A compound having a pyridinone structure and its medical use

Abstract

The present disclosure provides a compound having a pyridinone structure and its use in medicine. Specifically, the use of a compound of formula (I) of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer thereof as an aryl hydrocarbon receptor (AhR) modulator. The compound of the present disclosure provides a new option for treating immune-related diseases.

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 WO2023039278A1, is not part of this application. Summary of the Invention

[0007] This disclosure provides a compound represented by general formula (I), the structural formula of which is:

[0008]

[0009] in:

[0010] R1 is selected from phenyl groups that are unsubstituted or substituted with 1-3 halogens, or 5-6 heteroaryl groups that are unsubstituted or optionally substituted with 1 to 2 R2s;

[0011] R2 is independently selected from halogens, unsubstituted or substituted C1-C3 alkyl groups.

[0012] In one embodiment, the compounds disclosed herein and their pharmaceutically acceptable salts are characterized by a 5-6 member heteroaryl group selected from thienyl, furanyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiazolyl, thiazolyl, selenazole, pyridinyl, pyridinyl, pyrimidinyl, and pyrazinyl, preferably selected from pyridinyl, pyrimidinyl, thiazolyl, and isothiazolyl.

[0013] Furthermore, 5-6 quinary heterocycles are preferred from... , , or .

[0014] In one embodiment, the disclosed compound and its pharmaceutically acceptable salt are characterized in that R2 is selected from F, Cl, Br, CF3 or CH3.

[0015] In one embodiment, the disclosed compound and its pharmaceutically acceptable salt are characterized in that R1 is selected from... , , , , , , , , or .

[0016] In one embodiment, the compounds of the present disclosure and their pharmaceutically acceptable salts have the following structures:

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

[0018] Another aspect of this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) of this disclosure, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0019] This disclosure further relates to the use of compounds of general formula (I), or pharmaceutical compositions comprising thereof, in the preparation of medicaments for regulating AhR proteins; preferably in the preparation of medicaments for activating or antagonizing AhR proteins.

[0020] This disclosure further relates to the use of compounds of general formula (I), or pharmaceutical compositions comprising thereof, in the preparation of AhR modulators, preferably in the preparation of AhR agonists or AhR antagonists.

[0021] This disclosure further relates to the use of compounds of general formula (I), or pharmaceutical compositions comprising them, in the preparation of medicaments for treating and / or preventing AhR protein-mediated diseases or conditions.

[0022] This disclosure further relates to the use of compounds of general formula (I), or pharmaceutical compositions comprising thereof, in the preparation of medicaments for treating and / or preventing AhR protein-mediated diseases or conditions, wherein said diseases or conditions are selected from cancer, ophthalmological diseases, autoimmune diseases, viral infectious diseases, immune diseases, central nervous system diseases, inflammatory or obstructive respiratory diseases, inflammatory diseases, and other conditions or discomforts with immunological factors.

[0023] This disclosure further relates to compounds of general formula (I), or pharmaceutical compositions comprising thereof, in the preparation of treatments and / or preventive treatments for 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, hepatitis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, lung cancer, breast cancer, liver cancer, ovarian cancer, prostate cancer, melanoma, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, glioma, cervical cancer, endometrial cancer, colorectal cancer, and colorectal cancer.

[0024] This disclosure further relates to the use of compounds of general formula (I), or pharmaceutical compositions comprising them, in the preparation of medicaments for the treatment and / or prevention of skin diseases.

[0025] This disclosure further relates to a method of regulating AhR protein, comprising administering a therapeutically effective amount of a compound of general formula (I) or a pharmaceutical composition comprising the compound to a desired patient.

[0026] This disclosure further relates to a method of treating and / or preventing 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, hepatitis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, lung cancer, breast cancer, liver cancer, ovarian cancer, prostate cancer, melanoma, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, glioma, cervical cancer, endometrial cancer, colorectal cancer, and colorectal cancer; comprising administering to a patient a therapeutically effective amount of a compound of general formula (I), or a pharmaceutical composition comprising the compound.

[0027] 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.

[0028] 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.

[0029] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0030] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, wherein the ring contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5 to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., 5 or 6-membered monocyclic heteroaryl), or preferably a heteroaryl having 8 to 10 ring atoms (i.e., 8 to 10-membered polycyclic heteroaryl).

[0031] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, etc.

[0032] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, benzofuranyl, quinazolinyl, carbazole, pyrrolotriazinyl, 5,6,7,8-tetrahydro-triazolopyrazinyl, imidazopyridazinyl, and [1,2,4]triazolo[1,5-a]pyridinyl, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

[0033] , , , , , , , , , , , , , or wait.

[0034] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0035] "Optional" or "optional" means that the event or environment described below may but not necessarily occur, including both the occurrence and non-occurrence of the event or environment. For example, "optionally substituted alkyl group with halogen or cyano group" includes cases where the alkyl group is substituted with halogen or cyano group and cases where the alkyl group is not substituted with halogen or cyano group.

[0036] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene). Detailed Implementation

[0037] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0038] Example

[0039] 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.

[0040] 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.

[0041] High performance liquid chromatography (HPLC) analysis was performed using Shimadzu LC-20AB, Shimadzu LC-20ADXR, and Shimadzu LC-40D XR HPLC systems.

[0042] High performance liquid chromatography was performed using a Shimadzu LC-20AP and a Gilson GX-281 preparative chromatograph.

[0043] The CombiFlash rapid preparation system uses the CH-200P (Agela & Phenomenex).

[0044] 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 diameter of 0.15mm to 0.2mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4mm to 0.5mm.

[0045] Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh as the carrier.

[0046] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0047] 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.

[0048] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0049] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0050] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0051] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0052] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0053] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0054] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0055] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0056] 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.

[0057] In some embodiments, the compound is purified using preparative HPLC.

[0058] Example 1

[0059] Compound 1: N-(4-fluorophenyl)-1-methyl-2-oxoylide-5a,6-dihydro-4bH-cyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxamide

[0060]

[0061]

[0062] first step

[0063] Compound 1b: 2,3,4,4a-tetrahydro-1aH-cyclopropano[1,2-a][5]annulen-3-ol

[0064] The reaction proceeds via flow chemistry.

[0065] Solution 1: Under nitrogen protection, diiodomethane (334.33 g, 1.25 mol) and trifluoroacetic acid (142.33 g, 1.25 mol) were dissolved in dichloromethane (825 mL).

[0066] Solution 2: Diethylzinc (1.25 L, 1.25 mol, 1 M) under nitrogen protection.

[0067] Solution 3: Under nitrogen protection, 1a (50 g, 594.42 mmol) was dissolved in dichloromethane (550 mL).

[0068] Solution 1 is pumped to flow reactor 1 (FLR1, 100 mL, -30 °C) via pump 1 (S1, P1, flow rate 7.5 mL / min). Solution 2 is pumped to flow reactor 1 (FLR1, 100 mL, -30 °C) via pump 2 (S2, P2, flow rate 12 mL / min). Solution 3 is pumped to flow reactor 2 (FLR2, 250 mL, -15 °C) via pump 3 (S3, P3, flow rate 5 mL / min).

[0069] The residence time in flow reactor 1 was 5 minutes. The residence time in flow reactor 2 was 20 minutes. The reaction mixture was collected in a bottle containing saturated ammonium chloride solution (1000 mL) under nitrogen protection at 5 °C. Pumps 1 and 2 were started simultaneously. After 5 minutes, pump 3 was started. The reaction mixture was collected after 20 minutes of reaction. The collection of the reaction mixture was stopped after 43 minutes. The mixture was filtered and extracted with dichloromethane (200 mL × 3). The combined organic layers were washed with saturated brine (200 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 1b.

[0070] Step 2

[0071] Compound 1c: 2,3,4,4a-tetrahydro-1aH-cyclopropano[1,2-a][5]annulen-3-one

[0072] Compound 1b (50 g, 509.46 mmol) and 2-iodobenzoic acid (299.58 g, 1.07 mol) were mixed in ethyl acetate (1 L) and heated to 80 °C with stirring for 6 h. The system was cooled to room temperature, filtered, and concentrated to give compound 1c.

[0073] Step 3

[0074] Compound 1d: 2-[(E)-(dimethylamino)methylethylene]-2,3,4,4a-tetrahydro-1aH-cyclopropano[1,2-a][5]annulen-3-one

[0075] Compound 1c (50 g, 416.12 mmol) and N,N-dimethylformamide dimethyl acetal (148.76 g, 1.25 mol) were added to toluene (100 mL), and the mixture was heated to 110 °C and stirred for 16 h. The system was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography to give compound 1d.

[0076] Step 4

[0077] Compound 1e: methyl 2-oxoylide-1,4b,5a,6-tetrahydrocyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxylate

[0078] Methyl cyanoacetate (17.69 g, 178.57 mmol) was added to a methanol (90 mL) solution containing 1d (18 g, 119.04 mmol), and the mixture was heated to 70 °C and stirred for 16 h. The system was cooled to room temperature and concentrated. The residue was dissolved in toluene (90 mL), and acetic acid (7.15 g, 119.04 mmol) was added. The mixture was heated to 100 °C and stirred for 16 h. The system was cooled to room temperature, and the pH was adjusted to ~8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (200 mL). The organic phase was separated, washed with saturated brine (100 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was recrystallized from acetonitrile (200 mL), filtered, and dried to give 1e.

[0079] Step 5

[0080] Compound 1f: methyl 1-methyl-2-oxoylide-5a,6-dihydro-4bH-cyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxylic acid methyl ester

[0081] Compound 1e (3.07 g, 15 mmol) was dissolved in acetone (100 mL), and potassium carbonate (4.14 g, 30 mmol) and methyl iodide (4.26 g, 30 mmol) were added. The mixture was stirred at room temperature for 16 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 1f.

[0082] Step 6

[0083] Compound 1g: 1-Methyl-2-oxoylide-5a,6-dihydro-4bH-cyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxylic acid

[0084] Compound 1f (3.3 g, 15 mmol) was dissolved in methanol (40 mL), and then an aqueous sodium hydroxide solution (40 mL, 60 mmol, 1.5 M) was added. The mixture was heated to 60 °C and stirred for 4 h. The reaction mixture was cooled to room temperature and concentrated. The pH was adjusted to ~3 with 1 M hydrochloric acid solution, filtered, and the solid was collected and dried to give 1 g of compound.

[0085] Step 7

[0086] 1 g (205 mg, 1 mmol) of compound was dissolved in dichloromethane (10 mL), and 4-fluoroaniline (111 mg, 1 mmol), diisopropylethylamine (194 mg, 1.5 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (456 mg, 1.2 mmol) were added sequentially. The mixture was stirred at room temperature for 4 h. The solution was diluted with dichloromethane (30 mL), washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 1.

[0087] LCMS (ESI, m / z): 299.0 [M+H] + .

[0088] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.31 (s, 1H), 8.42 (s, 1H), 7.74-7.70 (m, 2H), 7.21-7.15 (m, 2H), 3.49 (s, 3H), 3.33-3.26 (m, 1H), 3.14-3.09(m, 1H), 2.42-2.36(m, 1H), 1.89-1.84(m, 1H), 1.07-1.01(m, 1H), 0.19-0.15(m, 1H).

[0089] 19 F NMR (376 MHz, DMSO-d6, ppm): δ -118.99 (1F).

[0090] Example 2

[0091] Compound 2: N-(5-fluoropyridin-2-yl)-1-methyl-2-oxoylide-5a,6-dihydro-4bH-cyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxamide

[0092]

[0093]

[0094] first step

[0095] 1 g (205 mg, 1 mmol) of compound was dissolved in dichloromethane (10 mL), and 5-fluoropyridine-2-amine (113 mg, 1 mmol), pyridine (640 mg, 8 mmol), and phosphorus oxychloride (230 mg, 1.5 mmol) were added sequentially. The mixture was stirred at room temperature for 4 h. The solution was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 2.

[0096] LCMS (ESI, m / z): 300.0 [M+H] + .

[0097] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.71 (s, 1H), 8.46 (s, 1H), 8.36-8.32 (m, 2H), 7.81-7.75 (m, 1H), 3.49 (s, 3H), 3.34-3.26 (m, 1H), 3.16-3.04(m, 1H), 2.42-2.36 (m, 1H), 1.91-1.84 (m, 1H), 1.07-1.01 (m, 1H), 0.21-0.15(m, 1H).

[0098] 19 F NMR (376 MHz, DMSO-d6, ppm): δ -133.20 (1F).

[0099] Example 3

[0100] Compound 3: N-(5-fluoropyrimidin-2-yl)-1-methyl-2-oxoylide-5a,6-dihydro-4bH-cyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxamide

[0101]

[0102]

[0103] first step

[0104] Title product 3 was prepared from 1 g of compound and 5-fluoropyrimidine-2-amine, following the synthetic method in the first step of Example 2.

[0105] LCMS (ESI, m / z): 301.0 [M+H] + .

[0106] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.95 (s, 1H), 8.78 (s, 2H), 8.44(s, 1H), 3.49 (s, 3H), 3.35-3.26 (m, 1H), 3.16-3.06 (m, 1H), 2.42-2.36 (m,1H), 1.91-1.84 (m, 1H), 1.07-1.01 (m, 1H), 0.21-0.16 (m, 1H).

[0107] 19 F NMR (376 MHz, DMSO-d6, ppm): δ -145.05 (1F).

[0108] Example 4

[0109] Compound 4: 1-Methyl-2-oxoylide-N-phenyl-5a,6-dihydro-4bH-cyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxamide

[0110]

[0111]

[0112] first step

[0113] Title product 4 was prepared from 1 g of compound and aniline using the synthesis method described in step 7 of Example 1.

[0114] LCMS (ESI, m / z): 281.1 [M+H] + .

[0115] 1H NMR (400 MHz, DMSO-d6, ppm): δ 12.30 (s, 1H), 8.43 (s, 1H), 7.71-7.65 (m, 2H), 7.38-7.31 (m, 2H), 7.12-7.05 (m, 1H), 3.49 (s, 3H), 3.33-3.26(m, 1H), 3.15-3.09 (m, 1H), 2.43-2.36 (m, 1H), 1.89-1.82 (m, 1H), 1.08-1.01(m, 1H), 0.19-0.15 (m, 1H).

[0116] Example 5

[0117] Compound 5: N-(5-chloropyrimidin-2-yl)-1-methyl-2-oxoylide-5a,6-dihydro-4bH-cyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxamide

[0118]

[0119]

[0120] first step

[0121] Title product 5 was prepared from 1 g of compound and 5-chloropyrimidine-2-amine, following the synthetic method in the first step of Example 2.

[0122] LCMS (ESI, m / z): 317.5 [M+H] + .

[0123] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 13.00 (s, 1H), 8.78 (s, 2H), 8.43(s, 1H), 3.49 (s, 3H), 3.35-3.26 (m, 1H), 3.16-3.11 (m, 1H), 2.44-2.36 (m,1H), 1.91-1.84 (m, 1H), 1.08-1.01 (m, 1H), 0.21-0.16 (m, 1H).

[0124] Example 6

[0125] Compound 6: N-[5-(trifluoromethyl)pyridin-2-yl]-1-methyl-2-oxoylide-5a,6-dihydro-4bH-cyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxamide

[0126]

[0127]

[0128] first step

[0129] Title product 6 was prepared from 1 g of compound and 5-(trifluoromethyl)pyridine-2-amine according to the synthesis method in the first step of Example 2.

[0130] LCMS (ESI, m / z): 350.0 [M+H] + .

[0131] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.99 (s, 1H), 8.72 (s, 1H), 8.49-8.42 (m, 2H), 8.25-8.19 (m, 1H), 3.50 (s, 3H), 3.34-3.26 (m, 1H), 3.18-3.12(m, 1H), 2.42-2.36 (m, 1H), 1.93-1.84 (m, 1H), 1.09-1.01 (m, 1H), 0.22-0.15(m, 1H).

[0132] 19 F NMR (376 MHz, DMSO-d6, ppm): δ -60.20 (3F).

[0133] Example 7

[0134] Compound 7: 1-Methyl-2-oxoylide-N-(thiazolyl-2-yl)-5a,6-dihydro-4bH-cyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxamide

[0135]

[0136]

[0137] first step

[0138] The title product 7 was prepared from 1 g of compound and thiazole-2-amine using the synthetic method described in step 7 of Example 1.

[0139] LCMS (ESI, m / z): 288.1 [M+H] + .

[0140] 1H NMR (400 MHz, DMSO-d6, ppm): δ 13.48 (s, 1H), 8.45 (s, 1H), 7.51 d,J = 3.2 Hz, 1H), 7.27 (d, J = 3.2 Hz, 1H), 3.51 (s, 3H), 3.36-3.28 (m, 1H), 3.18-3.11 (m, 1H), 2.44-2.36 (m, 1H), 1.92-1.84 (m, 1H), 1.09-1.01 (m, 1H), 0.23-0.16 (m, 1H).

[0141] Example 8

[0142] Compound 8: N-[5-(trifluoromethyl)pyrimidin-2-yl]-1-methyl-2-oxoylide-5a,6-dihydro-4bH-cyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxamide

[0143]

[0144]

[0145] first step

[0146] Title product 8 was prepared from 1 g of compound and 5-(trifluoromethyl)pyrimidine-2-amine, following the synthetic method in the first step of Example 2.

[0147] LCMS (ESI, m / z): 351.0 [M+H] + .

[0148] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 13.27 (s, 1H), 9.11 (s, 2H), 8.45 (s, 1H), 3.50 (s, 3H), 3.34-3.26 (m, 1H), 3.19-3.12 (m, 1H), 2.42-2.34 (m,1H), 1.94-1.84 (m, 1H), 1.09-1.01 (m, 1H), 0.23-0.15 (m, 1H).

[0149] 19 F NMR (376 MHz, DMSO-d6, ppm): δ -60.20 (3F).

[0150] Example 9

[0151] Compound 9: 1-Methyl-2-oxoylide-N-(5-fluoro-thiazolyl-2-yl)-5a,6-dihydro-4bH-cyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxamide

[0152]

[0153]

[0154] first step

[0155] Title product 9 was prepared from 1 g of compound and 5-fluoro-thiazol-2-amine using the synthetic method described in step 7 of Example 1.

[0156] LCMS (ESI, m / z): 306.0 [M+H] + .

[0157] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 13.44 (s, 1H), 8.43 (s, 1H), 7.35 d,J = 2.8 Hz, 1H), 3.51 (s, 3H), 3.38-3.28 (m, 1H), 3.18-3.11 (m, 1H), 2.44-2.37 (m, 1H), 1.93-1.84 (m, 1H), 1.09-1.01 (m, 1H), 0.23-0.16 (m, 1H).

[0158] 19 F NMR (376 MHz, DMSO-d6, ppm): δ -158.82 (1F).

[0159] Example 10

[0160] Compound 1c: 1-Methyl-2-oxoylide-N-(isothiazo-2-yl)-5a,6-dihydro-4bH-cyclopropano[1',2':3,4]cyclopentano[1,2-b]pyridine-3-carboxamide

[0161]

[0162]

[0163] first step

[0164] Title product 10 was prepared from 1 g of compound and isothiazol-2-amine according to the synthesis method in step 7 of Example 1.

[0165] LCMS (ESI, m / z): 288.0 [M+H] + .

[0166] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 13.23 (s, 1H), 8.44 (s, 1H), 8.28 d,J = 2.8 Hz, 1H), 7.27 (d, J = 3.2 Hz, 1H), 3.51 (s, 3H), 3.36-3.28 (m, 1H), 3.18-3.11 (m, 1H), 2.45-2.36 (m, 1H), 1.91-1.84 (m, 1H), 1.09-1.01 (m, 1H), 0.23-0.16 (m, 1H).

[0167] Biological evaluation

[0168] Test Example 1: Luciferase Reporter Gene Assay Experiment

[0169] 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 WO2023039278A1 for the control) on the AhR protein. The structure of the control is as follows:

[0170]

[0171] 1) Test cells

[0172] HepG2-Lucia, a human liver cancer cell line expressing AhR and luciferase, was purchased from InvivoGen (catalog number hpgl-ahr).

[0173] 2) Main instruments

[0174] Biosafety cabinet, model 307, ThermoFisher;

[0175] CO2 incubator, model CLM-240B-8-CN, ESCO;

[0176] Cell counter, model EVE-MC2, NanoEnTeK Corporation;

[0177] ECHO (Nano-Level Acoustic Plugging System), Model 655, LabCyte;

[0178] Microplate centrifuge, model PlatePro 3200, Monad Corporation;

[0179] Multifunctional microplate reader, model PHERAstar FSX, BMG LRBTECH.

[0180] 3) Main reagents

[0181] Penicillin-streptomycin, Gibco, catalog number 15140-122;

[0182] EMEM culture medium, ATCC, catalog number 30-2003;

[0183] Fetal bovine serum, Ausgenex, catalog number FBS500-S;

[0184] NEAA medium, Gibco, catalog number 11140-050;

[0185] Phosphate buffer, Gibco, catalog number 14190250;

[0186] DMSO (dimethyl sulfoxide), Solarbio, product number D8371;

[0187] FICZ (6-formylindolo[3,2-B]carbazole), MCE Corporation, catalog number HY-12451;

[0188] Zeocin (bleomycin), InvivoGen, catalog number ant-zn-1;

[0189] QUANTI-Luc Gold, InvivoGen, product number rep-qlcg5.

[0190] 4) Experimental Procedure

[0191] 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%.

[0192] 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;

[0193] c. Add different concentrations of the test compound using ECHO, 40 nL per well;

[0194] d. Continue to incubate the 384-well plate containing the compound in an incubator for 24 hours;

[0195] e. Take the supernatant, add QUANTI-Luc Gold detection reagent, and read the luminescence signal value using a multi-functional microplate reader.

[0196] 5) Test Results

[0197] 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.

[0198] Table 1

[0199]

[0200] The embodiments described above are some, but not all, embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. A compound having a pyridone structure, the general formula (I) of which is as follows: ,in: R1 is selected from phenyl groups substituted with 1-3 halogens, or 5-6 heteroaryl groups optionally substituted with 1 to 2 R2s; R2 is independently selected from halogens or C1-C3 alkyl groups substituted with 1-3 halogens.

2. The compound according to claim 1, characterized in that, The 5-6 aryl heteroaryl group is selected from thienyl, furanyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiazolyl, thiazolyl, selenozolyl, pyridinyl, pyrimidinyl, and pyrazinyl.

3. The compound according to any one of claims 1-2, characterized in that, 5-6 quinone heteroaryl groups selected from or .

4. The compound according to any one of claims 1-2, characterized in that, R2 is selected from F, Cl, Br, and CF3.

5. The compound according to any one of claims 1-2, characterized in that, R1 is selected from or .

6. The compound according to claim 1, having the following structure: 。 7. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 6, and one or more pharmaceutically acceptable excipients.

8. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for activating AhR protein.

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