Compound with fused ring structure and application of compound in medicine

Abstract

The invention provides a compound with a fused ring structure and application of the compound in medicine, and particularly relates to application of a compound shown in a formula (I) or pharmaceutically acceptable salt, tautomer and stereoisomer of the compound as an aromatic hydrocarbon receptor (AhR) modulator. The compound disclosed by the invention provides a new choice for treating immune related diseases. .

Description

TECHNICAL FIELD

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

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

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

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

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

[0006] The disclosed related AhR modulator patent applications include WO2024107555A1, which is not part of the present application. SUMMARY

[0007] The present disclosure provides a compound represented by general formula (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof:

[0008]

[0009] wherein:

[0010] X1is selected from N or CR1; X2is selected from N or CR2; X3is selected from N or CR3; X4is selected from N or CR4; X5is selected from N or CR5; X6is selected from N or CR6; X7is selected from N or CR7; X8is selected from N or CR8;

[0011] R1, R2, R3, R4, R5, R6, R7, R8are the same or different, independently selected from H, halogen, CN, C(O)OH, C(O)OC1-10alkyl, C1-10alkyl unsubstituted or substituted with 1-3 halogens, C1-10alkoxy;

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

[0013] Further, R a and R bindependently of one another from the group consisting of H, halogen, CN, NH2, C1-6alkyl which is unsubstituted or substituted by one or more halogen, C1-6alkoxy, C1-6alkyl-NH-, (C1-6alkyl)2-N-; further, preferably from the group consisting of H, CN, NH2, C1-4alkyl; further, preferably from the group consisting of H, methyl.

[0014] R1, R2, R3, R4, R5, R6, R7, R8are the same or different and independently of one another selected from the group consisting of H, halogen, CN, C(O)OH, C(O)OC1-6alkyl, C1-6alkyl which is unsubstituted or substituted by 1 to 3 halogen, C1-6alkoxy; further, preferably from the group consisting of H, halogen, CN, C(O)OH, C(O)OC1-4alkyl, C1-4alkyl which is unsubstituted or substituted by 1 to 3 halogen, C1-4alkoxy; further, preferably from the group consisting of H, halogen, CN, methyl, trifluoromethyl.

[0015] At most two of X1, X2, X3are selected from N; further, X2and X3are selected from N and X1is selected from CR1; further, X2and X3are selected from N and X1is selected from CH. At most two of X5, X6, X7, X8are selected from N; further, X5is N and X6, X8are selected from N or CH and X7is CR7.

[0016] In a preferred embodiment, R a and R b are independently of one another selected from the group consisting of H, C1-4alkyl, X2and X3are selected from N, X1is selected from CH, X4is selected from CH or N, X5is selected from CH, X6, X8are selected from N, and X7is selected from CR7.

[0017] In particular, the following specific compounds can be selected:

[0018] .

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

[0020] The present disclosure further relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for modulating AhR protein; preferably for the manufacture of a medicament for agonizing or antagonizing AhR protein.

[0021] The present disclosure further relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of an AhR modulator, preferably for the manufacture of an AhR agonist or an AhR antagonist.

[0022] The present disclosure further relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and / or prevention of a disease or condition mediated by AhR protein.

[0023] The present disclosure further relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and / or prevention of a disease or condition mediated by AhR protein, wherein the disease or condition is selected from cancer, ophthalmic related diseases, autoimmune diseases, viral infectious diseases, immune diseases, central nervous system diseases, inflammatory or obstructive airway diseases, inflammatory diseases and other conditions or discomforts with immunological factors.

[0024] The present disclosure further relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and / or prevention of skin diseases, acute lung injury, adult / acute respiratory distress syndrome, chronic obstructive pulmonary disease, oral ulcer, ocular allergy, conjunctivitis, dry eye, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, 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, large intestine cancer and colorectal cancer.

[0025] The present disclosure further relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and / or prevention of skin diseases.

[0026] The present disclosure further relates to a method of modulating AhR protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0027] The present disclosure further relates to a method of antagonizing (inhibiting) AhR protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0028] The present disclosure further relates to a method of agonizing AhR protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0029] The present disclosure further relates to a method of treating and / or preventing a disease or condition mediated by AhR protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0030] The present disclosure further relates to a method for treating and / or preventing a disease or disorder mediated by AhR protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or disorder is selected from the group consisting of cancer, ophthalmic related diseases, autoimmune diseases, viral infectious diseases, immunological diseases, central nervous system diseases, inflammatory or obstructive airway diseases, inflammatory diseases and other conditions or discomforts with immunological factors.

[0031] The present disclosure further relates to a method for treating and / or preventing skin diseases, acute lung injury, adult / acute respiratory distress syndrome, chronic obstructive pulmonary disease, oral ulcer, ocular allergy, conjunctivitis, dry eye, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, 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, large intestine cancer and colorectal cancer; comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0032] The present disclosure further relates to a method for treating and / or preventing skin diseases; comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

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

[0034] The present disclosure further relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0035] The present disclosure further relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an AhR protein modulator.

[0036] The present disclosure further relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an AhR protein antagonist (inhibitor).

[0037] The present disclosure further relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an AhR protein agonist.

[0038] The present disclosure further relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0039] The present disclosure further relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament in the treatment and / or prevention of a disease or condition mediated by AhR protein, wherein the disease or condition is selected from the group consisting of cancer, ophthalmic related diseases, autoimmune diseases, viral infectious diseases, immune diseases, central nervous system diseases, inflammatory or obstructive airway diseases, inflammatory diseases and other conditions or discomforts with immunological factors.

[0040] The present disclosure further relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament in the treatment and / or prevention of skin diseases, acute lung injury, adult / acute respiratory distress syndrome, chronic obstructive pulmonary disease, oral ulcer, ocular allergy, conjunctivitis, dry eye, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, 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, colon cancer and colorectal cancer.

[0041] The present disclosure further relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament in the treatment and / or prevention of skin diseases.

[0042] Preferably, the skin diseases according to the present disclosure are selected from the group consisting of psoriasis, acne, vitiligo, diabetic foot ulcer and atopic dermatitis.

[0043] Preferably, the hepatitis according to the present disclosure is non-alcoholic steatohepatitis (NASH).

[0044] The "aromatic hydrocarbon receptor (AhR) modulator" according to the present disclosure refers to an agent that causes or promotes a qualitative or quantitative change, alteration or modification of one or more processes, mechanisms, effects, responses, functions, activities or pathways mediated by AhR receptor. Such a change mediated by an AhR modulator (e.g. an inhibitor or a non-constitutive agonist of AhR as described herein) can refer to a decrease or an increase in AhR activity or function, such as a decrease, inhibition or diversion of AhR constitutive activity.

[0045] An "AhR antagonist" as described herein refers to an inhibitor of AhR that does not itself elicit a biological response upon specific binding to an AhR polypeptide or polynucleotide encoding AhR, but blocks or suppresses agonist-mediated or ligand-mediated responses, i.e., the AhR antagonist can bind to, but does not activate, an AhR polypeptide or polynucleotide encoding AhR, and the binding disrupts the interaction, displaces an AhR agonist, and / or inhibits the function of an AhR agonist. Thus, as used herein, AhR antagonists, when bound to AhR, do not act as inducers of AhR activity, i.e., they act as pure AhR inhibitors.

[0046] An "AhR-mediated" disease and / or disorder as described herein means any disease or other deleterious condition in which AhR or a mutant thereof is known to play a role. Thus, another embodiment of the present application relates to treating or lessening the severity of one or more diseases in which AhR or a mutant thereof is known to play a role.

[0047] "Cancer" as described herein includes, but is not limited to, the following cancers:

[0048] Oral cavity: mouth, lip, tongue, mouth, pharynx;

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

[0050] Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroid tumor, mesothelioma;

[0051] Gastrointestinal: esophagus (squamous cell carcinoma, throat, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, VIPoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, rectum;

[0052] Urinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);

[0053] Liver: hepatoma (hepatocellular carcinoma), biliary tract cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary duct;

[0054] Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma, benign chondroma, chondroblastoma, chondromyxofibroma, 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, germinoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, spinal cord neurofibroma;

[0056] Gynecology: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovary (ovarian carcinoma), 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 syndrome), Hodgkin's disease, non-Hodgkin's lymphoma hairy cell, lymphoid disease;

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

[0059] Thyroid: papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; and neuroblastoma.

[0060] The neurodegenerative diseases described in the present disclosure can affect many activities of the body, such as balance, movement, speech, breathing, and heart function. Neurodegenerative diseases can be inherited or can be caused by medical conditions such as alcoholism, tumors, stroke, toxins, chemicals, and viruses.

[0061] Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease or Charcot disease), Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, and spinal muscular atrophy.

[0062] Non-limiting examples of central nervous system (CNS) diseases or disorders contemplated by the present 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) diseases, stroke, Fahr disease, Menkes disease, Wilson's disease, cerebral ischemia, and prion disease.

[0063] As used herein, the phrase "disease" or "disorder" broadly refers to any of the diseases or disorders described above that can be treated and / or prevented by administering to a patient a compound or an aryl hydrocarbon receptor modulator (antagonist or agonist) described herein.

[0064] The compounds of the present disclosure, or compositions thereof, can be used to treat and / or prevent inflammatory or obstructive airway diseases, to reduce, for example, tissue damage, airway inflammation, bronchial hyperreactivity, remodeling, or disease progression. Inflammatory or obstructive airway diseases to which the present disclosure can be applicable include asthma of any type or etiology, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection. Treatment of asthma is also understood to encompass treatment of subjects, for example, less than 4 or 5 years of age, who exhibit wheezing symptoms and are diagnosed or diagnosable as "wheezy infants," which is an established patient category of primary medical concern and is now often identified as an early or incipient asthma patient.

[0065] Other inflammatory or obstructive airway diseases and / or disorders to which the present disclosure can be applicable and / or the diseases and / or disorders include acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, respiratory or pulmonary disorders including chronic bronchitis or dyspnea associated therewith, emphysema, and exacerbation of airway hyperreactivity resulting from other drug therapies, especially other inhaled drug therapies.

[0066] The present disclosure can also be used to treat inflammatory or allergic conditions of the skin and other diseases or conditions, for example, diseases or conditions having an inflammatory component, for example, to treat ocular diseases and conditions, for example, ocular allergies, conjunctivitis, dry eye, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology. The inflammatory diseases that can be treated according to the methods of the present disclosure are selected from the group consisting of acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

[0067] In some embodiments, the inflammatory disease treatable according to the methods of the disclosure is selected from TH17-mediated diseases. In some embodiments, the TH17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0068] "Subject" and "patient" as used herein refer to an organism, such as a human, who receives treatment for a particular disease or condition described herein. The term subject or patient as used herein can refer to a mammal, such as a dog, cat, horse, cow, pig, guinea pig, and the like. For example, a patient in need of an aryl hydrocarbon receptor antagonist, such as a human patient, can receive treatment including an aryl hydrocarbon receptor antagonist to treat a disease or condition described herein, such as a cancer, an autoimmune disease, or an inflammatory disease.

[0069] The active compounds can be prepared into various pharmaceutically acceptable dosage forms for administration by any of the routes conventionally used for drug delivery, using routine methods and one or more pharmaceutically acceptable carriers. Thus, the active compounds of the disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation or insufflation, and the like. The compounds of the disclosure can also be formulated into sustained-release dosage forms, such as tablets, hard or soft gel capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges, or syrups.

[0070] As a general guide, the active compounds are preferably in unit dosage form, or in a form suitable for self-administration by the patient in a single dose. The expression unit dose of the compounds or compositions of the disclosure can be tablets, capsules, cachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.

[0071] The pharmaceutical compositions of the disclosure can contain, in addition to the active compounds, one or more adjuvants selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants, or excipients, and the like. Depending on the method of administration, the compositions can contain 0.1 to 99% by weight of the active compounds.

[0072] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. The tablets can be uncoated or they can be coated by known techniques to mask the unpleasant taste or odor of the drug, to delay disintegration and absorption in the gastrointestinal tract, and thereby provide a sustained action over a longer period.

[0073] Oral preparations can also be provided in 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 vehicle.

[0074] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspensions can also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, depending on the desire.

[0075] Oil suspensions can be formulated by suspending the active ingredients in a vegetable oil, or a mineral oil. The oil suspensions can contain a thickening agent. Sweetening agents and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant.

[0076] The pharmaceutical compositions of this disclosure can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil or a mineral oil or a mixture of these. Suitable emulsifying agents can be naturally-occurring phosphatides, such as soybean phoshatide, and lecithin. The emulsions can also contain sweetening agents, flavoring agents, preservatives and antioxidants.

[0077] The pharmaceutical compositions of this disclosure can be in the form of a sterile injectable aqueous or oleaginous suspension. For this purpose, any of the injectable

[0078] The pharmaceutical compositions of this disclosure can be in the form of a sterile injectable aqueous or oleaginous suspension. For this purpose, any of the injectable

[0079] The compounds of this disclosure can be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0080] The compounds of this disclosure can be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[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 ... 1-6Non-limiting examples include: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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 various branched isomers thereof, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from the group consisting of D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0084] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, and the like. The alkoxy group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from the group consisting of D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0085] The compounds of the present disclosure can exist in particular stereoisomeric forms. The term "stereoisomers" refers to isomers having the same structure except they have non-identical arrangements of atoms in space. It includes cis- and trans- (or E- and Z-) isomers, (-)- and (+)- enantiomeric forms, (R)- and (S)- enantiomeric forms, diastereomers, (D)- and (L)- isomers, tautomers, atropisomers, conformational isomers, and mixtures thereof such as racemates, mixtures of diastereomers. Substituents in the compounds of the present disclosure can present additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are encompassed within the scope of the present disclosure. The optically active (-)- and (+)- isomers, (R)- and (S)- enantiomeric forms, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. One isomer of a compound of the present disclosure can be prepared by asymmetric synthesis, or by chiral auxiliary, or, when a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group) is present in the molecule, by forming a diastereomeric salt with an appropriate optically active acid or base, followed by separation of the diastereomeric salt by conventional means and, if desired, conversion to the pure isomer by means of conventional techniques. Additionally, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0086] In the chemical structures of the compounds of the present disclosure, the bond " " represents unspecified configuration, i.e. if chiral isomers are present in the chemical structure, the bond " " can be either " " or " ", or both " " and " " configurations.

[0087] The compounds of the present disclosure can exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomers" or "tautomeric forms" refers to structural isomers that exist in equilibrium with each other and are readily convertible to each other. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. An example of lactam-lactim equilibrium is shown below:

[0088] .

[0089] As used when referring to pyrazolyl, it is understood to include either of the following two structures, or a mixture of both tautomers:

[0090] .

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

[0092] The compounds of the present disclosure include all suitable isotopic variations of the compounds. The term "isotopic variations" means compounds wherein at least one atom has been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be introduced into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromine, and iodine, such as 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 etc., preferably deuterium.

[0093] Deuterated drugs have advantages of reducing side effects, increasing drug stability, enhancing efficacy, prolonging drug biological half-life, etc. compared to non-deuterated drugs. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each of the available hydrogen atoms attached to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and the partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.

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

[0095] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and encompasses the two instances of the event or circumstance occurring and not occurring. For example, "alkyl optionally substituted with halogen or cyano" includes instances where alkyl is substituted with halogen or cyano and instances where alkyl is not substituted with halogen and cyano.

[0096] "Substituted" or "substitution" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, of a group are independently of each other replaced by a corresponding number of substituents. It is within the skill of the person skilled in the art to determine, without undue effort, whether a substitution is possible or not (by experiment or theory). For example, an amino group with a free hydrogen or a hydroxyl group can not be stable in combination with a carbon atom having an unsaturated bond (e.g. an alkene).

[0097] The term "tautomer" refers to isomers of a functional group that result from the rapid movement of an atom in a molecule between two positions. The compounds of the present disclosure can exhibit tautomerism. Compounds that tautomerize can exist in two or more interconvertible forms. Proton-shift tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0098] Depending on their molecular structure, the compounds of the present disclosure can be chiral and thus can exist in various enantiomeric forms. The compounds can thus exist in racemic or optically active forms. The compounds of the present disclosure encompass the isomers of each chiral carbon in the R or S configuration or mixtures thereof, racemates. The compounds of the present disclosure or intermediates thereto can be separated into the enantiomeric compounds by chemical or physical methods known to those of ordinary skill in the art, or used as such in the synthesis. In the case of racemic amines, the diastereomeric amines are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, the appropriate N-protected amino acid, for example N-benzoyl proline or N-benzenesulfonyl proline, or the various optically active camphorsulfonic acids. Enantiomeric resolution by chromatography is also advantageously performed with optically active stationary phases, for example dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatizing agents, fixed on silica gel. Suitable eluents for this purpose are solvent mixtures containing water or alcohol, for example hexane / isopropanol / acetonitrile.

[0099] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or pharmaceutically acceptable salts thereof with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism, benefiting absorption, and thereby facilitating biological utilization.

[0100] "Pharmaceutically acceptable salt" means a salt of a compound of the present disclosure that is selected from inorganic or organic salts. Such salts are safe and effective for use in a mammal and possess the desirable biological activity. They can be prepared from the final isolation and purification of the compound, or by separately reacting a suitable agent with the appropriate compound in its base form. Alkali bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium and potassium hydroxides, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

[0101] The term "therapeutically effective amount" with respect to a pharmaceutical or pharmacological agent means an amount of the agent sufficient to achieve, at least partially, the intended effect. Determination of a therapeutically effective amount is within the capability of those skilled in the art, is dependent on the age and general condition of the recipient, as well as the particular active substance, and appropriate therapeutically effective amounts in individual cases can be determined by those skilled in the art according to routine tests.

[0102] The term "pharmaceutically acceptable" as used herein means that the compounds, materials, compositions, and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0103] As used herein, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise.

[0104] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be appreciated by those skilled in the art, numbers are often given only to the nearest integer for simplicity, not limitation, when the parameter is not critical.

[0105] The following examples are provided to further illustrate the present disclosure, but are not intended to limit the scope of the disclosure.

[0106] Examples

[0107] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) are given in 10 -6 (ppm) units. NMR measurements are made with a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0108] Liquid chromatography-mass spectrometry (LC-MS) was performed using a 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 a Shimadzu LC-20AB, Shimadzu LC-20AD XR and Shimadzu LC-40D XR high performance liquid chromatograph.

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

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

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

[0113] CombiFlash flash preparative instrument was used CH-200P (Agela & Phenomenex).

[0114] Thin layer chromatography silica gel plates were used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used in thin layer chromatography (TLC) had a thickness of 0.15 mm~0.2 mm. The silica gel plates used in thin layer chromatography separation and purification of products had a thickness of 0.4 mm~0.5 mm.

[0115] Silica gel column chromatography generally used Yantai Huanghai silica gel 200~300 mesh silica gel as a carrier.

[0116] Determination of average inhibition rate and IC 50 values of kinases was performed using a NovoStar microplate reader (Germany BMG Company).

[0117] Known starting materials of the present disclosure can be synthesized or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Shanghai, Darui Chemicals, etc.

[0118] Unless otherwise specified in the examples, the reactions were performed under an argon or nitrogen atmosphere.

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

[0120] Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

[0121] Pressurized hydrogenation reactions use a Parr 3916EKX hydrogenation apparatus and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenation apparatus.

[0122] Hydrogenation reactions are usually vacuumed, filled with hydrogen, and the operation is repeated 3 times.

[0123] Microwave reactions use a CEM Discover-S 908860 microwave reactor.

[0124] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0125] In the examples, unless otherwise specified, the reaction temperature is room temperature, which is 20-30°C.

[0126] In the examples, the monitoring of the reaction progress uses thin layer chromatography (TLC), and the system of the developing agent used in the reaction, the eluent used in the column chromatography for purifying the compound, and the developing agent system of the thin layer chromatography include: A: petroleum ether / ethyl acetate system, B: dichloromethane / methanol system, the volume ratio of the solvents is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagent such as triethylamine and acetic acid can also be added for adjustment.

[0127] In some examples, the purified compound uses preparative HPLC.

[0128] Example 1

[0129] (6S)-4-(1H-Indol-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[1,2-b][1,2,4]triazolo[3,4-f]pyridine 1

[0130]

[0131] First step

[0132] (6S)-4-(1H-Indol-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[1,2-b][1,2,4]triazolo[3,4-f]pyridine 1

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

[0134] Compound 1a (0.2 g, 920.71 μmol), boronic acid (170.79 mg, 2.76 mmol), pivalic anhydride (342.96 mg, 1.84 mmol), (1-tert-butoxycarbonylindol-2-yl)boronic acid (480.76 mg, 1.84 mmol) and triethylamine (163.04 mg, 1.61 mmol) were dissolved in dioxane (5 mL), replaced with nitrogen for three times, then palladium acetate (10.34 mg, 46.04 μmol) and 4-diphenylphosphinobutyl(diphenyl)phosphine (39.27 mg, 92.07 μmol) were added, stirred at 160 °C for 1 h under microwave. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated, the residue was purified by silica gel column chromatography to give a crude product, which was further washed with methanol to give 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

[0139] Isoquinoline 2

[0140]

[0141] First step

[0142] (6S)-N-(2-aminophenyl)-6-methyl-7,8-dihydro-6H-[1,2,4]triazolo[3,4- f]cyclopenta[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), followed by the addition of n-butylphosphonic anhydride (1.49 g, 2.07 mmol) and stirring at room temperature for 1 h. Dilution with ethyl acetate (50 mL), washing with water (50 mL) and saturated brine (50 mL) was followed by separation of the organic phase, drying over anhydrous sodium sulfate and filtration. The filtrate was concentrated to give compound 2a, which was used directly in the next step without further purification.

[0144] Second step

[0145] (6S)-4-(1H-benzo[d]imidazol-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[1,2- b][1,2,4]triazolo[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 stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by 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-cyclopenta[l,2-b][l,2,4]triazolo[3,4- f]pyridine 3

[0150]

[0151] First Step

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

[0153] The title product 3a was prepared from compound la and pyrimidine-4,5-diamine according to the synthetic procedure of the first step in Reference Example 2.

[0154] Second Step

[0155] (6S)-4-(9H-purin-8-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[l,2-b][l,2,4]triazolo[3,4- f]pyridine 3 The title product 3 was prepared from compound 3a according to the synthetic procedure of the second step in Reference 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-lH-benzo[d]imidazol-2-yl)-7,8-dihydro-6H- cyclopenta[l,2-b][l,2,4]triazolo[3,4-f]pyridine 4

[0160]

[0161] First Step

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

[0163] The title product 4a was prepared according to the procedure described in the first step of Example 2 from compound la and 4-methylaniline.

[0164] Second Step

[0165] (6S)-6-methyl-4-(6-methyl-lH-benzo[d]imidazol-2-yl)-7,8-dihydro-6H-cyclopenta[l,2-b][l,2,4]triazolo[3,4- f]pyridine 4 The title product 4 was prepared according to the procedure described in the second step of Example 2 from compound 4a.

[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-lH-benzo[d]imidazol-2-yl)-6-methyl-7,8-dihydro-6H-cyclopenta[l,2-b][l,2,4]triazolo[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]triazolo[3,4-f]cyclopenta[b]pyridine-4-carboxamide 5a

[0173] The title product 5a was prepared according to the procedure described in the first step of Example 2 from compound la and 4-fluoro-o-phenylenediamine.

[0174] Second step

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

[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- cyclopenta[1,2-b][1,2,4]triazolo[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]triazolo[3,4-f]cyclopenta[1,2-b]pyridine-4-carboxamide 6a

[0184] The title product 6a was prepared according to the procedure described in the first step of Example 2 from compound la and 4-chloro-o-phenylenediamine.

[0185] Second step

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

[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]triazolo[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]triazolo[3,4-f]cyclopenta[1,2-b]pyridine-4-carboxamide 7a

[0194] The title product 7a was prepared according to the procedure described in the first step of Example 2 from compound la and 4-(trifluoromethyl)aniline.

[0195] Second step

[0196] (6S)-6-methyl-4-[6-(trifluoromethyl)-lH-benzo[d]imidazol-2-yl]-7,8-dihydro-6H- cyclopenta[l,2-b][l,2,4]triazepino[3,4-f]pyridine 7 The title product 7 was prepared according to the procedure described in the second step of Example 2 from compound 7a.

[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[l,2-b][l,2,4]triazepino[3,4-f]pyridin-4-yl]- 3H-benzo[d]imidazole-5-carbonitrile 8

[0202]

[0203] First step

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

[0205] The title product 8 was prepared from compound 8a according to the synthetic procedure of the second step in Reference Example 2.

[0206] Second step

[0207] 2-[(6S)-6-methyl-7,8-dihydro-6H-cyclopenta[l,2-b][l,2,4]triazolo[3,4- f]pyridin-4-yl]-3H-benzo[d]imidazole-5-carbonitrile 8 The title product 8 was prepared from compound 8a according to the synthetic procedure of the second step in Reference 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 test experiment

[0212] This test example utilizes Method One to perform luciferase reporter gene test experiments to test the agonistic activity effect of the compounds of the present disclosure and the control examples (control examples can be found in WO2024107555A1) on AhR protein. The structures of the control examples are as follows:

[0213]

[0214] 1) Test cells

[0215] Human hepatoma cells HepG2-Lucia expressing AhR and luciferase were purchased from InvivoGen, Cat. No. hpgl-ahr.

[0216] 2) Main instruments

[0217] Biological safety cabinet, model 307, ThermoFisher Company;

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

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

[0220] ECHO (nanoliter acoustic liquid handling system), model 655, LabCyte;

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

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

[0223] 3) Main reagents

[0224] Penicillin-streptomycin, Gibco, cat# 15140-122;

[0225] EMEM medium, ATCC, cat# 30-2003;

[0226] Fetal bovine serum, Ausgenex, cat# FBS500-S;

[0227] NEAA medium, Gibco, cat# 11140-050;

[0228] Phosphate buffer, Gibco, cat# 14190250;

[0229] DMSO (dimethyl sulfoxide), Solarbio, cat# D8371;

[0230] FICZ (6-formylindolo[3,2-B]carbazole), MCE, cat# HY-12451;

[0231] Zeocin, InvivoGen, cat# ant-zn-1;

[0232] QUANTI-Luc Gold, InvivoGen, cat# rep-qlcg5.

[0233] 4) Experimental procedures

[0234] a. HepG2-Lucia AhR cells were cultured in EMEM medium containing 10% inactivated fetal bovine serum, 1x NEAA, penicillin-streptomycin, and 100 µg / ml Zeocin. The culture temperature was 37°C, and the carbon dioxide concentration was 5%;

[0235] b. Cells were grown to about 80% confluency, digested, centrifuged and resuspended for counting. Cells were seeded into 384-well plates at 40 μL per well;

[0236] c. Different concentrations of test compounds were added using ECHO at 40 nL per well;

[0237] d. The 384-well plates with added compounds were incubated in an incubator for 24 h;

[0238] e. The supernatant was taken and QUANTI-Luc Gold detection reagent was added. Luminescence signal values were read using a multifunctional microplate reader.

[0239] 5) Test results

[0240] The EC50values of the compounds of the present disclosure and the control examples for the activity of AhR protein are summarized in Table 1 below. 50 The EC50values of the compounds of the present disclosure and the control examples for the activity of AhR protein are summarized in Table 1 below. 50 (μM) are summarized in Table 1 below.

[0241] Table 1

[0242]

[0243] The embodiments described above are part of, but not all, embodiments of the present application. The detailed description of the embodiments of the present application is not intended to limit the scope of the claimed application, but merely represents selected embodiments of the application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work are within the scope of protection of the present application.

Claims

1. A compound having a fused ring structure, characterized by, having the general formula (I) ， wherein: X1is selected from N or CR1; X2is selected from N or CR2; X3is selected from N or CR3; X4is selected from N or CR4; X5is selected from N or CR5; X6is selected from N or CR6; X7is selected from N or CR7; X8is selected from N or CR8; R1, R2, R3, R4, R5, R6, R7, R8are the same or different, independently of each other selected from H, halogen, CN, C(O)OH, C(O)OC1-10alkyl, C1-10alkyl unsubstituted or substituted by one or more halogen, C1-10alkoxy; R a and R b are independently from each other selected from H, halogen, CN, NH2, Ci-10-alkyl which is unsubstituted or substituted by one or more halogens, Ci-10-alkoxy, Ci-10-alkyl-NH-, (Ci-10-alkyl)2-N-.

2. The compound of claim 1, wherein R a and R b are independently from each other selected from H, halogen, CN, NH2, Ci-6alkyl which is unsubstituted or substituted by one or more halogen, Ci-6alkoxy, Ci-6alkyl-NH-, (Ci-6alkyl)2-N-; further on, preferably from H, CN, NH2, Ci-4alkyl; further on, preferably from H, methyl.

3. The compound of any one of claims 1-2, wherein, R1, R2, R3, R4, R5, R6, R7, R8are the same or different, independently of each other selected from H, halogen, CN, C(O)OH, C(O)OC1-6alkyl, C1-6alkyl unsubstituted or substituted by 1-3 halogen, C1-6alkoxy; further, preferably from H, halogen, CN, C(O)OH, C(O)OC1-4alkyl, C1-4alkyl unsubstituted or substituted by 1-3 halogen, C1-4alkoxy; further, preferably from H, halogen, CN, methyl, trifluoromethyl.

4. The compound according to any one of claims 1 to 3, wherein At most two of X1, X2, X3are selected from N; further, X2and X3are selected from N, X1is selected from CR1; further, X2and X3are selected from N, X1is selected from CH.

5. The compound according to any one of claims 1 to 4, wherein At most two of X5, X6, X7, X8are selected from N; further, X5is N, X6, X8are selected from N or CH, X7is CR7.

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

8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for modulating AhR protein; preferably for the manufacture of a medicament for agonizing or antagonizing AhR protein.

9. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for the treatment and / or prevention of a disease or disorder mediated by AhR protein.

10. Use according to claim 9, characterized in that, The disease or condition is selected from the group consisting of skin diseases, mouth ulcers, acute lung injury, adult / acute respiratory distress syndrome, chronic obstructive pulmonary disease, ocular allergies, conjunctivitis, dry eye, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, lung cancer, breast cancer, liver cancer, non-alcoholic steatohepatitis, ovarian cancer, prostate cancer, melanoma, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, glioma, cervical cancer, endometrial cancer, colorectal cancer; preferably the skin disease is selected from the group consisting of psoriasis, acne, vitiligo, diabetic foot ulcers and atopic dermatitis; the inflammatory bowel disease is preferably Crohn's disease or ulcerative colitis. The disease or condition is selected from the group consisting of skin diseases, mouth ulcers, acute lung injury, adult / acute respiratory distress syndrome, chronic obstructive pulmonary disease, ocular allergies, conjunctivitis, dry eye, uveitis, age-related macular degeneration, gout, rheumatoid arthritis, diabetes, neurodegenerative diseases, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, lung cancer, breast cancer, liver cancer, non-alcoholic steatohepatitis, ovarian cancer, prostate cancer, melanoma, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, glioma, cervical cancer, endometrial cancer, colorectal cancer; preferably the skin disease is selected from the group consisting of psoriasis, acne, vitiligo, diabetic foot ulcers and atopic dermatitis; the inflammatory bowel disease is preferably Crohn's disease or ulcerative colitis.

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