Compounds with fused ring structures and their applications in medicine

Abstract

This disclosure provides compounds having fused ring structures and their pharmaceutical applications, specifically the use of compounds of formula (I), or pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, as modulators of aromatic hydrocarbon receptors (AhR). The compounds of this disclosure provide a new option for the treatment of immune-related diseases.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a compound with a fused ring structure and its pharmaceutical applications. Specifically, this disclosure relates to a fused ring compound of general formula (I), pharmaceutical compositions containing such compounds, and their use as AhR modulators, 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 disclosed relevant AhR modifier patent application, including WO2024107555A1, is not part of this application. Summary of the Invention

[0007] This disclosure provides a compound of general formula (I) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0008]

[0009] in:

[0010] X1 is selected from N or CR1; X2 is selected from N or CR2; X3 is selected from N or CR3; X4 is selected from N or CR4; X5 is selected from N or CR5; X6 is selected from N or CR6; X7 is selected from N or CR7; X8 is selected from N or CR8;

[0011] R1, R2, R3, R4, R5, R6, R7, and R8 may be the same or different and are independently selected from H, halogens, CN, C(O)OH, C(O)OC1-10 alkyl, unsubstituted or substituted with 1-3 halogens, and C1-10 alkoxy.

[0012] R a and R b They are independently selected from H, halogen, CN, NH2, C1-10 alkyl, C1-10 alkoxy, C1-10 alkyl-NH-, and (C1-10 alkyl)2-N-.

[0013] Furthermore, R a and R bThe components are independently selected from H, halogens, CN, NH2, unsubstituted or substituted C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl-NH-, (C1-6 alkyl)2-N-; further preferably from H, CN, NH2, C1-4 alkyl; and even more preferably from H and methyl.

[0014] R1, R2, R3, R4, R5, R6, R7, and R8 may be the same or different, and are independently selected from H, halogens, CN, C(O)OH, C(O)OC1-6 alkyl, unsubstituted or substituted with 1-3 halogens, and C1-6 alkoxy; further, preferably from H, halogens, CN, C(O)OH, C(O)OC1-4 alkyl, unsubstituted or substituted with 1-3 halogens, and C1-4 alkoxy; even further, preferably from H, halogens, CN, methyl, and trifluoromethyl.

[0015] At most two of X1, X2, and X3 are selected from N; further, X2 and X3 are selected from N, and X1 is selected from CR1; even further, X2 and X3 are selected from N, and X1 is selected from CH. At most two of X5, X6, X7, and X8 are selected from N; further, X5 is N, X6 and X8 are selected from N or CH, and X7 is CR7.

[0016] In a preferred embodiment, R a and R b Each of the components is independently selected from H, C1-4 alkyl, X2 and X3 are selected from N, X1 is selected from CH, X4 is selected from CH or N, X5 is selected from CH, X6 and X8 are selected from N, and X7 is selected from CR7.

[0017] Particularly preferred, the compounds may be selected from the following specific compounds:

[0018] .

[0019] Another aspect of this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0020] This disclosure further relates to the use of compounds of general formula (I) or pharmaceutically acceptable salts thereof, 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.

[0021] This disclosure further relates to the use of compounds of general formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of AhR modulators, preferably in the preparation of AhR agonists or AhR antagonists.

[0022] This disclosure further relates to the use of compounds of general formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of AhR protein-mediated diseases or conditions.

[0023] This disclosure further relates to the use of compounds of general formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of 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.

[0024] This disclosure further relates to compounds of general formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, for the preparation of treatment and / or prevention of 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.

[0025] This disclosure further relates to the use of compounds of general formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the treatment and / or prevention of skin diseases.

[0026] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, to a desired patient.

[0027] This disclosure further relates to a method of antagonizing (inhibiting) AhR protein, comprising administering a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, to a patient as required.

[0028] This disclosure further relates to a method of activating the AhR protein, comprising administering to a patient a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0029] This disclosure further relates to a method of treating and / or preventing AhR protein-mediated diseases or conditions, comprising administering to a desired patient a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0030] This disclosure further relates to a method of treating and / or preventing AhR protein-mediated diseases or conditions, comprising administering a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, to a desired patient, wherein the disease or condition is 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.

[0031] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound.

[0032] This disclosure further relates to a method of treating and / or preventing skin diseases, comprising administering to a patient a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0033] This disclosure further relates to a method for treating and / or preventing psoriasis, acne, vitiligo, diabetic foot ulcers, and atopic dermatitis; comprising administering to a patient a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0034] This disclosure further relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a medicine.

[0035] This disclosure further relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which acts as an AhR protein modulator.

[0036] This disclosure further relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which acts as an AhR protein antagonist (inhibitor).

[0037] This disclosure further relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which acts as an AhR protein agonist.

[0038] This disclosure further relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, for use in the treatment and / or prevention of AhR protein-mediated diseases or conditions.

[0039] This disclosure further relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, used for the treatment and / or prevention of 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.

[0040] This disclosure further relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, for the treatment and / or prevention of 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.

[0041] This disclosure further relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, used for the treatment and / or prevention of skin diseases.

[0042] Preferably, the skin diseases described in this disclosure are selected from psoriasis, acne, vitiligo, diabetic foot ulcers, and atopic dermatitis.

[0043] Preferably, the hepatitis described in this disclosure is non-alcoholic steatohepatitis (NASH).

[0044] 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.

[0045] 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.

[0046] 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.

[0047] The “cancer” referred to in this disclosure includes, but is not limited to, the following cancers:

[0048] Epidermal oral cavity: oral cavity, lips, tongue, mouth, pharynx;

[0049] Heart: Sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma;

[0050] Lungs: Bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoid hamartoma, mesothelioma;

[0051] 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;

[0052] 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);

[0053] Liver: Hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, bile duct;

[0054] 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;

[0055] 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;

[0056] 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;

[0057] 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;

[0058] Skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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).

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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. Detailed Implementation

[0082] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0083] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0084] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. The substituent is preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0085] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, trans-block isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0086] In the chemical structure of the compounds described in this disclosure, the bond " "" indicates that the configuration is not specified, meaning that if a chiral isomer exists in the chemical structure, the bond " "can be " "or" , or both contain " "and" "Two configurations."

[0087] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0088] .

[0089] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0090] .

[0091] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0092] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 I Deuterium is preferred.

[0093] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0094] In the compounds disclosed herein, when a position is specifically designated as "deuterium" or "D", that position should be understood to mean that the abundance of deuterium is at least 1000 times greater than the native abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0095] "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.

[0096] "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).

[0097] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds disclosed herein can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; while in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.

[0098] Based on their molecular structure, the compounds disclosed herein can be chiral, and therefore may exist in various enantiomeric forms. Consequently, these compounds can exist in racemic or optically active forms. The compounds disclosed herein cover isomers of each chiral carbon with an R or S configuration, or mixtures thereof, or racemates. The compounds disclosed herein, or intermediates thereof, can be isolated as enantiomers by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0099] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0100] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0101] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0102] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0103] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0104] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are generally given for illustrative purposes only and not as limitations.

[0105] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0106] Example

[0107] 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.

[0108] 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.

[0109] High performance liquid chromatography (HPLC) analysis was performed using Shimadzu LC-20AB, Shimadzu LC-20ADXR, and Shimadzu LC-40D XR HPLC systems.

[0110] Chiral HPLC analysis was performed using a Shimadzu LC-30AD high-performance liquid chromatograph.

[0111] High performance liquid chromatography was performed using a Shimadzu LC-20AP and a Gilson GX-281 preparative chromatograph.

[0112] Chiral preparation was performed using a Waters 150Mgm, Waters SFC 350 preparative chromatograph.

[0113] The CombiFlash rapid preparation system uses the CH-200P (Agela & Phenomenex).

[0114] 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.

[0115] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0116] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0117] 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.

[0118] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0119] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0120] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0121] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0122] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0123] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0124] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0125] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0126] 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.

[0127] In some embodiments, the compound is purified using preparative HPLC.

[0128] Example 1

[0129] (6S)-4-(1H-indol-2-yl)-6-methyl-7,8-dihydro-6H-cyclopentano[1,2-b][1,2,4]triazacyclopentano[3,4-f]pyridine

[0130]

[0131] first step

[0132] (6S)-4-(1H-indol-2-yl)-6-methyl-7,8-dihydro-6H-cyclopentano[1,2-b][1,2,4]triazacyclopentano[3,4-f]pyridine

[0133] Compound 1a was synthesized according to the method in WO2024107555.

[0134] Compound 1a (0.2 g, 920.71 μmol), boric acid (170.79 mg, 2.76 mmol), pentanoic anhydride (342.96 mg, 1.84 mmol), (1-tert-butoxycarbonylindole-2-yl)boronic acid (480.76 mg, 1.84 mmol), and triethylamine (163.04 mg, 1.61 mmol) were dissolved in dioxane (5 mL), and the mixture was purged with nitrogen three times. Palladium acetate (10.34 mg, 46.04 μmol) and 4-diphenylphosphine-butyl(diphenyl)phosphine (39.27 mg, 92.07 μmol) were then added, and the mixture was stirred in a microwave at 160 °C for 1 hour. 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 the crude product, which was then further slurried with methanol to obtain compound 1.

[0135] LCMS (ESI, m / z): 289.2 [M+H] + .

[0136] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 11.71 (s, 1H), 9.32 (s, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H),7.19-7.12 (m, 1H), 7.07-6.99 (m, 1H), 3.40-3.35 (m, 2H), 3.28-3.14 (m, 1H),2.59-2.56 (m, 1H), 1.89-1.79 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H).

[0137] Example 2

[0138] (6S)-4-(1H-benzo[d]imidazol-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[1,2-b][1,2,4]triazacyclopenta

[0139] Mannofa[3,4-f]pyridine 2

[0140]

[0141] first step

[0142] (6S)-N-(2-aminophenyl)-6-methyl-7,8-dihydro-6H-[1,2,4]triazacyclopentano[3,4-f]cyclopentano[1,2-b]pyridine-4-carboxamide 2a

[0143] Compound 1a (0.15 g, 690.53 μmol), o-phenylenediamine (149.35 mg, 1.38 mmol), and triethylamine (209.62 mg, 2.07 mmol) were dissolved in dichloromethane (5 mL), and butylphosphine anhydride (1.49 g, 2.07 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solution was 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 to give compound 2a, which was used directly in the next reaction without further purification.

[0144] Step 2

[0145] (6S)-4-(1H-benzo[d]imidazol-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[1,2-b][1,2,4]triazacyclopenta[3,4-f]pyridine 2. Compound 1a (0.2 g, 650.73 μmol) was dissolved in trifluoroacetic acid (3 mL), purged with nitrogen three times, and heated to 100 °C with stirring for 3 H. The reaction mixture was cooled to room temperature, diluted with dichloromethane (50 mL), and washed with saturated sodium bicarbonate aqueous 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 preparative HPLC to give compound 2.

[0146] LCMS (ESI, m / z): 290.2 [M+H] + .

[0147] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.82 (s, 1H), 9.46 (s, 1H), 8.38 (s, 1H), 7.88-7.80 (m, 1H), 7.72-7.65 (m, 1H), 7.28-7.19 (m, 2H), 3.46-3.38(m, 1H), 3.31-3.18 (m, 2H), 2.62-2.54 (m, 1H), 1.92-1.79 (m, 1H), 1.37 (d, J= 7.2Hz, 3H).

[0148] Example 3

[0149] (6S)-4-(9H-purin-8-yl)-6-methyl-7,8-dihydro-6H-cyclopentano[1,2-b][1,2,4]triazacyclopentano[3,4-f]pyridine 3

[0150]

[0151] first step

[0152] (6S)-N-(5-aminopyrimidin-4-yl)-6-methyl-7,8-dihydro-6H-[1,2,4]triazacyclopentano[3,4-f]cyclopentano[1,2-b]pyridine-4-carboxamide 3a

[0153] The title product 3a was prepared from compound 1a and pyrimidine-4,5-diamine using the synthetic method described in the first step of Example 2.

[0154] Step 2

[0155] (6S)-4-(9H-purin-8-yl)-6-methyl-7,8-dihydro-6H-cyclopentano[1,2-b][1,2,4]triazacyclopentano[3,4-f]pyridine 3 was prepared from compound 3a according to the synthetic method in step 2 of Example 2.

[0156] LCMS (ESI, m / z): 292.1 [M+H] + .

[0157] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 13.40 (br s, 1H), 9.52 (s, 1H), 9.21(s, 1H), 8.98 (s, 1H), 8.54 (s, 1H), 3.46-3.38 (m, 1H), 3.31-3.18 (m, 2H), 2.62-2.55 (m, 1H), 1.92-1.85 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H).

[0158] Example 4

[0159] (6S)-6-methyl-4-(6-methyl-1H-benzo[d]imidazol-2-yl)-7,8-dihydro-6H-cyclopentano[1,2-b][1,2,4]triazacyclopentano[3,4-f]pyridine 4

[0160]

[0161] first step

[0162] (6S)-N-(2-amino-5-methylphenyl)-6-methyl-7,8-dihydro-6H-cyclopentano[1,2-b][1,2,4]triazacyclopentano[3,4-f]pyridine-4-carboxamide 4a

[0163] The title product 4a was prepared from compound 1a and 4-methyl-o-phenylenediamine using the synthesis method described in the first step of Example 2.

[0164] Step 2

[0165] (6S)-6-methyl-4-(6-methyl-1H-benzo[d]imidazol-2-yl)-7,8-dihydro-6H-cyclopenta[1,2-b][1,2,4]triazacyclopenta[3,4-f]pyridine 4 was prepared from compound 4a according to the synthetic method in step 2 of Example 2.

[0166] LCMS (ESI, m / z): 304.3 [M+H] + .

[0167] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.70 (br s, 1H), 9.45 (s, 1H), 8.36-8.33 (m, 1H), 7.73-7.48 (m, 2H), 7.09-7.05 (m, 1H), 3.46-3.37 (m, 1H), 3.31-3.18 (m, 2H), 2.62-2.54 (m, 1H), 2.44 (s, 3H), 1.87-1.83 (m, 1H), 1.37(d, J = 6.8 Hz, 3H).

[0168] Example 5

[0169] (6S)-4-(6-fluoro-1H-benzo[d]imidazol-2-yl)-6-methyl-7,8-dihydro-6H-cyclopentano[1,2-b][1,2,4]triazacyclopentano[3,4-f]pyridine 5

[0170]

[0171] first step

[0172] (6S)-N-(2-amino-5-fluorophenyl)-6-methyl-7,8-dihydro-6H-[1,2,4]triazacyclopentano[3,4-f]cyclopentano[1,2-b]pyridine-4-carboxamide 5a

[0173] The title product 5a was prepared from compound 1a and 4-fluoro-o-phenylenediamine using the synthesis method described in the first step of Example 2.

[0174] Step 2

[0175] (6S)-4-(6-fluoro-1H-benzo[d]imidazol-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[1,2-b][1,2,4]triazacyclopenta[3,4-f]pyridine 5 was prepared from compound 5a according to the synthetic method in step 2 of Example 2.

[0176] LCMS (ESI, m / z): 308.2 [M+H] + .

[0177] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 9.47 (s, 1H), 8.37 (s, 1H), 7.83-7.58 (m, 2H), 7.15-7.08 (m, 1H), 3.46-3.37 (m, 1H), 3.31-3.18 (m, 2H), 2.61-2.54 (m, 1H), 1.90-1.83 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H).

[0178] 19 F NMR (376 MHz, DMSO-d6, ppm): δ -119.15 (s, 0.5F), -120.83 (s, 0.5F).

[0179] Example 6

[0180] (6S)-4-(6-chloro-1H-benzo[d]imidazol-2-yl)-6-methyl-7,8-dihydro-6H-cyclopentano[1,2-b][1,2,4]triazacyclopentano[3,4-f]pyridine 6

[0181]

[0182] first step

[0183] (6S)-N-(2-amino-5-chlorophenyl)-6-methyl-7,8-dihydro-6H-[1,2,4]triazacyclopentano[3,4-f]cyclopentano[1,2-b]pyridine-4-carboxamide 6a

[0184] The title product 6a was prepared from compound 1a and 4-chloro-o-phenylenediamine using the synthesis method described in the first step of Example 2.

[0185] Step 2

[0186] (6S)-4-(6-chloro-1H-benzo[d]imidazol-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[1,2-b][1,2,4]triazacyclopenta[3,4-f]pyridine 6 was prepared from compound 6a according to the synthetic method in step 2 of Example 2.

[0187] LCMS (ESI, m / z): 324.2 [M+H] + .

[0188] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 12.95 (br s, 1H), 9.48 (s, 1H), 8.40 (s, 1H), 7.91-7.70 (m, 2H), 7.29-7.27 (m, 1H), 3.46-3.37 (m, 1H), 3.31-3.18(m, 2H), 2.61-2.54 (m, 1H), 1.90-1.83 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H).

[0189] Example 7

[0190] (6S)-6-methyl-4-[6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl]-7,8-dihydro-6H-cyclopenta[1,2-b][1,2,4]triazacyclopenta[3,4-f]pyridine 7

[0191]

[0192] first step

[0193] (6S)-N-[2-amino-5-(trifluoromethyl)phenyl]-6-methyl-7,8-dihydro-6H-[1,2,4]triazacyclopentano[3,4-f]cyclopentano[1,2-b]pyridine-4-carboxamide 7a

[0194] The title product 7a was prepared from compound 1a and 4-(trifluoromethyl)o-phenylenediamine using the synthesis method in the first step of Example 2.

[0195] Step 2

[0196] (6S)-6-methyl-4-[6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl]-7,8-dihydro-6H-cyclopenta[1,2-b][1,2,4]triazacyclopenta[3,4-f]pyridine 7 was prepared from compound 7a according to the synthetic method in step 2 of Example 2 to obtain title product 7.

[0197] LCMS (ESI, m / z): 358.2 [M+H] + .

[0198] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 13.15 (br s, 1H), 9.49 (s, 1H), 8.44(s, 1H), 8.18-7.96 (m, 2H), 7.59-7.56 (m, 1H), 3.46-3.37 (m, 1H), 3.31-3.18(m, 2H), 2.61-2.54 (m, 1H), 1.89-1.83 (m, 1H), 1.37 (d, J = 7.2Hz, 3H).

[0199] 19 F NMR (376 MHz, DMSO-d6, ppm): δ -58.88 (s, 3F).

[0200] Example 8

[0201] 2-[(6S)-6-methyl-7,8-dihydro-6H-cyclopenta[1,2-b][1,2,4]triazacyclopenta[3,4-f]pyridin-4-yl]-3H-benzo[d]imidazol-5-carboxynitrile 8

[0202]

[0203] first step

[0204] (6S)-N-(2-amino-5-cyanophenyl)-6-methyl-7,8-dihydro-6H-[1,2,4]triazacyclopentano[3,4-f]cyclopentano[1,2-b]pyridine-4-carboxamide 8a

[0205] Title product 8a was prepared from compound 1a and 3,4-diaminophenyl-1-carboxynitrile using the synthesis method described in step 1 of Example 2.

[0206] Step 2

[0207] The title product 8 was prepared from compound 8a according to the synthetic method in step 2 of Example 2.

[0208] LCMS (ESI, m / z): 315.2 [M+H] + .

[0209] 1 H NMR (400 MHz, DMSO-d6, ppm): δ 9.52 (s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 7.97-7.94 (m, 1H), 7.67-7.64 (m, 1H), 3.46-3.37 (m, 1H), 3.31-3.18 (m,2H), 2.61-2.54 (m, 1H), 1.91-1.81 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H).

[0210] Biological evaluation

[0211] Test Example 1: Luciferase Reporter Gene Assay Experiment

[0212] 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 WO2024107555A1 for the control) on the AhR protein. The structure of the control is as follows:

[0213]

[0214] 1) Test cells

[0215] HepG2-Lucia, a human liver cancer cell line expressing AhR and luciferase, was purchased from InvivoGen (catalog number hpgl-ahr).

[0216] 2) Main instruments

[0217] Biosafety cabinet, model 307, ThermoFisher;

[0218] CO2 incubator, model CLM-240B-8-CN, ESCO;

[0219] Cell counter, model EVE-MC2, NanoEnTeK Corporation;

[0220] ECHO (Nano-Level Acoustic Plugging System), Model 655, LabCyte;

[0221] Microplate centrifuge, model PlatePro 3200, Monad Corporation;

[0222] Multifunctional microplate reader, model PHERAstar FSX, BMG LRBTECH.

[0223] 3) Main reagents

[0224] Penicillin-streptomycin, Gibco, catalog number 15140-122;

[0225] EMEM culture medium, ATCC, catalog number 30-2003;

[0226] Fetal bovine serum, Ausgenex, catalog number FBS500-S;

[0227] NEAA medium, Gibco, catalog number 11140-050;

[0228] Phosphate buffer, Gibco, catalog number 14190250;

[0229] DMSO (dimethyl sulfoxide), Solarbio, product number D8371;

[0230] FICZ (6-formylindolo[3,2-B]carbazole), MCE Corporation, catalog number HY-12451;

[0231] Zeocin (bleomycin), InvivoGen, catalog number ant-zn-1;

[0232] QUANTI-Luc Gold, InvivoGen, product number rep-qlcg5.

[0233] 4) Experimental Procedure

[0234] 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%.

[0235] 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;

[0236] c. Add different concentrations of the analyte compound using ECHO, 40 nL per well;

[0237] d. Continue to incubate the 384-well plate containing the compound in an incubator for 24 hours;

[0238] e. Take the supernatant, add QUANTI-Luc Gold detection reagent, and read the luminescence signal value using a multi-functional microplate reader.

[0239] 5) Test Results

[0240] 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.

[0241] Table 1

[0242]

[0243] 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 fused ring structure, characterized by, having the general formula (I) as shown below: ，， wherein: X1is CH; X2and X3are N; X4is CH or N; X5is CH; X6is CH or N; X7is CR8, wherein R8is H, halogen, CF3or CN; X8is CH or N; R a is unsubstituted C1-6alkyl; R b is H.

2. The compound according to claim 1, having any one of the following structures: 。 3. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 1 to 2 of general formula (I), and one or more pharmaceutically acceptable excipients.

4. Use of a compound according to any one of claims 1 to 2 of general formula (I) or a pharmaceutical composition according to claim 3 for the manufacture of an agonist for the modulation of AhR protein.

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