Compounds having a pyridinone structure and their use in medicine

Abstract

The present disclosure belongs to the field of medicine, and relates to a kind of compound with pyridinone structure and its application in medicine. Specifically, the present disclosure relates to a kind of pyridinone compound, 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 disease or disorder.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a compound with a pyridone structure and its pharmaceutical applications. Specifically, this disclosure relates to a pyridone compound of general formula (I), pharmaceutical compositions containing such compounds, and its use as an AhR modulator, particularly in the preparation of medicaments for the treatment and / or prevention of AhR protein-mediated diseases or conditions. Background Technology

[0002] Aryl hydrocarbon receptors (AhRs), also known as dioxin receptors, mediate the toxic effects of polycyclic aromatic hydrocarbons (PAHs), dioxins (such as TCDD), and polychlorinated biphenyls (PCBs). Therefore, for decades, AhR activation was excluded from consideration as a therapeutic approach. However, it is now understood that AhR activation not only acts as an environmental sensor, modulating the effects of environmental toxins, but also as a key immunomodulator, with its ligands inducing various cellular and epigenetic mechanisms to reduce inflammation. Consequently, the emergence of further in-depth research into ligand compounds capable of activating this receptor has prompted a reconsideration of its therapeutic applications.

[0003] Recent studies have shown that TCDD-induced activation of AhR in dendritic cells is the cause of observed thymic atrophy; in addition to thymic atrophy caused by AhR activation via TCDD, TCDD has been reported to induce apoptosis. Notably, other apoptotic mechanisms, such as p53-mediated apoptosis, are associated with TCDD-induced AhR activation; anti-inflammatory T regulatory cells (Tregs) play a crucial role in maintaining tolerance to self-antigens and in the regulatory mechanisms of immune-mediated inflammation. Numerous studies have shown that ligand-activated AhR can increase Tregs, thereby alleviating inflammation and improving disease; myeloid-derived suppressor cells (MDSCs) are a potent immunosuppressive cell type associated with suppressing T cell proliferation. Experiments have demonstrated that TCDD activation of AhR can suppress inflammation by inducing MDSCs; cytokine inhibition is partly responsible for the observed suppression of the inflammatory state induced by AhR. TCDD-induced AhR activation reverses IL-17 promoter demethylation in colitis through DNA methylation, thereby inhibiting Th17 cells and alleviating the inflammatory response. This study also provides evidence that AhR participates 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. Furthermore, it is noteworthy that miRNAs have also been shown to inhibit AhR expression.

[0004] Given the cellular and molecular mechanisms by which AhR regulates immune responses, activating this receptor shows potential in the prevention or treatment of inflammatory diseases. For example, studies have found that the AhR pathway activated by TCDD is associated with diseases such as pertussis, experimental autoimmune uveitis, multiple sclerosis, colitis, atopic dermatitis, and psoriasis. For instance, the AhR modulator benvitimod, a naturally derived small molecule produced by the bacterial symbiont of entomopathogenic nematodes, is the world's first marketed aryl hydrocarbon receptor agonist and can be used to treat various autoimmune diseases, such as psoriasis and eczema.

[0005] Currently, the development of AhR agonists is mainly limited to topical administration for the treatment of immune-related skin diseases. Therefore, there remains a significant clinical need to develop novel, highly active AhR agonists for oral administration to treat a wider range of immune-related diseases.

[0006] The published related AhR modifier patent application, including WO2023039278, is not part of this application. Summary of the Invention

[0007] This disclosure provides a compound having a pyridone structure, with the following general formula (I):

[0008]

[0009] in:

[0010] X1 is NR3, where R3 is H or C1-C6 alkyl;

[0011] 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.

[0012] R1 is selected from hydrogen, halogen, and C1-C6 alkyl;

[0013] R2 is H;

[0014] n is 1 or 2;

[0015] m can be 0, 1, or 2.

[0016] In one embodiment, the compound disclosed herein has the following structure:

[0017] , , , , , , , , , , , , , , , , or .

[0018] According to another aspect of this application, this application also provides the pharmaceutical composition and one or more pharmaceutically acceptable carriers containing a therapeutically effective amount of the compound represented by general formula (I).

[0019] According to another aspect of this application, this application also provides the use of the compound represented by the general formula (I) or the pharmaceutical composition thereof in the preparation of a medicament for regulating AhR protein.

[0020] According to another aspect of this application, this application also provides the use of the compound represented by the general formula (I) or the pharmaceutical composition thereof in the preparation of an AhR modulator.

[0021] According to another aspect of this application, this application also provides the use of the compound represented by the general formula (I) or the pharmaceutical composition thereof in the preparation of a medicament for treating and / or preventing AhR protein-mediated diseases or conditions.

[0022] Preferably, the disease or symptom is selected from cancer, ophthalmological diseases, autoimmune diseases, viral infectious diseases, central nervous system diseases, and inflammatory diseases.

[0023] Preferably, the disease or condition is 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. Detailed Implementation

[0024] The "aromatic hydrocarbon receptor (AhR) modulator" as described in this disclosure refers to an agent that causes or promotes qualitative or quantitative changes, alterations, or modifications to one or more processes, mechanisms, effects, responses, functions, activities, or pathways mediated by AhR receptors. Such changes mediated by AhR modulators (such as AhR inhibitors or nonconstitutive agonists as described herein) can refer to a decrease or increase in AhR activity or function, such as a decrease, inhibition, or shift in AhR constitutive activity.

[0025] The “AhR antagonists” described herein refer to AhR inhibitors that, upon specific binding to AhR peptides or polynucleotides encoding AhR, do not themselves induce a biological response, but rather block or inhibit agonist-mediated or ligand-mediated responses. In other words, AhR antagonists can bind to but not activate AhR peptides or polynucleotides encoding AhR, and this binding disrupts the interaction, displacing AhR agonists and / or inhibiting their function. Therefore, as used herein, AhR antagonists do not act as inducers of AhR activity when bound to AhR; that is, they are pure AhR inhibitors.

[0026] The term "AhR-mediated" diseases and / or conditions as used herein refers to any disease or other harmful symptom known to be affected by AhR or its mutants. Therefore, another embodiment of the invention relates to treating one or more diseases known to be affected by AhR or its mutants, or to reducing their severity.

[0027] The “cancer” referred to in this disclosure includes, but is not limited to, the following cancers:

[0028] Epidermal oral cavity: oral cavity, lips, tongue, mouth, pharynx;

[0029] Heart: Sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma;

[0030] Lungs: Bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoid hamartoma, mesothelioma;

[0031] Gastrointestinal tract: esophagus (squamous cell carcinoma, laryngeal carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, rectum;

[0032] Urogenital tract: Kidneys (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), Bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), Prostate (adenocarcinoma, sarcoma), Testes (seminomatous seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma);

[0033] Liver: Hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, bile duct;

[0034] Bone: Osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma, benign chondroma, chondroblastoma, chondromycinoma, osteoid osteoma, giant cell tumor;

[0035] Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, neurofibroma of the spinal cord;

[0036] Gynecology: Uterus (endometrial cancer), Cervix (cervical cancer, precancerous cervical dysplasia), Ovary (ovarian cancer), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma), Breast;

[0037] Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma hairy cell, lymphatic diseases;

[0038] Skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;

[0039] Thyroid glands include papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, undifferentiated thyroid carcinoma, type 2A multiple endocrine adenomas, type 2B multiple endocrine adenomas, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma, and neuroblastoma.

[0040] The neurodegenerative diseases described in this disclosure can affect many bodily functions, such as balance, movement, speech, breathing, and heart function. Neurodegenerative diseases can be hereditary or caused by medical conditions such as alcoholism, tumors, stroke, toxins, chemicals, and viruses.

[0041] Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease or Lou Gehrig's disease), Friedreich ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy.

[0042] Non-limiting examples of central nervous system (CNS) diseases or conditions described in this disclosure 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) disease, stroke, Fahr's disease, Menkes disease, Wilson's disease, cerebral ischemia, and prions.

[0043] As used herein, the phrase “disease” or “symptom” broadly refers to any of the aforementioned diseases or symptoms that can be treated and / or prevented by administering the compounds or aromatic hydrocarbon receptor modulators (antagonists or agonists) described herein to a patient.

[0044] The compounds or compositions thereof disclosed herein may be used to treat and / or prevent inflammatory or obstructive airway diseases, reducing, for example, tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression. Inflammatory or obstructive airway diseases to which this disclosure is applicable include asthma of any type or cause, 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 by bacterial infection. Treatment of asthma should also be understood to include treatment of subjects, for example, those under 4 or 5 years of age, who present with wheezing symptoms and are diagnosed or can be diagnosed as “wheezing infants,” a defined patient category with a primary medical problem and now often identified as patients with initial or early-stage asthma.

[0045] Other inflammatory or obstructive respiratory diseases and / or conditions to which this disclosure applies include acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, respiratory or lung diseases including chronic bronchitis or related dyspnea, emphysema, and exacerbations of tracheal hyperresponsiveness caused by other drug therapies, particularly other inhaled drug therapies.

[0046] This disclosure can also be used to treat inflammatory or allergic conditions of the skin and other diseases or conditions, such as those with inflammatory components; eye diseases and conditions, such as ocular allergies, conjunctivitis, dry eye, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or having autoimmune components or causes. Inflammatory diseases treatable according to the methods of this disclosure are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryptothermal protein-associated cycle syndrome (CAPS), and osteoarthritis.

[0047] In some embodiments, the inflammatory diseases treatable according to the methods of this disclosure are selected from TH17-mediated diseases. In some embodiments, TH17-mediated diseases are selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0048] In this disclosure, "subject" and "patient" refer to an organism, such as a human, that receives treatment for the specific disease or condition described herein. The terms "subject" or "patient" as used herein may refer to mammals, such as dogs, cats, horses, cattle, pigs, guinea pigs, etc. For example, a patient requiring an aryl hydrocarbon receptor antagonist, such as a human patient, may receive treatment including an aryl hydrocarbon receptor antagonist to treat the disease or condition described herein, such as cancer, autoimmune diseases, or inflammatory diseases.

[0049] The active compounds can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or blow-through administration. The compounds of this disclosure can also be formulated into sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0050] As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 1000 mg.

[0051] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0052] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0053] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0054] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions, used for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0055] Oil suspensions are prepared by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0056] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0057] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0058] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0059] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0060] The compounds disclosed herein can be administered by adding water to prepare water-soluble dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0061] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0062] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0063] Example

[0064] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were measured in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0065] The liquid chromatography-mass spectrometry (LC-MS) system used was Waters 2695+ZQ2000, Shimadzu MS-2020+LC-20AB, and Shimadzu LC-40D XR+MS-2020.

[0066] High performance liquid chromatography (HPLC) analysis was performed using Shimadzu LC-20AB, Shimadzu LC-20ADXR, and Shimadzu LC-40D XR HPLC systems.

[0067] Chiral HPLC analysis was performed using a Shimadzu LC-30AD high-performance liquid chromatograph.

[0068] High performance liquid chromatography was performed using a Shimadzu LC-20AP and a Gilson GX-281 preparative chromatograph.

[0069] Chiral preparation was performed using a Waters 150Mgm, Waters SFC 350 preparative chromatograph.

[0070] The CombiFlash rapid preparation system uses the CH-200P (Agela & Phenomenex).

[0071] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.15 mm to 0.2 mm, and the size used for thin-layer chromatography separation and purification of products is 0.4 mm to 0.5 mm.

[0072] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0073] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0074] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. (Shanghai), and Darui Chemicals.

[0075] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0076] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0077] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0078] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0079] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0080] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0081] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0082] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0083] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: petroleum ether / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0084] In some embodiments, the compound is purified using preparative HPLC.

[0085] Example 1

[0086] Compound 1: 3-(1H-indol-2-yl)-1-methyl-5,6,7,8-tetrahydroquinolin-2-one

[0087]

[0088]

[0089] first step

[0090] Compound 1b: (E)-2-[(dimethylamino)methylene]cyclohexyl-1-one

[0091] 5.33 g (30.5 mmol) of tert-butoxybis(dimethylaminomethane) was added to cyclohexanone (3.00 g, 30.5 mmol), nitrogen was purged three times, and the mixture was stirred at room temperature for 1.5 h. Then, the mixture was heated to 110 °C and stirred for 10 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL), and washed with water (100 mL) and saturated brine (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1b.

[0092] Step 2

[0093] Compound 1c: Methyl 2-oxo-5,6,7,8-tetrahydro-1H-quinoline-3-carboxylate

[0094] Compound 1b (2.70 g, 17.6 mmol) was dissolved in methanol (30 mL), and methyl cyanoacetate (1.92 g, 19.3 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was concentrated and purified by preparative HPLC to obtain compound 1c.

[0095] Step 3

[0096] Compound 1d: Methyl 1-methyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate

[0097] Compound 1c (500 mg, 2.41 mmol) was dissolved in acetone (5 mL), and then potassium carbonate (666 mg, 4.83 mmol) and methyl iodide (1.37 g, 9.65 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate (100 mL) and 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 silica gel column chromatography to give compound 1d.

[0098] Step 4

[0099] Compound 1e: 1-Methyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylic acid

[0100] Compound 1d (360 mg, 1.63 mmol) was dissolved in methanol (4 mL), followed by the addition of an aqueous solution of sodium hydroxide (260 mg, 6.51 mmol) (4 mL). The mixture was heated to 60 °C and stirred for 8 h. The reaction mixture was cooled to room temperature, the pH was adjusted to ~3 with 1 M hydrochloric acid aqueous 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.

[0101] Step 5

[0102] Compound 1f: 3-Iodo-1-methyl-5,6,7,8-tetrahydroquinoline-2-one

[0103] Compound 1e (1.00 g, 4.83 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of iodine (4.90 g, 19.3 mmol) and potassium phosphate (1.02 g, 4.83 mmol), and stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and a saturated aqueous solution of sodium thiosulfate (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1f.

[0104] Step 6

[0105] Compound 1f (350 mg, 1.21 mmol) and indole-2-borate pinacol ester (294 mg, 1.21 mmol) were dissolved in dioxane (5 mL) and water (2.5 mL), and the mixture was purged with nitrogen three times. Potassium carbonate (501 mg, 3.63 mmol) and (1,1'-bis(diphenylphosphine)ferrocene)palladium dichloride (88.5 mg, 121 μmol) were then added, and the mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and 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 obtain a crude product, which was further slurried with methanol to obtain compound 1.

[0106] LCMS (ESI, m / z): 279.10 [M+H] + .

[0107] 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).

[0108] Example 2

[0109] Compound 2: 3-(1H-benzo[d]imidazol-2-yl)-1-methyl-5,6,7,8-tetrahydroquinoline-2-one

[0110]

[0111]

[0112] first step

[0113] Compound 1e (200 mg, 965 μmol) and o-phenylenediamine (104 mg, 965 μmol) were added to polyphosphoric acid (2 g), and the mixture was heated to 180 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, slowly diluted with water (30 mL), and the pH of the system was adjusted to ~7 with saturated sodium bicarbonate aqueous solution. The mixture was 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.

[0114] LCMS (ESI, m / z): 280.10 [M+H] + .

[0115] 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).

[0116] Example 3

[0117] Compound 3: 3-(1H-indol-2-yl)-1,6-dimethyl-5,6,7,8-tetrahydroquinolin-2-one

[0118]

[0119]

[0120] first step

[0121] Compound 3b: 2-[(E)-(dimethylamino)methylethylenedimethyl]-4-methylcyclohexane-1-one

[0122] The title product 3b was prepared from compound 3a by referring to the synthesis method in the first step of Example 1.

[0123] Step 2

[0124] Compound 3c: Methyl 6-methyl-2-oxo-5,6,7,8-tetrahydro-1H-quinoline-3-carboxylate

[0125] The title product 3c was prepared from compound 3b by referring to the synthesis method in step 2 of Example 1.

[0126] Step 3

[0127] Compound 3d: Methyl 1,6-dimethyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate

[0128] The title product 3d was prepared from compound 3c by referring to the synthesis method in step 3 of Example 1.

[0129] Step 4

[0130] Compound 3e: 1,6-Dimethyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylic acid

[0131] The title product 3e was prepared from compound 3d by referring to the synthesis method in step 4 of Example 1.

[0132] Step 5

[0133] Compound 3f: 3-Iodo-1,6-dimethyl-5,6,7,8-tetrahydroquinoline-2-one

[0134] The title product 3f was prepared from compound 3e by referring to the synthesis method in step 5 of Example 1.

[0135] Step 6

[0136] Title product 3 was prepared from compound 3f using the synthetic method described in step 6 of Example 1.

[0137] LCMS (ESI, m / z): 293.23 [M+H] + .

[0138] 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).

[0139] Example 4

[0140] Compound 4: 3-(1H-indol-2-yl)-1,6,6-trimethyl-5,6,7,8-tetrahydroquinolin-2-one

[0141]

[0142]

[0143] first step

[0144] Compound 4b: 2-[(E)-(dimethylamino)methylethylenedimethyl]-4,4-dimethylcyclohexane-1-one

[0145] The title product 4b was prepared from compound 4a by referring to the synthesis method in the first step of Example 1.

[0146] Step 2

[0147] Compound 4c: Methyl 6,6-dimethyl-2-oxo-5,6,7,8-tetrahydro-1H-quinoline-3-carboxylate

[0148] The title product 4c was prepared from compound 4b by referring to the synthesis method in step 2 of Example 1.

[0149] Step 3

[0150] Compound 4d: Methyl 1,6,6-trimethyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate

[0151] The title product 4d was prepared from compound 4c by referring to the synthesis method in step 3 of Example 1.

[0152] Step 4

[0153] Compound 4e: 1,6,6-trimethyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylic acid

[0154] The title product 4e was prepared from compound 4d using the synthesis method described in step four of Example 1.

[0155] Step 5

[0156] Compound 4f: 3-Iodo-1,6,6-trimethyl-5,6,7,8-tetrahydroquinoline-2-one

[0157] The title product 4f was prepared from compound 4e by referring to the synthesis method in step 5 of Example 1.

[0158] Step 6

[0159] Title product 4 was prepared from compound 4f using the synthetic method described in step 6 of Example 1.

[0160] LCMS (ESI, m / z): 307.32 [M+H] + .

[0161] 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).

[0162] Example 5

[0163] Compound 5: 3-(1H-indol-2-yl)-1,2,5,6,7,8-hexahydroquinoline-2-one

[0164]

[0165]

[0166] first step

[0167] Compound 5a: Methyl 2-[(2-methoxyethyl)oxy]-5,6,7,8-tetrahydroquinoline-3-carboxylate

[0168] Title product 5a was prepared from compound 1c and 1-iodo-2-methoxyethane using the synthetic method described in step 3 of Example 1.

[0169] Step 2

[0170] Compound 5b: 2-[(2-methoxyethyl)oxy]-5,6,7,8-tetrahydroquinoline-3-carboxylic acid

[0171] The title product 5b was prepared from compound 5a by referring to the synthesis method in step four of Example 1.

[0172] Step 3

[0173] Compound 5c: 3-Iodo-1,2,5,6,7,8-hexahydroquinoline-2-one

[0174] The title product 5c was prepared from compound 5b by referring to the synthesis method in step 5 of Example 1.

[0175] Step 4

[0176] The title product 5 was prepared from compound 5c and indole-2-boronic acid pinacol ester using the synthetic method described in step 6 of Example 1.

[0177] LCMS (ESI, m / z): 265.33 [M+H] + .

[0178] 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).

[0179] Example 6

[0180] Compound 6: 3-(6-methoxy-1H-indol-2-yl)-1-methyl-1,2,5,6,7,8-hexahydroquinoline-2-one

[0181]

[0182]

[0183] first step

[0184] Compound 6a: 6-methoxy-2-(1-methyl-2-oxoylide-5,6,7,8-tetrahydroquinolin-3-yl)indol-1-carboxylic acid-2-methylpropyl-2-yl ester

[0185] Compound 6a was prepared from compound 1f and 1-tert-butoxycarbonyl-6-methoxyindole-2-boronic acid, following the synthetic method in step 6 of Example 1.

[0186] Step 2

[0187] Compound 6a (136 mg, 0.33 mmol) was dissolved in ethyl hydrochloride (4 mL, 4 M) and stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (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 compound 6.

[0188] LCMS (ESI, m / z): 309.37 [M+H] + .

[0189] 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).

[0190] Example 7

[0191] Compound 7: 3-(5-methoxy-1H-indol-2-yl)-1-methyl-1,2,5,6,7,8-hexahydroquinoline-2-one

[0192]

[0193] first step

[0194] Compound 7a: 5-methoxy-2-(1-methyl-2-oxoyne-5,6,7,8-tetrahydroquinolin-3-yl)indol-1-carboxylic acid-2-methylpropyl-2-yl ester 7a

[0195] Compound 7a was prepared from compound 1f and 1-tert-butoxycarbonyl-5-methoxyindole-2-boronic acid, following the synthetic method in step 6 of Example 1.

[0196] Step 2

[0197] Compound 7 was prepared from compound 7a by referring to the synthesis method in step 2 of Example 6.

[0198] LCMS (ESI, m / z): 309.37 [M+H] + .

[0199] 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).

[0200] Example 8

[0201] Compound 8: 3-(5-cyano-1H-indol-2-yl)-1-methyl-1,2,5,6,7,8-hexahydroquinoline-2-one

[0202]

[0203]

[0204] first step

[0205] Compound 8a: 5-cyano-2-(1-methyl-2-oxoylide-5,6,7,8-tetrahydroquinolin-3-yl)indol-1-carboxylic acid-2-methylpropyl-2-yl ester

[0206] Compound 8a was prepared from compound 1f and 1-tert-butoxycarbonyl-5-cyanoindole-2-boronic acid, following the synthetic method in step 6 of Example 1.

[0207] Step 2

[0208] Compound 8 was prepared from compound 8a by referring to the synthesis method in step 2 of Example 6.

[0209] LCMS (ESI, m / z): 304.38 [M+H] + .

[0210] 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 =6.0 Hz, 2H), 1.86-1.75 (m, 2H), 1.73-1.65 (m, 2H).

[0211] Example 9

[0212] Compound 9: 3-(1H-indol-2-yl)-1-methyl-2,5,6,7-tetrahydro-1H-cyclopentano[1,2-b]pyridin-2-one

[0213]

[0214]

[0215] first step

[0216] Compound 9b: 2-[(E)-(dimethylamino)methylethylene]cyclopentan-1-one

[0217] Title product 9b was prepared from compound 9a by referring to the synthesis method in the first step of Example 1.

[0218] Step 2

[0219] Compound 9c: methyl 2-oxoylide-1,5,6,7-tetrahydrocyclopentano[1,2-b]pyridine-3-carboxylate

[0220] The title product 9c was prepared from compound 9b by referring to the synthesis method in step 2 of Example 1.

[0221] Step 3

[0222] Compound 9d: Methyl 1-methyl-2-oxoylide-6,7-dihydro-5H-cyclopentano[1,2-b]pyridine-3-carboxylate

[0223] The title product 9d was prepared from compound 9c by referring to the synthesis method in step 3 of Example 1.

[0224] Step 4

[0225] Compound 9e: 1-Methyl-2-oxoylide-6,7-dihydro-5H-cyclopentano[1,2-b]pyridine-3-carboxylic acid

[0226] The title product 9e was prepared from compound 9d using the synthesis method described in step four of Example 1.

[0227] Step 5

[0228] Compound 9f: 3-Iodo-1-methyl-2,5,6,7-tetrahydro-1H-cyclopentano[1,2-b]pyridin-2-one

[0229] The title product 9f was prepared from compound 9e by referring to the synthesis method in step 5 of Example 1.

[0230] Step 6

[0231] Title product 9 was prepared from compound 9f and indole-2-boronic acid pinacol ester using the synthetic method described in step 6 of Example 1.

[0232] LCMS (ESI, m / z): 265.19 [M+H] + .

[0233] 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).

[0234] Biological evaluation

[0235] Test Example 1: Luciferase Reporter Gene Assay Experiment

[0236] This test case utilizes Method 1 to perform a luciferase reporter gene assay to test the agonistic activity of the disclosed compound and a control (see WO2023039278 for the control) on the AhR protein. The structure of the control is as follows:

[0237]

[0238] 1) Test cells

[0239] HepG2-Lucia, a human liver cancer cell line expressing AhR and luciferase, was purchased from InvivoGen (catalog number hpgl-ahr).

[0240] 2) Main instruments

[0241] Biosafety cabinet, model 307, ThermoFisher;

[0242] CO2 incubator, model CLM-240B-8-CN, ESCO;

[0243] Cell counter, model EVE-MC2, NanoEnTeK Corporation;

[0244] ECHO (Nano-Level Acoustic Plugging System), Model 655, LabCyte;

[0245] Microplate centrifuge, model PlatePro 3200, Monad Corporation;

[0246] Multifunctional microplate reader, model PHERAstar FSX, BMG LRBTECH.

[0247] 3) Main reagents

[0248] Penicillin-streptomycin, Gibco, catalog number 15140-122;

[0249] EMEM culture medium, ATCC, catalog number 30-2003;

[0250] Fetal bovine serum, Ausgenex, catalog number FBS500-S;

[0251] NEAA medium, Gibco, catalog number 11140-050;

[0252] Phosphate buffer, Gibco, catalog number 14190250;

[0253] DMSO (dimethyl sulfoxide), Solarbio, product number D8371;

[0254] FICZ (6-formylindolo[3,2-B]carbazole), MCE Corporation, catalog number HY-12451;

[0255] Zeocin (bleomycin), InvivoGen, catalog number ant-zn-1;

[0256] QUANTI-Luc Gold, InvivoGen, product number rep-qlcg5.

[0257] 4) Experimental Procedure

[0258] a. HepG2-Lucia AhR cells were cultured in EMEM medium containing 10% inactivated fetal bovine serum, 1×NEAA, penicillin, streptomycin, and 100 µg / ml zeocin. The culture temperature was 37℃ and the carbon dioxide concentration was 5%.

[0259] b. Once cells have grown to approximately 80% confluence, digest the cells, centrifuge, resuspend, and count them. Seed the cells into 384-well plates, 40 μL per well;

[0260] c. Add different concentrations of the analyte compound using ECHO, 40 nL per well;

[0261] d. Continue to incubate the 384-well plate containing the compound in an incubator for 24 hours;

[0262] e. Take the supernatant, add QUANTI-Luc Gold detection reagent, and read the luminescence signal value using a multi-functional microplate reader.

[0263] 5) Test Results

[0264] The disclosed compounds and control examples exhibit EC activity against AhR protein. 50 Data (luciferase-labeled human liver cancer cells (HepG2-Lucia) AhR agonist EC) 50 The results (μM) are summarized in Table 1 below.

[0265] Table 1. EC5 activation of AhR by the compounds disclosed herein. 50

[0266]

[0267] Conclusion: The above results indicate that the disclosed compound has good activation activity against AhR protein, which is significantly better than that of the control.

Claims

1. A compound having a pyridone structure, characterized in that, The compound has the following structure: , , , , , , , , , , , , , , , or .

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

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

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