Xn ), C(=O), C(=S), C(=NH), and C(=NR Xn Are they independently selected from the group consisting of )? (B) Each has 1 to 3 R Xc The R is optionally substituted with pyridinyl, pirmidinyl, pyrazinyl, pyridazinyl, or triazinyl, provided that R is ortho or para relative to the ring nitrogen of (B). Xc Are all the groups other than -OH, -SH, or NH2? (C) Formula (X-II): [ka] A part having, in the formula, X 7 However, it is either C or N, X 8 , X 9 , X 10 and X 11 However, CH, C(R Xc ), N, N(H), N(R Xn ), O, S, C(=O), C(=S), C(=NH), and C(=NR Xn Each of the groups consisting of ) is independently selected, each [ka] These are independently single or double bonds, However, X 7 ~X 111 to 4 of these are C, CH, C(R) Xc ), C(=O), C(=S), C(=NH), and C(=NR Xn Independently selected from the group consisting of ), (X-II) is aromatic or (D) 1 to 4 R Xc C is optionally replaced by 6-10 Is it an aryl, or (E) A bicyclic heteroaryl having 8 to 12 ring atoms, wherein 1 to 5 ring atoms are N, N(H), N(R) Xn ), O and S (=O) 0-2 A heteroatom independently selected from the group consisting of, and one or more ring carbon atoms of the heteroaryl are oxo and R Xc Each of these is optionally substituted with 1 to 4 substituents independently selected from the group consisting of the following: Each R Xc R c , R b and -(L b ) b -R b Independently selected from the group consisting of, Each R Xn R d , R b and -(L b ) b -R b Independently selected from the group consisting of, R 4a C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls, R 4b and R 5b teeth, ●-H, -OH, -SH, -halo, cyano, or azide; ● Each has 1 to 6 R a C is optionally replaced by 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6Alkinyl or C 2-6 Haloalkynyl; ● Each has 1 to 6 R a C is optionally replaced by 1-4 Alkoxy or C 1-4 Thioalkoxy; ●-OR 9 , -NR e R f ; ●-R b or -(L b ) b -R b ; ●-OP(=O)(OR')(OR”); and ● 1 to 6 R a -OC(=O)(C) is arbitrarily substituted. 1-6 Alkyl) They are independently selected from the group consisting of, or L 2 -O-, -S-, -NR L1 - and -C(R L2 )(R L2 Selected from the group consisting of )-, Y 0 It is selected from the group consisting of -OH and -SH, R 3 H, D, -halo, -OH, -SH, cyano, -OR 10 -OC(=O)R 10 , -NR e R f , -NR e C(=O)R 10 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 10 , C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R 1 , R 2 , R 6 and R 7 H, D, -halo, -OH, -SH, cyano, -OR 9 -OC(=O)R 9 , -NR e R f , -NR eC(=O)R 9 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 9 , C 1-6 Alkyl and C 1-6 Each is independently selected from the group consisting of haloalkyls, Each R 9 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl, C 2-6 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, Each R 10 C 1-20 Alkyl, C 1-20 Haloalkyl, C 2-20 Alkenil, C 2-20 Haloalkenil, C 2-20 Alkinyl, C 2-20 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, Each R L1 is -H;NR'R”, -OH, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Independently selected from the group consisting of haloalkynyl and -C(=O)R', Each R L2 -H;-Hallo;-OH;-OR 9 ;NR'R”, -OH, C 1-4 Alkoxy and C 1-4C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Independently selected from the group consisting of haloalkynyl and -C(=O)R', Each R a -H, -OH, -halo, -NR e R f , C 1-4 Alkoxy, C 1ー4 Haloalkoxy, -C(=O)O(C 1-4 Alkyl), -C(=O)(C 1-4 Alkyl), -C(=O)OH, -C(=O)NR'R'', -S(=O) 1-2 NR'R”, -S(=O) 1-2 (C 1-4 Independently selected from the group consisting of alkyl and cyano, Each R b teeth, ● Each has 1 to 4 R c C is optionally replaced by 3-10 Cycloalkyl or C 3-10 Cycloalkenyl; ● A heterocyclyl or heterocycloalkenyl having 3 to 10 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R) d ), O and S (=O) 0-2 Each heteroatom is independently selected from the group consisting of the following, and the heterocyclyl or heterocycloalkenyl has 1 to 4 R c A heterocyclyl or heterocycloalkenyl with 3 to 10 ring atoms optionally substituted; ●A heteroaryl with 5 to 10 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R) d ), O and S (=O) 0-2 These are heteroatoms independently selected from the group consisting of the following, and a heteroaryl is composed of 1 to 4 R cHeteroaryl ring atoms of 5 to 10 atoms that are optionally substituted; ● 1 to 4 R c C is optionally replaced by 6-10 Ariel Independently selected from the group consisting of, Each L b -O-, -NH-, -NR d -S(=O) 0-2 , C (=O) and 1 to 3 R a C is optionally replaced by 1-3 Independently selected from the group consisting of alkylenes, Each b is independently 1, 2, 3, or 4. Each R c This includes halo; cyano; and 1 to 6 independently selected Rs. a C is optionally replaced by 1-10 Alkyl; C 2-6 Alkenil; C 2-6 Alkinyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -S (=O) 1-2 (C 1-4 Alkyl);-NR e R f ;-OH;-SH;-S(=O) 1-2 NR'R”;-C 1-4 Thiokoxy;-NO2;-OC(=O)(C 1-4 Alkyl);-OC(=O)H;-C(=O)(C 1-4 Alkyl);-C(=O)H;-C(=O)O(C 1-4 Independently selected from the group consisting of alkyl);-C(=O)OH; and-C(=O)NR'R'', Each R d These are 1 to 3 independently selected R a C is optionally replaced by 1-6 Alkyl;-C(=O)(C 1-4 Alkyl);-C(=O)O(C 1-4 Alkyl);-C(=O)NR'R”;-S(=O) 1-2 NR'R”;-S(=O) 1-2 (C 1-4 Alkyl;-OH;and C1-4 Independently selected from the group consisting of alkoxys, R e and R f Each of these is -H;NR'R”, -OH, Haro, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl or C 1-6 Haloalkyl;-C(=O)R';-C(=O)OR';-C(=O)NR'R”;C(=NR”)NR'R”;-C(=O)C(=O)R';-S(=O) 1-2 NR'R”;-S(=O) 1-2 R';-OH;and C 1-4 Independently selected from the group consisting of alkoxys, R' and R'' are each -H; halo, cyano, C 1-4 Alkoxy, C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and -OH. 1-4 Alkyl or C 1-4 Compounds independently selected from the group consisting of haloalkyls, or pharmaceutically acceptable salts, stereoisomers, stable isotopes, prodrugs, or tautomers thereof.

[0211] 29.R X teeth, [ka] Preferably [ka] Preferably [ka] Preferably [ka] Preferably [ka] Preferably [ka] Preferably [ka] Preferably [ka] Preferably [ka] Preferably [ka] Selected from the group consisting of, R 4a C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 A group consisting of haloalkynyls, preferably containing 1 to 3 double or triple bonds. 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 A group consisting of haloalkynyls, preferably containing a cumulative double bond. 2-6 Alkenyl and C 2-6 A group consisting of haloalkenyls, preferably containing a conjugated double bond. 2-6 Alkenyl and C 2-6 A group consisting of haloalkenyls, preferably containing an independent double bond. 2-6 Alkenyl and C 2-6 A group consisting of haloalkenyls, preferably a group consisting of ethenyl, propenyl, ethinyl, and propynyl, preferably a group consisting of ethenyl and ethinyl, is selected from the group consisting of haloalkenyls. R 4b -H, -OH, -OR 9 -OC(=O)R 9 , -NR e R f A group consisting of -halo, preferably -F, -OH, -OR9 and -NR e R f A group consisting of -F, -OH, -OMe and -NH2, preferably selected from the group consisting of -F, -OH and -OMe, R 5b teeth, ●-H, -OH, -SH, -halo, cyano, or azide; ● Each has 1 to 6 R a C is optionally replaced by 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Haloalkynyl; ● Each has 1 to 6 R a C is optionally replaced by 1-4 Alkoxy or C 1-4 Thioalkoxy; ●-OR 9 , -NR e R f ; ● 1 to 6 R a -OC(=O)(C) is arbitrarily substituted. 1-6 Alkyl) Independently selected from the group consisting of, Preferably, R 5b is -OH, L 2 -O-, -S-, -NR L1 - and -C(R L2 )(R L2 Selected from the group consisting of )-, preferably -O-, Y 0 It is selected from the group consisting of -OH and -SH, and is preferably -SH. R 3 H, D, -halo, -OH, -SH, cyano, -OR 10 -OC(=O)R 10 , -NR e R f , -NR e C(=O)R 10, -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 10 , C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R 1 , R 2 , R 6 and R 7 H, D, -halo, -OH, -SH, cyano, -OR 9 -OC(=O)R 9 , -NR e R f , -NR e C(=O)R 9 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 9 , C 1-6 Alkyl and C 1-6 Each is independently selected from the group consisting of haloalkyls, Preferably, R 2 -HALO, -OH, or -OC(=O)R 9 Preferably, -OH or -OC(=O)R 9 Preferably -OH or -OC(=O)C 1-6 It is alkyl, preferably -OH, Preferably, R 3 -OH, -OR 10 and -OC(=O)R 10 Selected from the group consisting of -OH or -OC(=O)C 1-20 It is alkyl, preferably -OH, Preferably, R 1 , R 6 and R 7 These are independently -OH or -OC(=O)R 9 Preferably -OH or -OC(=O)C 1-6 It is alkyl, preferably -OH, Each R 9 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6Alkinyl, C 2-6 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls or 5-10 membered heteroaryls, Each R 10 C 1-20 Alkyl, C 1-20 Haloalkyl, C 2-20 Alkenil, C 2-20 Haloalkenil, C 2-20 Alkinyl, C 2-20 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls or 5-10 membered heteroaryls, Each R L1 is -H;NR'R”, -OH, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Independently selected from the group consisting of haloalkynyl and -C(=O)R', Each R L2 -H;-Hallo;-OH;-OR 9 ;NR'R”, -OH, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Independently selected from the group consisting of haloalkynyl and -C(=O)R', Each R a -H, -OH, -halo, -NR e Rf , C 1-4 Alkoxy, C 1ー4 Haloalkoxy, -C(=O)O(C 1-4 Alkyl), -C(=O)(C 1-4 Alkyl), -C(=O)OH, -C(=O)NR'R'', -S(=O) 1-2 NR'R”, -S(=O) 1-2 (C 1-4 Independently selected from the group consisting of alkyl and cyano, R e and R f Each of these is -H;NR'R”, -OH, Haro, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl or C 1-6 Haloalkyl;-C(=O)R';-C(=O)OR';-C(=O)NR'R”;C(=NR”)NR'R”;-C(=O)C(=O)R';-S(=O) 1-2 NR'R”;-S(=O) 1-2 R';-OH;and C 1-4 Independently selected from the group consisting of alkoxys, R' and R'' are each -H; halo, cyano, C 1-4 Alkoxy, C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and -OH. 1-4 Alkyl or C 1-4 A compound independently selected from the group consisting of haloalkyls, as described in technical solution 28.

[0212] 30.R X This is as defined in technical solution 29, R 4a C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 A group consisting of haloalkynyls, preferably containing 1 to 3 double or triple bonds. 2-6 Alkenil, C 2-6Haloalkenil, C 2-6 Alkinyl and C 2-6 A group consisting of haloalkynyls, preferably containing a cumulative double bond. 2-6 Alkenyl and C 2-6 A group consisting of haloalkenyls, preferably containing a conjugated double bond. 2-6 Alkenyl and C 2-6 A group consisting of haloalkenyls, preferably containing an independent double bond. 2-6 Alkenyl and C 2-6 A group consisting of haloalkenyls, preferably a group consisting of ethenyl, propenyl, ethinyl, and propynyl, preferably a group consisting of ethenyl and ethinyl, is selected from the group consisting of haloalkenyls. R 4b -H, -OH, -OR 9 -OC(=O)R 9 , -NR e R f A group consisting of -halo, preferably -F, -OH, -OR 9 and -NR e R f A group consisting of -F, -OH, -OMe and -NH2, preferably selected from the group consisting of -F, -OH and -OMe, R 5b teeth, ●-H, -OH, -SH, -halo, cyano, or azide; ● Each has 1 to 6 R a C is optionally replaced by 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Haloalkynyl; ●-OR 9 , -NR e R f Independently selected from the group consisting of, Preferably, R 5b is -OH, L 2 -O-, -S-, -NH-, -N(C 1-3Alkyl)-, -CH2-, -CF2-, -CHF-, -CH(C 1-3 Alkyl)- and -C(C 1-3 Selected from the group consisting of alkyl)OH-, preferably -O-, Y 0 It is selected from the group consisting of -OH and -SH, and is preferably -SH. R 2 -HALO, -OH, -OR 9 and -OC(=O)R 9 Selected from the group consisting of -halo, -OH, or -OC(=O)R 9 Preferably, -OH or -OC(=O)R 9 Preferably -OH or -OC(=O)C 1-6 It is alkyl, preferably -OH, R 3 -OH, -OR 10 and -OC(=O)R 10 Selected from the group consisting of -OH or -OC(=O)C 1-20 It is alkyl, preferably -OH, R 1 , R 6 and R 7 -OH, -OR 9 and -OC(=O)R 9 Each of the following is independently selected from the group consisting of, preferably -OH or -OC(=O)C 1-6 It is alkyl, preferably -OH, Each R 9 C 1-6 Alkyl and C 1-6 Independently selected from the group consisting of haloalkyls, Each R 10 C 1-20 Alkyl, C 1-20 Haloalkyl, C 2-20 Alkenil, C 2-20 Haloalkenil, C 2-20 Alkinyl, C 2-20 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, Each R a -H, -OH, -halo, -NR e R f , C 1-4 Alkoxy, C 1ー4 Haloalkoxy, -C(=O)O(C 1-4 Alkyl), -C(=O)(C 1-4 Alkyl), -C(=O)OH, -C(=O)NR'R'', -S(=O) 1-2 NR'R”, -S(=O) 1-2 (C 1-4 Independently selected from the group consisting of alkyl and cyano, R e and R f Each of these is -H;NR'R”, -OH, Haro, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl or C 1-6 Haloalkyl;-C(=O)R';-C(=O)OR';-C(=O)NR'R”;C(=NR”)NR'R”;-C(=O)C(=O)R';-S(=O) 1-2 NR'R”;-S(=O) 1-2 R';-OH;and C 1-4 Independently selected from the group consisting of alkoxys, R' and R'' are each -H; halo, cyano, C 1-4 Alkoxy, C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and -OH. 1-4 Alkyl or C 1-4 A compound independently selected from the group consisting of haloalkyls, as described in technical solution 28.

[0213] 31.R X This is as defined in technical solution 29, R 4a C 2-6 Alkenil, C 2-6 Haloalkenil, C2-6 Alkinyl and C 2-6 A group consisting of haloalkynyls, preferably containing 1 to 3 double or triple bonds. 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 A group consisting of haloalkynyls, preferably containing a cumulative double bond. 2-6 Alkenyl and C 2-6 A group consisting of haloalkenyls, preferably containing a conjugated double bond. 2-6 Alkenyl and C 2-6 A group consisting of haloalkenyls, preferably containing an independent double bond. 2-6 Alkenyl and C 2-6 A group consisting of haloalkenyls, preferably a group consisting of ethenyl, propenyl, ethinyl, and propynyl, preferably a group consisting of ethenyl and ethinyl, is selected from the group consisting of haloalkenyls. R 4b -OH, -OR 9 -OC(=O)R 9 , -NR e R f Selected from the group consisting of and -halo, R 5b -OH, -OR 9 , -NR e R f Selected from the group consisting of and -halo, L 2 is -O-, Y 0 It is selected from the group consisting of -OH and -SH, R 3 H, D, -halo, -OH, -SH, cyano, -OR 10 -OC(=O)R 10 , -NR e R f , -NR e C(=O)R 10 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 10 , C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R 1 , R2 , R 6 and R 7 H, D, -halo, -OH, -SH, cyano, -OR 9 -OC(=O)R 9 , -NR e R f , -NR e C(=O)R 9 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 9 , C 1-6 Alkyl and C 1-6 Each is independently selected from the group consisting of haloalkyls, Each R 9 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl, C 2-6 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, Each R 10 C 1-20 Alkyl, C 1-20 Haloalkyl, C 2-20 Alkenil, C 2-20 Haloalkenil, C 2-20 Alkinyl, C 2-20 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, R e and R f Each of these is -H;NR'R”, -OH, Haro, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl or C 1-6 Independently selected from the group consisting of haloalkyl and -C(=O)R', R' and R'' are each -H; halo, cyano, C 1-4 Alkoxy, C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and -OH. 1-4 Alkyl or C 1-4 A compound independently selected from the group consisting of haloalkyls, as described in technical solution 28.

[0214] 32.R X This is as defined in technical solution 29, R 4a C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 A group consisting of haloalkynyls, preferably containing 1 to 3 double or triple bonds. 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 A group consisting of haloalkynyls, preferably containing a cumulative double bond. 2-6 Alkenyl and C 2-6 A group consisting of haloalkenyls, preferably containing a conjugated double bond. 2-6 Alkenyl and C 2-6 A group consisting of haloalkenyls, preferably containing an independent double bond. 2-6 Alkenyl and C 2-6 A group consisting of haloalkenyls, preferably a group consisting of ethenyl, propenyl, ethinyl, and propynyl, preferably a group consisting of ethenyl and ethinyl, is selected from the group consisting of haloalkenyls. R 4b -OH, -OR 9 , -NR e R f A group consisting of -HALO, preferably selected from the group consisting of -OH and -HALO, R 5b -OH, -OR 9 and -NR e R f Selected from the group consisting of, L 2 is -O-, Y0 It is selected from the group consisting of -OH and -SH, R 2 -HALO, -OH, -OR 9 and -OC(=O)R 9 Selected from the group consisting of, R 3 -OH, -OR 10 and -OC(=O)R 10 Selected from the group consisting of, R 1 , R 6 and R 7 -OH, -OR 9 and -OC(=O)R 9 Each is independently selected from the group consisting of, Each R 9 C 1-6 Alkyl and C 1-6 Independently selected from the group consisting of haloalkyls, Each R 10 C 1-20 Alkyl, C 1-20 Haloalkyl, C 2-20 Alkenil, C 2-20 Haloalkenil, C 2-20 Alkinyl, C 2-20 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, R e and R f Each of these is -H;NR'R”, -OH, Haro, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl or C 1-6 Independently selected from the group consisting of haloalkyl and -C(=O)R', R' and R'' are each -H; halo, cyano, C 1-4 Alkoxy, C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and -OH. 1-4Alkyl or C 1-4 A compound independently selected from the group consisting of haloalkyls, as described in technical solution 28.

[0215] 33.R X This is as defined in technical solution 29, R 4a C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 A haloalkynyl, preferably containing 1 to 3 double or triple bonds. 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 A haloalkynyl, preferably containing a cumulative double bond. 2-6 Alkenyl or C 2-6 A haloalkenyl, preferably containing a conjugated double bond. 2-6 Alkenyl or C 2-6 A haloalkenyl, preferably containing an independent double bond. 2-6 Alkenyl or C 2-6 It is a haloalkenyl, preferably ethenyl, propenyl, ethinyl, or propynyl, preferably ethenyl or ethinyl. R 4b It is selected from the group consisting of -OH, -OMe, -NH2 and -F, and is preferably -F. R 5b It is selected from the group consisting of -OH, -NH2, -NHMe, -NMe2 and -NHAc, and is preferably -OH. L 2 is -O-, Y 0 It is selected from the group consisting of -OH and -SH, and is preferably -SH. R 2 It is selected from the group consisting of -F, -OH, and -OAc, preferably -OH or -OAc, and preferably -OH. R 3 These are -OH and -OC(=O)C 1-20Selected from the group consisting of alkyl groups, preferably from the group consisting of -OH and -OAc, and preferably -OH. R 1 , R 6 and R 7 The compound according to technical solution 28, wherein each is independently selected from the group consisting of -OH and -OAc, and is preferably -OH.

[0216] 34.R X teeth, [ka] Preferably, [ka] Preferably, [ka] Preferably, [ka] Selected from the group consisting of, R 4a C 2-6 Alkenyl or C 2-6 It is a haloalkenyl, preferably ethenyl, propenyl, ethinyl or propynyl, preferably ethenyl or ethinyl, preferably ethenyl, R 4b It is selected from the group consisting of H, -OH, -OMe, -NH2 and -F, preferably from the group consisting of -OH and -F, and preferably -OH. R 5b It is selected from the group consisting of -OH, -NH2, -NHMe, -NMe2 and -NHAc, and is preferably -OH. L 2 is -O-, Y 0 It is selected from the group consisting of -OH and -SH, and is preferably -SH. R 2 These are -F, -OH, and -OC(=O)C 1-6Selected from the group consisting of alkyl groups, preferably -OH or -OAc, preferably -OAc, R 3 These are -OH and -OC(=O)C 1-20 Selected from the group consisting of alkyl groups, preferably from the group consisting of -OH and -OAc, and preferably -OAc. R 1 , R 6 and R 7 The compound according to technical solution 28, wherein each is independently selected from the group consisting of -OH and -OAc, and is preferably -OAc.

[0217] 35.Formula (Ik), (Ik-1), (Ik-2), (Ik-3), (Ik-4) or (Ik-5): [ka] [ka] [ka] [ka] [ka] [ka] A compound represented by, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug or tautomer thereof, wherein the formula, R X teeth, (A) Equations (X-Ia), (X-Ib), or (X-Ic): [ka] (X-Ia); (X-Ib); or (X-Ic) A part having, in the formula, X 1However, it is selected from the group consisting of C(=O), C-OH, C=S, C-SH, C-NH2, and C(=NH), X 3 , X 5 and X 6 However, N, NH, N(R Xn ), CH, CR Xc , C(=O), C(=S), C(=NH), and C(=NR Xn Each of the groups consisting of ) is independently selected, X 4 However, it is either N or C. R X2 However, -H, R Xn Either or R X2 However, the double bond is NR X2 It does not exist when it is present between adjacent ring atoms. each [ka] These are independently single or double bonds, ●However, formulas (X-Ia), (X-Ib), and (X-Ic) each contain 1 to 2 intraring double bonds. ●However, X 4 If it is C, then the double bond is X 4 It exists between the adjacent ring atom, ●However, if formulas (X-Ia), (X-Ib), and (X-Ic) each contain only one intraring double bond, then X 4 is N and / or X 3 , X 5 and X 6 One or more of these are N, NH, N(R Xn ), C(=O), C(=S), C(=NH), and C(=NR Xn Are they independently selected from the group consisting of )? (B) Each has 1 to 3 R Xc The R is optionally substituted with pyridinyl, pirmidinyl, pyrazinyl, pyridazinyl, or triazinyl, provided that R is ortho or para relative to the ring nitrogen of (B). Xc Are all the groups other than -OH, -SH, or NH2? (C) Formula (X-II): [ka] A part having, in the formula, X 7 However, it is either C or N, X 8 , X 9 , X 10 and X 11 However, CH, C(R Xc ), N, N(H), N(R Xn ), O, S, C(=O), C(=S), C(=NH), and C(=NR Xn Each of the groups consisting of ) is independently selected, each [ka] These are independently single or double bonds, However, X 7 ~X 11 1 to 4 of these are C, CH, C(R) Xc ), C(=O), C(=S), C(=NH), and C(=NR Xn Independently selected from the group consisting of ), (X-II) is aromatic or (D) 1 to 4 R Xc C is optionally replaced by 6-10 Is it an aryl, or (E) A bicyclic heteroaryl having 8 to 12 ring atoms, wherein 1 to 5 ring atoms are N, N(H), N(R) Xn ), O and S (=O) 0-2 A heteroatom independently selected from the group consisting of, and one or more ring carbon atoms of the heteroaryl are oxo and R Xc Each of these is optionally substituted with 1 to 4 substituents independently selected from the group consisting of the following: Each R Xc R c , R b and -(L b ) b -R b Independently selected from the group consisting of, Each R Xn R d , R b and -(L b ) b -R b Independently selected from the group consisting of, R 4a and R 5b teeth, ●-H, -OH, -SH, -halo, cyano, or azide; ● Each has 1 to 6 R a C is optionally replaced by 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Haloalkynyl; ● Each has 1 to 6 R a C is optionally replaced by 1-4 Alkoxy or C 1-4 Thioalkoxy; ●-OR 9 , -NR e R f ; ●-R b or -(L b ) b -R b ; ●-OP(=O)(OR')(OR”); and ● 1 to 6 R a -OC(=O)(C) is arbitrarily substituted. 1-6 Alkyl) Independently selected from the group consisting of, L 2 -O-, -S-, -NR L1 - and -C(R L2 )(R L2 Selected from the group consisting of )-, Y 0 It is selected from the group consisting of -OH and -SH, R 3 H, D, -halo, -OH, -SH, cyano, -OR 10 -OC(=O)R 10 , -NRe R f , -NR e C(=O)R 10 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 10 , C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R 1 , R 2 , R 6 and R 7 H, D, -halo, -OH, -SH, cyano, -OR 9 -OC(=O)R 9 , -NR e R f , -NR e C(=O)R 9 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 9 , C 1-6 Alkyl and C 1-6 Each is independently selected from the group consisting of haloalkyls, Each R 9 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl, C 2-6 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, Each R 10 C 1-20 Alkyl, C 1-20 Haloalkyl, C 2-20 Alkenil, C 2-20 Haloalkenil, C 2-20 Alkinyl, C 2-20 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, Each R L1 is -H;NR'R”, -OH, C1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Independently selected from the group consisting of haloalkynyl and -C(=O)R', Each R L2 -H;-Hallo;-OH;-OR 9 ;NR'R”, -OH, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Independently selected from the group consisting of haloalkynyl and -C(=O)R', Each R a -H, -OH, -halo, -NR e R f , C 1-4 Alkoxy, C 1ー4 Haloalkoxy, -C(=O)O(C 1-4 Alkyl), -C(=O)(C 1-4 Alkyl), -C(=O)OH, -C(=O)NR'R'', -S(=O) 1-2 NR'R”, -S(=O) 1-2 (C 1-4 Independently selected from the group consisting of alkyl and cyano, Each R b teeth, ● Each has 1 to 4 R c C is optionally replaced by 3-10 Cycloalkyl or C 3-10 Cycloalkenyl; ● A heterocyclyl or heterocycloalkenyl having 3 to 10 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R) d ), O and S (=O) 0-2 Each heteroatom is independently selected from the group consisting of the following, and the heterocyclyl or heterocycloalkenyl has 1 to 4 R c A heterocyclyl or heterocycloalkenyl with 3 to 10 ring atoms optionally substituted; ●A heteroaryl with 5 to 10 ring atoms, wherein 1 to 3 ring atoms are N, N(H), N(R) d ), O and S (=O) 0-2 These are heteroatoms independently selected from the group consisting of, and the heteroaryl has 1 to 4 R c Heteroaryl ring atoms of 5 to 10 atoms that are optionally substituted; ● 1 to 4 R c C is optionally replaced by 6-10 Ariel Independently selected from the group consisting of, Each L b -O-, -NH-, -NR d -S(=O) 0-2 , C (=O) and 1 to 3 R a C is optionally replaced by 1-3 Independently selected from the group consisting of alkylenes, Each b is independently 1, 2, 3, or 4. Each R c This includes halo; cyano; and 1 to 6 independently selected Rs. a C is optionally replaced by 1-10 Alkyl; C 2-6 Alkenil; C 2-6 Alkinyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -S (=O) 1-2 (C 1-4 Alkyl);-NR e R f ;-OH;-SH;-S(=O) 1-2 NR'R”;-C 1-4 Thiokoxy;-NO2;-OC(=O)(C1-4 Alkyl);-OC(=O)H;-C(=O)(C 1-4 Alkyl);-C(=O)H;-C(=O)O(C 1-4 Independently selected from the group consisting of alkyl);-C(=O)OH; and-C(=O)NR'R'', Each R d These are 1 to 3 independently selected R a C is optionally replaced by 1-6 Alkyl;-C(=O)(C 1-4 Alkyl);-C(=O)O(C 1-4 Alkyl);-C(=O)NR'R”;-S(=O) 1-2 NR'R”;-S(=O) 1-2 (C 1-4 Alkyl;-OH;and C 1-4 Independently selected from the group consisting of alkoxys, R e and R f Each of these is -H;NR'R”, -OH, Haro, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl or C 1-6 Haloalkyl;-C(=O)R';-C(=O)OR';-C(=O)NR'R”;C(=NR”)NR'R”;-C(=O)C(=O)R';-S(=O) 1-2 NR'R”;-S(=O) 1-2 R';-OH;and C 1-4 Independently selected from the group consisting of alkoxys, or R e and R f Together with the N atoms connecting them, they form saturated or unsaturated 3-7 member heterocyclines. R' and R'' are each -H; halo, cyano, C 1-4 Alkoxy, C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and -OH. 1-4 Alkyl or C 1-4Compounds independently selected from the group consisting of haloalkyls, or pharmaceutically acceptable salts, stereoisomers, stable isotopes, prodrugs, or tautomers thereof.

[0218] 36.R X teeth, [ka] Preferably [ka] Preferably [ka] Preferably [ka] Preferably [ka] Preferably [ka] Preferably [ka] Preferably [ka] Preferably [ka] Selected from the group consisting of, R 4a and R 5b teeth, ●-H, -OH, -SH, -halo, cyano, or azide; ● Each has 1 to 6 R a C is optionally replaced by 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6Haloalkenil, C 2-6 Alkinyl or C 2-6 Haloalkynyl; ● Each has 1 to 6 R a C is optionally replaced by 1-4 Alkoxy or C 1-4 Thioalkoxy; ●-OR 9 , -NR e R f ; ● 1 to 6 R a -OC(=O)(C) is arbitrarily substituted. 1-6 Alkyl) Independently selected from the group consisting of, Preferably, R 4a is -H, and R 5b is -OH, L 2 -O-, -S-, -NR L1 - and -C(R L2 )(R L2 Selected from the group consisting of )-, Y 0 It is selected from the group consisting of -OH and -SH, R 3 H, D, -halo, -OH, -SH, cyano, -OR 10 -OC(=O)R 10 , -NR e R f , -NR e C(=O)R 10 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 10 , C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R 1 , R 2 , R 6 and R 7 H, D, -halo, -OH, -SH, cyano, -OR 9 -OC(=O)R 9 , -NR e R f , -NR e C(=O)R 9, -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 9 , C 1-6 Alkyl and C 1-6 Each is independently selected from the group consisting of haloalkyls, Each R 9 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl, C 2-6 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls or 5-10 membered heteroaryls, Each R 10 C 1-20 Alkyl, C 1-20 Haloalkyl, C 2-20 Alkenil, C 2-20 Haloalkenil, C 2-20 Alkinyl, C 2-20 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls or 5-10 membered heteroaryls, Each R L1 is -H;NR'R”, -OH, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Independently selected from the group consisting of haloalkynyl and -C(=O)R', Each R L2 -H;-Hallo;-OH;-OR 9 ;NR'R”, -OH, C 1-4 Alkoxy and C 1-4C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Independently selected from the group consisting of haloalkynyl and -C(=O)R', Each R a -H, -OH, -halo, -NR e R f , C 1-4 Alkoxy, C 1ー4 Haloalkoxy, -C(=O)O(C 1-4 Alkyl), -C(=O)(C 1-4 Alkyl), -C(=O)OH, -C(=O)NR'R'', -S(=O) 1-2 NR'R”, -S(=O) 1-2 (C 1-4 Independently selected from the group consisting of alkyl and cyano, R e and R f Each of these is -H;NR'R”, -OH, Haro, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl or C 1-6 Haloalkyl;-C(=O)R';-C(=O)OR';-C(=O)NR'R”;C(=NR”)NR'R”;-C(=O)C(=O)R';-S(=O) 1-2 NR'R”;-S(=O) 1-2 R';-OH;and C 1-4 Independently selected from the group consisting of alkoxys, or R e and R f Together with the N atoms connecting them, they form saturated or unsaturated 3-7 member heterocyclines. R' and R'' are each -H; halo, cyano, C 1-4 Alkoxy, C 1-4C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and -OH. 1-4 Alkyl or C 1-4 Independently selected from the group consisting of haloalkyls, Preferably, R e and R f Both are C, such as -Me. 1-6 A compound described in technical solution 35, which is alkyl.

[0219] 37.R X This is as defined in technical solution 36, R 4a is -H, -halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls, R 5b teeth, ●-H, -OH, -SH, -halo, cyano, or azide; ● Each has 1 to 6 R a C is optionally replaced by 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl or C 2-6 Haloalkynyl; ●-OR 9 , -NR e R f Independently selected from the group consisting of, Preferably, R 4a is -H, and R 5b is -OH, L 2 -O-, -S-, -NH-, -N(C 1-3 Alkyl)-, -CH2-, -CF2-, -CHF-, -CH(C 1-3 Alkyl)- and -C(C 1-3Selected from the group consisting of alkyl)OH-, Y 0 It is selected from the group consisting of -OH and -SH, R 2 -HALO, -OH, -OR 9 and -OC(=O)R 9 Selected from the group consisting of, R 3 -OH, -OR 10 and -OC(=O)R 10 Selected from the group consisting of, R 1 , R 6 and R 7 -OH, -OR 9 and -OC(=O)R 9 Each is independently selected from the group consisting of, Each R 9 C 1-6 Alkyl and C 1-6 Independently selected from the group consisting of haloalkyls, Each R 10 C 1-20 Alkyl, C 1-20 Haloalkyl, C 2-20 Alkenil, C 2-20 Haloalkenil, C 2-20 Alkinyl, C 2-20 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, Each R a -H, -OH, -halo, -NR e R f , C 1-4 Alkoxy, C 1ー4 Haloalkoxy, -C(=O)O(C 1-4 Alkyl), -C(=O)(C 1-4 Alkyl), -C(=O)OH, -C(=O)NR'R'', -S(=O) 1-2 NR'R”, -S(=O) 1-2 (C 1-4 Independently selected from the group consisting of alkyl and cyano, R e and Rf Each of these is -H;NR'R”, -OH, Haro, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl or C 1-6 Haloalkyl;-C(=O)R';-C(=O)OR';-C(=O)NR'R”;C(=NR”)NR'R”;-C(=O)C(=O)R';-S(=O) 1-2 NR'R”;-S(=O) 1-2 R';-OH;and C 1-4 Independently selected from the group consisting of alkoxys, R' and R'' are each -H; halo, cyano, C 1-4 Alkoxy, C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and -OH. 1-4 Alkyl or C 1-4 Independently selected from the group consisting of haloalkyls, Preferably, R e and R f Both are C, such as -Me. 1-6 A compound described in technical solution 35, which is alkyl.

[0220] 38.R X This is as defined in technical solution 36, R 4a is -H, -halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls, R 5b -OH, -OR 9 , -NR e R f Selected from the group consisting of and -halo, L 2 is -O-, Y 0It is selected from the group consisting of -OH and -SH, R 3 H, D, -halo, -OH, -SH, cyano, -OR 10 -OC(=O)R 10 , -NR e R f , -NR e C(=O)R 10 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 10 , C 1-6 Alkyl and C 1-6 Selected from the group consisting of haloalkyls, R 1 , R 2 , R 6 and R 7 H, D, -halo, -OH, -SH, cyano, -OR 9 -OC(=O)R 9 , -NR e R f , -NR e C(=O)R 9 , -OP(=O)(OR')(OR”), -OS(=O) 1-2 R 9 , C 1-6 Alkyl and C 1-6 Each is independently selected from the group consisting of haloalkyls, Each R 9 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl, C 2-6 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, Each R 10 C 1-20 Alkyl, C 1-20 Haloalkyl, C 2-20 Alkenil, C 2-20 Haloalkenil, C 2-20 Alkinyl, C 2-20 Haloalkynyl, C 3-7Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, R e and R f Each of these is -H;NR'R”, -OH, Haro, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl or C 1-6 Independently selected from the group consisting of haloalkyl and -C(=O)R', R' and R'' are each -H; halo, cyano, C 1-4 Alkoxy, C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and -OH. 1-4 Alkyl or C 1-4 Independently selected from the group consisting of haloalkyls, Preferably, R e and R f Both are C, such as -Me. 1-6 A compound described in technical solution 35, which is alkyl.

[0221] 39.R X This is as defined in technical solution 36, R 4a is -H, -halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Haloalkenil, C 2-6 Alkinyl and C 2-6 Selected from the group consisting of haloalkynyls, R 5b -OH, -OR 9 and -NR e R f Selected from the group consisting of, L 2 is -O-, Y 0 It is selected from the group consisting of -OH and -SH, R 2 -HALO, -OH, -OR 9 and -OC(=O)R 9 Selected from the group consisting of, R 3 -OH, -OR 10 and -OC(=O)R 10 Selected from the group consisting of, R 1 , R 6 and R 7 -OH, -OR 9 and -OC(=O)R 9 Each is independently selected from the group consisting of, Each R 9 C 1-6 Alkyl and C 1-6 Independently selected from the group consisting of haloalkyls, Each R 10 C 1-20 Alkyl, C 1-20 Haloalkyl, C 2-20 Alkenil, C 2-20 Haloalkenil, C 2-20 Alkinyl, C 2-20 Haloalkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, R e and R f Each of these is -H;NR'R”, -OH, Haro, C 1-4 Alkoxy and C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys. 1-6 Alkyl or C 1-6 Independently selected from the group consisting of haloalkyl and -C(=O)R', R' and R'' are each -H; halo, cyano, C 1-4 Alkoxy, C 1-4 C is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and -OH. 1-4 Alkyl or C 1-4 Independently selected from the group consisting of haloalkyls, Preferably, R e and R f Both are C, such as -Me. 1-6 A compound described in technical solution 35, which is alkyl.

[0222] 40.R X This is as defined in technical solution 36, R 4a is -H or Me, preferably -H. R 5b It is selected from the group consisting of -OH, -NH2, -NHMe, -NMe2 and -NHAc, and is preferably -OH. L 2 is -O-, Y 0 It is selected from the group consisting of -OH and -SH, and is preferably -SH. R 2 It is selected from the group consisting of -F, -OH, and -OAc, and is preferably -OH. R 1 , R 3 , R 6 and R 7 Each is independently selected from the group consisting of -OH and -OAc, and is preferably -OH. R e and R f Each of them is -H, C 1-6 Alkyl or -C(=O)C 1-4 It is alkyl, preferably -H or C 1-6 It is alkyl, preferably R e and R f Both are C, such as -Me. 1-6 A compound described in technical solution 35, which is alkyl.

[0223] 41.R X teeth, [ka] Selected from the group consisting of, preferably [ka] And, R 4a is -H or Me, preferably -H. R 5b It is selected from the group consisting of -OH, -NH2, -NHMe, -NMe2 and -NHAc, and is preferably -OH. L 2 is -O-, Y 0 It is selected from the group consisting of -OH and -SH, and is preferably -SH. R 2 It is selected from the group consisting of -F, -OH, and -OAc, and is preferably -OAc. R 3 These are -OH and -OC(=O)C 1-20 Selected from the group consisting of alkyl groups, preferably from the group consisting of -OH and -OAc, and preferably -OAc. R 1 , R 6 and R 7 Each is independently selected from the group consisting of -OH and -OAc, and is preferably -OAc. R e and R f Each of them is -H, C 1-6 Alkyl or -C(=O)C 1-4 It is alkyl, preferably -H or C 1-6 It is alkyl, preferably R e and R f Both are C, such as -Me. 1-6 A compound described in technical solution 35, which is alkyl.

[0224] 42. Compounds selected from the group consisting of the compounds shown in Table 1, or pharmaceutically acceptable salts, stereoisomers, stable isotopes, prodrugs, or tautomers thereof.

[0225] 43. A compound described in any one of Technical Solutions 1 to 42, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug or tautomer thereof, Pharmacologically acceptable excipients, Selectively, one or more other therapeutic drugs A pharmaceutical composition containing the following:

[0226] 44. A first container comprising a compound described in any one of Technical Solutions 1 to 42, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug or tautomer thereof, A second container containing one or more other therapeutic agents as optional, A third container comprising, optionally, a pharmaceutically acceptable excipient for diluting or suspending the compound and / or other therapeutic agents, A kit that includes the following:

[0227] 45. Use of any compound described in any one of technical solutions 1 to 42, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug or tautomer thereof, in the manufacture of a pharmaceutical product for the treatment of an immune and / or inflammatory disease.

[0228] 46. ​​Compounds described in any one of Technical Solutions 1 to 42, or pharmaceutically acceptable salts, stereoisomers, stable isotopes, prodrugs or tautomers thereof, for use in the treatment of immune and / or inflammatory-related diseases.

[0229] 47. A method for treating an immune and / or inflammatory disease in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound described in any one of Technical Solutions 1 to 42, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug, or tautomer thereof.

[0230] 48. An immune and / or inflammation-related disease is inflammatory bowel disease, using the compound described in technical solution 45, the compound described in technical solution 46, or the method described in technical solution 47.

[0231] 49. An immune and / or inflammation-related disease is ulcerative colitis, using the compound described in technical solution 45, the compound described in technical solution 46, or the method described in technical solution 47.

[0232] 50. An immune and / or inflammation-related disease is Crohn's disease, using the compound described in technical solution 45, the compound described in technical solution 46, or the method described in technical solution 47.

[0233] 51. Use of any compound described in any one of technical solutions 1 to 42, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug, or tautomer thereof, in the manufacture of a drug for the treatment of cancer.

[0234] 52. A compound described in any one of Technical Solutions 1 to 42 for use in the treatment of cancer, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug or tautomer thereof.

[0235] 53. A method for treating a cancer of a subject in need, comprising administering to the subject a therapeutically effective amount of a compound described in any one of Technical Solutions 1 to 42, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug, or tautomer thereof.

[0236] 54. Cancer is selected from the group consisting of brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, hepatocellular carcinoma, prostate cancer, colorectal cancer, hematological cancer, lung cancer, and bone cancer, and is used as described in technical solution 51, the compound described in technical solution 52, or the method described in technical solution 53.

[0237] 55. Cancer selected from the group consisting of small cell lung cancer, non-small cell lung cancer, colorectal cancer, melanoma, renal cell carcinoma, head and neck cancer, Hodgkin lymphoma, and bladder cancer, using the method described in technical solution 51, the compound described in technical solution 52, or the method described in technical solution 53.

[0238] 56. Use of any compound described in any one of technical solutions 1 to 42, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug, or tautomer thereof, in the manufacture of a pharmaceutical product for enhancing the efficacy of a vaccine.

[0239] 57. Compounds described in any one of Technical Solutions 1 to 42, or pharmaceutically acceptable salts, stereoisomers, stable isotopes, prodrugs, or tautomers thereof, for use in enhancing the efficacy of vaccines.

[0240] 58. A method for enhancing the efficacy of a vaccine for a target subject, comprising administering to the subject a therapeutically effective dose of any one of the technical solutions 1 to 42, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug, or tautomer thereof.

[0241] 59. The vaccine is a cancer vaccine, the use described in technical solution 56, the compound described in technical solution 57, or the method described in technical solution 58.

[0242] 60. The vaccine is a bacterial vaccine, used as described in technical solution 56, the compound described in technical solution 57, or as described in technical solution 58.

[0243] 61. The vaccine is a viral vaccine, the use described in technical solution 56, the compound described in technical solution 57, or the method described in technical solution 58.

[0244] 62. The vaccine is a parasitic vaccine, the use described in technical solution 56, the compound described in technical solution 57, or the method described in technical solution 58.

[0245] 63. The compound is an adjuvant, used as described in technical solution 56, the compound described in technical solution 57, or the method described in technical solution 58.

[0246] 64. Use of any compound described in any one of Technical Solutions 1 to 42, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug, or tautomer thereof, in the manufacture of a pharmaceutical product for enhancing innate immunity.

[0247] 65. Compounds described in any one of Technical Solutions 1 to 42, or pharmaceutically acceptable salts, stereoisomers, stable isotopes, prodrugs, or tautomers thereof, for use in enhancing innate immunity.

[0248] 66. A method for enhancing the innate immunity of a subject in need, comprising administering to the subject a therapeutically effective amount of any one of the technical solutions 1 to 42, or a pharmaceutically acceptable salt, stereoisomer, stable isotope, prodrug, or tautomer thereof.

[0249] 67. Administration includes intramuscular, intraperitoneal, intratumoral, or intravenous administration of the compound described in technical solution 64, the compound described in technical solution 65, or the method described in technical solution 66.

[0250] 68. Administration further comprising one or more immunotherapeutic agents, the use described in technical solution 64, the compound described in technical solution 65, or the method described in technical solution 66.

[0251] 69.1 or more immunotherapeutic agents, including small molecules, antibodies, or cytokines, used as described in technical solution 64, compounds as described in technical solution 65, or methods as described in technical solution 66.

[0252] Pharmaceutical composition and administration overview In some embodiments, a chemical substance (e.g., a compound that modulates (e.g., stimulates) ALPK1, or a pharmaceutically acceptable salt and / or hydrate and / or cocrystal and / or stable isotope and / or prodrug and / or compound) is administered as a pharmaceutical composition comprising the chemical substance, one or more pharmaceutically acceptable excipients, and one or more additional therapeutic agents as optionally described herein.

[0253] In some embodiments, the chemical may be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), e.g., d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, e.g., Tween, poloxamer, or other similar polymer delivery matrices, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of vegetable saturated fatty acids, water, salts, or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, waxes, polyethylene-polyoxypropylene block polymers, and lanolin. Cyclodextrins such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives may also be used to improve the delivery of the compounds described herein. Dosage forms or compositions can be prepared containing the chemicals described herein in an amount ranging from 0.005% to 100%, with the remainder consisting of non-toxic excipients. The intended compositions may contain the chemicals provided herein in an amount ranging from 0.001% to 100%, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in a further embodiment. Practical methods for preparing such dosage forms are known to those skilled in the art or will be obvious to those skilled in the art. For example, Remington: The Science and Practice of Pharmacy, 22 nd Please refer to the Edition (Pharmaceutical Press, London, UK, 2012).

[0254] Route of administration and compositional components In some embodiments, the chemical substances or pharmaceutically active compositions thereof described herein may be administered to the subject in need via any permissible route of administration. Permissible routes of administration include buccal administration, cutaneous administration, intracervical administration, intrasinus administration, intratracheal administration, intraintestinal administration, epidural administration, interstitial administration, intraperitoneal administration, intraarterial administration, intrabronchial administration, intracapsular administration, intracerebral administration, intracisional administration, intracoronary artery administration, intradermal administration, intraluminal administration, intraduodenal administration, intradural administration, intraepidermal administration, intraesophageal administration, intragastric administration, intragingival administration, intraileal administration, intralymphatic administration, intramedullary administration, intrameningeal administration, intramuscular administration, intraovarian administration, intraperitoneal administration, Administration methods include, but are not limited to, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratesticular, subarachnoid, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, local, transdermal, transmucosal, tracheal, ureteral, urethral, ​​and vaginal administration. In certain embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0255] The composition may be formulated for parenteral administration (for example, for injection via intravenous, intramuscular, subcutaneous, or intraperitoneal routes). Typically, such composition can be prepared as either a solution or a suspension for injection, and a solid form suitable for use in preparing the solution or suspension when added to the liquid before injection can also be prepared, and the formulation can be emulsified. The preparation of such dosage forms will be known to those skilled in the art in light of this disclosure.

[0256] Suitable pharmaceutical forms for use in injectable formulations include sterile aqueous solutions or dispersions; dosage forms containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the immediate preparation of injectable sterile solutions or dispersions. In all cases, the form must be sterile and fluid enough to be easily injected. It must also be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi.

[0257] The carrier may also be a solvent or dispersion medium containing water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained by the use of coatings such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants. Inhibition of microbial activity can be achieved by various antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In many cases, it is preferable to include an isotonic agent such as sugar or sodium chloride. Sustained absorption of the injectable composition can be achieved by using absorption-delaying agents in the composition, such as aluminum monostearate and gelatin.

[0258] Injectable sterile solutions are prepared by compounding the required amount of active compound in a suitable solvent, along with various other components as needed, and then sterilizing by filtration. Generally, dispersions are prepared by compounding various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other necessary components listed above. In the case of sterile powders for preparing injectable sterile solutions, preferred preparation methods are vacuum drying and freeze-drying techniques, which yield powder of the active ingredient with any desired additional components added from its pre-sterilized filtered solution.

[0259] Intratumoral injection is discussed, for example, in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems,” Neoplasia. 2006, 10, 788-795.

[0260] Pharmacologically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or anal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (PEG ointment, etc.), glycerin, glycerin gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycol and fatty acid esters of polyethylene glycol of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, and p-oxy Examples of the following are but are not limited to: sodium methylbenzoate, sodium p-propylbenzoate, diethylamine, carbomer, Carbopol, methyloxybenzoate, macrogelcetostearyl ether, cocoyl caprylate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxymethabites, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0261] In certain embodiments, suppositories may be prepared by mixing the chemicals described herein with a suitable non-irritating excipient or carrier (such as core butter, polyethylene glycol, or suppository wax) that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum to release the active compound. In other embodiments, the rectal administration composition is in the form of an enema.

[0262] In other embodiments, the compounds or pharmaceutical compositions described herein are suitable for local delivery to the gastrointestinal tract or GI tract by oral administration (e.g., in solid or liquid dosage forms).

[0263] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical is mixed with one or more pharmaceutically acceptable excipients such as sodium citrate or dicalcium phosphate, and / or: a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) water-retaining agents such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar, or high molecular weight polyethylene glycol.

[0264] In one embodiment, the composition takes the form of a unit dosage form such as a pill or tablet, and the composition may contain, along with the chemicals provided herein, diluents such as lactose, sucrose, and dicalcium phosphate; lubricants such as magnesium stearate; and binders such as starch, acacia gum, polyvinylpyrrolidone, gelatin, cellulose, and cellulose derivatives. In another solid dosage form, a powder, marmé, solution, or suspension (e.g., propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulosic capsule). Unit dosage forms in which one or more chemicals or additional active agents provided herein are physically separated are also intended. For example, capsules containing granules of each drug (or tablets within capsules); bilayer tablets, two-compartment gel capsules, etc. Enteric-coated or delayed-release oral dosage forms are also intended.

[0265] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersants, or preservatives particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known, such as phenol and ascorbic acid.

[0266] In certain embodiments, the excipients are sterile and generally free of undesirable substances. These compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not required for excipients in various oral dosage forms, such as tablets and capsules. USP / NF standards are usually sufficient.

[0267] In certain embodiments, the oral solid dosage form may further include one or more components that chemically and / or structurally facilitate the delivery of the chemical to the stomach or lower GI, such as the ascending colon and / or transverse colon and / or distal colon and / or small intestine. Exemplary formulation techniques are described, for example, Filipski, KJ et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, the entirety of which is incorporated herein by reference.

[0268] Examples include upper GI targeting technologies such as accordion pills (Intec Pharma), floating capsules, and materials that can adhere to mucosal walls.

[0269] Other examples include lower GI targeting technologies. Several enteric / pH-responsive coatings and excipients are available to target various regions within the intestinal tract. These materials are typically polymers designed to dissolve or erode within a specific pH range selected based on the desired GI region for drug release. These materials also function to protect acid-unstable drugs from gastric juice or to limit exposure when the active ingredient may irritate the upper GI (e.g., the hydroxymethylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, the Eudragit series (methacrylate-methyl methacrylate copolymer), and Marcoat). Other technologies include dosage forms that correspond to the local microbiota of the GI tract, pressure-controlled colon delivery capsules, and Pulsincap.

[0270] Examples of ophthalmic compositions include, but are not limited to, one or more of the following: biscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic® (triblock copolymer), cyclodextrin); and preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0271] Topical compositions may include ointments and creams. Ointments are typically semi-solid formulations based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquids or semi-solid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically washable with water and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes called the “internal” phase, generally consists of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol, while the aqueous phase usually, though not necessarily, exceeds the volume of the oil phase and generally contains a water-retaining agent. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing.

[0272] In any of the embodiments described herein, the pharmaceutical composition may include one or more of the following: lipids, internal bilayer crosslinked multilayer vesicles, biodegradable poly(D,L-lactic acid-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0273] Dosage The dosage may vary depending on the patient's requirements, the severity of the condition being treated, and the specific compound used. Determining the appropriate dosage for a given situation can be done by a person skilled in the pharmaceutical art. The total daily dose may be divided and administered throughout the day or by means of continuous delivery.

[0274] In some embodiments, the compounds described herein are present in concentrations of about 0.001 mg / kg to about 500 mg / kg (for example, about 0.001 mg / kg to about 200 mg / kg, about 0.01 mg / kg to about 200 mg / kg, about 0.01 mg / kg to about 150 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 5 mg / kg, about 0.01 mg / kg to about 1 mg It is administered in doses of approximately 0.01 mg / kg to 0.5 mg / kg, 0.01 mg / kg to 0.1 mg / kg, 0.1 mg / kg to 200 mg / kg, 0.1 mg / kg to 150 mg / kg, 0.1 mg / kg to 100 mg / kg, 0.1 mg / kg to 50 mg / kg, 0.1 mg / kg to 10 mg / kg, 0.1 mg / kg to 5 mg / kg, 0.1 mg / kg to 1 mg / kg, and 0.1 mg / kg to 0.5 mg / kg.

[0275] regimen The aforementioned dosages can be administered daily (for example, as a single dose or as two or more divided doses) or non-daily (for example, every other day, every two days, every three days, once a week, twice a week, once every two weeks, or once a month).

[0276] In some embodiments, the duration of administration of the compounds described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In further embodiments, the period during which administration is stopped is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In one embodiment, the therapeutic compound is administered to an individual for a set period, followed by administration for a separate period. In another embodiment, the therapeutic compound is administered for a first period and a second period after the first period, with administration stopped during the second period, administration of the therapeutic compound being started in a third period thereafter, and then administration being stopped in a fourth period after the third period. In one aspect of this embodiment, the period of administration of the therapeutic compound and the subsequent period of administration being stopped are repeated for a determined or undetermined period. In further embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In further embodiments, the period during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer.

[0277] immunogenic composition In another aspect, the Disclosure provides an immunogenic composition (e.g., a vaccine) comprising (i) one or more active agents (e.g., one or more antigens) that induce an immunological response in a subject (e.g., a human or animal subject) and (ii) one or more adjuvants having a formula described herein.

[0278] In another embodiment, the Disclosure provides immunogenic combinations as one or more kits or packs. In certain embodiments, the kit or pack comprises two or more separately contained / packaged components, e.g., two components, which, when mixed, provide the desired immunogenic composition described herein. In certain embodiments, the two-component system comprises a first component and a second component, where (i) the first component is a vaccine, and (ii) the second component comprises one or more adjuvants having the formulas described herein.

[0279] In some embodiments, the observed immunological response is greater than the immunological response observed in the absence of one or more adjuvants.

[0280] In some embodiments, the immunological response stimulates the immune system of a target (e.g., a human or animal target) to generate immunity against a particular disease or condition.

[0281] In some embodiments, the immunological response may be a cellular and / or antibody-mediated immune response to the immunogenic compositions described herein. For example, “immunological response” includes, but is not limited to, one or more effects of producing or activating antibodies, B cells, helper T cells, suppressor T cells and / or cytotoxic T cells and / or gamma delta T cells that are specific to the antigen contained in the immunogenic compositions described herein. Preferably, the subject exhibits either an immunological protective response or a therapeutically effective response.

[0282] An "immunological defense response" can be demonstrated by a reduction or absence of clinical signs normally shown by an infected host, a faster recovery time and / or a shorter duration of infection, or a decrease in the pathogen's potency in the infected host's tissues, fluids, or excretions.

[0283] In some embodiments, the one or more active agents that induce an immunological response in a subject are one or more antigens.

[0284] In some embodiments, a “vaccine” is a pharmaceutical preparation used for the purpose of preventing infection and contains an inactivated or attenuated antigen. When administered to a human or animal subject, a vaccine induces an immune response that prevents infection (including allergic reactions) caused by the antigen contained in the vaccine and the exacerbation of any subsequent infection. A vaccine typically contains an active agent that resembles a disease-causing microorganism, and is typically made from a microorganism, its toxin, or one attenuated or dead form of its surface protein. While we do not wish to be bound by theory, an active agent stimulates the body’s immune system to recognize and destroy the active agent as a threat, and further recognize and destroy any microorganism associated with the active agent that may be encountered in the future. A vaccine may be prophylactic (preventing or mitigating the effects of future infections by natural or “wild” pathogens) or therapeutic (fighting an already established disease, such as cancer).

[0285] As used herein, the term “adjuvant” means a substance administered with an antigen that thereby enhances the antigenicity of the antigen and promotes the induction of an immune response.

[0286] As used herein, the term “antigen” refers to a general term for foreign substances or parts thereof (e.g., toxins, or other foreign substances that induce an immune response in the body, particularly the production of antibodies) that enter the body from the outside. Antigens include foreign pathogens that cause various infectious diseases (e.g., bacteria and viruses), and allergens that cause allergic reactions in pollen, food, etc.

[0287] antigen When administered to a target, the antigen typically interacts specifically with antigen-recognizing molecules of the immune system, such as immunoglobulins (antibodies) or T cell antigen receptors (TCRs), to induce an immune response, leading to the development of cellular responses (e.g., memory cells (e.g., memory B cells and T cells) or cytotoxic cells) and / or humoral (antibody) responses.

[0288] As used herein, “antigen” refers to, but is not limited to, a component that induces an immunological response in a host to such antigen or an immunogenic composition or vaccine of interest containing such antigen or an immunoactive component thereof. The antigen or immunoactive component may be a whole microorganism (a living, inactivated, or modified form) or any fragment or part thereof that, when administered to a host, can induce an immunological response in the host. The antigen may be a living, complete organism, either in its original form or as an attenuated organism in a so-called modified live vaccine (MLV), or may include such an organism. The antigen may further include suitable elements of the organism (subunit vaccine), thereby producing these elements by disrupting the whole organism or a growing culture of such organism and obtaining the desired structure in a subsequent purification step, or by a synthetic process induced by appropriately manipulating a suitable system such as bacteria, insects, mammals, or other species, and optionally by subsequent isolation and purification steps, or by inducing the synthetic process in an animal requiring the vaccine by directly incorporating genetic material using a suitable pharmaceutical composition (polynucleotide vaccination). Antigens can include entire organisms that have been inactivated in an appropriate manner in so-called dead bacterial vaccines (KVs). When the organism is a bacterium, the dead bacterial vaccine is called a bacterin.

[0289] The compositions, combinations, and methods described herein may be used with any type of antigen, such as whole pathogens (cells, viruses, etc.) or fragments or parts thereof (proteins, polypeptides, peptides, nucleic acids, lipids, etc.). Pathogens may be any active substance capable of infecting animals such as humans, birds (e.g., chickens, turkeys, ducks, pigeons, etc.), dogs, cats, cattle, pigs, or horses. Antigens may be, for example, whole pathogens, pathogens, or "surface antigens" that are naturally expressed on the surface of infected or diseased (e.g., tumor) cells.

[0290] More specifically, an antigen may be any pathogenic or non-pathogenic microorganism, such as a virus, bacterium, any other parasite, or antigen. These may be living microorganisms, attenuated microorganisms, inactivated microorganisms, or dead microorganisms, either the whole microorganism or a subunit of a microorganism, inactivated chimeric or recombinant microorganisms, destroyed microorganisms, mutant microorganisms, deficient microorganisms, or combinations thereof. An antigen may also be one or more epitopes or antigenic portions of an entire microbial structure such as a virus, bacterium, or parasite, such as a pathogen-derived antigenic protein, recombinant protein, preferably a viral antigen, e.g., viral capsid protein, cell wall protein, peptide, or part of a bacterial or parasitic structure, e.g., preparations of polysaccharides, lipopolysaccharides, and glycoproteins. An antigen may also be DNA or recombinant DNA. Antigens may be supplied in purified or unpurified form.

[0291] When an antigen is a weakened microorganism such as a virus, bacterium, or other pathogen, the weakened pathogen retains immunogenicity but is essentially non-pathogenic. Weakening can be achieved through natural or artificial weakening processes, such as subculturing, in living animals or various natural media, including organs, cells, and embryos. Artificial weakening can also be achieved through chemical treatment, drying, aging, low temperatures, adaptation to specific culture conditions, or gene deletion.

[0292] Antigens may also contain dead, inactivated microorganisms. The preparation of inactivated viruses for vaccination is generally achieved by chemical or physical means. Chemical inactivation can be achieved by treating the virus with, for example, enzymes, formaldehyde, β-propiolactone, binary ethylene-imine, or derivatives thereof. The inactivated viruses thus obtained can then be neutralized or stabilized. Physical inactivation can be performed by exposing the virus to high-energy radiation such as UV light, X-rays, or gamma rays.

[0293] Bacteria (including spores) can be inactivated by heat, pressure, and / or the use of chemical agents, often referred to as disinfectants. For example, corrosive compositions such as formaldehyde and sodium hypochlorite (bleach) have been used to inactivate bacteria. Alternatively, bacterial inactivation can be achieved by ethylene oxide exposure, carbon dioxide irradiation, steam sterilization, or near-critical and supercritical carbon dioxide treatment. Bacteria can also be inactivated or made non-pathogenic by genetically modifying one or more genes associated with pathogenicity. Examples of such genetic modifications are disclosed, for example, in International Publication No. 2012 / 092226.

[0294] Such attenuated or inactivated microorganisms, such as viruses, bacteria, or other avian parasites, can also be purchased from commercially available sources.

[0295] Antigens can be of the same type or different type.

[0296] The vaccine or composition of the present invention may contain a combination of living antigens, synthetic antigens, or fragments or parts thereof. The composition may contain antigens derived from various pathogens to produce a broad immune response.

[0297] Antigens may be viruses that cause common diseases such as avian pox, Newcastle disease, infectious bronchitis, quail bronchitis, lymphocytic leukemia, Marek's disease, infectious bursal disease, infectious laryngotracheitis, egg-laying deficit syndrome, reovirus infection, infectious tenosynovitis, avian encephalomyelitis, cranial swelling syndrome, turkey rhinotracheitis, or avian influenza, as described by GDButcher, JPJacob, and FBMather (PS47, Veterinary Medicine-Large Animal Clinical Sciences Department, Florida Cooperative Extension Service, Institute of Food and Agricultural Sciences, University of Florida; May 1999), bacteria that cause mycoplasma diseases, pasteurellosis, salmonellosis, and bordetella disease, and / or other avian parasites that cause coccidiosis and campylobacteriosis. A preferred vaccine used in the vaccine composition of the present invention comprises the entire attenuated live virus strain.

[0298] Non-limiting examples of viral antigens include inactivated or attenuated preparations of at least one virus selected from the group consisting of influenza virus, norovirus, rotavirus, human papillomavirus, varicella virus, measles virus, mumps virus, poliovirus, adenovirus, herpesvirus, human coronavirus, rubella virus, HIV, smallpox virus, Ebola virus, hepatitis virus, Japanese encephalitis virus, parvovirus, coronavirus, Zika and cowpox virus, or parts or components thereof.

[0299] In some embodiments, the antigen is derived from at least one virus that causes hand, foot, and mouth disease in humans, such as EV71, CA6, and CA16. Advantageously, the antigen may include at least one adaptive mutation that enables production in cultured non-human cell lines, such as Vero cells. Furthermore, as disclosed herein, the vaccines and immunogenic compositions of this disclosure have been demonstrated to induce a protective immune response against viruses that cause hand, foot, and mouth disease in humans.

[0300] In some embodiments, the antigen is the PPV viral protein 2 (VP2) antigen.

[0301] In some embodiments, the antigen is a coronavirus antigen. Examples of MERS-CoV antigens include viral antigens encoded by structural protein genes: spike (S), envelope (E), membrane (M), and nucleocapsid (N). MERS-CoV also expresses polymerase. The spike (S) protein aggregates to form a trimer, creating a peplomer on the surface of the viral particle that gives its name to the Coronaviridae family. Typically, an immunogen or vaccine comprising the CD40-targeted polypeptide (a polypeptide for or targeting CD40 on an antigen-presenting cell) of the present invention comprises only the viral S protein or only the S1 protein epitope, and does not include, for example, epitopes derived from other MERS-CoV antigens, and an S1-specific immunogen does not include the S2 epitope. However, in some embodiments, such a vaccine may substitute or include one or more other antigens or epitopes of non-S1 MERS-CoV antigens as part of the CD40-targeted polypeptide or as a separate component of the immunogenic composition or vaccine.

[0302] In addition to MERS-CoV, other types of human coronaviruses are known. These include 229E (alpha coronavirus), NL63 (alpha coronavirus), OC43 (beta coronavirus), HKU1 (beta coronavirus), and SARS-CoV (beta coronavirus that causes severe acute respiratory syndrome, i.e., SARS) and SARS-CoV-2 (coronavirus that causes COVID-19). The viral proteins of these other coronaviruses (such as the coronavirus S protein) that are involved in the recognition, attachment, and entry of human host cells can be substituted for the S or S1 protein of MERS-CoV in the polypeptides according to the present invention. Combined with the CD40 ligand, these polypeptides may provide substantial immunity against coronaviruses and reduce the severity of vaccine-related side effects, such as vaccine-induced inflammation or immunological hypersensitivity to exogenous antigens.

[0303] Animal coronaviruses include infectious bronchitis virus (IBV), which causes infectious bronchitis in avian birds; swine coronavirus (infectious gastroenteritis virus of pigs, TGEV); bovine coronavirus (BCV), which causes widespread severe enteritis in calves; feline coronavirus (FCoV) (another variant of the same virus), which causes moderate enteritis and severe feline infectious peritonitis in cats; two types of canine coronavirus (CCoV) (one causing enteritis and the other seen in respiratory diseases); turkey coronavirus (TCV), which causes enteritis in turkeys; ferret enteric coronavirus, which causes epidemic catarrhal enteritis in ferrets; ferret systemic coronavirus, which causes FIP-like systemic syndrome in ferrets; panaffinity canine coronavirus; and porcine epidemic diarrhea virus (PED or PEDV), which is appearing worldwide and whose economic importance remains unclear, but which shows high mortality rates in piglets. In some embodiments, the present invention relates to an immunogenic polypeptide comprising a CD40-targeting ligand and an S1 protein analog derived from another coronavirus that replaces the MERS-CoVS1 determinant in a CD40-targeted MERS-CoVS1 fusion protein.

[0304] Other viral antigens, fragments thereof, or variants thereof include, but are not limited to, viruses derived from one of the following families: Adenoviridae, Arenaviridae, Bunyaviridae, Caliciviridae, Coronaviridae, Filoviridae, Hepadnaviridae, Herpesviridae, Orthomyxoviridae, Papovaviridae, Paramyxoviridae, Parvoviridae, Picornaviridae, Poxviridae, Reoviridae, Retroviridae, Rhabdoviridae, or Togaviridae. Viral antigens include human papillomavirus (HPV), human immunodeficiency virus (HIV), poliovirus, hepatitis B virus, hepatitis C virus, and smallpox virus (Variola major and Variola It may be derived from minor types of vaccinia virus, influenza virus, rhinovirus, dengue virus, equine encephalitis virus, rubella virus, yellow fever virus, Norwalk virus, hepatitis A virus, human T-cell leukemia virus (HTLV-I), hair cell leukemia virus (HTLV-II), California encephalitis virus, hantavirus (hemorrhagic fever), rabies virus, Ebola virus, Marburg virus, measles virus, mumps virus, respiratory syncytial virus (RSV), herpes simplex virus type I, herpes simplex virus type II, varicella-zoster virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), flavivirus, foot-and-mouth disease virus, chikungunya virus, lassa virus, arenavirus, nipah virus, or cancer-causing viruses.

[0305] The influenza virus strains used in vaccines vary seasonally. In the current interpandemic period, vaccines typically contain two influenza A strains (H1N1 and H3N2) and one influenza B strain, and trivalent vaccines are typical. The present invention may also use viruses derived from pandemic strains (i.e., strains to which vaccine recipients and the general human population are immunologically unsensitized), such as H2, H5, H7, or H9 subtype strains (in particular strains of influenza A virus), and influenza vaccines for pandemic strains may be monovalent or based on a standard trivalent vaccine supplemented with pandemic strains. However, depending on the season and the nature of the antigens contained in the vaccine, the present invention may provide protection against one or more of the influenza A virus hemagglutinin subtypes H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, or H16. The present invention can provide protection against one or more of the influenza A virus NA subtypes N1, N2, N3, N4, N5, N6, N7, N8, or N9.

[0306] The adjuvant compositions of the present invention are suitable for immunization against inter-pandemic strains and are useful for immunization against pandemic strains. Characteristics of influenza strains that have the potential to cause a global pandemic include (a) a new hemagglutinin compared to the hemagglutinins of currently circulating human strains, i.e., one that has not been identified in human populations for more than 10 years (e.g., H2), or one that has never been seen in human populations before (e.g., H5, H6, or H9, which were generally only found in avian populations), and therefore the human population is immunologically insensitive to the hemagglutinin of this strain; (b) the ability to be transmitted horizontally in human populations; and (c) pathogenic to humans. Viruses with the H5 hemagglutinin type are preferred for immunization against pandemic influenza strains such as H5N1. Other available strains include H5N3, H9N2, H2N2, H7N1, and H7N7, as well as other emerging potential pandemic strains. Within the H5 subtype, viruses can be classified into HA clade 1, HA clade 1', HA clade 2, or HA clade 3, with clades 1 and 3 being particularly related.

[0307] Other strains that may be usefully included in the composition are strains resistant to antiviral therapy (e.g., resistant to oseltamivir

[22] and / or zanamivir), including resistant pandemic strains.

[0308] The composition of the present invention may contain antigens from one or more (e.g., one, two, three, or four or more) influenza virus strains, including influenza A virus and / or influenza B virus. Monovalent vaccines are undesirable, and when a vaccine contains more than one influenza strain, the strains are typically grown separately, the viruses are recovered, and the antigens are prepared before being mixed. Therefore, the process of the present invention may include a step of mixing antigens derived from more than one influenza strain. A trivalent vaccine containing two influenza A virus strains and one influenza B virus strain is preferred.

[0309] In some embodiments of the present invention, the composition may contain an antigen derived from a single influenza A strain. In some embodiments, the composition may contain antigens derived from two influenza A strains, provided that these two strains are not H1N1 and H3N2. In some embodiments, the composition may contain antigens derived from more than two influenza A strains.

[0310] Influenza viruses can be reassortant strains and may be obtained by reverse genetics techniques. Reverse genetics techniques [e.g. 24-28] make it possible to prepare influenza viruses with desired genomic segments in vitro using plasmids. Typically, this involves expressing (a) a DNA molecule encoding a desired viral RNA molecule, such as a poll promoter, and (b) a DNA molecule encoding a viral protein, such as a polII promoter, so that by expressing both types of DNA in cells, an assembly of completely intact infectious viral particles is obtained. The DNA preferably provides all of the viral RNA and protein, but it is also possible to use a helper virus to provide some of the RNA and protein. Plasmid-based methods using separate plasmids to produce each viral RNA are preferred [29-31]. These methods also involve the use of plasmids to express all or some of the viral proteins (e.g., only PB1, PB2, PA, and NP proteins), and some methods use 12 plasmids.

[0311] In addition to containing diphtheria toxoid, tetanus toxoid, pertussis toxoid, and / or poliovirus antigen, the immunogenic composition of the present invention may contain further pathogen-derived antigens. For example, these antigens may be HBsAg, conjugated Hib capsule sugar, conjugated meningococcal capsule sugar (one or more of serotypes A, C, W135, and / or Y), or conjugated S. pnetimonide capsule sugar. For example, any of the preferred antigenic components PEDIARIX, MENVEO, MENACTRA, NIMENRIX, PREVNAR, or SYNFLORIX may be used.

[0312] Antigens are cellular pathogens of bacterial or fungal origin, or derived from them, such as Actinobacillus pluprneumonier, Pasteurella multocida, Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Salmonella, Sigella, Yersinia, Campylobacter, Clostridium, Vibrio and Giardia, Entamoeba and Cryptosporidium.

[0313] In certain embodiments, at least one antigen comprises a bacterial cell, preferably a live bacterium, a weakened bacterium, or an inactivated bacterium. In the context of the present invention, the bacterial cell may comprise a whole cell, a fraction of a cell, or its debris or pellet.

[0314] In one embodiment, the bacterial cells are Salmonella, preferably selected from strains of Salmonella enteritidis, Salmonella kentucky, Salmonella tiphimulium, Salmonella heidelberg, or a combination thereof. More specifically, the antigen comprises several different bacterial cells, more preferably various strains of Salmonella, and / or combinations thereof. In a preferred embodiment, the antigen comprises at least two different Salmonella cells selected from Salmonella enteritidis, Salmonella tiphimulium, and Salmonella kentucky.

[0315] Non-limiting examples of bacterial antigens include inactivated or attenuated preparations of at least one bacterium selected from the group consisting of Haemophilus influenzae, Streptococcus pneumoniae, Bordetella pertussis, Clostridium tetani, Neisseria diphtheriae, Mycobacterium tuberculosis, Escherichia coli such as enterohemorrhagic Escherichia coli, Vibrio cholerae, Salmonella, and methicillin-resistant Staphylococcus aureus, or some of these or their components.

[0316] Non-specific examples of allergens include pollen (such as cedar pollen, grass pollen, and daisy pollen), fungi, insects, foods (such as soybeans, eggs, and milk), and drugs (such as penicillin).

[0317] According to further embodiments of the present invention, the antigen is a pathogen selected from the group consisting of bacteria or viruses such as Chlamydia, Clostridium, Brucella, and Yersinia, particularly outer membrane protein 2 (OMP2), class I accessible protein 1 (Cap1), cysteine-rich protein A (CrpA), Chlamydia polymorphic membrane proteins (Pmps), specifically PmpA to Pmpl, Chlamydia heat shock protein 60 (HSP60), Chlamydia heat shock protein 10 (HSP10), Chlamydia protease-like activator (CPAF), and Yersinia pseudotuberculosis (Y The pathogen originates from a pathogen selected from the group consisting of opD) or its homologue, enolase, arginine-binding protein (ArtJ), type V ATP synthase subunit A (AtpA), peptidyl-prolyl cis-trans isomerase (Mip), glycogen synthase (GlgA), iron-binding protein (YtgA), type V ATP synthase subunit E (AtpE), type III secretory chaperone (SycD), type III secretory protein SctC or SctJ, tetanus toxoid, herpes simplex virus, varicella-zoster virus, or any combination, fragments, or derivatives thereof.

[0318] Cancer vaccines are designed to treat cancer by enhancing the body's innate ability to defend itself through the immune system. They have always presented a very attractive treatment approach, especially given the many shortcomings of conventional surgery, radiation, and chemotherapy in cancer management. However, the effectiveness of such cancer vaccines remains low due to the low immunogenicity of cancer carbohydrate antigens and the fact that many systemic vaccines primarily induce IgM antibodies, with fewer induced IgG antibodies. Various approaches, such as the use of adjuvants to aid in immune recognition and activation, are being studied.

[0319] Among the reported tumor-associated glycans, the glycolipid antigen Globo H (Fuc.alpha.1.fwdarw.2 Gal.beta.1.fwdarw.3 GalNAc.beta.1.fwdarw.3 Gal.alpha.1.fwdarw.4 Gal.beta.1.fwdarw.4 Glc) was first isolated and identified in 1984 by Hakomori et al. from breast cancer MCF-7 cells (Bremer EG, et al. (1984) J Biol Chem 259:14773-14777). Further studies of anti-globo H monoclonal antibodies have shown that globo H is present in many other cancers, including prostate, gastric, pancreatic, lung, ovarian, and colon cancers, and is expressed only minimally on the luminal surface of normal secretory tissues that cannot easily access the immune system (Ragupathi G, et al. (1997) Angew Chem Int Ed 36:125-128). In addition, it has been shown that the serum of breast cancer patients contains high levels of anti-globo-H antibodies (Gilewski T et al. (2001) Proc Natl Acad Sci USA 98:3270-3275; Huang CY, et al. (2006) Proc Natl Acad Sci USA 103:15-20; Wang CC, et al. (2008) Proc Natl Acad Sci USA 105(33):11661-11666), and patients with globo-H positive tumors showed shorter survival times compared to patients with globo-H negative tumors (Chang, YJ, et al. (2007) Proc Natl Acad Sci USA 104(25):10299-10304). Based on these findings, globo-H, a hexasaccharide epitope, is an attractive tumor marker and a feasible target for cancer vaccine development.

[0320] Other vaccines and antigens contained herein that can be used in the compositions, combinations, and methods described herein include the following: ● Adenovirus ●Anthrax · AVA (BioThrax) ● Cholera ·Vaxchora ● Diphtheria • DTaP (Daptacel, Infanrix) • Td (Tenivac, generic) ·DT (Generic) • Tdap (Adacel, Boostrix) ·DTaP-IPV (Kinrix, Quadracel) · DTaP-HepB-IPV (Pediarix) · DTaP-IPV / Hib (Pentacel) ●Hepatitis A · HepA (Havrix, Vaqta) · HepA-HepB (Twinrix) ●Hepatitis B ·HepB (Engerix-B, Recombivax HB, Heplisav-B) · DTaP-HepB-IPV (Pediarix) · HepA-HepB (Twinrix) ● Haemophilus influenzae type b (Hib) ·Hib(ActHIB, PedvaxHIB, Hiberix) · DTaP-IPV / Hib (Pentacel) ● Human papillomavirus (HPV) • HPV9 (Gardasil9) (In scientific papers, the preferred abbreviation is 9vHPV) ●Whooping cough • DTaP (Daptacel, Infanrix) • Tdap (Adacel, Boostrix) ·DTaP-IPV (Kinrix, Quadracel) · DTaP-HepB-IPV (Pediarix) · DTaP-IPV / Hib (Pentacel) ●Pneumococcus PCV13 (Prevnar13) PPSV23 (Pneumovax23) ● Polio • Polio (Ipol) ·DTaP-IPV (Kinrix, Quadracel) · DTaP-HepB-IPV (Pediarix) · DTaP-IPV / Hib (Pentacel) ●Rabies ·Rabies (Imovax Rabies, RabAvert) ● Rotavirus ·RV1 (Rotarix) RV5 (RotaTeq) ●Rubella · MMR (MMR II) ·MMRV(ProQuad) ● Herpes zoster · RZV (Shingrix) ●Smallpox ·Vaccinia (ACAM2000): ● Seasonal influenza (Flu) only ·IIV* (Afluria, Fluad, Flublok, Flucelvax, FluLaval, Fluarix, Fluvirin, Fluzone, Fluzone high dose, Fluzone intradermal) *Inactivated flu vaccines have various acronyms - IIV3, IIV4, RIV3, RIV4, and ccIIV4. · LAIV (FluMist) ● Japanese encephalitis · JE (Ixiaro) ●Measles · MMR (MMR II) ·MMRV(ProQuad) ●Meningococcus MenACWY (Menactra, Menveo) ·MenB (Bexsero, Trumenba) ● Mumps · MMR (MMR II) ·MMRV(ProQuad) ●Tetanus • DTaP (Daptacel, Infanrix) • Td (Tenivac, generic) ·DT (Generic) • Tdap (Adacel, Boostrix) ·DTaP-IPV (Kinrix, Quadracel) · DTaP-HepB-IPV (Pediarix) · DTaP-IPV / Hib (Pentacel) ●Tuberculosis ● Typhoid fever • Typhoid (Vivotif) taken orally ·Typhoid polysaccharide (Typhim Vi) ●Chickenpox · VAR (Varivax) • MMRV (ProQuad): ● Yellow fever • YF (YF-Vax)

[0321] Other adjuvants and ingredients Other adjuvants can be used in conjunction with the chemicals described herein having formula I, etc., and include aluminum hydroxide and aluminum phosphate, saponins, e.g., Quil A, QS-21 (Cambridge Biotech Inc., Cambridge Mass.), GPI-0100 (Galenica Pharmaceuticals, Inc., Birmingham, Ala.), water-in-oil emulsions, oil-in-water emulsions, and water-in-oil-in-water emulsions. The emulsions may be based particularly on light liquid paraffin oil (European Pharmacopoeia type); isoprenoid oils such as squalane or squalene; oils resulting from the oligomerization of alkenes, particularly isobutene or decene; esters of acids or alcohols containing linear alkyl groups, more specifically vegetable oils, ethyl oleate, propylene glycol di-(caprylate / caprate), glyceryl tri-(caprylate / caprate) or propylene glycol dioleate; and esters of branched-chain fatty acids or alcohols, particularly isostearate esters. Oils are used in combination with emulsifiers to form emulsions. The emulsifiers are preferably nonionic surfactants, particularly sorbitan esters, mannide esters (e.g., anhydrous mannitol oleate), glycol esters, polyglycerol esters, propylene glycol esters, optionally ethoxylated oleic acid, isostearic acid, ricinoleic acid or hydroxystearic acid esters, and polyoxypropylene-polyoxyethylene copolymer blocks, particularly Pluronic products, especially L121. See Hunter et al., The Theory and Practical Application of Adjuvants (Ed. Stewart-Tull, DES). John Wiley and Sons, NY, pp 51-94 (1995) and Todd et al., Vaccine 15:564-570 (1997).For example, the SPT emulsion described on page 147 of "Vaccine Design, The Subunit and Adjuvant Approach," edited by M. Powell and M. Newman, Plenum Press, 1995, and the emulsion MF59 described on page 183 of the same book can be used. Further preferred adjuvants include, but are not limited to, the RIBI adjuvant system (Ribi Inc.) block copolymer (CytRx, Atlanta GA), SAF-M (Chiron, Emeryville Calif.), monophosphoryl lipid A, abridine lipid-amine adjuvants, heat-unstable enterotoxins (recombinant or otherwise) derived from E. coli, cholera toxin, IMS1314, or muramyl dipeptide. Among the copolymers of maleic anhydride and alkenyl derivatives is copolymer EMA (Monsanto), which is a copolymer of maleic anhydride and ethylene. Dissolving these polymers in water yields an acidic solution, which is neutralized to preferably a physiological pH, thereby obtaining an adjuvant solution into which the immunogenic, immunological, or vaccine composition itself is incorporated.

[0322] In one aspect of the present invention, pharmaceutically acceptable carriers are adjuvants selected from the group consisting of aluminum hydroxide, aluminum phosphate, saponins, water-in-oil emulsions, oil-in-water emulsions, water-in-oil emulsions, polymers of acrylic acid or methacrylic acid, copolymers of maleic anhydride and alkenyl derivatives, RIBI adjuvants, block copolymers, SAF-M, monophosphoryl lipid A, abridine lipid-amines, heat-unstable enterotoxins derived from Escherichia coli (recombinant or otherwise), cholera toxin, IMS1314, muramyl dipeptide, and combinations thereof. Therefore, according to one embodiment, the present application provides an immunogenic composition comprising: a) one or more antigens of M. hyorhinis; and one or more antigens of M. hyosynoviae; and b) a pharmaceutically acceptable carrier, which is an adjuvant selected from the group consisting of aluminum hydroxide, aluminum phosphate, saponin, water-in-oil emulsion, oil-in-water emulsion, water-in-oil emulsion, polymer of acrylic acid or methacrylic acid, copolymer of maleic anhydride and alkenyl derivatives, RIBI adjuvant systems, block copolymers, SAF-M, monophosphoryl lipid A, abridine lipid-amine, heat-unstable enterotoxin derived from Escherichia coli (recombinant or otherwise), cholera toxin, IMS1314, muramyl dipeptide, and combinations thereof. Such a vaccine may also contain one or more antigens of M. hyopneumoniae. Furthermore, one or more mycoplasma antigens of such mycoplasma species may be provided as an inactivated bacterin as described herein above.

[0323] Further examples of adjuvants are polymers of acrylic or methacrylic acid, and compounds selected from copolymers of maleic anhydride and alkenyl derivatives. Favorable adjuvant compounds are polymers of acrylic or methacrylic acid crosslinked with polyalkenyl ethers of sugars or polyalcohols. These compounds are known by the term carbomer (Pharmeuropa Vol. 8, No. 2, June 1996). Those skilled in the art can also refer to U.S. Patent No. 2,909,462, which describes such acrylic polymers crosslinked with polyhydroxylated compounds having at least three, preferably eight or fewer, hydroxyl groups, where at least three hydroxyl hydrogen atoms are substituted by unsaturated aliphatic radicals having at least two carbon atoms. Preferred radicals are those containing two to four carbon atoms, such as vinyl, allyl, and other ethylenically unsaturated groups. The unsaturated radicals may themselves contain other substituents such as methyl. Products marketed under the name CARBOPOL.RTM. (BF Goodrich, Ohio, USA) are particularly suitable. These are polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycol, or allyl clucrose or allyl pentaerythritol. Among these, CARBOPOL.RTM.974P, 934P, and 971P are examples. The use of CARBOPOL.RTM.971P is most preferred.

[0324] Surfactants are typically selected, combined, or used under conditions that result in an appropriate hydrophilic-lipophilic ratio (HLB) for the dosage form. The HLB of a surfactant or combination of surfactants is a measure of the degree of hydrophilicity or lipophilicity, determined by calculating the values ​​of various regions of the molecule, as described by Griffin (Journal of the Society of Cosmetic Chemists, 1949, 1(5), 311-26 and Journal of the Society of Cosmetic Chemists, 1954, 5(4), 249-56).

[0325] Examples of surfactants used in emulsion vaccines include, but are not limited to, sorbitan monooleate (Span 80), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan sesquioleate (Span 83), lecithin and monooleic acid mannide, or mixtures thereof.

[0326] The vaccines and compositions of the present invention optionally further comprise one or more types of salts. Adding salts can suppress the penetration of water into oily particles and further stabilize the oily particles. Examples of such salts include, but are not limited to, sodium chloride, magnesium chloride, sodium sulfate, or magnesium sulfate. In certain embodiments, the salt is sodium chloride.

[0327] The composition of the present invention may further contain one or more preservatives that are acceptable in the field of veterinary medicine. Examples of preferred preservatives, but are not limited to, include acids such as benzoic acid and sorbic acid and their sodium or potassium salts; esters such as methylparaben, ethylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol, phenoxyethanol, chlorocresol and o-phenylphenol; mercury compounds such as thimerosal, nitromerzol, phenylmercury nitrate and phenylmercury acetate; and quaternary ammonium compounds such as benzalkonium chloride and cetylpyridium chloride. In preferred embodiments, the preservative is a thimerosal solution, typically a 10% thimerosal solution.

[0328] Treatment method In some embodiments, the Disclosure provides a method for promoting an immune response in a subject of need, comprising administering to the subject a therapeutically effective amount of a composition comprising a chemical substance described herein (e.g., a compound disclosed herein) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In some embodiments, the compound is selected from the group consisting of UDPS-heptose, CDPS-heptose, and ADPS-heptose.

[0329] Peritumoral injection of the chemicals described herein (e.g., UDPS-heptose) resulted in rejection of tumor growth in several mouse tumor models. The chemicals described herein (e.g., UDPS-heptose) also exhibited systemic immune-promoting functions. ALPK1 is widely expressed in humans (https: / / www.proteinatlas.org / ENSG00000073331-ALPK1 / tissue). Therefore, although we do not wish to be constrained by theory, it is conceivable that the chemicals disclosed herein may have beneficial effects in treating multiple types of cancer through the activation of ALPK1.

[0330] Accordingly, in some embodiments, the Disclosure provides a method for using chemicals described herein, such as compounds of the formulas disclosed herein, including UDPS-heptose, ADPS-heptose, and CDPS-heptose (for example, functioning as ALPK1 agonists), to treat cancer. The method comprises administering to a patient in need a therapeutically effective amount of an ALPK1 agonist selected from the group consisting of the chemicals described herein (for example, compounds of the formulas disclosed herein), or pharmaceutically acceptable salts or prodrugs thereof. In some embodiments, the ALPK1 agonist is selected from the group consisting of UDPS-heptose, ADPS-heptose, and CDPS-heptose.

[0331] Administration of the chemicals disclosed herein (e.g., compounds of the formulas disclosed herein), or pharmaceutically acceptable salts thereof, may be by any of the acceptable methods of administration, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, percutaneous, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, ontologically, neuro-otological, intraocular, subconjunctival, anterior chamber injection, intravitreous, intraperitoneal, intrathecal, intrasacral, intrapleural, wound lavage, intrachuka, intraperitoneal, intraarticular, intraaural, bronchial, intrasacral, intrameningeal, inhalation, intratracheal or intrabronchial infusion, direct injection into the pulmonary cavity, intrathecal, intraarticular, intrathoracic, thoracic opening lavage, epidural, intratympanic, intrasacral, intravascular, intraventricular, intraosseous, lavage of infected bone, or application as part of any mixture with prosthetic devices. In some embodiments, the methods of administration include oral or parenteral administration.

[0332] This specification provides a method for treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of a chemical substance described herein (e.g., a compound disclosed herein), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, in combination with one or more cancer immunotherapeutic agents / immunomodulators. The cancer immunotherapeutic agents used herein are effective in enhancing, stimulating, and / or upregulating the immune response in the subject. Administering the compounds disclosed herein together with cancer immunotherapeutic agents may have a synergistic effect in cancer treatment.

[0333] In some embodiments, immunotherapeutic agents are agonists of stimulative (including costimulatory) receptors or antagonists of inhibitory (including coinhibitory) signals to immune cells (including T cells, dendritic cells, and natural killer cells), both of which result in amplification of antigen-specific T cell responses (often referred to as immune checkpoint regulators).

[0334] In some embodiments, the immunotherapy drug may include, but is not limited to, small molecule drugs, antibodies, or other biological molecules. In some embodiments, the biological immunotherapy drug may include, but is not limited to, cancer vaccines, antibodies, or genetically modified immune cells for therapeutic use. In some embodiments, the genetically modified immune cells for therapeutic use may be chimeric antigen receptor T cells (CAR-T), chimeric antigen receptor natural killer cells (CAR-NK), or T cell receptor genetically modified T cells (TCR-T). In some embodiments, the biological immunotherapy drug is an antibody. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is humanized.

[0335] In some embodiments, the antibody is an agonist of a stimulating (including co-stimulating) ligand / receptor to immune cells. In some embodiments, the antibody is an antagonist of an inhibitory (including co-inhibitory) ligand / receptor to immune cells.

[0336] In some embodiments, stimulant or inhibitory ligands / receptors include, but are not limited to, members of the B7 family, including B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), B7-H6, and B7-H7.

[0337] In some embodiments, the stimulative or inhibitory ligand / receptor is CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137(4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, EDAR, Members of the TNF / TNF receptor family include, but are not limited to, XEDAR, TACI, APRIL, BCMA, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNF-R1, lymphotoxin α / TNFβ, TNFR2, TNFa, LTBR, ​​lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0338] The T cell response involves anti-CD40 antibodies as described herein, such as 3C3 and 3G5, and one or more antagonists (inhibitors or blockers) of proteins that inhibit T cell activation, such as CTLA-4, PD-1, PD-L1, PD-L2, and LAG-3 (e.g., immune checkpoint inhibitors), as well as the following proteins: TIM-3, galectin-9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, and GPR5. 6. It can be stimulated in combination with any of the following: VISTA, B7-H3, B7-H4, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM4-4, and / or one or more agonists of proteins that stimulate T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, CD70, CD27, CD40, DR3, and CD28H.

[0339] In some embodiments, the inhibitory ligand / receptor is selected from PD-1, PD-L1, PD-L2, CTLA4, LAG-3, TIM-3, VISTA, and TIGIT. In some embodiments, the inhibitory ligand / receptor is selected from PD-1, PD-L1, and CTLA4. In certain embodiments, the inhibitory ligand / receptor is PD-1 or PD-L1.

[0340] In some embodiments, the stimulating ligand / receptor is selected from B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H. In a particular embodiment, the stimulating ligand / receptor is 4-1BB (CD137), 4-1BBL, OX40, or OX40L.

[0341] In some embodiments, the antibody is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, semiprimab, camrelizumab, tisrelizumab, BMS-936559, atezolizumab, durvalumab, and avelumab. In some embodiments, the antibody is nivolumab or pembrolizumab. In some embodiments, the immune checkpoint is CTLA-4. In some embodiments, the antibody is ipilimumab. In some embodiments, the immune checkpoint is TIGIT.

[0342] In some embodiments, the immunotherapy is a therapeutic genetically modified immune cell, which is a chimeric antigen receptor T cell (CAR-T), a chimeric antigen receptor natural killer cell (CAR-NK), or a T cell receptor genetically modified T cell (TCR-T). In some embodiments, the CAR-T therapy is Kymriah (tisagenlecleucel), Yescarta (axicabutagensilolucel), or Tecartas (brexcabutagenautolucel).

[0343] Examples of immunotherapies that can be modified and combined with those described herein to treat cancer include Yervoy® (ipilimumab) or tremelimumab (for CTLA-4), galiximab (for B7.1), BMS-936558 / nivolumab (for PD-1), MK-3475 / pembrolizumab (for PD-1), AMP224 (for B7DC), B MS-936559 (for B7-H1), MPDL3280A / Atezolizumab (for B7-H1), MEDI-570 (for ICOS), AMG557 (for B7H2), MGA271 (for B7H3) , IMP321 (for LAG-3), BMS-663513 (for CD137), PF-05082566 (for CD137), CDX-1127 (for CD27), anti-OX40 (Providence Examples include Health Services, huMAbOX40L (for OX40L), ataxept (for TACI), CP-870893 (for CD40), lucatumumab (for CD40), dasetuzumab (for CD40), muromonab-CD3 (for CD3), and ipilumumab (for CTLA-4).

[0344] In some embodiments, the compound is selected from the group consisting of compounds of the formulas disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof. In some embodiments, the ALPK1 agonist is selected from the group consisting of UDPS-heptose, ADPS-heptose, and CDPS-heptose.

[0345] Therefore, in some embodiments, the types of cancer include, but are not limited to, the following.

[0346] 1) Breast cancer, e.g., ER + Breast cancer, ER - Breast cancer, HER2 - Breast cancer, HER2 +Breast cancer, stromal tumors such as fibroadenoma, phyllodes tumor and sarcoma, and epithelial tumors such as macrotubular papilloma; cell tumors of the breast, such as in situ (non-invasive) cell tumors including in situ ductal carcinoma (including Paget's disease) and in situ lobular carcinoma, and invasive (invasive) cell tumors including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma and invasive papillary carcinoma; and various malignant neoplasms. Further examples of breast cancer include luminal A, luminal B, basal A, basal B, and triple-negative breast cancer (estrogen receptor negative (ER)). ー ), progesterone receptor negative, and HER2 negative (HER2 ー Examples include: ) ) ). In some embodiments, breast cancer may have a high-risk oncotype score.

[0347] 2) Cardiac cancers, such as sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas.

[0348] 3) Lung cancer, such as bronchogenic lung cancer (squamous cell, anaplastic small cell, anaplastic large cell, and adenocarcinoma), alveolar carcinoma and bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrotoxic hamartoma and mesothelioma.

[0349] 4) Gastrointestinal cancers, such as esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma); gastric cancer (e.g., cell tumor, lymphoma, and leiomyosarcoma); pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, and VIP-producing tumor); small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma); and colorectal cancer (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, and leiomyoma).

[0350] 5) Cancers of the genitourinary tract, such as cancers of the kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, and leukemia); cancers of the bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma); cancers of the prostate (adenocarcinoma and sarcoma); cancers of the testes (seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell tumor, fibroma, fibroadenoma, adenomatous tumor, and lipoma).

[0351] 6) Liver cancers, such as hepatoma (hepatocellular carcinoma, etc.); cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.

[0352] 7) Bone cancers, such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (chondrodystostoma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid, and giant cell tumor.

[0353] 8) Cancers of the nervous system, such as cancers of the skull (osteoma, hemangioma, granuloma, xanthomas and degenerative osteitis, etc.); cancers of the meninges (meningioma, meningiosarcoma and gliomas, etc.); cancers of the brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma and congenital tumors, etc.); cancers of the spinal cord (neurofibroma, meningioma, glioma and sarcoma, etc.).

[0354] 9) Gynecological cancers, such as uterine cancer (endometrial cancer, etc.); cervical cancer (cervical cancer and preneoplastic cervical dysplasia, etc.); ovarian cancers, such as ovarian cancer, such as serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cell tumor, granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor and malignant teratoma; vulvar cancers (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma and melanoma, etc.); vaginal cancers (clear cell carcinoma, squamous cell carcinoma, staphylosarcoma and embryonal rhabdomyosarcoma, etc.); and cancers of the Fallopian tube (cell tumors, etc.).

[0355] 10) Hematological cancers, such as blood cancers (acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma and myelodysplastic syndromes, Hodgkin lymphoma, non-Hodgkin lymphoma (malignant lymphoma), and Waldenström macroglobulinemia, etc.).

[0356] 11) Skin cancers and skin disorders, such as malignant melanoma and metastatic melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid and scleroderma.

[0357] 12) Adrenal cancer, such as neuroblastoma.

[0358] Cancer can also arise as diffuse tissue, like leukemia. Therefore, the term “tumor cell” as provided herein includes cells suffering from any one of the disorders identified above.

[0359] In certain embodiments, cancer is metastatic. In certain embodiments, cancer is refractory.

[0360] In certain embodiments, cancers include neuroblastoma, intestinal cancers such as rectal cancer, colon cancer, familial adenomatous colorectal cancer and hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, peritoneal cancer, soft tissue sarcoma, urothelial carcinoma, sweat gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, pancreatic cancer, hepatocellular carcinoma, prostate cancer, testicular cancer, breast cancer including HER2-negative cancers, bladder cancer, melanoma, brain cancers such as glioblastoma, astrocytoma, meningioma, and medulla The group consists of blastomas and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia / lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, multiple myeloma, seminoma, osteosarcoma, chondrosarcoma, anal canal cancer, adrenocortical carcinoma, chordoma, fallopian duct cancer, gastrointestinal stromal tumors, myeloproliferative disorders, mesothelioma, biliary tract cancer, Ewing's sarcoma, and other rare tumor types.

[0361] In certain embodiments, cancer is selected from the group consisting of brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, hepatocellular carcinoma, prostate cancer, colorectal cancer, hematological cancer, lung cancer, and bone cancer. In certain embodiments, cancer is selected from the group consisting of small cell lung cancer, non-small cell lung cancer, colorectal cancer, melanoma, renal cell carcinoma, head and neck cancer, Hodgkin lymphoma, or bladder cancer.

[0362] In certain embodiments, the methods described herein may further include the application of one or more additional cancer therapies. These additional therapies may include, but are not limited to, surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, hepatitis B vaccine, Oncophage, Provenge), and gene therapy, as well as combinations thereof. Immunotherapy may include, but is not limited to, adoptive cell therapy, induction of hepatocytes and / or dendritic cells, transfusion, lavage, and / or other treatments (including, but not limited to, tumor cryopreservation).

[0363] In some embodiments, the Disclosure provides a method for treating an immune or inflammation-related disorder in a subject in need, comprising administering to the subject a therapeutically effective amount of a composition comprising a chemical substance described herein (e.g., a compound of a formula disclosed herein), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof (e.g., UDPS-heptose, ADPS-heptose, CDPS-heptose, TDPS-heptose, or a derivative thereof). In some embodiments, the compound is selected from the group consisting of UDPS-heptose, CDPS-heptose, and ADPS-heptose.

[0364] Non-exclusive examples of immune or inflammation-related diseases include inflammatory bowel disease (IBD), which is a polygenic chronic inflammatory state, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn's disease (CD), and ulcerative colitis (UC). In certain embodiments, the disease is inflammatory bowel disease (IBD). In certain embodiments, the disease is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapy agents, colitis induced by adoptive cell therapy, colitis associated with one or more alloimmune diseases (such as graft-versus-host diseases including acute and chronic graft-versus-host diseases), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In these specific embodiments, the conditions are alloimmune diseases (such as graft-versus-host diseases including acute and chronic graft-versus-host diseases), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis, or intestinal mucositis).

[0365] In certain embodiments, immune or inflammation-related diseases are autoimmune diseases. Non-limiting examples of autoimmune diseases include arthritis (including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, and psoriatic arthritis), multiple sclerosis, myasthenia gravis, systemic lupus erythematosus, autoimmune thyroiditis (e.g., Hashimoto's thyroiditis), dermatitis (including atopic dermatitis and eczematous dermatitis), psoriasis, Sjögren's syndrome (including keratoconjunctivitis sicca secondary to Sjögren's syndrome), alopecia areata, allergic responses due to arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, These include allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drug eruption, leprosy reversal reaction, erythema nodosum with leprosy, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral sensorineural hearing loss, aplastic anemia, pure red cell aplasia, idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis, chronic active hepatitis, Stevens-Johnson syndrome, idiopathic sprue, lichen planus, Crohn's disease, Graves' ophthalmopathy, sarcoidosis, primary biliary cirrhosis, posterior uveitis, and interstitial pulmonary fibrosis.

[0366] In some embodiments, the Disclosure provides a method for promoting a systemic immune response in a subject in need, comprising administering to the subject a therapeutically effective amount of a chemical substance described herein (e.g., a compound of a formula disclosed herein), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof (e.g., UDPS-heptose, ADPS-heptose, CDPS-heptose, TDPS-heptose, or a derivative thereof).

[0367] In some embodiments, the Disclosure provides a method for inducing cytokine production and / or NF-κB pathway activation in a subject of need, comprising administering to the subject a therapeutically effective amount of a chemical substance described herein (e.g., a compound of a formula disclosed herein), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof (e.g., UDPS-heptose, ADPS-heptose, CDPS-heptose, TDPS-heptose, or a derivative thereof).

[0368] Accordingly, in some embodiments, the present disclosure provides methods for treating diseases or disorders related to NF-κB, p38, and / or JNK cell signaling pathways in subjects of interest. In certain embodiments, suppression or impairment of the NF-κB pathway, p38, and JNK cell signaling contributes to the pathogenesis and / or symptoms and / or progression of a disease.

[0369] In certain embodiments, the disease or disorder is an autoimmune disease, such as chronic rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis, Sjögren's syndrome, vasculitis, antiphospholipid antibody syndrome, Still's disease, Behçet's disease, polyarteritis nodosa, ulcerative colitis, Crohn's disease, chronic active hepatitis, glomerulonephritis and chronic nephritis, chronic pancreatitis, gout, atherosclerosis, multiple sclerosis, arteriosclerosis, endothelial hypertrophy, psoriasis, psoriatic arthritis, contact dermatitis, atopic dermatitis, allergic diseases, For example, hay fever, asthma, bronchitis, interstitial pneumonia, lung diseases with granulomas, chronic obstructive pulmonary disease, chronic pulmonary thromboembolism, inflammatory bowel disease, insulin resistance, obesity, diabetes and its complications (nephropathy, retinopathy, neuropathy, hyperinsulinemia, arteriosclerosis, hypercentioma, peripheral vascular occlusion, etc.), diseases with abnormal vascular proliferation, such as hyperlipidemia, retinopathy and pneumonia, Alzheimer's disease, encephalomyelitis, acute hepatitis, chronic hepatitis, drug-induced toxic liver injury, alcoholic hepatitis, viral hepatitis, jaundice, cirrhosis, liver failure, and atrial fibrillation. Myxoma, Castleman disease, mesangial nephritis, kidney cancer, lung cancer, liver cancer, breast cancer, uterine cancer, pancreatic cancer, other solid tumors, sarcoma, osteosarcoma, metastatic invasion of cancer, malignant transformation of inflammatory foci, cancer cachexia, cancer metastasis, leukemia, e.g., acute myeloblastic leukemia, multiple myeloma, Rennard lymphoma, malignant lymphoma, development of cancer resistance, malignant transformation of foci, e.g., viral hepatitis and cirrhosis, malignant transformation from colon polyps, brain tumors, neurotumors, endotoxin shock, sepsis, cytomegalovirus The following conditions are selected from the group consisting of pneumonia, cytomegalovirus retinopathy, adenovirus flu, adenovirus pharyngoconjunctival fever, adenovirus ophthalmitis, conjunctivitis, AIDS, uveitis, diseases or complications induced by other bacterial, viral and fungal infections, postoperative complications such as generalized inflammatory syndrome, restenosis after percutaneous coronary intervention, reperfusion injury after vascular occlusion, such as ischemia-reperfusion injury, rejection of organ transplants and perfusion disorders of the heart, liver, kidneys, etc., itching, loss of appetite, malaise, and chronic fatigue syndrome.

[0370] In certain embodiments, the disease or disorder is selected from the group consisting of tuberculosis, meningitis, pneumonia, ulcers, sepsis, rhinitis, asthma, allergies, COPD, inflammatory bowel disease, arthritis, obesity, radiation-induced inflammation, psoriasis, atopic dermatitis, non-alcoholic steatohepatitis (NASH), Alzheimer's disease, systemic lupus erythematosus (SLE), autoimmune thyroiditis (Graves' disease), multiple sclerosis, ankylosing spondylitis, actinic keratosis, ulcerative colitis, Crohn's disease, alopecia areata, and diseases and disorders caused by hepatitis C virus (HCV), hepatitis B virus (HBV), or human immunodeficiency virus (HIV).

[0371] In some embodiments, the Disclosure provides a method for treating a disease in which suppressed or impaired ALPK1 signaling contributes to its pathogenesis and / or symptoms and / or progression, comprising administering to a subject in need of treatment an effective amount of a chemical substance described herein (e.g., a compound of a formula disclosed herein), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof (e.g., UDPS-heptose, ADPS-heptose, CDPS-heptose, TDPS-heptose, or a derivative thereof). Non-limiting examples of diseases include cancer or immune or inflammatory diseases as described elsewhere in this Spec.

[0372] In some embodiments, the Disclosure provides a therapeutic method comprising administering an effective amount of a chemical substance described herein (e.g., a compound of a formula disclosed herein), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof (e.g., UDPS-heptose, ADPS-heptose, CDPS-heptose, TDPS-heptose, or a derivative thereof) to a subject having a disease in which suppressed or impaired ALPK1 signaling contributes to the pathogenesis and / or symptoms and / or progression of the disease. Non-limiting examples of diseases include cancer or immune or inflammatory diseases as described elsewhere in this Spec.

[0373] In some embodiments, the present disclosure provides a therapeutic method comprising administering to a subject a chemical substance described herein (e.g., a compound of a formula disclosed herein), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof (e.g., UDPS-heptose, ADPS-heptose, CDPS-heptose, TDPS-heptose, or a derivative thereof), wherein the chemical substance is administered in an effective amount to treat a disease in which suppressed or impaired ALPK1 signaling contributes to the pathogenesis and / or symptoms and / or progression of the disease, thereby providing a method for treating the disease. Non-limiting examples of diseases include cancer or immune or inflammatory diseases as described elsewhere in this specification.

[0374] Enhanced vaccine effectiveness In another embodiment, the Disclosure provides a method for enhancing the efficacy of a vaccine, comprising administering a therapeutically effective amount of a chemical substance described herein (e.g., a compound of a formula disclosed herein), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In some embodiments, the compound is selected from the group consisting of UDPS-heptose, CDPS-heptose, and ADPS-heptose. In some embodiments, the vaccine is a cancer vaccine. In some embodiments, the vaccine is a bacterial vaccine. In some embodiments, the vaccine is a viral vaccine. In some embodiments, the vaccine is a parasitic vaccine.

[0375] Methods for enhancing innate immunity in a subject in need are also provided herein, comprising administering to the subject a therapeutically effective amount of a chemical substance described herein (e.g., a compound of a formula disclosed herein), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In some embodiments, the compound is selected from the group consisting of UDPS-heptose, CDPS-heptose, and ADPS-heptose.

[0376] Methods for enhancing innate immunity in a subject in need are also provided herein, comprising administering to the subject a therapeutically effective amount of a chemical substance described herein (e.g., a compound of a formula disclosed herein), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In some embodiments, the compound is selected from the group consisting of UDPS-heptose, CDPS-heptose, and ADPS-heptose.

[0377] In some embodiments, the vaccine contains Neisseria species (including Neisseria meningitidis and Neisseria gonorrhoeae), Escherichia species (including Escherichia coli), Klebsiella species (including Klebsiella pneumoniae), Salmonella species (including Salmonella tiphimuria), Shigella species (including Shigella shigaensis, Shigella flexinella, and Shigella sonneyi), Vibrio species (including Vibrio cholerae), Helicobacter species (including Helicobacter pylori), Pseudomonas species (including Pseudomonas aeruginosa), and Bark Genus Holderia (including Percholderia multivolans), Haemophilus (including Haemophilus influenzae), Moraxella (including Moraxella catarrhalis), Bordetella (including Bordetella pertussis), Francisella (including Bordetella tularensis), Pasteurella (including Pasteurella multocida), Legionella (including Legionella pneumophila), Borrelia (including Borrelia burgdorferi), Campylobacter (Campylobacter jezoensis) Gram-negative bacterial pathogens belonging to the genera Yersinia (including Yersinia pestis and Yersinia enterocolitica), Rickettsia (including Rickettsia rickettii), Treponema (including Treponema parsmum), Chlamydia (including Chlamydia trachomatis and Chlamydia pneumoniae), and Brucella, as well as Staphylococcus (including Staphylococcus aureus) and Streptococcus (Streptococcus pneumoniae, Streptococcus pyogenes) The composition contains, but is not limited to, antigens of infectious substances such as infectious bacteria, viruses, or parasitic pathogens, including Gram-positive bacterial pathogens belonging to the genera Listeria (including Listeria monocytogenes), Corynebacterium (including Corynebacterium diphtheriae), Enterococcus (including Enterococcus faecalis), Clostridium, and Mycobacterium (including Mycobacterium tuberculosis, Mycobacterium leprae, and Mycobacterium avium).

[0378] In some embodiments, the vaccine contains adenoviridae (including adenoviruses), herpesviridae (including Epstein-Barr virus, herpes simplex virus, cytomegalovirus, varicella-zoster virus), papillomaviridae, poxviridae (including papillomaviruses), hepadnaviridae (including hepatitis B virus), parvoviridae, astroviridae, caliciviridae, picornaviridae (including coxsackievirus, hepatitis A virus, poliovirus), coronavirusidae, flaviviridae ( The composition contains, but is not limited to, antigens of infectious agents such as pathogenic viruses including hepatitis C virus and dengue fever virus, Togaviridae (including rubella virus), Hepeviridae, Retroviridae (including HIV), Orthomyxoviridae (including influenza virus), Arenaviridae, Bunyaviridae, Filoviridae, Paramyxoviridae (including measles virus, mumps virus, parainfluenza virus, respiratory syncytial virus), Rhabdoviridae (including rabies virus), or Reoviridae.

[0379] In some embodiments, compounds of the formulas disclosed herein act as vaccine adjuvants for vaccines in the treatment or prevention of anthrax, dental caries, pneumococcal disease, polio, rabies, rubella, Chagas disease, severe acute respiratory syndrome (SARS), herpes zoster, smallpox, syphilis, dengue fever, diphtheria, ehrlichiosis, hepatitis A or B, herpes, seasonal influenza, Japanese encephalitis, leprosy, Lyme disease, malaria, measles, mumps, meningococcal diseases including meningitis and sepsis, onchocerciasis (river blindness), pertussis, schistosomiasis, scleralis, tuberculosis, tularemia, tick-borne encephalitis virus, typhoid fever, trypanosomiasis, yellow fever, or visceral leishmaniasis.

[0380] According to any of these embodiments, compounds of the formulas disclosed herein, as well as their prodrugs, analogs, and derivatives, may function as adjuvants to vaccine compositions for the treatment or prevention of diseases or disorders caused by infectious agents, or for the treatment of cancers described herein, or for the treatment of other diseases or disorders (including, for example, Alzheimer's disease) that can be treated with the vaccine composition. In one embodiment, the antigen is selected from amyloid proteins in the treatment of Alzheimer's disease. In one embodiment, the antigen is selected from glycoprotein 100 (gpl00), mucin 1 (MUC1), and melanoma-associated antigen 3 (MAGEA3) in the treatment of cancer. In one embodiment, the cancer is selected from breast cancer, ovarian cancer, hepatocellular carcinoma, or prostate cancer. In one embodiment, the cancer is HTLV-1T lymphotropic leukemia.

[0381] In some embodiments, the vaccine is a composition containing, but not limited to, antigens of infectious agents such as pathogenic fungal infections, including those caused by Candida, Aspergillus, Cryptococcus, Histoplasma, Pneumocystis, or Coccidioides.

[0382] In some embodiments for the treatment or prevention of infectious diseases, the compounds of the formulas described herein, as well as their prodrugs, analogs, and derivatives, function as adjuvants to vaccine compositions for the treatment or prevention of diseases or disorders caused by adenovirus, coxsackievirus B, Haemophilus influenzae type b (Hib), hepatitis C virus (HCV), herpesvirus, cytomegalovirus, Eastern equine encephalitis virus, hookworm, Marburg virus, norovirus, respiratory syncytial virus (RSV), rotavirus, Ebola virus, enterovirus 71, Epstein-Barr virus, human immunodeficiency virus (HIV), human papillomavirus (HPV), Salmonella tifi, Staphylococcus aureus, Streptococcus pyogenes, varicella, West Nile virus, Yersinia pestis, and Zika virus.

[0383] Combination therapy This disclosure intends to cover both monotherapy regimens and combination therapy regimens. In some embodiments, the methods described herein may further include the application of one or more additional therapies (e.g., one or more additional therapeutic agents or regimens (e.g., one or more immunotherapeutic agents and / or one or more immunotherapy regimens)) in combination with the administration of the compounds described herein. One or more additional therapeutic agents and / or regimens (e.g., immunotherapeutic agents and / or one or more immunotherapy regimens) may include examples described generally or specifically elsewhere in this specification.

[0384] In certain embodiments, the methods described herein may further include the application of one or more additional cancer therapies.

[0385] One or more additional cancer therapies may include, but are not limited to, surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, hepatitis B vaccine, Oncophage, Provenge), and gene therapy, as well as combinations thereof. Immunotherapy includes, but is not limited to, adoptive cell therapy, induction of hepatocytes and / or dendritic cells, transfusion, lavage, and / or other treatments (including, but not limited to, tumor cryopreservation).

[0386] In some embodiments, one or more additional cancer therapies are chemotherapy and may include the administration of one or more additional chemotherapeutic agents. In some embodiments, one or more additional cancer therapies are immunotherapy and may include the administration of one or more additional immunotherapeutic agents.

[0387] In certain embodiments, the additional immunotherapy component is an immunomodulatory portion such as an immune checkpoint inhibitor. In these specific embodiments, the immune checkpoint inhibitor is CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin-9-TIM3, phosphatidylserine-TIM3, lymph Sphere activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA- CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2, TMIGD2, butyrophyllines including BTNL2, members of the Siglec family, TIGIT and PVR families, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244 The target is an immune checkpoint receptor selected from the group consisting of CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 adenosine-CD39-CD73, CXCR4-CXCL12, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1). See, for example, Postow, MJClin.Oncol.2015,33,1.

[0388] In these specific embodiments, the immune checkpoint inhibitor is selected from the group consisting of urelumab, PF-05082566, MEDI6469, TRX518, valrirumab, CP-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-L1), avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, lirirumab, IPH2201, emactuzumab, INCB024360, garnicertib, urocuprumab, BKT140, bavituximab, CC-90002, bevacizumab, and MNRP1685A and MGA271.

[0389] In certain embodiments, the additional chemotherapeutic agent is an alkylating agent. Alkylating agents are so named for their ability to alkylate many nucleophilic functional groups under conditions present in cells, including but not limited to cancer cells. In further embodiments, alkylating agents include, but are not limited to, cisplatin, carboplatin, mechloretamine, cyclophosphamide, chlorambucil, ifosfamide, and / or oxaliplatin. In one embodiment, alkylating agents can function by forming covalent bonds with amino groups, carboxyl groups, sulfhydryl groups, and phosphate groups in biologically important molecules, thereby impairing cellular function, or by modifying cellular DNA. In further embodiments, alkylating agents are synthetics, semi-synthetic products, or derivatives.

[0390] In certain embodiments, the additional chemotherapeutic agent is an antimetabolite. Antimetabolites impersonate purines or pyrimidines, which are the building blocks of DNA, and generally prevent these substances from being incorporated into DNA during the "S" phase (of the cell cycle), thereby halting normal development and division. Antimetabolites can also affect RNA synthesis. In one embodiment, the antimetabolite includes, but is not limited to, azathioprine and / or mercaptopurine. In further embodiments, the antimetabolite is a synthetic, semi-synthetic, or derivative.

[0391] In certain embodiments, additional chemotherapeutic agents are plant alkaloids and / or terpenoids. These alkaloids are plant-derived and generally inhibit cell division by inhibiting microtubule function. In one embodiment, the plant alkaloids and / or terpenoids are vinca alkaloids, podophyllotoxin and / or taxanes. Vinca alkaloids generally bind to specific sites on tubulin and generally inhibit tubulin from associating with microtubules during the M phase of the cell cycle. In one embodiment, the vinca alkaloids are derived from, but are not limited to, Madagascar periwinkle and Catalanthus rosia (formerly known as Vinca rosia). In one embodiment, the vinca alkaloids include, but are not limited to, vincristine, vinblastine, vinorelbine and / or vindesine. In one embodiment, the taxanes include, but are not limited to, taxol, paclitaxel and / or docetaxel. In further embodiments, the plant alkaloid or terpenoid is a synthetic, semi-synthetic, or derivative. In further embodiments, the podophyllotoxin is etoposide and / or teniposide. In one embodiment, the taxane is docetaxel and / or ortataxel. In one embodiment, the cancer drug is topoisomerase. Topoisomerase is an essential enzyme that maintains the topology of DNA. Inhibition of type I topoisomerase or type II topoisomerase interferes with both DNA transcription and replication by disrupting proper DNA higher-order coil formation. In further embodiments, the topoisomerase is a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, the type I topoisomerase inhibitor is camptothecin. In another embodiment, the camptothecin is, but is not limited to, exatecan, irinotecan, lulutotecan, topotecan, BNP1350, CKD602, DB67 (AR67), and / or ST1481. In one embodiment, the type II topoisomerase inhibitor is, but is not limited to, epipodophyllotoxin.In further embodiments, epipodophyllotoxin is, but is not limited to, amsacrin, etoposide, etoposide phosphate, and / or teniposide. In further embodiments, topoisomerase is a synthetic, semi-synthetic, or derivative, including, but not limited to, epipodophyllotoxin, a naturally occurring substance found in the roots of Podophyllum peltatum, and other naturally occurring substances.

[0392] In certain embodiments, the additional chemotherapeutic agent is a stilbenoid. In further embodiments, stilbenoids include, but are not limited to, resveratrol, picetanol, pinosylvin, pterostilbene, α-viniferin, ampelopsin A, ampelopsin E, diptoindonesin C, diptoindonesin F, epsilon-viniferin, flexosol A, gnetin H, hemsleyanol D, hopeaphenol, trans-dyptoindonesin B, astringin, piseid, and diptoindonesin A. In further embodiments, the stilbenoid is a synthetic, semi-synthetic, or derivative.

[0393] In certain embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. In one embodiment, the cytotoxic antibiotic is, but is not limited to, actinomycin, anthracendione, anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and / or clofazimine. In one embodiment, actinomycin is, but is not limited to, actinomycin D, bacitracin, colistin (polymyxin E), and / or polymyxin B. In another embodiment, anthracendione is, but is not limited to, mitoxantrone, and / or picantrone. In further embodiments, anthracycline is, but is not limited to, bleomycin, doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin, and / or barurubicin. In further embodiments, the cytotoxic antibiotic is a synthetic, semi-synthetic, or derivative.

[0394] In certain embodiments, additional chemotherapeutic agents include abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-L-proline-t-butylamide, kaketin, semadin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'-deoxy-8'-norbin-caloicoblastine, docetaxol, docetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, and dacarbazine (DTIC). The following are selected: dactinomycin, daunorubicin, decitabine, dorastatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea taxanes, ifosfamide, rialozol, ronidamine, lomustine (CCNU), MDV3100, mechloretamine (nitrogen mustard), melphalan, isethionate mybobrin, rhizoxin, certenef, streptozocin, mitomycin, methotrexate, taxane, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, strumustine phosphate, tamoxifen, tasonelmin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunin.

[0395] In certain embodiments, additional chemotherapeutic agents include platinum, cisplatin, carboplatin, oxaliplatin, mechloretamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrin, etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide and doxorubicin. Additional drugs include, but are not limited to, mTOR (mammalian target of rapamycin) inhibitors such as rapamycin, everolimus, temsirolimus, and deforolimus.

[0396] In further embodiments, additional chemotherapeutic agents may be selected from those described in U.S. Patent No. 7,927,613 (the entirety of which is incorporated herein by reference).

[0397] In certain embodiments, additional therapeutic agents include endostatin, angiogenin, angiostatin, chemokine, angioarrestin, angiostatin (plasminogen fragment), basement membrane collagen-derived anti-angiogenic factor (tumstatin, canstatin, or arrestin), anti-angiogenic antithrombin III, signaling inhibitors, cartilage-derived inhibitors (CDI), CD59 complement fragment, fibronectin fragment, globulin β, heparinase, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon α / β / γ, interferon-inducible protein (IP-10), and interleukin. These are chemotherapy and / or immunotherapy agents selected from the group consisting of N-12, Kringle-5 (plasminogen fragment), metanoproteinase inhibitors (TIMP), 2-methoxyestradiol, placental ribonuclease inhibitors, plasminogen activator inhibitors, platelet factor-4 (PF4), prolactin 16kD fragment, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth factor-β (TGF-β), vascularostatin, vasostatin (calreticulin fragment), etc.

[0398] In certain embodiments, the additional therapeutic agent is an anti-cancer antibody. Non-limiting examples include those generally or specifically described in the table below.

[0399] [Table 1-1] [Table 1-2]

[0400] In certain embodiments, additional therapeutic agents or regimens are administered to the subject before contact with the chemical or before the chemical is administered (for example, about 1 hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

[0401] In other embodiments, the additional therapeutic agent or regimen is administered to the subject at approximately the same time as or at the same time as the chemical substance is administered. For example, the additional therapeutic agent or regimen and the chemical substance are provided to the subject simultaneously in the same dosage form. In another example, the additional therapeutic agent or regimen and the chemical substance are provided to the subject simultaneously in separate dosage forms.

[0402] In further embodiments, additional therapeutic agents or regimens are administered to the subject after contact with the chemical or after administration of the chemical (for example, about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month).

[0403] Patient selection In some embodiments, the methods described herein further include the step of identifying subjects (e.g., patients) who are in need of such treatment (e.g., by biopsy, endoscopy or other conventional methods known in the art). In certain embodiments, the ALPK1 protein can function as a biomarker for certain types of cancer, such as hepatocellular carcinoma, colon cancer, and prostate cancer. In other embodiments, identifying subjects may include assaying the tumor microenvironment of a patient for the absence of T cells and / or the presence of exhausted T cells (e.g., a patient with one or more cold cancers). Such patients may include those who are resistant to treatment with checkpoint inhibitors. In certain embodiments, such patients may be treated with the chemicals herein, for example, to mobilize T cells into the tumor, and optionally, if the T cells are exhausted, they may be further treated with one or more checkpoint inhibitors.

[0404] In some embodiments, the chemicals, methods, and compositions described herein may be administered to a particular patient population with treatment resistance (e.g., patients resistant to checkpoint inhibitors; e.g., patients with one or more cold tumors, e.g., tumors lacking T cells or patients with exhausted T cells).

[0405] Preparation of compounds As can be understood by those skilled in the art, the methods for synthesizing the compounds of the formulas described herein will be obvious to them. For example, the compounds described herein can be synthesized by using one or more of the methods described herein. Useful synthetic chemical transformations and protecting group methodologies (protection and deprotection) for synthesizing the compounds described herein are known in the art, for example, R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. The starting materials used to prepare the compounds described herein are known, prepared by known methods, or commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein can be substituted with alternative, known equivalents in the art. For example, in many reactions, triethylamine can be substituted with other bases such as non-nucleophilic bases (e.g., diisopropylethylamine, 1,8-diazabicycloundeca-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

[0406] Those skilled in the art will recognize various analytical methods that can be used to reveal the properties of the compounds described herein (for example, 1 This list will recognize (including 1H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy). The above list is a subset of, but is not intended to be limiting, of characterization methods available to those skilled in the art.

[0407] General synthesis scheme For example, compounds of formula (X) and its subformula can be synthesized as shown in schemes 1 to 11.

[0408] Preparation of Compounds of Formula I and Exemplary Compounds Compound I of formula I (compound I) can be prepared by a general synthetic method as shown in Scheme 1. Compound Ib (where R refers to a protecting group) can be obtained by reacting compound Ia with a protecting phosphorochloride under basic conditions, or with a suitable protecting phosphate under Mitsunobu reaction conditions. Compound Ib can be obtained as a mixture of α-isomers and β-isomers that can be separated by silica gel chromatography. The β-isomer of compound Ib is deprotected under H2 at 1-4 atm catalyzed with Pd / C or PtO2 to obtain compound Ic. Compound Id can be obtained by coupling compound Ic with 1,1'-carbonyldiimidazole (CDI) in a suitable solution such as N,N-dimethylformamide (DMF). Compound I can be obtained by coupling compound Ie and compound Id in a suitable solvent such as DMF at room temperature using a suitable catalyst such as zinc(II) chloride. Starting with the stereoisomer of formula Ia, R 2 This allows us to obtain compound I having different stereochemistry. [ka]

[0409] Compound I (compound II) can be prepared by a general synthetic method as shown in Scheme 2. Compound 2 can be obtained by oxidizing the unprotected hydroxyl group of compound 1 in the presence of an oxidizing agent, and this is treated with a Grignard reagent to form compound 3. The resulting hydroxyl group can be protected with BzCl to form compound 4, which is then treated with HR X (In the formula, R XCompound 5 is obtained by coupling it with a basic group (for example). Then, the protecting group of compound 5 is removed under basic conditions to obtain compound 6, which is treated with PSCl3 to form phosphorothioate compound 7. Finally, compound II is obtained by coupling compound 7 and compound 8 in a suitable solvent such as DMF using a suitable catalyst such as zinc(II) chloride at room temperature. [ka]

[0410] The compound of formula I (compound III) can be prepared by a general synthetic method as shown in scheme 3. By protecting the two hydroxyl groups of compound 1, compound 2 can be formed, which was treated with Tf2O in the presence of DMAP to produce compound 3. The OTf group of compound 3 was treated with sodium azide to form compound 4, and then the protecting group was removed in the presence of a fluorine reagent to obtain compound 5. At low temperatures, a phosphorothioate compound 6 could be formed from compound 5 and PSCl3, which was coupled with compound 8 to form compound 7. The azide group was then reduced to amino to form the final product, compound III. [ka]

[0411] The compound of formula I (compound IV) can be prepared by a general synthetic method as shown in scheme 4. Commercial compound 1 was treated with PSCl3 at low temperature to form compound 2, which was then coupled with compound 8 in the presence of a catalyst to form the final compound IV. [ka]

[0412] The preparation of compounds having a 2'-F disubstituted compound (Compound V), a 2'-OMe disubstituted compound (Compound VI), a 3'-substituted compound (Compound VII), a 4'-F and 2'-disubstituted compound (Compound VIII), a 4'-Me and 2'-disubstituted compound (Compound IX), a 2'-disubstituted compound (Compound X), and a 2'-disubstituted and 3'-substituted compound (Compound XI) is shown in the following schemes 5 to 11. [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0413] Preparation example On a Varian device operating at 400MHz 1 1H NMR spectra were recorded. Using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone, or (CD3)2CO as solvents, and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone or (CD3)2CO: 2.05 ppm) as a reference standard, 11H NMR spectra were obtained. When peak multiplicity is reported, the following abbreviations are used: s (singular), d (double), t (tripular), q (quadular), qn (quintular), sx (hexatular), m (multiple), br (broad), dd (double of double), dt (double of triple). Coupling constants are reported in Hertz (Hz) if given. All compound names except for reagents were created using Chemdraw version 12.0.

[0414] In the following embodiments, the following abbreviations are used: Acetic acid (ACOH) AQ water-based Brine saturated sodium chloride solution CH2Cl2 (Dichloromethane) DMF (N,N-dimethylformamide) Dppf 1,1'-bis(diphenylphosphino)ferrocene DBU 1,8-Diazabicyclo[5.4.0]Undeca-7-Ene DIEA N,N-diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) eq equivalent HCl ethyl acetate EtOH Ethanol Et2O or ether diethyl ether g grams h or hr hours HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methaneaminium HCl (hydrochloric acid) HPLC (High-Performance Liquid Chromatography) IPA or i-PrOH 2-propanol mg milligrams mL or ml (milliliter) mmol millimol MeCN acetonitrile MeOH methanol Minutes ms or MS mass spectrum Sodium sulfate (Na2SO4) PPA polyphosphate PPh3 Triphenylphosphine PSCl3 thiophosphoryl chloride Rt retention time rt room temperature TEAB (Triethylammonium Bicarbonate) TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) TLC (Thin-Layer Chromatography) TMSCl trimethylsilyl chloride μL or μl microliter

[0415] Example 1C Synthesis of Example 1C [ka]

[0416] Step 1: Synthesis of Compound 2 To a solution of compound 1 (13 g, 30.63 mmol) in pyridine (65 mL), DMAP (374 mg, 3.06 mmol), followed by Ac2O (6.25 g, 61.25 mmol), was added, and the mixture was stirred at room temperature for 2 hours. The desired product was identified by LC-MS. EA (100 mL) was added to the reaction mixture, which was washed with 1N HCl (100 mL x 2), dried, concentrated, and purified by column chromatography (PE / EA = 3 / 1) to obtain the title compound (14 g, 93%) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 7.41(d,J=7.0 Hz,2H),7.38-7.33(m,2H),7.31-7.26(m,1H),5.96-5.86(m,1H),5.44-5.39(m,1H),5.27-5.17(m,2H),4.79-4.71(m,2H),4.64(d,J=12.2 Hz,1H),4.03-3.96(m,1H),3.87(dd,J=10.2,3.0 Hz,1H),3.67-3.61(m,2H),3.23(s,3H),3.15(s,3H),3.06(s,3H),2.06(s,3H),1.23(s,3H),1.16(s,3H).

[0417] Step 2: Synthesis of Compound 3 A mixture of compound 2 (14 g, 30 mmol) in DCM / MeOH=1:1 (280 mL) was stirred at -78 °C for 40 minutes under an O3 atmosphere, then quenched with (CH3)2S (11.2 mL), and the mixture was stirred overnight at room temperature. The mixture was concentrated and dissolved in MeOH:H2O=2:1 (240 mL), NaBH4 (4.5 g, 120 mmol) was added at 0 °C, then warmed to room temperature and stirred for 2 hours, and the desired product was identified by LC-MS. The reaction mixture was concentrated and extracted using DCM (100 mL × 2), the combined organic layer was dried and concentrated to obtain the title compound (13 g, 90%) as a colorless oil. MS(ESI)m / z [M+H] + 450.9.

[0418] Step 3: Synthesis of Compound 4 To a solution of compound 3 (13.6 g, 31.74 mmol) in pyridine (100 mL), DMAP (388 mg, 3.17 mmol), followed by Ac2O (9.7 g, 95.22 mmol), was added. The mixture was stirred at room temperature for 3 hours, and the desired product was identified by TLC (PE / EA = 1:1). EA (100 mL) was added, the mixture was washed with 1N HCl (100 mL x 2), the organic layer was dried over Na2SO4, filtered, and concentrated. The crude product (16 g) was used in the next step without further purification.

[0419] Step 4: Synthesis of Compound 5 The crude product (16 g) from Step 3 was dissolved in DCM (250 mL), TFA (50 mL) and water (5 mL) were added, the mixture was stirred for 2 hours, concentrated, the residue was dissolved in EtOH (200 mL), Pd / C (1.6 g, 10 wt%) was added, the mixture was stirred overnight at room temperature under an H2 atmosphere, filtered, concentrated, and the residue was purified using CombiFlash (40 g, EA in PE, 0-40%) to obtain the title compound (5.6 g, 54% in the two steps) as a colorless oil. 1 H NMR(400 MHz,CDCl3)δ 5.45-5.37(m,1H),4.77-4.74(m,1H),4.40-4.28(m,2H),3.99-3.94(m,1H),3.87-3.7 9(m,1H),3.72-3.67(m,1H),3.58-3.51(m,1H),3.36(s,3H),2.20(s,3H),2.07(s,3H).

[0420] Step 5: Synthesis of Compound 6 To a solution of compound 5 (5.6 g, 18.16 mmol) in Ac2O (25 mL), concentrated H2SO4 (0.25 mL) was added at 0°C, and the mixture was stirred at room temperature for 3 hours and monitored by TLC (PE / EA = 2 / 3). Water (50 mL) was added, and extraction was performed using EA (50 mL x 2). The organic layers were combined, washed with brine, dried, concentrated, and used in the next step without further purification. 1 H NMR(400 MHz,CDCl3)δ 6.10(d,J=1.7 Hz,1H),5.36-5.31(m,2H),5.28-5.22(m,2H),4.27(dd,J=11.6,5.1 Hz,1H),4.21-4.14(m,2H),2.20(s,3H),2.17(s,3H),2.14(s,3H),2.03(d,J=1.6 Hz,6H),2.00(s,3H).

[0421] Step 6: Synthesis of Compound 7 To a solution of compound 6 (8 g, 17.3 mmol) in DMF (50 mL), hydrazine acetate (2.4 g, 25.95 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction product was quenched with water (100 mL) and extracted with EA (50 mL x 2). The combined organic layer was washed with brine, dried, and concentrated. The crude product was dissolved in DCM (140 mL), and DMAP (8.4 g, 68.51 mmol) in DCM (140 mL) was added, followed by diphenyl chlorophosphonate (4.8 g, 17.98 mmol) in DCM (100 mL) over 6 hours. The mixture was then stirred overnight at room temperature, monitored by TLC, concentrated, and purified with Flash (80 g, EA in PE, 0-30%) to obtain the title compound (900 mg, 8%) as a colorless oil. 1 H NMR(400 MHz,CDCl3)δ 7.39-7.27(m,6H),7.25-7.19(m,2H),7.18-7.13(m,2H),5.57(dd,J=7.0,1.1 Hz,1H),5.52(d,J=3.2 Hz,1H),5.35-5.30(m,1H),5.28-5.24(m,1H),5.06(dd,J=10.1,3.3 Hz,1H),4.26(dd,J=11.5,5.2 Hz,1H),4.15-4.11(m,1H),3.83(dd,J=10.0,2.4 Hz,1H),2.13(d,J=0.7 Hz,6H),2.02(d,J=2.0 Hz, 6H), 1.98(s, 3H).

[0422] Step 7: Synthesis of Compound 8 To a solution of compound 7 (900 mg, 1.38 mmol) in EtOH / EA=1 / 1 (18 mL), PtO2 (156 mg) was added, and the mixture was stirred overnight at room temperature under an H2 atmosphere. The mixture was then filtered and concentrated to obtain the title compound (600 mg) as a white solid. 1H NMR(400 MHz,CDCl3)δ 5.58-5.55(m,1H),5.52-5.48(m,1H),5.35-5.32(m,1H),5.30-5.26(m,1H), 5.20-5.15(m,1H),4.48-4.42(m,1H),4.23-4.17(m,1H),3.91(dd,J=9.9,2.3 Hz,1H),2.24(s,3H),2.13(s,3H),2.08(s,3H),2.03(s,3H),1.99(s,3H).

[0423] Step 8: Synthesis of Key Intermediate 1 To a solution of compound 8 (600 mg, 0.93 mmol) in DMF (5 mL) packed with N2, CDl (1.5 g, 9.32 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The desired product was found in a completely converted state based on LC-MS. The reaction mixture was quenched with MeOH (1 mL), stirred at room temperature for 10 minutes, concentrated, and the crude product was used in the next step without further purification. MS(ESI)m / z [M+H] + 550.9; [MH] - 549.1.

[0424] Step 9: Synthesis of Compound 10 To a solution of compound 9 (5 g, 8.6 mmol) and 6-chloro-9H-purine (1.3 g, 8.6 mmol) in ACN (80 mL), N,O-bis(trimethylsilyl)acetamide (5.6 g, 27.5 mmol) was added at 25 °C. TMSOTf (8.23 g, 37 mmol) was added to this solution at 0 °C. The mixture was stirred at 25 °C for 1 hour, followed by 60 °C for 1 hour, and the desired product was identified by LC-MS. The reaction product was quenched with aqueous sodium bicarbonate (20 mL) and extracted using EA (30 mL x 3). The combined organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by column chromatography (EA in PE, 0-50%) to obtain the title compound (3 g, 51.1%) as a yellow oil. MS(ESI)m / z [M+H] + 612.6.

[0425] Step 10: Synthesis of Compound 11 To a solution of compound 10 (1.4 g, 2.28 mmol) in dioxane (15 mL), NH3·H2O (45 mL) was added. The mixture was stirred overnight in a sealed tube at 110°C. The mixture was concentrated to obtain the crude product. This was washed with DCM to obtain the title compound (1.2 g, 93%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.44(s,1H),8.10(s,1H),7.30-7.23(m,2H),5.91(s,1H),4.04(d,J=9.1 Hz,1H),3.91-3.85(m,1H),3.82-3.77(m,1H),3.69-3.63(m,1H),0.73(s,3H).MS(ESI)m / z [M+H] + 282.0.

[0426] Step 11: Synthesis of Compound 12 To a solution of compound 11 (630 mg, 2.23 mmol) in pyridine (10 mL), TrtCl (1.56 g, 5.6 mmol) and DMAP (219 mg, 1.79 mmol) were added. The reaction mixture was stirred at 80°C for 16 hours. The mixture was then concentrated and purified by column chromatography (EA in PE, 0-100%) to obtain the title compound (950 mg, 47%) as a colorless oil. 1 H NMR(400 MHz,DMSO-d6)δ 8.33(s,1H),7.80(s,1H),7.50(s,1H),7.43-7.17(m,30H),5.99(s,1H),5.33 -5.17(m,2H),4.28-4.16(m,1H),4.14-4.05(m,1H),0.84(s,3H).MS(ESI)m / z [M+H] + 765.7.

[0427] Step 12: Synthesis of Compound 13 To a solution of compound 12 (950 mg, 1.24 mmol) in acetone (45 mL), 2,2-dimethoxypropane (9 mL) and p-TsOH·H2O (282.8 mg, 1.45 mmol) were added. The reaction mixture was stirred overnight at 25°C. This was then diluted with brine, carefully quenched with saturated NaHCO3 (30 mL), and extracted with RINKAN (50 mL x 3). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated and purified by column chromatography (EA in PE, 0-80%) to obtain the title compound (550 mg, 70%) as a colorless oil. 1 H NMR(400 MHz,MeOD)δ 8.30(s,1H),7.77(s,1H),7.29-7.08(m,15H),6.19(s,1H),4.55(d,J=2.2 Hz,1H),4.29-4.17(m,1H),3.85-3.75(m,1H),3.72-3.66(m,1H),1.52(s,3H),1.31(s,3H),1.12-1.04(m,3H).MS(ESI)m / z [M+H] + 563.8.

[0428] Step 13: Synthesis of Compound 14 To a solution of compound 13 (320 mg, 0.56 mmol) in pyridine (5 mL), diphenylphosphonate (532 mg, 2.27 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. Then, TEA (344 mg, 3.4 mmol) and H2O (122.7 mg, 2.8 mmol) were added, and the mixture was stirred at 25°C for 0.5 hours. The resulting mixture was concentrated to obtain the crude product. The residue was applied to a silica gel column eluted using DCM / MeOH (10 / 1) to obtain the title compound (1.5 g, purity 20%, 84%) as a colorless oil. 1 H NMR(400 MHz,DMSO-d6)δ 8.55(s,1H),7.92(s,1H),7.32-7.16(m,15H),6.22(s,1H),4.67-4.56(m,1H),4.36-4. 29(m,1H),4.03-3.85(m,2H),1.54(s,3H),1.35(s,3H),1.27-1.20(m,3H).MS(ESI)m / z [M+H] +627.8.

[0429] Step 14: Synthesis of Compound 15 To a solution of compound 14 (600 mg, 0.95 mol) in pyridine (6 mL) and TEA (6 mL), TMSCl (830.8 mg, 7.65 mmol) was added. The reaction mixture was stirred at 0°C for 2 hours. Then S8 (290.6 mg, 9.08 mmol) was added. The mixture was stirred at 0°C for 1 hour. This was quenched with H2O, then concentrated, and purified by preparative HPLC (water containing 0.5% TFA in MeCN = 75%-40%) to obtain the title compound (300 mg, 45%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.88(s,1H),7.42(s,1H),7.32-7.10(m,15H),6.20(s,1H),4.67(s,1H),4.35(s, 1H),4.02-3.84(m,2H),1.49(s,3H),1.30(s,3H),1.19-1.09(m,3H).MS(ESI)m / z [M+H] + 659.6.

[0430] Step 15: Synthesis of Compound 16 ZnCl2 (78.1 mg, 0.57 mmol) was added to a mixture of compound 15 (30 mg, 0.04 mmol) and important intermediate 1 (28 mg, 0.05 mmol) in DMF (1.5 mL). The mixture was stirred overnight at 25°C. This was then concentrated and purified using preparative HPLC (10 mM aqueous solution of NH4HCO3 in MeCN = 70%-40%) to obtain the title compound (40 mg, 68%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.70-8.55(m,1H),7.90(s,1H),7.47-7.02(m,15H),6.22(s,1H),5.75-5.55(m,1H),5.48-5.29(m,1H),5.22-4.95(m,3H) ,4.88-4.62(m,1H),4.44-4.27(m,2H),4.23-3.90(m,4H),2.14-1.80(m,12H),1.52(s,3H),1.36-1.00(m,6H).MS(ESI)m / z [M+H]+ 1141.7.

[0431] Step 16: Synthesis of Example 1C To a solution of compound 16 (40 mg, 0.035 mmol) in H2O (2 mL), TFA (3 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 7 using TEA, and purified by preparative HPLC (10 mM aqueous solution of NH4HCO3 in MeCN = 90%-70%) to obtain Example 1C (10 mg, 30%) as a white solid. 1 H NMR(400 MHz,MeOD)δ 8.81-8.64(m,1H),8.17(s,1H),6.15-6.05(m,1H),5.71-5.49(m,2H),5. 33-5.20(m,1H),5.20-5.06(m,2H),4.61-4.49(m,1H),4.48-4.35(m,2H) ,4.33-4.21(m,2H),4.20-4.11(m,1H),4.02-3.78(m,1H),2.24-2.07(m, 3H),2.07-1.99(m,3H),1.98-1.85(m,9H),0.96-0.84(m,3H).MS(ESI)m / z [M+H] + 860.0.

[0432] Example 1D Synthesis of Example 1D [ka]

[0433] A solution of Example 1C (5 mg, 0.0044 mmol) in 0.1 M TEAB / MeOH / TEA = 4:3:0.05 (1.5 mL) was stirred at 25°C for 6 hours. The solution was freeze-dried to obtain the crude product. This was then purified with preparative HLPC (water / MeCN with 0.1% FA = 98%-95%) to obtain Example 1D (2.7 mg, 88.6%) as a white solid. 1H NMR(400 MHz,D2O)δ 8.59(s,1H),8.22(s,1H),6.10(s,1H),5.18(d,J=8.5 Hz,1H),4.41-4.34(m,1H),4.31-4.23(m,2H),4.20-4.13(m,1H),4.04-3.98(m,1H),3.84-3. 80(m,1H),3.72-3.66(m,1H),3.67-3.55(m,3H),3.28-3.23(m,1H),0.86(s,3H).MS(ESI)m / z [MH] - 647.6.

[0434] Example 1A Synthesis of Example 1A [ka]

[0435] Step 1: Synthesis of Compound 2 To a solution of compound 1 (450 g, 2.32 mol) in DMF (4.5 L), 1H-imidazole (346.7 g, 5.1 mol) was added, followed by TBDPSCl (764 g, 2.78 mol) at 0°C. The mixture was stirred overnight at room temperature, and the desired product was identified by LC-MS. Water (5 L) was added, and the mixture was extracted using EA (5 L x 2). The combined organic layers were dried over Na2SO4, concentrated, and purified by column chromatography (PE / EA = 5 / 1-2 / 1) to obtain the title compound (700 g, 69%) as a colorless oil. 1 H NMR(400 MHz,MeOD)δ 7.80-7.72(m,4H),7.46-7.37(m,6H),4.70(d,J=1.4 Hz,1H),4.05(dd,J=10.8,1.8 Hz,1H),3.87-3.81(m,2H),3.70-3.64(m,2H),3.61-3.54(m,1H),3.43(s,3H),1.05(s,9H).

[0436] Step 2: Synthesis of Compound 3 A mixture of compound 2 (700 g, 1.62 mol) and (bromomethyl)benzene (1.1 L, 9.72 mmol) in DMF (7 L) was mixed with NaH (388.8 g, 60%) at 0°C. The mixture was stirred overnight at room temperature, and the desired product was identified by LC-MS. Water (10 L) was added, and the mixture was extracted using EA (1 L x 2). The combined organic layers were washed with brine, dried, concentrated, and purified by column chromatography (EA in PE, 0-9%) to obtain the title compound (700 g, 59.7%) as a colorless oil. 1 H NMR(400 MHz,MeOD)δ 7.72-7.64(m,4H),7.41-7.37(m,4H),7.35-7.24(m,13H),7.21-7.18(m,2H),7.12-7.10(m,2H),4.85-4.78(m,2H),4. 73-4.66(m,2H),4.60-4.52(m,3H),4.04-3.96(m,1H),3.87-3.80(m,4H),3.59-3.53(m,1H),3.31(s,3H),1.01(s,9H).

[0437] Step 3: Synthesis of Compound 4 To a solution of compound 3 (700 g, 0.99 mol) in THF (7 L), 1 M TBAF (1.99 L, 1.99 mol) was added. The mixture was stirred overnight at room temperature, monitored by TLC, concentrated, and purified by column chromatography (EA in PE, 0-30%) to obtain the title compound (350 g, 71.87%) as a colorless oil. MS(ESI)m / z [M+Na] + 486.8.

[0438] Step 4: Synthesis of Compound 5 To a solution of oxalyl chloride (205 g, 1.6 mol) in THF (2.2 L), DMSO (252 g, 3.2 mol) in THF (540 mL) was added at -70°C, and the mixture was stirred at this temperature for 15 minutes. Compound 4 (300 g, 0.65 mol) in THF (1.5 L) was added, and the mixture was stirred at -60°C for 1 hour. Trimethylamine (654 g, 6.5 mmol) was added, and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was cooled to -70°C, vinyl magnesium bromide (3.23 L, 3.23 mol) was slowly added, and the mixture was stirred at -70°C for 2 hours. Saturated NH4Cl (3000 mL) was added, and the mixture was extracted using EA (3 L x 2). The combined organic layers were dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1-5 / 1) to obtain the title compound (190 g, 56.97%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ 7.38-7.28(m,15H),6.04-5.96(m,1H),5.37(d,J=17.2 Hz,1H),5.20(d,J=10.5 Hz,1H),4.98(d,J=10.8 Hz,1H),4.77-4.65(m,4H),4.63(s,2H),4.42(d,J=2.7 Hz,1H),4.17-4.10(m,1H),3.90(dd,J=9.4,3.0 Hz,1H),3.78(dd,J=2.5,2.1 Hz,1H),3.56(dd,J=9.7,1.3 Hz,1H),3.26(s,3H).

[0439] Step 5: Synthesis of Compound 6 To a solution of compound 5 (220 g, 0.45 mol) in pyridine (2.2 L), Ac2O (91.5 g, 0.9 mol) was added, followed by DMAP (5.5 g, 45 mmol). The mixture was stirred overnight at room temperature, and the desired product was identified by LC-MS. The reaction product was concentrated, water (3 L) was added, and extraction was performed using EA (1.5 L x 2). The combined organic layer was dried, concentrated, and purified by column chromatography (PE / EA = 4 / 1) to obtain the title compound (220 g, 87.5%) as a colorless oil. 1H NMR(400 MHz,CDCl3)δ 7.35-7.26(m,15H),6.02-5.94(m,1H),5.78(dd,J=6.5,1.3 Hz,1H),5.39-5.34(m,1H),5.29-5.25(m,1H),4.86(dd,J=27.7,5.8 Hz,2H),4.79-4.71(m,2H),4.58(s,2H),4.48(d,J=10.0 Hz,1H),3.92-3.86(m,2H),3.81-3.77(m,1H),3.67(dd,J=9.3,1.7 Hz,1H),3.27(s,3H),2.16(s,3H).

[0440] Step 6: Synthesis of Compound 7 A mixture of compound 6 (22 g × 10, 0.41 mol) in DCM / MeOH=1:1 (220 mL × 10) was stirred at -78°C for 40 minutes under an O3 atmosphere, then quenched with (CH3)2S, and the mixture was stirred overnight at room temperature. This was then concentrated and dissolved in MeOH / H2O=2 / 1 (2.1 L), to which NaBH4 (62.50 g, 1.65 mol) was added at 0°C. The mixture was then warmed to room temperature and stirred for 3 hours. The mixture was concentrated and extracted using DCM (2 L × 2). The combined organic layers were dried, concentrated, and purified by column chromatography (PE / EA=2 / 1) to obtain the title compound (206 g, 95%) as a colorless oil. MS(ESI)m / z [M+Na] + 512.2.

[0441] Step 7: Synthesis of Compound 8 To a mixture of compound 7 (190 g, 0.38 mol) in DCM (2 L), TEA (78 g, 0.76 mmol) and DMAP (24 g, 0.19 mol), followed by triphenylmethyl chloride (214 g, 0.76 mol), were added. The mixture was stirred at 50°C for 24 hours. This was then concentrated and purified by column chromatography (PE / EA = 10 / 1-4 / 1 from 1% TEA in PE) to obtain the title compound (200 g, 67.1%) as a yellow solid. 1H NMR(400 MHz,CDCl3)δ 7.36-7.19(m,30H),4.97(d,J=11.0 Hz,1H),4.73(dd,J=11.7,5.7 Hz,2H),4.67-4.59(m,4H),4.13-4.09(m,2H),3.90(dd,J=9.4,3.1 Hz,1H),3.75-3.70(m,2H),3.37(dd,J=9.1,6.4 Hz,1H),3.10-3.06(m,1H),3.06(s,3H).

[0442] Step 8: Synthesis of Compound 9 To a solution of compound 8 (200 g, 0.28 mol) in DCM (2 L), 4A molecular sieve (200 g) and NMO (158 g, 1.4 mol) were added and stirred at room temperature for 0.5 hours. Then TPAP (9.54 g, 0.028 mol) was added at 0°C and the mixture was stirred at room temperature for 2 hours. The mixture was then filtered, concentrated, and purified by column chromatography (PE / EA with 1% TEA = 20 / 1-5 / 1) to obtain the title compound (140 g, 70%) as a colorless oil. 1 H NMR(400 MHz,CDCl3)δ 7.33-7.22(m,30H),4.74-4.64(m,4H),4.62-4.50(m,3H),4.22(d,J=8.5 Hz,1H),4.10-4.05(m,1H),4.02-3.98(m,2H),3.82(dd,J=8.3,3.0 Hz,1H),3.68(t,J=2.9 Hz,1H),3.22(s,3H).

[0443] Step 9: Synthesis of Compound 10 To a solution of compound 9 (140 g, 0.19 mol) in THF (1.4 L), Zn(BH4)2 (1 M, 209 mL) was added at 0°C. The mixture was stirred at 0°C for 1 hour, and the desired product was identified by LC-MS. Water (1.5 L) was added, and the product was extracted using EA (1 L x 2). The combined organic layer was dried, concentrated, and purified by column chromatography (EA = 0-20% in PE) to obtain the title compound (100 g, 70%) as a colorless oil. 1H NMR(400 MHz,CDCl3)δ 7.44-7.39(m,4 H),7.28-7.20(m,26H),4.87(d,J=10.8 Hz,1H),4.70-4.59(m,3H),4.55(d,J=1.7 Hz,2H),4.40(d,J=10.8 Hz,1H),4.16-4.08(m,1H),3.95-3.84(m,2H),3.73-3.69(m,1H),3.66(dd,J=9.2,4.1 Hz,1H),3.36(dd,J=9.9,7.0 Hz,1H),3.29-3.24(m,1H),3.19(s,3H).

[0444] Step 10: Synthesis of Compound 11 To a solution of compound 10 (100 g, 0.135 mol) in DCM (1 L), DAST (109 g, 0.67 mol) and pyridine (106.6 g, 1.35 mmol) were added at 0°C. The mixture was stirred overnight at room temperature. This was then concentrated and purified by column chromatography (EA = 0-80% in PE containing 1% TEA) to obtain the title compound (50 g, 49.6%) as a colorless oil. MS(ESI)m / z [M+Na] + 761.3.

[0445] Step 11: Synthesis of Compound 12 To a solution of compound 11 (50 g, 67.6 mmol) in DCM (500 mL), TFA (100 mL) was added. The mixture was stirred at room temperature for 1 hour. This was then concentrated and purified by column chromatography (PE / EA = 10 / 1-1 / 1) to obtain the title compound (21 g, 62.5%) as a yellow oil. MS(ESI)m / z [M+H2O+H] + 514.2.

[0446] Step 12: Synthesis of Compound 13 To a solution of compound 12 (21 g, 42.29 mmol) in AcOH (105 mL) and Ac2O (105 mL), concentrated H2SO4 (9.4 mL) was added at 0°C. The mixture was stirred at 0°C for 1 hour, monitored by LC-MS, EA (200 mL) was added, the mixture was poured into cold water, and extracted using EA (200 mL x 2). The combined organic layer was washed with brine, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1-5 / 1) to obtain the title compound (12 g, 47%) as a colorless oil. MS(ESI)m / z [M+H2O+H] + 584.2.

[0447] Step 13: Synthesis of Compound 14 To a solution of compound 13 (700 mg, 1.24 mmol) in MeOH / THF / H2O / AcOH = 10:5:1:0.25 (10 ml), Pd(OH)2 / C (700 mg) was added. The mixture was stirred at 40°C for 48 hours under an H2 atmosphere. The mixture was then filtered and concentrated to obtain the title compound (500 mg, crude product) as a colorless oil. MS(ESI)m / z [M+H2O+H] + 314.1.

[0448] Step 14: Synthesis of Compound 15 To a solution of compound 14 (500 mg, 1.69 mmol) in pyridine (5 mL), Ac2O (861 mg, 8.44 mmol) and DMAP (103 mg, 0.84 mmol) were added. The mixture was stirred at room temperature for 30 minutes, water (10 mL) was added, and the mixture was extracted using EA (10 mL x 2). The combined organic layer was washed with brine, dried, concentrated, and purified using Flash (12 g, EA in PE = 0-25%) to obtain the title compound (500 mg, 66%) as a yellow oil. 1H NMR(400 MHz,CDCl3)δ 6.10(d,J=1.9 Hz,1H),5.60-5.50(m,1H),5.39-5.31(m,1H),5.26-5.24(m,1H),4.75-4.55(m,1H),4.44- 4.35(m,1H),4.34-4.22(m,1H),4.01-3.92(m,1H),2.20-2.16(m,6H),2.09(dd,J=6.6,3.6 Hz,6H),2.01(s,3H).

[0449] Step 15: Synthesis of Compound 16 To a solution of compound 15 (500 mg, 1.18 mmol) in DMF (5 mL), hydrazine acetate (164 mg, 1.78 mmol) was added. The mixture was stirred at room temperature for 30 minutes, water (10 mL) was added, and extraction was performed using EA (10 mL x 2). The combined organic layer was dried, concentrated, and purified using Flash (EA in PE, 0-60%) to obtain the title compound (230 mg, 48%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ 5.52-5.47(m,1H),5.44-5.39(m,1H),5.30-5.22(m,2H),4.78-4.60(m,1H),4.43-4 .25(m,2H),4.11-4.04(m,1H),2.16(s,3H),2.10(s,3H),2.06(s,3H),1.99(s,3H).

[0450] Step 16: Synthesis of Compound 17 A mixture of compound 15 (230 mg, 0.6 mmol) and 4-dimethylaminopyridine (362 mg, 2.96 mmol) in DCM (12 mL) was to be mixed with diphenylchlorophosphonate (481 mg, 1.79 mmol) in DCM (12 mL) over 30 minutes. The mixture was then heated to room temperature and stirred overnight. The reaction product was concentrated and purified using Flash (EA in PE, 0-30%) to obtain the title compound (160 mg, 41%) as a colorless oil. MS(ESI)m / z [M+Na] + 635.1.

[0451] Step 17: Synthesis of Compound 18 To a solution of compound 17 (160 mg, 0.26 mmol) in EA / EtOH = 1 / 1 (5 mL), PtO2 (44 mg, 0.6 equivalents) was added. The mixture was stirred at room temperature for 48 hours under an H2 atmosphere. The resulting mixture was filtered and concentrated to obtain (2S,3S,5S,6S)-2-((S)-2-acetoxy-1-fluoroethyl)-6-(phosphonooxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate (120 mg, crude product) as a colorless oil. This was used in the next step without further purification.

[0452] Step 18: Synthesis of Important Intermediate 2 To a solution of compound 18 (120 mg, 0.26 mmol) in DMF (1 mL), CDl (420 mg, 2.6 mmol) was added. The mixture was stirred at room temperature for 1 hour, and the desired product was identified by LC-MS. MeOH (0.13 mL) was then slowly added. The mixture was concentrated and used in the next step without further purification. MS (ESI) m / z [MH] - 509.0.

[0453] Steps 19 and 20: Synthesis of Example 1A The title compound (24 mg, 50%) was obtained from the important intermediate 2 as a white solid using the same procedure as described in Example 1C. 1 H NMR(400 MHz,MeOD)δ 8.63(d,J=34.0 Hz,1H),8.11(s,1H),6.03(s,1H),5.66(t,J=9.5 Hz,1H),5.58(dd,J=6.7,3.1 Hz,1H),5.27(t,J=10.0 Hz,1H),5.13(dd,J=10.1,3.2 Hz,1H),4.65(d,J=8.4 Hz,1H),4.53-4.27(m,4H),4.25-4.19(m,1H),4.09(d,J=6.7 Hz,1H),3.82-3.73(m,1H),2.06(d,J=2.3 Hz,3H),1.94(dd,J=6.1,3.7 Hz,6H),1.84(s,3H),0.83(d,J=5.6 Hz,3H).MS(ESI)m / z [M+H] + 820.0.

[0454] Example 8C Synthesis of Example 8C [ka]

[0455] Step 1: Synthesis of Compound 2 A solution of compound 1 (0.2 g, 0.78 mmol) in trimethyl phosphate (3 mL) was charged with argon three times and cooled to 0°C using ice water. Pyridine (0.123 g, 1.56 mmol) and PSCl3 (0.39 g, 2.34 mmol) were added successively. The mixture was then stirred at 0°C for 2 hours. The mixture was quenched with H2O, extracted using DCM, dried, and concentrated. The crude product was purified by preparative HPLC (Daisogel-C18-5-100, 100% water, retention time: 10-20 min), and subsequently lyophilized to obtain the desired product (0.2 g, 73%) as a pale yellow solid. 1 H NMR(400 MHz,D2O)δ=8.06(d,J=8.1 Hz,1H),5.91(s,1H),5.86(d,J=8.1 Hz,1H),4.16-4.09(m,1H),4.03(d,J=9.3 Hz,1H),4.00-3.93(m,2H),1.09(s,3H).MS(ESI)m / z [MH] - 353.0.

[0456] Step 2: Synthesis of Example 8C Argon was charged three times to a solution of compound 2 (0.15 g, 0.42 mmol) and key intermediate 1 (0.3 g of crude product, 0.42 mmol) in DMF (2 mL). ZnCl2 (4.2 mL, 1 M in THF, 4.2 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The mixture was quenched with H2O, purified by preparative HPLC (Daisogel-C18-5-100, 25% acetonitrile in water, retention time: 25-35 minutes), and subsequently lyophilized to obtain the desired product (80 mg, 22.6%) as a white solid. 1H NMR(400 MHz,D2O)δ 7.94(t,J=8.1 Hz,1H),5.95-5.82(m,2H),5.51(d,J=14.3 Hz,2H),5.27-5.12(m,2H),5.00(dd,J=19.9 Hz,9.8,1H),4.36(ddd,J=23.2 Hz,15.8,6.4,2H),4.26-4.09(m,2H),4.08-3.98(m,2H),3.90(d,J=9.2 Hz,1H),2.13(s,3H),2.04(s,3H),1.95(s,6H),1.87(s,3H),1.09(s,3H).MS(ESI)m / z [MH] - 834.8.

[0457] Example 59C Synthesis of Example 59C [ka]

[0458] Step 1: Synthesis of Compound 2 To a solution of compound 1 (44.0 g, 165 mmol) in pyridine (300 mL), TIPDSCl (57.1 g, 181 mmol, 57.9 mL) was added at 25°C, and the reaction mixture was stirred at 25°C for 14 hours. TLC (petroleum ether / ethyl acetate = 1 / 2) showed consumption of the starting material and the formation of one new major spot. The reaction mixture was diluted with saturated NaHCO3 (600 mL) and ethyl acetate (900 mL), the organic phase was separated, washed with water (300 mL x 2) and brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (65.0 g, 72.9%) as a yellow solid. The crude product was used in the next step without further purification. 1 H NMR(400 MHz,CDCl3)δ 8.59(d,J=4.0 Hz,1H),8.18(s,1H),8.11(s,1H),6.20(d,J=6.0 Hz,1H),6.09(br s,2H),4.62(d,J=7.6 Hz,2H),4.04(d,J=3.2 Hz,2H),3.90-3.80(m,1H),1.20-1.00(m,28H).

[0459] Step 2: Synthesis of Compound 3 To a solution of compound 2 (56.5 g, 111 mmol) in DCM (600 mL), DMAP (40.6 g, 333 mmol) was added at -30 to -50°C and stirred for 30 minutes. Then, Tf2O (39.1 g, 139 mmol, 22.9 mL) in DCM (100 mL) was added at -30 to -50°C and the reaction mixture was stirred at 25°C for 5.5 hours. TLC (petroleum ether / ethyl acetate = 1 / 2) revealed a new major spot that had formed. The reaction mixture was washed with 20% citric acid solution (100 mL x 5), the organic layer was washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (70.0 g, 69.8%) as a yellow oil. The crude product was used in the next step without further purification. 1 H NMR(400 MHz,CDCl3)δ 8.33(s,1H),7.93(s,1H),6.40(d,J=6.0 Hz,1H),5.69(br s,2H),5.51-5.46(m,1H),5.41(d,J=7.2 Hz,1H),4.27-4.19(m,1H),4.09(dd,J=3.3,12.3 Hz,1H),3.97(br dd,J=3.6,6.8 Hz,1H),1.12-1.04(m,28H).

[0460] Step 3: Synthesis of Compound 4 To a solution of compound 3 (23.0 g, 35.8 mmol) in DMF (140 mL), NaN3 (4.14 g, 63.7 mmol) was added at 25°C, and the reaction mixture was stirred at 25°C for 28 hours. TLC (petroleum ether / ethyl acetate = 2 / 1) revealed a new major spot. The reaction mixture was diluted with water (2.50 L) and pharmaceutically acceptable ethyl acetate (1.00 L) and extracted with ethyl acetate (600 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1-5 / 1, petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (25.6 g, 44.5%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.22(s,1H),8.06(s,1H),7.38(br s,2H),5.83(d,J=1.2 Hz,1H),5.44(dd,J=6.0,8.4 Hz,1H),5.01(dd,J=1.2,6.0 Hz,1H),4.08-3.90(m,3H),1.15-0.98(m,28H).

[0461] Step 4: Synthesis of Compound 5 To a solution of compound 4 (25.6 g, 47.9 mmol) in MeOH (250 mL), NH4F (21.3 g, 574 mmol) was added at 25°C, and the reaction mixture was stirred at 60°C for 5 hours. TLC (dichloromethane / methanol = 10 / 1) revealed a new major pot formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was triturated with petroleum ether (100 mL) at 25°C for 1 hour, the mixture was filtered, and the filtered cake was triturated with water (100 mL) at 25°C for 1 hour, the mixture was filtered to obtain the title compound (10.5 g, 35.9 mmol, 75.0%) as a white solid. The crude product was used in the next step without further purification. 1H NMR(400 MHz DMSO-d6)δ 8.39(s,1H),8.15(s,1H),7.37(s,2H),6.09-5.99(m,2H),5.29(t,J=5.6 Hz,1H),4.64(t,J=5.6 Hz,1H),4.58-4.48(m,1H),3.99(q,J=3.6 Hz,1H),3.74-3.63(m,1H),3.58(br dd,J=4.0,6.4 Hz,1H).

[0462] Step 5: Synthesis of Compound 6 To a solution of compound 5 (5.00 g, 17.1 mmol) and 2,6-dimethylpyridine (7.40 g, 68.4 mmol) in trimethyl phosphate (35.0 mL), PSCl3 (5.80 g, 34.2 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 25°C for 4 hours. LC-MS showed the formation of one main product peak. The reaction mixture was quenched with ice water (5.00 mL). The reaction mixture was adjusted to pH=6 using saturated NaHCO3. The residue was purified by preparative HPLC (column: Nano100*250*10 μm; mobile phase: [H2O-1M TEAB], B%: 1%-100%, 20 min) to obtain the title compound (1.70 g, containing 2 equivalents of TEA, 16.2%) as a white solid. 1 H NMR(400 MHz,D2O)δ 8.64(s,1H),8.16(s,1H),6.08(d,J=6.4 Hz,1H),4.80-4.73(m,2H),4.32(br s,1H),4.01(br dd,J=2.4,5.2 Hz,2H). 31 P NMR(162 MHz,D2O)δ 43.37.MS(ESI)m / z [MH] - 387.0.

[0463] Step 6: Synthesis of Example 59C The title compound was obtained using the same procedure as described for Example 8C (10.6 mg, 5%). 1H NMR(400 MHz,D2O)δ 8.75-8.72(m,1H),8.45(s,1H),6.23-6.21(m,1H),5.68-5.60(m,2H),5.32-5.26(m,2H),5.15-5.09(m,1H),4.48-4.40(m,2) H),4.37-4.24(m,3H),4.17-4.12(m,1H),2.21(s,3H),2.15-2.14(m,3H),2.06-2.05(m,3H),2.03-2.01(m,3H),1.97(s,3H). 31 P NMR(162 MHz,D2O)δ 44.04,-15.22.MS(ESI)m / z [MH] - 868.8.

[0464] Example 59A Synthesis of Example 59A [ka]

[0465] The title compound was obtained from key intermediate 2 using the same procedure as described for Example 59C (35 mg, 41.4%). 1 H NMR(400 MHz,D2O)δ 8.71-8.68(m,1H),8.41(s,1H),6.17(d,J=5.2 Hz,1H),5.65-5.54(m,2H),5.35-5.22(m,2H),4.90-4.85(m,1H),4.81-4.77(m,2H),4.46-4.33( m,3H),4.26-4.14(m,2H),4.08-3.94(m,1H),2.16-2.15(m,3H),2.08-2.03(m,6H),1.95(s,3H). 31 P NMR(162 MHz,D2O)δ 43.71,-15.29. 19 F NMR(376 MHz,D2O)δ-206.38.MS(ESI)m / z [MH] - 828.8.

[0466] Example 104C Synthesis of Example 104C [ka]

[0467] Compound 3 was obtained using the same procedure as described in Example 110C.

[0468] Step 3: Synthesis of Compound 4 To a solution of methyltriphenylphosphonium bromide (3.57 g, 9.99 mmol) in THF (50 mL), N2 was charged three times, and bis(trimethylsilyl)azanide potassium (1 M, 9.99 mL) was added dropwise at 0°C. The mixture was stirred for 20 minutes, and a solution of compound 3 (2.42 g, 4.99 mmol) in THF was added. The mixture was stirred at room temperature for 2 hours, then at 35°C for 3 hours. The product was observed as the major peak by LC-MS. The mixture was quenched with aqueous NH4Cl solution, extracted with EA, and the organic layer was isolated. It was dried over anhydrous Na2SO4, filtered, concentrated, and the residue purified over silica gel Combiflash (EA / PE = 0-40%) to obtain the title compound (1.2 g, 49.8%) as a white foam. MS(ESI)m / z [M+Na] + 505.2.

[0469] Step 4: Synthesis of Compound 5 To a solution of compound 4 (1 g, 2.07 mmol) in N-diazo-4-methylbenzenesulfonamide (4.90 g, 24.86 mmol), 4,6,17,19-tetratert-butyl-11,11,12,12-tetramethyl-2,21-dioxa-10,13-diaza-1-cobaltapentacyclo[11.8.0.01,10.03,8.015,20]henicosa-3(8),4,6,9,13,15(20),16,18-octaene (62.74 mg, 0.10 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and a solution of triethylsilane (1.20 g, 10.36 mmol, 1.65 mL) in ethanol (5 mL) was added. The resulting mixture was stirred at 50°C for 16 hours. EA (50 mL) was added to the mixture, washed with Na2CO3 aqueous solution (40 mL), water (50 mL), and brine (50 mL), dried on anhydrous Na2SO4, filtered, and concentrated. The crude product was purified with silica gel CombiFlash (EA / PE = 0-50%) to obtain the title compound as a yellow solid (235 mg, 21.6%). MS(ESI)m / z [M+H] + 526.3

[0470] Step 5: Synthesis of Compound 6 A 40 mL vial was evacuated and flushed three times with nitrogen. Compound 5 (200 mg, 0.38 mmol), TBAF (298.39 mg, 1.14 mmol, 330.44 μL), and THF (1.83 mL) were added. The resulting solution was stirred at 25°C for 1 hour. The solution was concentrated under reduced pressure, and the residue was purified by flash chromatography (MeOH / EA = 0-25%) on silica gel to obtain the title compound (90 mg, 83.5%) as a white solid. MS(ESI)m / z [M+H] + 284.0.

[0471] Steps 6 and 7: Synthesis of Example 104C The title compound was obtained using the same procedure as described for Example 8C (32 mg, 11.7% in two steps). 1H NMR(400 MHz,D2O)δ 7.96(d,J=8.1Z Hz,1H),5.91(s,2H),5.58-5.47(m,2H),5.24-5.16(m,2H),5.03(t,J=9.9 Hz,1H),4.42-4.35(m,1H),4.34-4.28(m,1H),4.27-4.21(m,1H),4.18-4.12(m,1H),4.09-4.02(m,3 H),2.15(s,3H),2.05(s,3H),1.97(s,3H),1.95-1.94(m,3H),1.90(s,3H),1.31(s,3H).MS(ESI)m / z [MH] - 860.0.

[0472] Example 21C Synthesis of Example 21C [ka]

[0473] Step 1: Synthesis of Compound 2 To a solution of compound 1 (5 g, 17.44 mmol) in pyridine (50 mL), 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (5.5 g, 17.44 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The desired product was identified by LC-MS. The solvent was then removed under vacuum. The crude product was purified by silica gel column chromatography (ÂTED / PE = 0-60%) to obtain the title compound (5 g, 54%) as an off-white solid. MS(ESI)m / z [M+H] + 528.9.

[0474] Step 2: Synthesis of Compound 3 To a solution of compound 2 (5 g, 9.45 mmol) in MeCN (50 mL), IBX (5.82 g, 20.66 mmol) was added, and the mixture was stirred at 80°C for 5 hours. Complete conversion was shown by TLC (PE / EA = 3 / 1). After filtration, the filtrate was concentrated to obtain the title compound (4.5 g, 90%) as a white solid. MS(ESI) m / z [M+H] + 526.7.

[0475] Step 3: Synthesis of Compound 4 To a solution of trimethylsilylacetylene (4.2 g, 42.8 mmol) in THF (75 mL), n-BuLi (17.8 mL, 2.4 M in hexane) was added at -78°C. The solution was stirred at -78°C for 30 minutes, then warmed to -55°C and stirred for 20 minutes. The mixture was then cooled to -78°C, compound 3 (4.5 g, 8.56 mmol) in THF (20 mL) was added, and the mixture was stirred at -78°C for 1 hour, then warmed to -30°C and stirred for 2 hours, monitored by TLC until the starting materials were completely converted. The reaction mixture was cooled to -78°C, saturated NH4Cl (100 mL) was slowly added, and the mixture was extracted using EA (100 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified using CombiFlash (40g silica gel, EA / PE = 0-12%) to obtain the title compound (3g, 85%) as an off-white solid. 1 H NMR(400 MHz,CDCl3)δ 8.73(s,1H),8.54(s,1H),6.35(s,1H),4.45(d,J=7.5 Hz,1H),4.17-4.05(m,3H),1.17-1.03(m,28H),0.20-0.16(m,9H).MS(ESI)m / z [M+H] + 625.2.

[0476] Step 4: Synthesis of Compound 5 To a solution of compound 4 (3 g, 4.8 mmol) in toluene (60 mL), DAST (4.6 g, 28.4 mmol) was added at -20°C, and the mixture was stirred at room temperature for 1.5 hours. Complete conversion was shown by TLC. EA (60 mL) was added, the mixture was poured into NaHCO3 (60 mL), stirred for 5 minutes, extracted with EA (60 mL x 2), the combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and the residue purified with CombiFlash (40 g, EA / PE = 0-10%) to obtain the title compound (1.6 g, 53%) as a yellow oil. MS(ESI)m / z [M+H] + 626.8.

[0477] Step 5: Synthesis of Compound 6 To a solution of compound 5 (1.6 g, 2.56 mmol) in MeOH (12 mL), NH4F (1.2 g, 33.28 mmol) was added, and the mixture was stirred at 70°C for 2 hours. The desired product was identified by LC-MS and concentrated. The residue was purified using CombiFlash (24 g, MeOH / DCM = 0-9%) to obtain the title compound (700 mg, 87%) as a yellow solid. MS(ESI)m / z [M+H] + 312.8.

[0478] Step 6: Synthesis of Compound 7 A solution of compound 6 (760 mg, 2.43 mmol) in 7M NH3 (15 mL) in MeOH was stirred in a sealed tube at 90°C for 4 hours. The desired product was identified by LC-MS and concentrated. The residue was purified using CombiFlash (4 g, MeOH / DCM = 0-15%) to obtain the title compound (200 mg, 32%) as an off-white solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.39(s,1H),8.17(d,J=5.4 Hz,1H),7.37(s,2H),6.34(d,J=17.1 Hz,1H),6.22(d,J=7.6 Hz,1H),5.31(t,J=5.3 Hz,1H),4.73-4.59(m,1H),3.96(d,J=9.2 Hz,1H),3.85(ddd,J=12.4,4.8,1.9 Hz,1H),3.77(d,J=5.4 Hz,1H),3.75-3.68(m,1H). 19 F NMR(376 MHz,DMSO-d6)δ-158.34.MS(ESI)m / z [M+H] + 294.1.

[0479] Steps 7 and 8: Synthesis of Example 21C The title compound was obtained using the same procedure as described for Example 8C (42.5 mg, 14% in two steps). 1H NMR(400 MHz,D2O)δ 8.63-8.60(m,1H),8.37(s,1H),6.49-6.44(m,1H),5.57-5.52(m,2H),5.21-5.15(m,2H),5.02(t,J=10.0 Hz,1H),4.46-4.33(m,2H),4.33-4.18(m,3H),4.06-4.02(m,1H),2.95-2.93( m,1H),2.13(s,3H),2.05(s,3H),1.95(s,3H),1.91-1.90(m,3H),1.87(s,3H). 31 P NMR(162 MHz,D2O)δ 44.07,43.69;-15.13,-15.29. 19 F NMR(376 MHz,D2O)δ-159.90,-160.05.MS(ESI)m / z [MH] - 828.1.

[0480] Example 21D Synthesis of Example 21D [ka]

[0481] The title compound was obtained from Example 21C using the same procedure as described for Example 1D (1.6 mg, 10.8%). 1 H NMR(400 MHz,D2O)δ 8.84-8.73(m,1H),8.50(s,1H),6.67-6.62(m,1H),5.41-5.31(m,1H),5.03-4.8 8(m,1H),4.59-4.52(m,1H),4.47-4.39(m,2H),4.18-4.15(m,1H),3.98(t,J=6.5 Hz,1H),3.90-3.66(m,4H),3.42-3.39(m,1H),3.11-3.08(m,1H). 19 F NMR (376 MHz, D2O) δ-159.66. 31 P NMR(162 MHz,D2O)δ 43.41,-14.22.MS(ESI)m / z [MH] - 660.0.

[0482] Example 22C Synthesis of Example 22C [ka]

[0483] Step 1: Synthesis of Compound 2 To a solution of compound 1 (25 g, 0.102 mol) in dried pyridine (100 mL), 1,3-dichloro-1,1,3,3-tetraisopropyldioxane (32.3 g, 0.102 mol) was added. The resulting solution was stirred at room temperature for 4 hours. The solvent was then removed under vacuum. The crude product was purified by silica gel column chromatography (EA / PE = 0-40%) to obtain the title compound (33 g, 62.8%) as a white solid. MS(ESI)m / z [M+H] + 486.9.

[0484] Step 2: Synthesis of Compound 3 To a solution of compound 2 (33 g, 67.8 mmol) in dry ACN (160 ml), IBX (37.9 g, 135.6 mmol) was added. The resulting solution was stirred at 80°C for 5 hours. After cooling to room temperature, the solid was filtered off. The filtrate was concentrated under vacuum to obtain the title compound (33 g, crude product). This was used in the next step without further purification. MS(ESI)m / z [M+H] + 485.0.

[0485] Step 3: Synthesis of Compound 4a and Compound 4b To a solution of ethynyltrimethylsilane (10.1 g, 20.8 mmol) in THF (100 mL), n-BuLi (43 mL, 2.4 M) was added at -78°C, stirred at -78°C for 30 minutes, and then stirred at -55°C for 30 minutes. A solution of compound 3 (10 g, 20.63 mmol) in THF (40 mL) was added dropwise, and the mixture was stirred for 2 hours. A saturated aqueous solution of NH4Cl (200 mL) was added to the mixture and extracted using EA (300 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by flash chromatography (EA / PE = 0-60%) to obtain compound 4a (400 mg, 3.3%) as a brown oil and compound 4b (5 g, 41.2%) as an off-white solid. MS(ESI)m / z [M+H] + 583.3.

[0486] Step 4: Synthesis of Compound 5 A solution of compound 4b (0.5 g, 0.86 mmol) in toluene (9.73 mL) was charged with N2 three times and then cooled to -78°C. DAST (414.79 mg, 2.57 mmol) was then added dropwise, and the mixture was stirred for 2 hours. The mixture was quenched at -78°C with an aqueous solution of Na2CO3 (30 mL) and then extracted with EA (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified over silica gel CombiFlash (EA / PE = 0-40%) to obtain the title compound as a yellow oil (0.4 g, 79.7%). MS(ESI)m / z [M+H] + 585.3,[M+Na] + 607.3.

[0487] Step 5: Synthesis of Compound 6 To a solution of compound 5 (0.4 g, 0.68 mmol) in THF, tetrabutylammonium fluoride trihydrate (431.5 mg, 1.37 mmol) was added. The mixture was stirred at room temperature for 3 hours, then concentrated, and the residue was purified by silica gel column (MeOH / EA = 1-10%) to obtain the title compound (0.1 g, 54.11%) as a yellow oil. MS(ESI)m / z [M+H] + 271.1,[M+Na] + 293.1.

[0488] Steps 6 and 7: Synthesis of Example 22C The title compound was obtained using the same procedure as described for Example 8C (35 mg, 11% in two steps). 1 H NMR(400 MHz,D2O)δ 7.87-7.85(m,1H),6.19-6.15(m,1H),5.87-5.85(m,1H),5.51-5.47( m,2H),5.19-5.11(m,2H),5.01-4.96(m,1H),4.38-4.26(m,3H),4.22- 4.17(m,1H),4.16-4.06(m,2H),4.00-3.98(m,1H),3.25-3.24(m,1H), 2.09(s,3H),2.01(s,3H),1.93-1.89(m,6H),1.85(s,3H).MS(ESI)m / z [MH] - 847.1.

[0489] Example 22D Synthesis of Example 22D [ka]

[0490] The title compound was obtained from Example 22C using the same procedure as described for Example 1D (1 mg, 8%). 1 H NMR(400 MHz,D2O)δ 7.87-7.85(m,1H),6.20-6.16(m,1H),5.87-5.85(m,1H),5.15-5.14(m,1H),4.40-4.32(m,2H),4.17- 4.11(m,2H),4.00-3.98(m,1H),3.81-3.79(m,1H),3.69-3.53(m,4H),3.26-3.23(m,2H).MS(ESI)m / z [MH] - 637.1.

[0491] Example 25C Synthesis of Example 25C [ka]

[0492] Step 1: Synthesis of Compound 2 To a solution of compound 1 (30 g, 65 mmol) in ACN (300 mL), IBX (36.35 g, 0.13 mol) was added. The reaction mixture was stirred at 80°C for 3 hours. The mixture was then cooled to room temperature, filtered, and the filtrate was concentrated without purification to obtain the title compound (27 g, 90.3%) as a yellow oil. 1 H NMR(400 MHz,MeOD)δ 8.18-8.03(m,6H),7.66-7.55(m,3H),7.52-7.36(m,6H),6.40(s,1H),5.37-5.29(m,1H),4.74-4.66(m,1H),4.65-4.52(m,2H).MS(ESI)m / z [M+H2O+Na] + 500.8.

[0493] Step 2: Synthesis of Compound 3 To a solution of compound 2 (12 g, 26 mmol) in THF (120 mL), bromo(ethynyl)magnesium (188 mL, 94 mmol) was added at -78°C. The solution was stirred at -78°C for 0.5 hours and then poured into an ice-collapsed saturated NH4Cl solution (300 mL). After extraction with siRNA (100 mL x 3), the combined organic matter was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound as a yellow oil (12 g). MS(ESI)m / z [M+Na] + 508.8.

[0494] Step 3: Synthesis of Compound 4 To a solution of compound 3 (11.5 g, 23.6 mmol) in DCM (120 mL), 4-dimethylaminopyridine (5.77 g, 47.2 mmol), TEA (7.15 g, 70.8 mmol), and BzCl (9.95 g, 70.8 mmol) were added at 0°C. The solution was stirred at 25°C for 16 hours, then diluted with brine and carefully quenched with saturated NaHCO3 (80 mL). After extraction with toluene (100 mL x 3), the combined organic matter was dried over Na2SO4 and evaporated to obtain the crude product. This was purified by column chromatography (EA / PE = 0-60%) to obtain the title compound (8.6 g, 55.5%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ 8.20-8.08(m,5H),8.04-7.95(m,2H),7.93-7.88(m,1H),7.62-7.39(m,9H),7.35-7.25(m,2H),7.22-7.10(m,2 H),6.47-5.95(m,1H),5.05-4.82(m,1H),4.80-4.60(m,2H),4.60-4.42(m,1H),2.78-2.71(m,1H).MS(ESI)m / z [M+Na] + 612.7.

[0495] Step 4: Synthesis of Compound 5 Compound 4 (8.6g, 14.56 mmol) and 6- in ACN (90mL) Chlorine To a solution of -9H-purine (4.5 g, 29.12 mmol), DBU (12.4 g, 81.5 mmol) was added at 0°C and the mixture was stirred for 15 minutes. TMSOTf (25.9 g, 116.5 mmol) was added to this solution at 0°C. The solution was stirred at 0°C for 15 minutes, then at 70°C for 16 hours. The resulting reaction product was diluted with brine and carefully quenched with saturated NaHCO3 (100 mL). After extraction with Depositphotos (100 mL x 3), the combined organic matter was dried over Na2SO4 and evaporated to obtain the crude product. This was purified by column chromatography (EA / PE = 0-70%) to obtain the title compound (2.8 g, 27.8%) as a yellow solid. MS(ESI)m / z [M+H] + 623.0.

[0496] Step 5: Synthesis of Compound 6 To a solution of compound 5 (2 g, 3.21 mmol) in dioxane (20 mL), NH3·H2O (60 mL) was added. The mixture was stirred overnight in a sealed tube at 110°C. The mixture was then concentrated to obtain the crude product. The residue was applied to a silica gel column using DCM / MeOH (10:1) to obtain the title compound (760 mg, 73%) as a brown solid. 1 H NMR(400 MHz,MeOD)δ 8.48(s,1H),8.17(s,1H),6.16(s,1H),4.57(d,J=8.8 Hz,1H),4.09-3.94(m,2H),3.86-3.77(m,1H),2.65(s,1H).MS(ESI)m / z [M+H] + 292.1.

[0497] Steps 6 and 7: Synthesis of Example 25C The title compound was obtained using the same procedure as described for Example 8C (11 mg, 4% in two steps). 1 H NMR(400 MHz,D2O)δ 8.65(s,1H),8.36(s,1H),6.17(s,1H),5.56(d,J=10.8 Hz,2H),5.27-5.17(m,2H),5.03(t,J=9.9 Hz,1H),4.53(d,J=8.5 Hz,1H),4.42-4.36(m,2H),4.28-4.20(m,3H),4.09-4.04(m,1H),2.58(d,J=4.3 Hz,1H),2.14(s,3H),2.05(s,3H),1.96(s,3H),1.92(s,3H),1.89(s,3H). 31 P NMR(162 MHz,D2O)δ 44.00,-14.81.MS(ESI)m / z [MH] - 867.8.

[0498] Example 25D Synthesis of Example 25D [ka]

[0499] The title compound was obtained from Example 25C using the same procedure as described for Example 1D (1.58 mg, 10.4%). 1 1H NMR (400 MHz, D2O)δ 8.66(s,1H),8.34(s,1H),6.21(s,1H),5.20(d,J=8.4 Hz,1H),4.58(d,J=8.5 Hz,1H),4.40-4.36(m,1H),4.31-4.22(m,2H),4.04(s,1H),3.84(t,J=6.5 Hz,1H),3.78-3.64(m,2H),3.64-3.54(m,2H),3.29-3.26(m,1H),3.09(q,J=7.3 Hz,5H),2.58(s,1H),1.17(t,J=7.3 Hz,7H). 31 P NMR(162 MHz,D2O)δ 43.77,-14.25.MS(ESI)m / z [MH] - 658.0.

[0500] Example 26C Synthesis of Example 26C [ka]

[0501] Compound 4a, the starting material, was isolated in step 3 of Example 22C.

[0502] Step 4: Synthesis of Compound 5 To a solution of compound 4a (400 mg, 0.69 mmol) in MeOH (10 mL), ammonium fluoride (254 mg, 6.9 mmol) was added. The resulting solution was stirred at 70°C for 3 hours. The solvent was then removed under vacuum. The crude product was purified by silica gel column chromatography (MeOH / DCM, 0-10%) to obtain the title compound (139 mg, 74.2%) as an off-white solid. 1H NMR(400 MHz,DMSO-d6)δ 11.31(s,1H),7.67(d,J=8.2 Hz,1H),6.44(s,1H),6.10(s,1H),5.85(d,J=5.7 Hz,1H),5.59(d,J=8.2 Hz,1H),5.10(t,J=5.4 Hz,1H),3.88-3.83(m,1H),3.79-3.73(m,1H),3.66-3.54(m,3H).MS(ESI)m / z [M+H] + 268.9.

[0503] Steps 5 and 6: Synthesis of Example 26C The title compound was obtained using the same procedure as described for Example 8C (7.5 mg, 1.7% in two steps). 1 H NMR(400 MHz,D2O)δ 7.97-7.93(m,1H),5.93-5.92(m,1H),5.85-5.83(m,1H),5.52-5.47(m,2H),5.17 -5.12(m,2H),5.00-4.95(m,1H),4.39-4.33(m,1H),4.32-4.25(m,1H),4.20-4.1 7(m,2H),4.13-4.02(m,2H),4.00-3.96(m,1H),2.88-2.87(m,1H),2.10-2.09(m, 3H...

Claims

1. Equation (I-h-1) or (I-h-4): 【Chemistry 1】 【Chemistry 2】 A compound represented by, or a pharmaceutically acceptable salt, stereoisomer, deuterium isotope or tautomer thereof, wherein the formula, R Ｘ but, 【Transformation 3】 Selected from the group consisting of, R ４ａ However, C ２－６ Alkenil, C ２－６ Haloalkenil, C ２－６ Alkinyl and C ２－６ Selected from the group consisting of haloalkynyls, R ５ｂ is -OH, R ４ｂ but, -H, -OH, -SH, or -halo; C １－６ alkyl or C １－６ haloalkyl; and -OR ９ ; Each is independently selected from the group consisting of, L ２ However, it is -O-, Y ０ However, selected from the group consisting of -OH and -SH, R ３ However, -OH and -OC(=O)R １０ Selected from the group consisting of, R １ , R ６ and R ７ However, -OH and -OC(=O)R ９ Each is independently selected from the group consisting of, R ２ -HALO, -OH, and -OC(=O)R ９ Selected from the group consisting of, Each R ９ However, C １－６ Alkyl and C １－６ Independently selected from the group consisting of haloalkyls, Each R １０ However, C １－２０ Alkyl and C １－２０ A compound, or a pharmaceutically acceptable salt thereof, stereoisomer, deuterium isotope, or tautomer, independently selected from the group consisting of haloalkyl compounds.

2. R Ｘ but, 【Chemistry 4】 Selected from the group consisting of, R ４ａ However, C contains one double or triple bond. ２－６ Alkenil, C ２－６ Haloalkenil, C ２－６ Alkinyl and C ２－６ Selected from the group consisting of haloalkynyls, R ４ｂ However, -H, -OH, -OR ９ Selected from the group consisting of and -halo, R ５ｂ is -OH, L ２ However, it is -O-, Y ０ However, it is -SH, R ３ However, -OH and -OC(=O)R １０ Selected from the group consisting of, R １ , R ６ and R ７ However, -OH and -OC(=O)R ９ Each is independently selected from the group consisting of, R ２ However, -halo, -OH, or -OC(=O)R ９ And, Each R ９ However, C １－６ Alkyl and C １－６ Independently selected from the group consisting of haloalkyls, Each R １０ However, C １－２０ Alkyl and C １－２０ A compound according to claim 1, independently selected from the group consisting of haloalkyls, or a pharmaceutically acceptable salt, stereoisomer, deuterium isotope, or tautomer thereof.

3. R Ｘ but, 【Transformation 5】 Selected from the group consisting of, R ４ａ However, selected from the group consisting of ethenyl, propenyl, ethinyl, and propynyl, R ４ｂ However, -F, -OH and -OR ９ Selected from the group consisting of, R ５ｂ is -OH, L ２ However, it is -O-, Y ０ However, it is -SH, R ２ However, -halo, -OH and -OC(=O)R ９ Selected from the group consisting of, R ３ However, -OH and -OC(=O)R １０ Selected from the group consisting of, R １ , R ６ and R ７ However, -OH and -OC(=O)R ９ Each is independently selected from the group consisting of, Each R ９ However, C １－６ Alkyl and C １－６ Independently selected from the group consisting of haloalkyls, Each R １０ However, C １－２０ Alkyl and C １－２０ A compound according to claim 1, independently selected from the group consisting of haloalkyls, or a pharmaceutically acceptable salt, stereoisomer, deuterium isotope, or tautomer thereof.

4. R Ｘ but, 【Transformation 6】 Selected from the group consisting of, R ４ａ However, selected from the group consisting of ethenyl and ethynyl, R ４ｂ However, -OH and -OR ９ Selected from the group consisting of, R ５ｂ However, it is -OH, L ２ is -O-, Y ０ However, selected from the group consisting of -OH and -SH, R ３ However, -OH and -OC(=O)R １０ Selected from the group consisting of, R １ , R ６ and R ７ However, -OH and -OC(=O)R ９ Each is independently selected from the group consisting of, R ２ However, -halo, -OH and -OC(=O)R ９ Independently selected from the group consisting of, Each R ９ is independently selected from the group consisting of C １－６ alkyl and C １－６ haloalkyl Each R １０ However, C １－２０ Alkyl and C １－２０ Independently selected from the group consisting of haloalkyls, The compound described in claim 1, or a pharmaceutically acceptable salt, stereoisomer, deuterium isotope, or tautomer thereof.

5. R Ｘ but, 【Transformation 7】 Selected from the group consisting of, R ４ａ However, it is etenyl, R ４ｂ is selected from the group consisting of H, -OH, -OMe and -F, R ５ｂ However, it is -OH, L ２ is -O-, Y ０ However, it is -SH, R ２ However, it is -OH or -OAc, R ３ However, -OH and -OC(=O)C １－２０ Selected from the group consisting of alkyl groups, R １ , R ６ and R ７ The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, deuterium isotope, or tautomer thereof, each independently selected from the group consisting of -OH and -OAc.

6. Equation (I-k-1) or (I-k-4): 【Transformation 8】 【Chemistry 9】 A compound represented by, or a pharmaceutically acceptable salt, stereoisomer, deuterium isotope or tautomer thereof, wherein the formula, R Ｘ but, 【Chemistry 10】 Selected from the group consisting of, R ５ｂ However, it is -OH, R ４ａ but, -H, -OH, -SH, or -halo; C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Haloalkenil, C ２－６ Alkinyl or C ２－６ Haloalkynyl; Independently selected from the group consisting of, L ２ However, it is -O-, Y ０ However, selected from the group consisting of -OH and -SH, R ３ However, -OH and -OC(=O)R １０ Selected from the group consisting of, R １ , R ６ and R ７ However, -OH and -OC(=O)R ９ Each is independently selected from the group consisting of, R ２ However, -halo, -OH and -OC(=O)R ９ Each is independently selected from the group consisting of, Each R ９ However, C １－６ Alkyl and C １－６ Independently selected from the group consisting of haloalkyls, Each R １０ However, C １－２０ Alkyl and C １－２０ Independently selected from the group consisting of haloalkyls, R ｅ and R ｆ Each of these is -H;C １－６ Alkyl and C １－６ A compound, or a pharmaceutically acceptable salt thereof, stereoisomer, deuterium isotope, or tautomer, independently selected from the group consisting of haloalkyl compounds.

7. R Ｘ but, 【Chemistry 11】 Selected from the group consisting of, R ５ｂ However, it is -OH, R ４ａ but, -H, -OH, -SH, or -halo; C １－６ Alkyl or C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Haloalkenil, C ２－６ Alkinyl or C ２－６ Haloalkynyl; Independently selected from the group consisting of, L ２ However, it is -O-, Y ０ However, selected from the group consisting of -OH and -SH, R ３ However, -OH and -OC(=O)R １０ Selected from the group consisting of, R １ , R ６ and R ７ However, -OH and -OC(=O)R ９ Each is independently selected from the group consisting of, R ２ However, halo, -OH, or -OC (=O)R ９ Each is independently selected from the group consisting of, Each R ９ However, C １－６ Alkyl and C １－６ Independently selected from the group consisting of haloalkyls, Each R １０ However, C １－２０ Alkyl and C １－２０ Independently selected from the group consisting of haloalkyls, R ｅ and R ｆ Each of these is -H;C １－６ Alkyl and C １－６ A compound according to claim 6, independently selected from the group consisting of haloalkyls, or a pharmaceutically acceptable salt, stereoisomer, deuterium isotope, or tautomer thereof.

8. R Ｘ but, 【Chemistry 12】 Selected from the group consisting of, R ４ａ However, -H, -Haro, C １－６ Alkyl and C １－６ Selected from the group consisting of haloalkyls, R ５ｂ is -OH, L ２ However, it is -O-, Y ０ However, selected from the group consisting of -OH and -SH, R ２ However, -halo, -OH and -OC(=O)R ９ Selected from the group consisting of, R ３ However, -OH and -OC(=O)R １０ Selected from the group consisting of, R １ , R ６ and R ７ However, -OH and -OC(=O)R ９ Each is independently selected from the group consisting of, Each R ９ However, C １－６ Alkyl and C １－６ Independently selected from the group consisting of haloalkyls, Each R １０ However, C １－２０ Alkyl and C １－２０ Independently selected from the group consisting of haloalkyls, R ｅ and R ｆ Each of these is -H;C １－６ Alkyl and C １－６ A compound according to claim 6, independently selected from the group consisting of haloalkyls, or a pharmaceutically acceptable salt, stereoisomer, deuterium isotope, or tautomer thereof.

9. R Ｘ but, 【Chemistry 13】 Selected from the group consisting of, R ４ａ However, it is -H or Me, R ５ｂ However, it is -OH, L ２ is -O-, Y ０ However, it is -SH, R ２ However, selected from the group consisting of -F, -OH, and -OAc, R ３ However, -OH and -OC(=O)C １－２０ Selected from the group consisting of alkyl groups, R １ , R ６ and R ７ However, they are independently selected from the group consisting of -OH and -OAc, R ｅ and R ｆ Each of these is -H or C １－６ The compound according to claim 6, or a pharmaceutically acceptable salt, stereoisomer, deuterium isotope, or tautomer thereof, which is alkyl.

10. below 【Chemistry 14-1】 【Chemistry 14-2】 【Chemistry 14-3】 【Chemistry 14-4】 【Chemistry 14-5】 Compounds selected from the group consisting of the compounds shown, or pharmaceutically acceptable salts, stereoisomers, deuterium isotopes, or tautomers thereof.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, deuterium isotope, or tautomer thereof, Pharmacologically acceptable excipients, Selectively, one or more other therapeutic drugs A pharmaceutical composition containing the following:

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, deuterium isotope or tautomer thereof, for treating immune and / or inflammation-related diseases, treating cancer, enhancing the efficacy of a vaccine, or enhancing innate immunity.

13. The above-mentioned immune and / or inflammation-related disease is inflammatory bowel disease, ulcerative colitis, or Crohn's disease. The above cancers are selected from the group consisting of brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, hepatocellular carcinoma, prostate cancer, colorectal cancer, hematological cancer, lung cancer, and bone cancer, or from the group consisting of small cell lung cancer, non-small cell lung cancer, colorectal cancer, melanoma, renal cell carcinoma, head and neck cancer, Hodgkin lymphoma, and bladder cancer. The above vaccine is a cancer vaccine, a bacterial vaccine, a viral vaccine, or a parasitic vaccine, or the above compound is an adjuvant. To enhance innate immunity, a therapeutically effective amount of the above compound, or a pharmaceutically acceptable salt, stereoisomer, deuterium isotope, or tautomer thereof, is administered intramuscularly, intraperitoneally, intratumorally, or intravenously, or is administered in combination with one or more immunotherapeutic agents. The pharmaceutical composition according to claim 12, wherein selectively, one or more of the above-mentioned immunotherapeutic agents include small molecules, antibodies, or cytokines.

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