Compound with pyridone structure and application of compound in medicine

Abstract

The invention belongs to the field of medicine, and relates to a compound with a pyridone structure and application of the compound in medicine. Specifically, the invention relates to a pyridone compound, a pharmaceutical composition containing the compound and application of the pyridone compound as an AhR regulator, in particular to application of the pyridone compound in preparation of drugs for treating and / or preventing AhR protein mediated diseases or symptoms.

Description

TECHNICAL FIELD

[0001] The present disclosure belongs to the field of medicine, and relates to a kind of compound of pyridinone structure and its application in medicine. Specifically, the present disclosure relates to a kind of pyridinone compound shown in general formula (I), the pharmaceutical composition containing such compound and its use as AhR modulator, especially in the preparation of drug for treating and / or preventing AhR protein-mediated diseases or conditions. BACKGROUND

[0002] Aryl hydrocarbons Receptor (AhR), also known as dioxin receptor, mediates the toxic response of polycyclic aromatic hydrocarbons, dioxins (such as TCDD) and polychlorinated biphenyls, etc. Therefore, for decades, the activation of AhR has been ruled out as a treatment method. However, it is now known that AhR activation not only acts as an environmental sensor to regulate the effects of environmental toxins, but also as a key immunomodulator, whose ligands induce various cellular and epigenetic mechanisms to reduce inflammation. Therefore, the emergence of further in-depth research on ligand compounds capable of activating this receptor has prompted people to reconsider its use in treatment.

[0003] Recent studies have shown that AhR activation in TCDD-induced dendritic cells is the cause of the observed thymic atrophy; in addition to thymic atrophy caused by AhR activation by TCDD, it has been reported that TCDD can induce apoptosis. Notably, other apoptosis mechanisms, such as p53-mediated, are associated with TCDD-induced AhR activation; Anti-inflammatory T regulatory cells (Tregs) play an important role in maintaining tolerance to self-antigens and in the regulation mechanisms of immune-mediated inflammation. Many studies have shown that ligand-activated AhR can increase Tregs, thereby reducing inflammation and improving disease; Myeloid-derived suppressor cells (MDSCs) are an effective immune suppressor cell type, which is associated with the suppression of T cell proliferation. Experiments have shown that TCDD-activated AhR can inhibit inflammation by inducing MDSCs; cytokine suppression is partly responsible for the observed inhibition of AhR-induced inflammatory states. TCDD-induced AhR activation reverses the demethylation of IL-17 promoters in colitis through DNA methylation mechanisms, thereby inhibiting Th17 cells and reducing inflammatory responses; studies have also provided evidence that AhR is involved in regulating chromatin remodeling through histone acetylation and methylation. DNA methylation, histone modification and non-coding RNA processes also include AhR mechanisms dependent on TCDD activation. In addition, it is also worth noting that miRNAs have been shown to inhibit the expression of AhR.

[0004] Given the cellular and molecular mechanisms by which AhR is used to modulate immune responses, activation of this receptor shows potential in preventing or treating inflammatory diseases. For example, studies have found that TCDD-activated AhR pathways are associated with diseases such as pertussis infection, experimental autoimmune uveitis, multiple sclerosis, colitis, atopic dermatitis, and psoriasis. For example, the AhR modulator, beloxamide, is a naturally derived small molecule produced by the bacterial symbiont of an entomopathogenic nematode, and is the first aromatic hydrocarbon receptor agonist to be marketed globally, and can be used to treat a variety of autoimmune diseases, such as psoriasis, eczema, etc.

[0005] Currently, the development of AhR agonists is still mainly limited to external administration for the treatment of immune skin diseases. Therefore, there is still a huge clinical need to develop novel, high-activity AhR agonists for oral administration for the treatment of more immune-related diseases.

[0006] The disclosed related AhR modulator patent applications include WO2023039278, which is not part of the present application. SUMMARY

[0007] The present disclosure provides a compound having a pyridinone structure, which has the general formula (I) as follows:

[0008]

[0009] wherein:

[0010] X1is NR3, wherein R3is H or C1-C6alkyl;

[0011] X2is N or CH; X3is NH or S; R4is selected from halogen, cyano, amino, -O-(C1-C6alkyl), C1-C6alkyl unsubstituted or substituted with 1-3 halogens, and p is 0 or 1 or 2 or 3;

[0012] R1is selected from hydrogen, halogen, C1-C6alkyl;

[0013] R2is H;

[0014] n is 1 or 2;

[0015] m is 0, 1 or 2.

[0016] In one embodiment, the compound of the present disclosure has the following structure:

[0017] , , , , , , 、 、

[0018] 、 、 、 、

[0019] 、 、 、 、 or .

[0020] According to another aspect of the present application, the present application also provides the pharmaceutical composition and one or more pharmaceutically acceptable carriers, containing a therapeutically effective amount of the compound of the general formula (I).

[0021] According to another aspect of the present application, the present application also provides the use of the compound of the general formula (I) or the pharmaceutical composition in the preparation of a medicament for modulating AhR protein.

[0022] According to another aspect of the present application, the present application also provides the use of the compound of the general formula (I) or the pharmaceutical composition in the preparation of an AhR modulator.

[0023] According to another aspect of the present application, the present application also provides the use of the compound of the general formula (I) or the pharmaceutical composition in the preparation of a medicament for treating and / or preventing a disease or disorder mediated by AhR protein.

[0024] Preferably, the disease or disorder is selected from cancer, ophthalmology-related diseases, autoimmune diseases, viral infectious diseases, central nervous system diseases, inflammatory diseases.

[0025] Preferably, the disease or disorder is selected from skin diseases, acute lung injury, adult / acute respiratory distress syndrome, chronic obstructive pulmonary disease, oral ulcer, ocular allergy, conjunctivitis, dry eye, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, lung cancer, breast cancer, liver cancer, non-alcoholic fatty liver disease, ovarian cancer, prostate cancer, melanoma, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, glioma, cervical cancer, endometrial cancer, colon cancer, and colorectal cancer. DETAILED DESCRIPTION

[0026] An "aryl hydrocarbon receptor (AhR) modulator" as described herein refers to an agent that causes or promotes a qualitative or quantitative change, alteration, or modification of one or more processes, mechanisms, effects, responses, functions, activities, or pathways mediated by the AhR receptor. Such a change mediated by an AhR modulator (e.g., an inhibitor or non-constitutive agonist of AhR as described herein) can refer to a decrease or increase in AhR activity or function, such as a decrease, inhibition, or diversion of constitutive activity of AhR.

[0027] An "AhR antagonist" as described herein refers to an inhibitor of AhR that, by itself, does not elicit a biological response upon specific binding to an AhR polypeptide or polynucleotide encoding AhR, but blocks or suppresses an agonist-mediated or ligand-mediated response, i.e., an AhR antagonist can bind to, but does not activate, an AhR polypeptide or polynucleotide encoding AhR, and this binding disrupts the interaction, displaces an AhR agonist, and / or suppresses the function of an AhR agonist. Thus, as used herein, AhR antagonists, when bound to AhR, do not act as inducers of AhR activity, i.e., they act as pure AhR inhibitors.

[0028] An "AhR-mediated" disease and / or disorder as described herein means any disease or other deleterious condition in which AhR or a mutant thereof is known to play a role. Thus, another embodiment of the present application relates to treating or lessening the severity of one or more diseases in which AhR or a mutant thereof is known to play a role.

[0029] "Cancer" as described herein includes, but is not limited to, the following cancers:

[0030] Oral cavity: mouth, lips, tongue, mouth, pharynx;

[0031] Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;

[0032] Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroid tumor, mesothelioma;

[0033] Gastrointestinal: esophagus (squamous cell carcinoma, throat, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, VIPoma), small bowel (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, rectum;

[0034] Urogenital tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratocarcinoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma);

[0035] Liver: hepatoma (hepatocellular carcinoma), biliary duct carcinoma, hepatoblastoma, hemangiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;

[0036] Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma, benign chondroma, chondroblastioma, chondromyxofibroma, osteoid osteoma, giant cell tumors;

[0037] Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, spinal cord neurofibroma;

[0038] Gynecologic: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma), breast;

[0039] Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma hairy cell, lymphoma;

[0040] Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;

[0041] Thyroid: papillary thyroid carcinoma, follicular thyroid carcinoma, thyroid medullary carcinoma, anaplastic thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; and neuroblastoma.

[0042] The neurodegenerative diseases described herein can affect many activities of the body, such as balance, movement, speech, breathing, and heart function. Neurodegenerative diseases can be inherited or can be caused by medical conditions such as alcoholism, tumors, stroke, toxins, chemicals, and viruses.

[0043] Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease or Charcot disease), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy.

[0044] Non-limiting examples of central nervous system (CNS) diseases or disorders described herein include brain injury, spinal cord injury, dementia, stroke, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine (polyQ) diseases, stroke, Fahr disease, Menkes disease, Wilson's disease, cerebral ischemia, and prion disease.

[0045] As used herein, the phrase "disease" or "disorder" refers broadly to any of the diseases or disorders described above that can be treated and / or prevented by administering to a patient a compound or an aryl hydrocarbon receptor modulator (antagonist or agonist) described herein.

[0046] The compounds of the disclosure, or compositions thereof, can be used to treat and / or prevent inflammatory or obstructive airway diseases, to reduce, for example, tissue damage, airway inflammation, bronchial hyperreactivity, remodeling, or disease progression. Inflammatory or obstructive airway diseases to which the disclosure can be applicable include asthma of any type or etiology, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection. Treatment of asthma is also understood to encompass treatment of subjects, for example, less than 4 or 5 years of age, who exhibit wheezing symptoms and are diagnosed or diagnosable as "wheezy infants," which is an established patient category of primary medical concern and is now often identified as an early or incipient asthma patient.

[0047] Other inflammatory or obstructive airway diseases and / or disorders to which the disclosure can be applicable and that are encompassed by the diseases and / or disorders include acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, respiratory or pulmonary disorders, including chronic bronchitis or dyspnea associated therewith, emphysema, and exacerbation of airway hyperreactivity resulting from other drug therapies, especially other inhaled drug therapies.

[0048] The present disclosure can also be used to treat inflammatory or allergic conditions of the skin and other diseases or conditions, e.g., diseases or conditions having an inflammatory component, e.g., to treat ocular diseases and conditions, e.g., ocular allergies, conjunctivitis, dry eye, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology. The inflammatory diseases that can be treated according to the methods of the present disclosure are selected from the group consisting of acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

[0049] In some embodiments, the inflammatory diseases that can be treated according to the methods of the present disclosure are selected from the group consisting of TH17-mediated diseases. In some embodiments, the TH17-mediated diseases are selected from the group consisting of systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0050] A "subject" and "patient" as described herein refers to an organism, e.g., a human, who receives treatment for a particular disease or condition described herein. The term subject or patient as used herein can refer to a mammal, e.g., a dog, cat, horse, cow, pig, guinea pig, etc. For example, a patient in need of an aryl hydrocarbon receptor antagonist, such as a human patient, can receive treatment including an aryl hydrocarbon receptor antagonist to treat a disease or condition described herein, such as a cancer, an autoimmune disease, or an inflammatory disease.

[0051] The active compounds can be prepared in a form suitable for administration by any of the routes conventionally used for drug delivery, and the composition of the present disclosure can be formulated using conventional methods and carriers. Thus, the active compounds of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation or insufflation, and the compounds of the present disclosure can also be formulated into sustained release dosage forms, such as tablets, hard or soft gel capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges, or syrups.

[0052] As a general guide, the active compounds are preferably in unit dosage form, or in a form suitable for administration in a single dose. The expression unit dose of the compounds or compositions of the present disclosure can be in the form of a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid preparation. Suitable unit doses can be 0.1 to 1000 mg.

[0053] The pharmaceutical composition of the present disclosure can contain one or more auxiliary agents selected from the following ingredients: a filler (diluent), a binder, a wetting agent, a disintegrant, or an excipient, etc. in addition to the active compound. Depending on the method of administration, the composition can contain 0.1 to 99% by weight of the active compound.

[0054] The tablets contain the active ingredient and suitable non-toxic pharmaceutically-acceptable excipients that are used in mixing the tablets. These excipients can be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. The tablets can be uncoated or they can be coated by known techniques to mask the unpleasant taste or odor of the drug or delay the disintegration and absorption of the drug in the gastrointestinal tract and thereby provide a sustained action over a longer period. For formulation examples, see, e.g., "Remington's Pharmaceutical Sciences" by E.W. Martin.

[0055] Oral preparations can also be provided in the form of soft gelatin capsules wherein the active ingredient is dissolved or suspended in an inert solid diluent or wherein the active ingredient is dissolved or suspended in a water-soluble carrier or an oil vehicle.

[0056] The aqueous suspension contains the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspension can also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0057] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspensions can contain a thickening agent. Sweetening agents and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant.

[0058] The pharmaceutical composition of the present disclosure can also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil or a mineral oil or a mixture of these. Suitable emulsifying agents can be naturally-occurring phosphatides, such as soybean phospholipids, and the like. The emulsions can also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such formulations can also contain a demulcent, a preservative, a coloring agent and an antioxidant.

[0059] The pharmaceutical composition of the present disclosure can be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. The oil- in-water microemulsions can be injected intravenously by local massive injection or by infusion into the blood stream of the patient. Alternatively, the solution or the microemulsion can be administered in a manner to maintain a constant circulating concentration of the compound of the present disclosure. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS. TM. Model 5400 intravenous pump.

[0060] The pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular and subcutaneous administration. This suspension can be formulated according to known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, the sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0061] The compounds of the present disclosure can be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are

[0062] The compounds of the present disclosure can be administered in the form of water suspensions, dispersible powders or granules. These compositions can be prepared by combining the active ingredient with a dispersing or wetting agent, suspending agent and one or more preservatives.

[0063] The dosage of the drug to be administered depends on various factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the body weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc. as well known to those skilled in the art. In addition, the optimal treatment regime, such as the mode of treatment, the daily amount of the compound or the type of the pharmaceutically acceptable salt, can be verified according to the conventional treatment regime.

[0064] The present disclosure is further described in connection with the following examples, which are not intended to limit the scope of the present disclosure.

[0065] Examples

[0066] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shifts (δ) are given in 10 -6 (ppm) units. The NMR measurements are performed on a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0067] Liquid chromatography-mass spectrometry is performed on waters 2695+ZQ2000, Shimadzu MS-2020+LC-20AB and Shimadzu LC-40D XR+MS-2020.

[0068] High performance liquid chromatography (HPLC) analysis used Shimadzu LC-20AB, Shimadzu LC-20ADXR and Shimadzu LC-40D XR high performance liquid chromatograph.

[0069] Chiral HPLC analysis determination used Shimadzu LC-30AD high performance liquid chromatograph.

[0070] High performance liquid preparation used Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

[0071] Chiral preparation used Waters 150Mgm, Waters SFC 350 preparative chromatograph.

[0072] CombiFlash rapid preparation instrument used CH-200P (Agela & Phenomenex).

[0073] Thin layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of silica gel plate used in thin layer chromatography (TLC) was 0.15 mm~0.2 mm, and the specification of thin layer chromatography separation and purification product was 0.4 mm~0.5 mm.

[0074] Silica gel column chromatography generally used Yantai Huanghai silica gel 200~300 mesh silica gel as carrier.

[0075] Determination of average inhibition rate and IC 50 value of kinase used NovoStar microplate reader (Germany BMG company).

[0076] Known starting materials of the present disclosure can be synthesized or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, etc. according to methods known in the art.

[0077] Unless otherwise specified in the examples, the reactions can be carried out under argon or nitrogen atmosphere.

[0078] Argon or nitrogen atmosphere refers to that the reaction bottle is connected with an argon or nitrogen balloon with a volume of about 1L.

[0079] Hydrogen atmosphere refers to that the reaction bottle is connected with a hydrogen balloon with a volume of about 1L.

[0080] The pressurized hydrogenation reaction used a Parr 3916EKX hydrogenation apparatus and a Qianlan QL-500 hydrogen generator or an HC2-SS hydrogenation apparatus.

[0081] The hydrogenation reaction was usually vacuumed, filled with hydrogen, and repeated 3 times.

[0082] The microwave reaction used a CEM Discover-S 908860 microwave reactor.

[0083] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0084] In the examples, unless otherwise specified, the reaction temperature is room temperature, which is 20-30°C.

[0085] In the examples, the reaction progress was monitored by thin layer chromatography (TLC), and the developing agent used in the reaction, the eluent used in column chromatography for purifying compounds, and the developing agent used in thin layer chromatography included: A: petroleum ether / ethyl acetate system, B: dichloromethane / methanol system, the volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of triethylamine and acetic acid or other basic or acidic reagents could also be added for adjustment.

[0086] In some examples, the purified compound was prepared by HPLC.

[0087] Example 1

[0088] Compound 1: 3-(1H-indol-2-yl)-1-methyl-5,6,7,8-tetrahydroquinolin-2-one

[0089]

[0090]

[0091] First step

[0092] Compound 1b: (E)-2-[(dimethylamino)methylene]cyclohexyl-1-one

[0093] Tert-butoxybismethylamino-methane (5.33 g, 30.5 mmol) was added to cyclohexanone (3.00 g, 30.5 mmol), replaced with nitrogen three times, stirred at room temperature for 1.5 h, and then heated to 110°C and stirred for 10 h. The reaction was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with water (100 mL) and saturated brine (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1b.

[0094] Second step

[0095] Compound 1c: methyl 2-oxo-5,6,7,8-tetrahydro-lH-quinoline-3-carboxylate

[0096] Compound 1b (2.70 g, 17.6 mmol) was dissolved in methanol (30 mL), methyl cyanoacetate (1.92 g, 19.3 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was concentrated and purified by preparative HPLC to give compound 1c.

[0097] Third step

[0098] Compound 1d: methyl l-methyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate

[0099] Compound 1c (500 mg, 2.41 mmol) was dissolved in acetone (5 mL), potassium carbonate (666 mg, 4.83 mmol) and iodomethane (1.37 g, 9.65 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL) and saturated brine (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel to give compound 1d.

[0100] Fourth step

[0101] Compound 1e: l-methyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylic acid

[0102] Compound 1d (360 mg, 1.63 mmol) was dissolved in methanol (4 mL), and an aqueous solution of sodium hydroxide (260 mg, 6.51 mmol) in water (4 mL) was added, and the mixture was stirred at 60 °C for 8 h. The reaction mixture was cooled to room temperature, adjusted to pH ~ 3 with 1 M aqueous hydrochloric acid solution, and extracted with ethyl acetate (50 mL). The organic phase was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1e.

[0103] Fifth step

[0104] Compound 1f: 3-iodo-l-methyl-5,6,7,8-tetrahydroquinolin-2-one

[0105] Compound 1e (1.00 g, 4.83 mmol) was dissolved in acetonitrile (10 mL), then iodine (4.90 g, 19.3 mmol) and potassium phosphate (1.02 g, 4.83 mmol) were added, and stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL) and saturated aqueous sodium thiosulfate (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1f.

[0106] Sixth step

[0107] Compound 1f (350 mg, 1.21 mmol) and indole-2-boronic acid pinacol ester (294 mg, 1.21 mmol) were dissolved in dioxane (5 mL) and water (2.5 mL), replaced with nitrogen three times, and then potassium carbonate (501 mg, 3.63 mmol) and (1,1'-bis(diphenylphosphino)ferrocene) palladium dichloride (88.5 mg, 121 μmol) were added, and stirred at 80 ℃ for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give a crude product, which was slurried with methanol to give compound 1.

[0108] LCMS (ESI, m / z): 279.10 [M+H] + .

[0109] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.48 (s, 1H), 7.87 (s, 1H), 7.48(t, J = 8.0 Hz, 2H), 7.12 (d, J = 1.6 Hz, 1H), 7.05-7.01 (m, 1H), 6.98-6.94(m, 1H), 3.54 (s, 3H), 2.74 (t, J = 6.0 Hz, 2H), 2.59 (t, J = 6.0 Hz, 2H),1.83-1.77 (m, 2H), 1.71-1.65 (m, 2H).

[0110] Example 2

[0111] Compound 2: 3-(1H-Benzo[d]imidazol-2-yl)-1-methyl-5,6,7,8-tetrahydroquinolin-2-one

[0112]

[0113]

[0114] First step

[0115] Compound 1e (200 mg, 965 μmol) and o-phenylenediamine (104 mg, 965 μmol) were added to polyphosphoric acid (2 g), heated to 180 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, slowly diluted with water (30 mL), the pH of the system was adjusted to ~7 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL). The organic phase was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC to obtain compound 2.

[0116] LCMS (ESI, m / z): 280.10 [M+H] + .

[0117] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.56 (s, 1H), 8.36 (s, 1H), 7.69-7.63 (m, 1H), 7.60-7.53 (m, 1H), 7.19-7.09 (m, 2H), 3.60 (s, 3H), 2.80 (t, J= 6.0 Hz, 2H), 2.64 (t, J = 6.0 Hz, 2H), 1.86-1.78 (m, 2H), 1.73-1.65 (m,2H).

[0118] Example 3

[0119] Compound 3: 3-(1H-indol-2-yl)-1,6-dimethyl-5,6,7,8-tetrahydroquinolin-2-one

[0120]

[0121]

[0122] First step

[0123] Compound 3b: 2-[(E)-(dimethylamino)methylidene]-4-methylcyclohexan-1-one

[0124] The title product 3b was prepared from compound 3a according to the synthetic procedure of the first step in Reference Example 1.

[0125] Second step

[0126] Compound 3c: 6-methyl-2-oxo-5,6,7,8-tetrahydro-lH-quinoline-3-carboxylic acid methyl ester

[0127] The title product 3c was prepared from compound 3b according to the synthetic procedure of the second step in Example 1.

[0128] Third Step

[0129] Compound 3d: 1,6-dimethyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylic acid methyl ester

[0130] The title product 3d was prepared from compound 3c according to the synthetic procedure of the third step in Example 1.

[0131] Fourth Step

[0132] Compound 3e: 1,6-dimethyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylic acid

[0133] The title product 3e was prepared from compound 3d according to the synthetic procedure of the fourth step in Example 1.

[0134] Fifth Step

[0135] Compound 3f: 3-iodo-l,6-dimethyl-5,6,7,8-tetrahydroquinolin-2-one

[0136] The title product 3f was prepared from compound 3e according to the synthetic procedure of the fifth step in Example 1.

[0137] Sixth Step

[0138] The title product 3 was prepared from compound 3f according to the synthetic procedure of the sixth step in Example 1.

[0139] LCMS (ESI, m / z): 293.23 [M+H] + .

[0140] 1H NMR (400 MHz, DMSO-d6, ppm): δ 11.48 (s, 1H), 7.85 (s, 1H), 7.48(t, J = 7.2 Hz, 2H), 7.10 (d, J = 1.6 Hz, 1H), 7.07-7.02 (m, 1H), 6.98-6.93(m, 1H), 3.55 (s, 3H), 2.87-2.62 (m, 3H), 2.28-2.20 (m, 1H), 1.93-1.75 (m,2H), 1.44-1.35 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H).

[0141] Example 4

[0142] Compound 4: 3-(1H-indol-2-yl)-1,6,6-trimethyl-5,6,7,8-tetrahydroquinolin-2-one

[0143]

[0144]

[0145] First step

[0146] Compound 4b: 2-[(E)-(dimethylamino)methylidene]-4,4-dimethylcyclohexan-1-one

[0147] The title product 4b was prepared from compound 4a according to the synthetic procedure described in the first step of Example 1.

[0148] Second step

[0149] Compound 4c: Methyl 6,6-dimethyl-2-oxo-5,6,7,8-tetrahydro-1H-quinoline-3-carboxylate

[0150] The title product 4c was prepared from compound 4b according to the synthetic procedure described in the second step of Example 1.

[0151] Third step

[0152] Compound 4d: Methyl 1,6,6-trimethyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate

[0153] The title product 4d was prepared from compound 4c according to the synthetic procedure described in the third step of Example 1.

[0154] Fourth step

[0155] Compound 4e: 1,6,6-trimethyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylic acid

[0156] The title product 4e was prepared from compound 4d according to the synthetic procedure of Example 1, fourth step.

[0157] Fifth step

[0158] Compound 4f: 3-lodo-l,6,6-trimethyl-5,6,7,8-tetrahydroquinolin-2-one

[0159] The title product 4f was prepared from compound 4e according to the synthetic procedure of Example 1, fifth step.

[0160] Sixth step

[0161] The title product 4 was prepared from compound 4f according to the synthetic procedure of Example 1, sixth step.

[0162] LCMS (ESI, m / z): 307.32 [M+H] + .

[0163] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.50 (s, 1H), 7.84 (s, 1H), 7.48(t, J = 6.8 Hz, 2H), 7.10 (d, J = 1.6 Hz, 1H), 7.07-7.02 (m, 1H), 6.98-6.93(m, 1H), 3.57 (s, 3H), 2.76 (t, J = 6.4 Hz, 2H), 2.39 (s, 2H), 1.57 (t, J =6.4 Hz, 2H), 0.98 (s, 6H).

[0164] Example 5

[0165] Compound 5: 3-(lH-indol-2-yl)-l,2,5,6,7,8-hexahydroquinolin-2-one

[0166]

[0167]

[0168] First step

[0169] Compound 5a: methyl 2-[(2-methoxyethyl)oxy]-5,6,7,8-tetrahydroquinoline-3- carboxylate

[0170] The title product 5a was prepared from compound 1c and l-iodo-2-methoxyethane according to the synthetic procedure of Example 1, third step.

[0171] Second step

[0172] Compound 5b: 2-[(2-methoxyethyl)oxy]-5,6,7,8-tetrahydroquinoline-3-carboxylic acid

[0173] The title product 5b was prepared from compound 5a according to the synthetic procedure described in the fourth step of Example 1.

[0174] Third step

[0175] Compound 5c: 3-iodo-1,2,5,6,7,8-hexahydroquinolin-2-one

[0176] The title product 5c was prepared from compound 5b according to the synthetic procedure described in the fifth step of Example 1.

[0177] Fourth step

[0178] The title product 5 was prepared from compound 5c and indole-2-boronic acid pinacol ester according to the synthetic procedure described in the sixth step of Example 1.

[0179] LCMS (ESI, m / z): 265.33 [M+H] + .

[0180] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.80 (s, 1H), 11.45 (s, 1H), 7.86(s, 1H), 7.48 (t, J = 6.4 Hz, 2H), 7.10-6.93 (m, 3H), 2.55-2.50 (m, 4H),1.78-1.65 (m, 4H).

[0181] Example 6

[0182] Compound 6: 3-(6-methoxy-1H-indol-2-yl)-1-methyl-1,2,5,6,7,8-hexahydroquinolin-2-one

[0183]

[0184]

[0185] First step

[0186] Compound 6a: 6-methoxy-2-(1-methyl-2-oxo-5,6,7,8-tetrahydroquinolin-3-yl)indole-1- carboxylic acid-2-methylprop-2-yl ester

[0187] Compound 6a was prepared from compound If and l-tert-butoxycarbonyl-6- methoxyindole-2-boronic acid according to the synthetic method of the sixth step in Reference Example 1.

[0188] Second step

[0189] Compound 6a (136 mg, 0.33 mmol) was dissolved in hydrochloric acid ethyl acetate (4 mL, 4 M) and stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel to give compound 6.

[0190] LCMS (ESI, m / z): 309.37 [M+H] + .

[0191] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.32 (s, 1H), 7.77 (s, 1H), 7.36(d, J = 8.4 Hz, 1H), 7.05-7.00 (m, 2H), 6.63 (dd, J = 8.4 Hz, 2.0 Hz, 1H),3.76 (s, 3H), 3.53 (s, 3H), 2.73 (t, J = 6.0 Hz, 2H), 2.58 (t, J = 6.0 Hz,2H), 1.86-1.75 (m, 2H), 1.73-1.65 (m, 2H).

[0192] Example 7

[0193] Compound 7: 3-(5-methoxy-lH-indol-2-yl)-l-methyl-l,2,5,6,7,8-hexahydroquinolin- 2-one

[0194]

[0195] First step

[0196] Compound 7a: 2-methylprop-2-yl 5-methoxy-2-(l-methyl-2-oxo-5,6,7,8- tetrahydroquinolin-3-yl)indole-l-carboxylate 7a

[0197] Compound 7a was prepared from compound If and l-tert-butoxycarbonyl-5- methoxyindole-2-boronic acid according to the synthetic method of the sixth step in Reference Example 1.

[0198] Second Step

[0199] Compound 7 was prepared from compound 7a according to the synthetic procedure of the second step in Reference Example 6.

[0200] LCMS (ESI, m / z): 309.37 [M+H] + .

[0201] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.36 (s, 1H), 7.83 (s, 1H), 7.36(d, J = 8.8 Hz, 1H), 7.03-6.97 (m, 2H), 6.69 (dd, J = 8.8 Hz, 2.0 Hz, 1H),3.75 (s, 3H), 3.54 (s, 3H), 2.74 (t, J = 6.0 Hz, 2H), 2.59 (t, J = 6.0 Hz,2H), 1.86-1.75 (m, 2H), 1.73-1.65 (m, 2H).

[0202] Example 8

[0203] Compound 8: 3-(5-cyano-lH-indol-2-yl)-l-methyl-l,2,5,6,7,8-hexahydroquinolin-2-one

[0204]

[0205]

[0206] First Step

[0207] Compound 8a: 2-methylprop-2-yl 5-cyano-2-(l-methyl-2-oxo-5,6,7,8- tetrahydroquinolin-3-yl)indole-l-carboxylate

[0208] Compound 8a was prepared from compound If and l-tert-butoxycarbonyl-5- cyanoindole-2-boronic acid according to the synthetic procedure of the sixth step in Reference Example 1.

[0209] Second Step

[0210] Compound 8 was prepared from compound 8a according to the synthetic procedure of the second step in Reference Example 6.

[0211] LCMS (ESI, m / z): 304.38 [M+H] + .

[0212] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.03 (s, 1H), 8.02 (s, 1H), 7.93(s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.24(d, J = 1.2 Hz, 1H), 3.55 (s, 3H), 2.75 (t, J = 6.0 Hz, 2H), 2.59 (t, J = 6.0Hz, 2H), 1.86-1.75 (m, 2H), 1.73-1.65 (m, 2H).

[0213] Example 9

[0214] Compound 9: 3-(1H-indol-2-yl)-1-methyl-2,5,6,7-tetrahydro-1H- cyclopenta[1,2-b]pyridin-2-one

[0215]

[0216]

[0217] First Step

[0218] Compound 9b: 2-[(E)-(dimethylamino)methylidene]cyclopentan-1-one

[0219] The title product 9b was prepared from compound 9a according to the synthetic procedure described in the first step of Example 1.

[0220] Second Step

[0221] Compound 9c: Methyl 2-oxoacetyl-1,5,6,7-tetrahydrocyclopenta[1,2-b]pyridine-3- carboxylate

[0222] The title product 9c was prepared from compound 9b according to the synthetic procedure described in the second step of Example 1.

[0223] Third Step

[0224] Compound 9d: Methyl 1-methyl-2-oxoacetyl-6,7-dihydro-5H-cyclopenta[1,2-b]pyridine- 3-carboxylate

[0225] The title product 9d was prepared from compound 9c according to the synthetic procedure described in the third step of Example 1.

[0226] Fourth Step

[0227] Compound 9e: 1-methyl-2-oxo-6,7-dihydro-5H-cyclopenta[l,2-b]pyridine-3-carboxylic acid

[0228] The title product 9e was prepared from compound 9d according to the synthetic procedure of the fourth step in Example 1.

[0229] Fifth step

[0230] Compound 9f: 3-iodo-l-methyl-2,5,6,7-tetrahydro-lH-cyclopenta[l,2-b]pyridin-2-one

[0231] The title product 9f was prepared from compound 9e according to the synthetic procedure of the fifth step in Example 1.

[0232] Sixth step

[0233] The title product 9 was prepared from compound 9f and indole-2-boronic acid pinacol ester according to the synthetic procedure of the sixth step in Example 1.

[0234] LCMS (ESI, m / z): 265.19 [M+H] + .

[0235] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.51 (s, 1H), 8.05 (s, 1H), 7.49(t, J = 7.6 Hz, 2H), 7.11 (d, J = 1.6 Hz, 1H), 7.08-7.02 (m, 1H), 6.99-6.93(m, 1H), 3.54 (s, 3H), 3.01 (t, J = 7.6 Hz, 2H), 2.83 (t, J = 7.6 Hz, 2H),2.14-2.07 (m, 2H).

[0236] Biological evaluation

[0237] Test Example 1: Luciferase reporter gene test experiment

[0238] This test example utilizes Method One to perform luciferase reporter gene test experiments to test the agonistic activity effect of the compounds of the present disclosure and the control examples (control examples please see WO2023039278) on AhR protein. The structures of the control examples are as follows:

[0239]

[0240] 1) Test cells

[0241] Human liver cancer cells expressing AhR and luciferase, HepG2-Lucia, were purchased from InvivoGen, Cat. No. hpgl-ahr.

[0242] 2) Main instruments

[0243] Bio-safety cabinet, Model 307, ThermoFisher;

[0244] CO2 incubator, Model CLM-240B-8-CN, ESCO;

[0245] Cell counter, Model EVE-MC2, NanoEnTeK;

[0246] ECHO (nanoliter acoustic liquid handling system), Model 655, LabCyte;

[0247] Microplate centrifuge, Model PlatePro 3200, Monad;

[0248] Multifunctional microplate reader, Model PHERAstar FSX, BMG LABTECH.

[0249] 3) Main reagents

[0250] Penicillin-streptomycin, Gibco, Cat. No. 15140-122;

[0251] EMEM medium, ATCC, Cat. No. 30-2003;

[0252] Fetal bovine serum, Ausgenex, Cat. No. FBS500-S;

[0253] NEAA medium, Gibco, Cat. No. 11140-050;

[0254] Phosphate buffer, Gibco, Cat. No. 14190250;

[0255] DMSO (dimethyl sulfoxide), Solarbio, Cat. No. D8371;

[0256] FICZ (6-formylindolo[3,2-B]carbazole), MCE, Cat. No. HY-12451;

[0257] Zeocin (bleomycin), InvivoGen, Cat. No. ant-zn-1;

[0258] QUANTI-Luc Gold, InvivoGen, Cat. No. rep-qlcg5.

[0259] 4) Experimental steps

[0260] a. HepG2-Lucia AhR cells were cultured in EMEM medium containing 10% inactivated fetal bovine serum, 1x NEAA, penicillin-streptomycin and 100 μg / ml Zeocin. The culture temperature was 37°C and the carbon dioxide concentration was 5%;

[0261] b. Cells were grown to about 80% confluence, digested, centrifuged and resuspended for counting. Cells were seeded into 384-well plates at 40 μL per well;

[0262] c. Different concentrations of test compounds were added using ECHO at 40 nL per well;

[0263] d. The 384-well plates with added compounds were incubated in an incubator for 24 h;

[0264] e. The supernatant was taken, QUANTI-Luc Gold detection reagent was added and the luminescence signal value was read using a multifunctional microplate reader.

[0265] 5) Test results

[0266] The EC 50 of the compounds of the present disclosure and the control example for the activity of AhR protein are summarized in Table 1 below. 50 (μM) using luciferase-labeled human hepatoma cells (HepG2-Lucia) AhR agonist EC

[0267] Table 1 EC 50

[0268]

[0269] Conclusion: The above results show that the compounds of the present disclosure have good activation activity for AhR protein, which is significantly better than the control example.

Claims

1. A compound having a pyridone structure, characterized in that, Its general formula is as follows (I): ， in: X1 is NR3, where R3 is H or C1-C6 alkyl; X2 is N or CH; X3 is NH or S; R4 is selected from halogen, cyano, amino, -O-(C1-C6 alkyl), unsubstituted or C1-C6 alkyl substituted with 1-3 halogens, and p is 0, 1, 2 or 3. R1 is selected from hydrogen, halogen, and C1-C6 alkyl; R2 is H; n is 1 or 2; m can be 0, 1, or 2.

2. The compound according to claim 1, characterized in that, The compound has the following structure: 、 、 、 、 、 、 、 、 、 、 、 、 , , , , or .

3. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains a therapeutically effective amount of the compound according to claim 1 or 2, and one or more pharmaceutically acceptable carriers.

4. Use of the compound according to claim 1 or 2 or the pharmaceutical composition according to claim 3 in the preparation of a medicament for regulating AhR protein.

5. Use of the compound according to claim 1 or 2 or the pharmaceutical composition according to claim 3 in the preparation of an AhR modulator.

6. Use of the compound according to claim 1 or 2 or the pharmaceutical composition according to claim 3 in the preparation of a medicament for treating and / or preventing AhR protein-mediated diseases or conditions.

7. The use according to claim 6, characterized in that, The diseases or symptoms mentioned are selected from cancer, ophthalmological diseases, autoimmune diseases, viral infectious diseases, central nervous system diseases, and inflammatory diseases.

8. The use according to claim 7, characterized in that, The diseases or conditions described are selected from skin diseases, acute lung injury, adult / acute respiratory distress syndrome, chronic obstructive pulmonary disease, oral ulcers, eye allergies, conjunctivitis, dry eye syndrome, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, lung cancer, breast cancer, liver cancer, non-alcoholic steatohepatitis, ovarian cancer, prostate cancer, melanoma, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, glioma, cervical cancer, endometrial cancer, colorectal cancer, and colorectal cancer.

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