A compound having prmt1 degradation activity and preparation method and use thereof

Abstract

The present application relates to a kind of compound shown in general formula I or its stereoisomer, solvate, hydrate, prodrug, stable isotopic derivative and pharmaceutically acceptable salt, the compound has very high degradation activity to PRMT1 and has excellent selectivity, while having excellent drug efficacy, solubility, in vitro / in vivo pharmacokinetic properties and safety, high clinical application prospect.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a compound with PRMT1 degradation activity, its preparation method, and its uses. Background Technology

[0002] Histone methylation is a highly dynamic and reversible process regulated by histone methyltransferases and demethylases. The protein arginine methyltransferase (PRMT) family, as one of the major classes of histone methyltransferases, has catalytic activity dependent on S-adenosyl-L-methionine (SAM) as a cofactor.

[0003] Based on their catalytic products, the PRMT family can be divided into three types (I-III): Type I PRMTs (including PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8) catalyze the methylation of arginine residues to form ω-NG-monomethylarginine (MMA) or ω-NG,NG-asymmetric dimethylarginine (aDMA); Type II PRMTs (PRMT5 and PRMT9) catalyze MMA or ω-NG,N'G-symmetric dimethylarginine (sDMA); while PRMT7 is separately classified as Type III, possessing unique catalytic specificity and only producing MMA. Notably, PRMT1, as the main enzyme of Type I PRMTs, has been reported to account for approximately 85% of cellular aDMA levels. Under physiological conditions, PRMT1 regulates various biological processes, such as gene transcription, maintenance of genome stability, DNA damage response, RNA splicing, RNA metabolism, and signal transduction. However, dysregulation of PRMT1 expression or activity has been shown to be closely related to the development and progression of various diseases, especially cancer.

[0004] Given the profound involvement of PRMT1 in physiological and pathological processes, the development of inhibitors targeting PRMT1 has become a research hotspot in the biomedical field. However, due to the high structural conservation among type I PRMTs, developing PRMT1 inhibitors with both high potency and high selectivity remains a persistent challenge. This limitation has prompted the exploration of alternative strategies such as targeting protein degradation. Among these, protein-targeting chimeras (PROTACs) are bifunctional compounds that can simultaneously bind to both the target protein and an E3 ubiquitin ligase. These compounds can be recognized by the cell's proteasome, inducing the degradation of the target protein and effectively reducing its concentration in the cell. This technology provides a potential pathway to overcome selectivity limitations by completely degrading the target protein.

[0005] Currently, there are no effective PROTAC degraders targeting PRMT1 reported in this field, so there is an urgent need to develop a novel degrader that can target PRMT1. Summary of the Invention

[0006] This invention provides a compound of general formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotopic derivative, and a pharmaceutically acceptable salt thereof: ; in: X is selected from NH, O, S and C (=O); R 1 Selected from alkyl groups, wherein one or more methylene groups in the alkyl group are optionally surrounded by one or more groups selected from R 3 Group substitution; Y is selected from alkylene groups, wherein one or more methylene groups in the alkylene group are optionally replaced by one or more groups selected from R. 4 Group substitution; R 2 Selected from and ; Each time it occurs, the R 3 Each is independently selected from bonds, O, C (=O), S, SO, S (=O)2, NH and N (CH3); Each time it occurs, the R 4 Each is independently selected from bonds, O, C (=O), S, SO, S (=O)2 and NH; A1, A2, A3, A4, and A5 are each independently selected from N and CR. 5 ; Each time it occurs, the R 5 Each is independently selected from hydrogen, deuterium, amino, hydroxyl, and halogen; B1, B2, B3, B4, and B5 are each independently selected from N and CR. 6 ; Each time it occurs, the R 6 Each is independently selected from hydrogen, deuterium, amino, hydroxyl and halogen.

[0007] The effects of the invention The compounds disclosed herein exhibit high degradation activity and excellent selectivity for PRMT1, along with superior efficacy, solubility, in vitro / in vivo pharmacokinetic properties, and safety, making them promising candidates for clinical application. Attached Figure Description

[0008] Figure 1 Immunoblot images of PRMT1 expression in the breast cancer cell line MCF-7 after administration of the compounds of Examples 1-10.

[0009] Figure 2 Bar chart showing the relative expression levels of PRMT1 in the breast cancer cell line MCF-7 after application of the compounds from Examples 1-10.

[0010] Figure 3 Immunoblotting and quantitative analysis of PRMT1 expression in MCF-7 breast cancer cell line after application of different concentrations of the compound from Example 4.

[0011] Figure 4 Immunoblotting and quantitative analysis of PRMT1 expression in melanoma cell line A2058 after application of different concentrations of the compound from Example 4.

[0012] Figure 5 Immunoblotting and quantitative analysis of PRMT1 expression in MCF-7 breast cancer cell line after administration of the compound of Example 4 at different treatment times.

[0013] Figure 6 Immunoblotting and quantitative analysis of PRMT1 expression in MCF-7 breast cancer cell line after administration of the compound of Example 4 at different treatment times.

[0014] Figure 7 Immunoblot images showing the expression of PRMT1 / PRMT3 / PRMT4 / PRMT6 / PRMT8 in the breast cancer cell line MCF-7 after administration of the compound of Example 4 at different treatment times.

[0015] Figure 8 An immunoblot image of aDMA expression in the breast cancer cell line MCF-7 after application of the compound of Example 4.

[0016] Figure 9 Line graph showing the effect of 5 μM of the compound from Example 4 on the proliferation of breast cancer cell line MCF-7 over time.

[0017] Figure 10 Line graph showing the effect of applying 2.5 μM of the compound from Example 4 on the proliferation ability of the breast cancer cell line MCF-7 over time.

[0018] Figure 11 Line graph showing the effect of 1.25 μM of the compound from Example 4 on the proliferation of breast cancer cell line MCF-7 over time.

[0019] Figure 12 Line graph showing the effect of 5 μM of the compound from Example 4 on the proliferation of melanoma cell line A2058 over time.

[0020] Figure 13 Line graph showing the effect of 2.5 μM of the compound from Example 4 on the proliferation of melanoma cell line A2058 over time.

[0021] Figure 14 Line graph showing the effect of 1.25 μM of the compound from Example 4 on the proliferation of melanoma cell line A2058 over time.

[0022] Figure 15 Plasma drug concentration-time curves in mice after a single intraperitoneal injection of 20 mg / kg of the compound from Example 4. Detailed Implementation

[0023] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0024] This invention provides a compound of general formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotopic derivative, and a pharmaceutically acceptable salt thereof: ; in: X is selected from NH, O, S and C (=O); R 1 Selected from alkyl groups, wherein one or more methylene groups in the alkyl group are optionally surrounded by one or more groups selected from R 3 Group substitution; Y is selected from alkylene groups, wherein one or more methylene groups in the alkylene group are optionally replaced by one or more groups selected from R. 4 Group substitution; R 2 Selected from and ; Each time it occurs, the R 3 Each is independently selected from bonds, O, C (=O), S, SO, S (=O)2, NH and N (CH3); Each time it occurs, the R 4 Each is independently selected from bonds, O, C (=O), S, SO, S (=O)2 and NH; A1, A2, A3, A4, and A5 are each independently selected from N and CR. 5 ; Each time it occurs, the R 5Each is independently selected from hydrogen, deuterium, amino, hydroxyl, and halogen; B1, B2, B3, B4, and B5 are each independently selected from N and CR. 6 ; Each time it occurs, the R 6 Each is independently selected from hydrogen, deuterium, amino, hydroxyl and halogen.

[0025] In some implementations, X is selected from O.

[0026] In some implementations, A1, A2, A3, A4, and A5 are each independently selected from CR. 5 , wherein R 5 Each of these elements is independently selected from hydrogen, deuterium, amino, hydroxyl, and halogen in each occurrence.

[0027] In some implementations, A1, A2, A3, A4, and A5 are each independently selected from CR. 5 , wherein R 5 Each time it appears, it is independently selected from hydrogen.

[0028] In some implementations, A1, A2, A3, A4 and A5 are each independently selected from CH.

[0029] In some implementations, B1, B2, B3, B4, and B5 are each independently selected from CR. 6 , wherein R 6 Each of these elements is independently selected from hydrogen, deuterium, amino, hydroxyl, and halogen in each occurrence.

[0030] In some implementations, B1, B2, B3, B4, and B5 are each independently selected from CR. 6 , wherein R 6 Each time it appears, it is independently selected from hydrogen.

[0031] In some implementations, B1, B2, B3, B4 and B5 are each independently selected from CH.

[0032] In some embodiments, the present invention provides compounds of general formula II or their stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts: ; in: R 1 Selected from alkyl groups, wherein one or more methylene groups in the alkyl group are optionally surrounded by one or more groups selected from R 3 Group substitution; Y is selected from alkylene groups, wherein one or more methylene groups in the alkylene group are optionally replaced by one or more groups selected from R.4 Group substitution; R 2 Selected from and ; Each time it occurs, the R 3 Each is independently selected from bonds, O, C (=O), S, SO, S (=O)2, NH and N (CH3); Each time it occurs, the R 4 Each is independently selected from bond, O, C (=O), S, SO, S (=O)2 and NH.

[0033] In some implementations, the R 1 Selected from C 4-12 Alkyl, the C 4-12 One or more methylene groups in the alkyl group are optionally surrounded by one or more groups selected from R 3 Group substitution.

[0034] In some implementations, the R 3 Each time it appears, it is independently selected from NH and N(CH3).

[0035] In some implementations, the R 1 Selected from C 5-7 Alkyl, the C 5-7 One or more methylene groups in the alkyl group are optionally surrounded by one or more groups selected from R 3 Group substitution.

[0036] In some implementations, the R 3 Each time it appears, it is independently selected from NH and N(CH3).

[0037] In some implementations, the R 1 Choose an alkyl group, wherein one or more methylene groups in the alkyl group are optionally surrounded by one or more groups selected from R. 3 Group substitution.

[0038] In some implementations, the R 3 Each time it appears, it is independently selected from NH and N(CH3).

[0039] In some implementations, the R 1 Selected from .

[0040] In some embodiments, the present invention provides compounds of general formula III or general formula IV or their stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts: ; ; in: Y is selected from alkylene groups, wherein one or more methylene groups in the alkylene group are optionally replaced by one or more groups selected from R. 4 Group substitution; Each time it occurs, the R 4 Each is independently selected from bond, O, C (=O), S, SO, S (=O)2 and NH.

[0041] In some implementations, Y is selected from C. 5-20 Alkylene, the C 5-20 One or more methylene groups in the alkylene group are optionally surrounded by one or more groups selected from R 4 Group substitution.

[0042] In some implementations, the R 4 Each time it appears, it is independently selected from O, C (=O) and NH.

[0043] In some implementations, Y is selected from C. 9-15 Alkylene, the C 9-15 One or more methylene groups in the alkylene group are optionally surrounded by one or more groups selected from R 4 Group substitution.

[0044] In some implementations, the R 4 Each time it appears, it is independently selected from O, C (=O) and NH.

[0045] In some embodiments, Y is selected from nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, and pentadecyl, and one or more methylene groups selected from nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, and pentadecyl are optionally replaced by one or more methylene groups selected from R. 4 Group substitution.

[0046] In some implementations, the R 4 Each time it appears, it is independently selected from O, C (=O) and NH.

[0047] In some implementations, Y is selected from... , , , , , , , , and Where * represents the relationship between Y and R. 2 The connection site.

[0048] In some embodiments, the present invention provides a compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, or pharmaceutically acceptable salt, said compound being any of the following: , , , , , , , , , .

[0049] This disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0050] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0051] In some embodiments, the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound.

[0052] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable carriers, diluents, or excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable carriers, diluents, or excipients.

[0053] All compounds disclosed herein, as well as mixtures and compositions comprising compounds of the present invention, can be administered to a living organism via any route of administration. Routes of administration may include oral, intravenous, intramuscular, subcutaneous, rectal, vaginal, sublingual, nasal, oral, ophthalmic, or local or systemic transdermal administration.

[0054] All compounds disclosed herein, as well as mixtures and compositions containing compounds of the present invention, can be formulated into single doses containing the active compounds of the present invention, as well as carriers, excipients, etc. The dosage forms can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalers, suspensions, dry suspensions, patches, lotions, etc. These dosage forms may contain commonly used pharmaceutical ingredients, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH adjusters, antioxidants, antibacterial agents, isotonic adjusters, anti-adhesives, etc. In some embodiments, the single dose includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, etc. The compounds of the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, in doses of 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg.

[0055] Suitable formulations for the aforementioned dosage forms are available from publicly available sources, such as Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, 2006, and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005. Therefore, those skilled in the art can readily prepare them.

[0056] Depending on the nature and severity of the disease suffered by different individuals, the patient's age, sex, weight, route of administration, and other factors, different dosages can be selected. The dosage of the compound of the present invention can be from 0.01 to 500 mg / kg daily, preferably 1-100 mg / kg daily, and can be administered once or multiple times. Examples of daily dosages include, but are not limited to, 0.01-500 mg, 0.01-400 mg, 0.01-300 mg, 0.01-200 mg, 0.01-100 mg, 0.01-50 mg, 0.1-500 mg, 0.1-400 mg, 0.1-300 mg, 0.1-200 mg, 0.1-100 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-2 00mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-50mg, 1-40mg, 1-25mg, 1-20mg, 5-500mg, 5-400mg , 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5- 50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10- 40mg, 10-30mg, 10-20mg; 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-250mg, 20-200mg, 20-1 50mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg.

[0057] This disclosure also provides the use of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions in the preparation of a medicament having PRMT1 degradation activity.

[0058] In some embodiments, the drug having PRMT1 degradation activity is used to treat diseases selected from cancer, cardiovascular disease, diabetes, renal failure, asthma, chronic non-obstructive disease, neurodegenerative disease, malaria, AIDS, gout, chronic lung disease, oculopharyngeal muscular dystrophy, cocaine addiction, pulmonary hypertension, amyotrophic lateral sclerosis, and alcoholic cirrhosis.

[0059] In some embodiments, the tumor is selected from leukemia, lymphoma, brain cancer, glioblastoma, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, breast cancer, Wilms' tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, gastric cancer, bladder cancer, skin cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, and thyroid cancer.

[0060] This disclosure also provides the use of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions in the preparation of PRMT1 degrading agents.

[0061] In some embodiments, the PRMT1 degrading agent is used to treat diseases selected from cancer, cardiovascular disease, diabetes, renal failure, asthma, chronic non-obstructive disease, neurodegenerative disease, malaria, AIDS, gout, chronic lung disease, oculopharyngeal muscular dystrophy, cocaine addiction, pulmonary hypertension, amyotrophic lateral sclerosis, and alcoholic cirrhosis.

[0062] In some embodiments, the tumor is selected from leukemia, lymphoma, brain cancer, glioblastoma, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, breast cancer, Wilms' tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, gastric cancer, bladder cancer, skin cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, and thyroid cancer.

[0063] This disclosure also provides the preparation of medicaments for treating or preventing mammalian diseases associated with abnormal regulation of the PRMT1 protein by the aforementioned compounds or their stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives and pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions. In some embodiments, the disease is selected from tumors, cardiovascular diseases, diabetes, renal failure, asthma, chronic non-obstructive diseases, neurodegenerative diseases, malaria, AIDS, gout, chronic lung diseases, oculopharyngeal muscular dystrophy, cocaine addiction, pulmonary hypertension, amyotrophic lateral sclerosis, and alcoholic cirrhosis.

[0064] In some embodiments, the tumor is selected from leukemia, lymphoma, brain cancer, glioblastoma, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, breast cancer, Wilms' tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, gastric cancer, bladder cancer, skin cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, and thyroid cancer.

[0065] Terminology Explanation: Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0066] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. 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. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. 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, etc. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. The substituents are preferably independently selected independently from one or more substituents chosen from the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0067] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a residue derived from a parent alkane by removing two hydrogen atoms from the same carbon atom or two different carbon atoms. It is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably alkylene containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. The alkylene group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclic alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0068] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl substituents.

[0069] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl substituents.

[0070] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0071] The term "spirocyclic ring" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between the rings, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocyclic alkyl groups are classified as monospirocyclic, bispirocyclic, or polyspirocyclic based on the number of shared spiro atoms between the rings, with monospirocyclic and bispirocyclic alkyl groups being preferred. More preferably, they are 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocyclic alkyl groups. Non-limiting examples of spirocyclic alkyl groups include: .

[0072] The term "fused ring" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include: .

[0073] The term "bridging ring" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridging cycloalkyl groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridging cycloalkyl groups include:

[0074] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... , , etc.; preferred and .

[0075] The cycloalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0076] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), where alkyl and cycloalkyl are defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, they are preferably one or more of the following groups, independently selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0077] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but excluding the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0078] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include: .

[0079] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0080] and .

[0081] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include: .

[0082] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include: and wait.

[0083] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0084] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include: and .

[0085] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable linker. The substituent is preferably independently selected independently from one or more substituents chosen from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include: and .

[0086] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0087] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0088] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0089] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0090] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0091] The term "hydroxyl group" refers to -OH.

[0092] The term "amino" refers to -NH2.

[0093] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, that are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0094] In the chemical structure of the compounds described in this disclosure, the bond " "No configuration specified, i.e., key" "can be " "or" , or both contain " "and" "Two configurations. Bond" " indicates a single configuration, which is " "or" In the chemical structure of the compounds described in this disclosure, the bond " "No configuration is specified, which means it can be Z configuration or E configuration, or both configurations at the same time."

[0095] The term "stereoisomer" refers to compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, and hindered isomers, etc.

[0096] The term "isotope derivative" refers to compounds whose structure differs only in the presence of one or more isotope-enriched atoms. For example, compounds having the structure disclosed herein, using "deuterium" or "tritium" instead of hydrogen, or using... 18 F-fluorine labeling ( 18 F isotopes) can be used instead of fluorine, or... 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which carbon atoms are replaced by C-isotopes are within the scope of this disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. The various deuterated forms of compounds disclosed herein refer to compounds in which each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds by referring to relevant literature. Commercially available deuteration starting materials can be used in the preparation of deuterated forms of compounds, or they can be synthesized using conventional techniques with deuteration reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain activity comparable to undeuterated compounds, and better metabolic stability can be achieved when deuterated at certain specific sites, resulting in certain therapeutic advantages.

[0097] The term "pharmaceutically acceptable salt" means that the compounds of the present invention exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in SMBerge's description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (Vol. 66: 1-19, 1977). In the present invention, a pharmaceutically acceptable non-toxic acid addition salt means a salt formed by the compounds of the present invention with an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds of this invention with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and organic base salts, such as ammonium salts or N-containing organic bases. + (C 1-6Alkyl)4 salt.

[0098] The term "solvent" refers to the physical combination of a compound of this disclosure with one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical combination includes hydrogen bonds. In some cases, such as when one or more, preferably one to three, solvent molecules are incorporated into the lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0099] The term "hydrate" refers to the case where the solvent in the aforementioned term "solvent" is water.

[0100] The term "prodrug" refers to a compound that can be converted in the body to produce an active drug substance under physiological conditions, such as through hydrolysis in the blood.

[0101] The term "pharmaceutical composition" refers to a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically 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 the exertion of its biological activity.

[0102] The terms involved in this invention have been defined above. Those skilled in the art can also understand the above terms in conjunction with the prior art. The following is a further description based on the content of this invention and the definition of the terms.

[0103] The following examples further describe the preparation of the compounds and pharmaceutically acceptable salts described in this disclosure, but these examples are not intended to limit the scope of this disclosure.

[0104] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0105] First, the reactions in the examples are generally carried out under nitrogen protection.

[0106] Furthermore, the intermediates and final products were separated and purified using chromatographic columns, preparative chromatographic plates, and the ISCO rapid preparative chromatography system. The chromatographic columns were packed with silica gel (300-400 mesh), manufactured by Shanghai Titan Technology Co., Ltd.; the preparative chromatographic plates were manufactured by Yantai Jiangyou Silica Gel Development Co., Ltd.; and the ISCO columns (particle size 40-63 µm, 60 Å) were manufactured by Changzhou Santai Technology Co., Ltd.

[0107] Furthermore, the LC-MS system used was a Waters ACQUITY Arc equipped with a QDaDetector. A Waters XBridge C18 column (2.1 × 50 mm, 3.5 µm) was used. Mass spectrometry (MS) employed an ESI source, indicating only the molecular weight M of the parent molecule, typically reporting [M+H]. + The injection volume was determined by the sample concentration; the flow rate was 1.2 mL / min; HPLC peak values ​​were recorded and read using UV-Vis wavelengths at 220 nm and 254 nm. The mobile phases were an ultrapure aqueous solution of 0.01% formic acid (mobile phase A) and an acetonitrile solution of 0.01% formic acid (mobile phase B). Gradient elution conditions are shown in Tables 1 and 2 below:

[0108] Table 1: Gradient elution conditions 1

[0109] Table 2: Gradient elution conditions 2

[0110] Furthermore, the NMR spectrum was used Varian 400MHz nuclear magnetic resonance spectrometer Data is obtained using CDCl3 or DMSO-d6 as solvents, and chemical shifts are reported in ppm. The various peaks are described as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet). Coupling constants are expressed in Hz.

[0111] Example

[0112] Example 1

[0113] Step i:

[0114] Methylparaben (1a, 0.15 g, 1.0 mmol) and 2-fluorobenzaldehyde (0.1 mL, 0.95 mmol) were dissolved in N,N-dimethylacetamide solution (15 mL), and potassium carbonate (0.41 g, 3.0 mmol) was added. The mixture was heated to 140 °C and stirred for 2 h. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. The target compound, methyl 4-(2-formylphenoxy)benzoate (compound 1b), was isolated as a pale yellow solid in 88% yield.

[0115]

[0116] Step ii: Compound 1b (0.26 g, 1.0 mmol) was dissolved in anhydrous dichloromethane (8 mL). A solution of tert-butylmethyl (2-(methylamino)ethyl)carbamate (0.25 mL, 1.2 mmol) dissolved in dichloromethane and acetic acid (0.1 mL) was added to the reaction vessel. After the reaction proceeded for half an hour, sodium triacetoxyborohydride (0.42 g, 2.0 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, water was slowly added until the mixture was completely dissolved. After adding sodium triacetoxyborohydride, the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound 1c as a pale yellow oil in 82% yield.

[0117]

[0118] Step iii: Compound 1c (0.43 g, 1.0 mmol) was dissolved in a methanol / water solution (v:v = 4:1), followed by the addition of sodium hydroxide (0.24 g, 6.0 mmol). The reaction was carried out at room temperature for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to remove most of the methanol. The pH of the reaction mixture was adjusted to acidic using 2 M dilute hydrochloric acid, followed by extraction with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 1d as a pale yellow oil. This crude product could be used directly in the next reaction without further purification.

[0119]

[0120] Step iv: Compound 1e was dissolved in N,N-dimethylformamide. Then, N,N-diisopropylethylamine (0.33 mL, 2.0 mmol) and N-Boc-1,6-hexanediamine (compound 1f, 0.26 g, 1.2 mmol) were added. After stirring, the reaction mixture was heated to 90 °C and reacted for 4 hours. After the reaction was complete, the reaction mixture was cooled, quenched with water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the Boc-protected intermediate. The intermediate was then dissolved in ethyl acetate solution (4 mL) of hydrochloric acid and stirred overnight at room temperature. After the reaction was complete, a yellow solid precipitated. After the reaction was complete, the mixture was filtered, washed with ethyl acetate and n-hexane, and dried to give the target product (compound 1 g) as a yellow solid, with a two-step yield of 73%.

[0121]

[0122] Step v: Compound 1d (0.41 g, 1.0 mmol), triethylamine (0.35 mL, 2.5 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.46 g, 1.2 mmol) were dissolved in N,N-dimethylformamide (8 mL) and reacted for 15 min. Then, compound 1 g (0.37 g, 1.0 mmol) was added, and the reaction was carried out at room temperature for 6 h. After the reaction was complete, the reaction system was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give a Boc-protected intermediate. This intermediate was dissolved in ethyl acetate solution (4 mL) of hydrochloric acid and stirred overnight at room temperature, resulting in the precipitation of a solid. After the reaction was complete, the solid was filtered, washed with ethyl acetate and n-hexane, and dried to give the target product (compound 1) as a yellow oil, with an overall yield of 77% for both steps.

[0123]

[0124] Characterization data of compound 1: 1 H NMR (400 MHz, D2O) δ 7.65 (d, J = 6.7 Hz, 2H), 7.52 (d, J = 6.5 Hz, 1H), 7.36 – 7.11 (m, 3H), 6.94 (d, J = 6.1 Hz, 2H), 6.79– 6.52 (m, 3H), 4.85 (s, 1H), 4.38 (br, 2H), 3.65 – 3.56 (m, 2H), 3.56 – 3.45(m, 2H), 3.08 – 2.26 (m, 12H), 2.02 – 1.65 (m, 2H), 1.48 – 1.27 (m, 4H), 1.19– 1.00 (m, 4H); HRMS (ESI): m / z [M+H] + calcd. for C 37 H 45 N6O6 669.3395, found 669.3429.

[0125] Examples 2 to 6

[0126] Compounds of Examples 2-6 were prepared using the same or similar methods as in Example 1. The structures of the specific compounds are as follows:

[0127] Example 7

[0128] Steps i to iii are exactly the same as in Example 1; The difference between step iv and step iv in Example 1 is that in this example, compound VHL-1 and compound Boc-8-aminooctanoic acid (compound 7f) were used as raw materials to produce 7g of compound, with a yield of 72%;

[0129] The difference between step v and step v in Example 1 is that in this example, the target compound (compound 7) was prepared from compound 7d and compound 1d as raw materials. It was a white oily substance with a yield of 56%.

[0130]

[0131] Characterization data of compound 7: 1 H NMR (400 MHz, (CD3)2SO) δ 9.48 (s, 1H), 9.39 (s,1H), 9.13 – 8.99 (m, 1H), 8.56 – 8.43 (m, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.86(d, J = 8.5 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.49 – 7.42 (m, 1H), 7.36 (d,J = 7.9 Hz, 2H), 7.29 – 7.23 (m, 1H), 7.18 (d, J = 8.3 Hz, 2H), 6.96 – 6.86(m, 1H), 4.90 – 4.80 (m, 1H), 4.60 – 4.38 (m, 4H), 3.84 (s, 10H), 3.29 – 3.18(m, 2H), 2.80 (s, 3H), 2.61 – 2.54 (m, 3H), 2.44 (s, 3H), 2.29 – 2.18 (m,1H), 2.14 – 2.06 (m, 1H), 2.04 – 1.97 (m, 1H), 1.94 – 1.89 (m, 1H), 1.56 –1.43 (m, 4H), 1.38 (d, J = 6.8 Hz, 3H), 1.30 – 1.21 (m, 6H), 0.87 (s, 9H); HRMS (ESI): m / z [M+H] + calcd. for C 49 H 68N7O6S 882.4946, found 882.4970.

[0132] Examples 8 to 10

[0133] The compounds of Examples 8-10 were prepared using the same or similar methods as in Example 7, and the structures of the specific compounds are as follows:

[0134] Example 11

[0135] Compounds from Examples 1-10 were serially diluted, and 100 nL of each was transferred together with the DMSO group and the positive control group (SAH) to a reaction plate. 5 μL of enzyme solution (PRMT1) was added to the assay plate and incubated at room temperature for 15 minutes. 5 μL of a mixture of substrate peptide and SAM was added to each well to initiate the reaction, and incubated at room temperature for 60 minutes. 15 μL of acceptor and donor bead solution was added, and incubated at room temperature under low light for 60 minutes. All reaction solutions were transferred to a Flashplate and incubated for another 60 minutes. Signal values ​​were read using an Enspire microplate reader with Alpha mode. The results are shown in Table 3.

[0136] Table 3. Results of AlphaLISA in vitro activity assays of compounds from Examples 1 to 10.

[0137] Example 12

[0138] This embodiment uses Western blotting analysis of the compounds from Examples 1 to 10 to demonstrate that the compounds of this invention, represented by these compounds, effectively degrade the PRMT1 target protein.

[0139] MCF-7 tumor cells were treated with compounds from Examples 1-10 at concentrations of 5 μM, 1 μM, and 0.2 μM, respectively, for 48 hours. Cells were then collected and lysed. The supernatant was used for PRMT1 protein immunoblotting, and the grayscale values ​​were calculated (e.g., ...). Figure 1 and Figure 2 (As shown). The results showed that the compounds in Examples 3 and 4 significantly reduced the protein level of PRMT1 in MCF-7 cells.

[0140] Example 13

[0141] This embodiment uses Western blotting analysis of the compound from Example 4 to demonstrate that the compound represented by this compound effectively degrades the PRMT1 target protein.

[0142] MCF-7 or A2058 tumor cells were treated with compounds from Example 4 at concentrations of 5 μM, 3 μM, 1 μM, 0.3 μM, and 0.1 μM, respectively, for 48 hours. Cells were then collected and lysed. The supernatant was used for PRMT1 protein immunoblotting, and grayscale values ​​were calculated (e.g., ...). Figure 3 and Figure 4 (As shown). The results showed that the compound in Example 4 significantly reduced PRMT1 protein levels in MCF-7 and A2058 cells in a concentration-dependent manner, and its DCs degraded PRMT1 protein levels in both MCF-7 and A2058 cells. 50 The values ​​were 0.77 μM and 0.65 μM, respectively.

[0143] Example 14

[0144] This embodiment uses Western blotting analysis of the compound from Example 4 to demonstrate that the compound represented by this compound effectively degrades the PRMT1 target protein.

[0145] MCF-7 tumor cells were treated with 5 μM of the compound from Example 4 for 3, 6, 12, 24, and 48 hours, respectively. Cells were then collected and lysed. The supernatant was used for PRMT1 protein immunoblotting, and grayscale values ​​were calculated (e.g., ...). Figure 5 As shown); and after treating MCF-7 tumor cells with 2 μM of the compound from Example 4 for 12 hours, 24 hours, 48 ​​hours, 72 hours, and 96 hours respectively, the cells were collected and lysed, and the supernatant was used for PRMT1 protein immunoblotting and the gray value was calculated (as shown). Figure 6 (As shown). The results showed that the compound in Example 4 significantly reduced PRMT1 protein levels in MCF-7 cells in a time-dependent manner.

[0146] Example 15

[0147] This embodiment uses Western blotting analysis of the compound from Example 4 to demonstrate that the structure of the compound series of the present invention, represented by this compound, selectively degrades the PRMT1 target protein.

[0148] MCF-7 tumor cells were treated with 2 μM of the compound from Example 4 for 12, 24, 48, 72, and 96 hours, respectively. Cells were then collected and lysed. The supernatant was used for Western blotting experiments on PRMT1 / PRMT3 / PRMT4 / PRMT6 / PRMT8 proteins, and grayscale values ​​were calculated (e.g., ...). Figure 7 (As shown). The results showed that the compound in Example 4 could selectively degrade PRMT1 protein in MCF-7 cells, while having no significant effect on other type I PRMT family proteins.

[0149] Example 16

[0150] In this example, breast cancer cell line MCF-7 was treated with 2 μM of the compound from Example 4 for 12 hours, 24 hours, 48 ​​hours, 72 hours, and 96 hours. The results showed that the compound from Example 4 reduced the global aDMA level in a time-dependent manner. Figure 8 The above results confirm that the compound of Example 4 can affect the asymmetric dimethylation level of PRMT1 substrate in the cellular environment by degrading the protein level of PRMT1.

[0151] Example 17

[0152] This example uses breast cancer cell line MCF-7 and melanoma cell line A2058 as cell models to investigate the effect of the compound in Example 4 on the inhibition of cell proliferation. First, the appropriate culture medium (DMEM medium) with 10% fetal bovine serum was added. After cell counting, 1000-3000 cells / 100 μL were seeded in 96-well plates, and the compound was administered simultaneously, with a concentration gradient starting at 100 μM and then serially diluted twofold. Changes in cell proliferation 1-5 days after administration were detected using the Cell Counting-Lite assay, and the single-probe compound DCPT2145 (… ( ) served as the control group. A graph was plotted with fluorescence signal value on the ordinate and number of days of administration on the x-axis. The results are as follows: Figures 9 to 14 As shown. The results indicate that compound 4 of Example 4 can effectively inhibit the proliferation of the aforementioned tumor cells.

[0153] Example 18

[0154] To investigate the in vivo pharmacokinetic effects of the compound of Example 4, a pharmacokinetic study was conducted in mice after intraperitoneal injection of the compound of Example 4. Three mice were used as a group, and all mice were administered the compound of Example 4 via intraperitoneal injection. Blood samples of approximately 0.05 mL were collected from the cheek of the intraperitoneal injection group at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The concentration of the compound of Example 4 in the mouse plasma samples was determined using LC-MS / MS, and the pharmacokinetic parameters were calculated using WinNolin software. The results are as follows: Figure 15 As shown.

[0155] Pharmacokinetic results showed that after a single intraperitoneal injection of 20 mg / kg of the compound from Example 4 into mice, the main pharmacokinetic parameters after intraperitoneal administration were: C max The concentration was 1257 ng / mL, T max It is 0.667 h, T 1 / 2 The AUC was 7.03 h. 0-T5020 hr*ng / mL, AUC 0-∞ The concentration was 5292 hr*ng / mL, MRT 0-t For 4.26 h, MRT 0-∞ The time was 5.78 h. This indicates that the compound in Example 4 has good pharmacokinetic parameters.

[0156] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A compound of general formula I or a stereoisomer thereof, solvate, hydrate, prodrug, stable isotopic derivative thereof, or pharmaceutically acceptable salt thereof: ； in: X is selected from NH, O, S and C (=O); R 1 Selected from alkyl groups, wherein one or more methylene groups in the alkyl group are optionally surrounded by one or more groups selected from R 3 Group substitution; Y is selected from alkylene groups, wherein one or more methylene groups in the alkylene group are optionally replaced by one or more groups selected from R. 4 Group substitution; R 2 Selected from and ; Each time it occurs, the R 3 Each is independently selected from bonds, O, C (=O), S, SO, S (=O)2, NH and N (CH3); Each time it occurs, the R 4 Each is independently selected from bonds, O, C (=O), S, SO, S (=O)2 and NH; A1, A2, A3, A4, and A5 are each independently selected from N and CR. 5 ; Each time it occurs, the R 5 Each is independently selected from hydrogen, deuterium, amino, hydroxyl, and halogen; B1, B2, B3, B4, and B5 are each independently selected from N and CR. 6 ; Each time it occurs, the R 6 Each is independently selected from hydrogen, deuterium, amino, hydroxyl and halogen.

2. The compound of general formula I according to claim 1, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts, characterized in that, X is selected from O.

3. The compound of general formula I according to claim 1 or 2, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts, characterized in that, A1, A2, A3, A4, and A5 are each independently selected from CR. 5 , wherein R 5 Each of the elements A1, A2, A3, A4, and A5 is independently selected from hydrogen, deuterium, amino, hydroxyl, and halogen, respectively, each in its respective element. Preferably, A1, A2, A3, A4, and A5 are each independently selected from CR. 5 , wherein R 5 Each of the elements is independently selected from hydrogen each time it appears; more preferably, A1, A2, A3, A4 and A5 are each independently selected from CH. And / or, B1, B2, B3, B4 and B5 are each independently selected from CR 6 , wherein R 6 Each of the elements B1, B2, B3, B4, and B5 is independently selected from hydrogen, deuterium, amino, hydroxyl, and halogen, respectively, each occurring independently. 6 , wherein R 6 Each of the five elements is independently selected from hydrogen each time it appears; more preferably, B1, B2, B3, B4 and B5 are each independently selected from CH.

4. The compound of general formula I according to any one of claims 1-3, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that, The compound has the structure of Formula II: ； Wherein, the R 1 Y and R 2 As defined in any one of claims 1-3.

5. The compound of general formula I according to any one of claims 1-4, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that, The R 1 Selected from C 4-12 Alkyl, the C 4-12 One or more methylene groups in the alkyl group are optionally surrounded by one or more groups selected from R 3 The group substitution; the R 3 Each time it appears, it is independently selected from NH and N(CH3); Preferably, the R 1 Selected from C 5-7 Alkyl, the C 5-7 One or more methylene groups in the alkyl group are optionally surrounded by one or more groups selected from R 3 The group substitution; the R 3 Each time it appears, it is independently selected from NH and N(CH3); More preferably, the R 1 Choose an alkyl group, wherein one or more methylene groups in the alkyl group are optionally surrounded by one or more groups selected from R. 3 The group substitution; the R 3 Each time it appears, it is independently selected from NH and N(CH3); Most preferably, the R 1 Selected from .

6. The compound of general formula I according to any one of claims 1-5, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that, The compound has a structure of formula III or formula IV: ； ； Wherein, Y is as defined in any one of claims 1-5.

7. The compound of general formula I according to any one of claims 1-6, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that, The Y is selected from C. 5-20 Alkylene, the C 5-20 One or more methylene groups in the alkylene group are optionally surrounded by one or more groups selected from R 4 The group substitution; the R 4 Each time it appears, it is independently selected from O, C (=O) and NH; Preferably, the Y is selected from C. 9-15 Alkylene, the C 9-15 One or more methylene groups in the alkylene group are optionally surrounded by one or more groups selected from R 4 The group substitution; the R 4 Each time it appears, it is independently selected from O, C (=O) and NH; More preferably, the Y is selected from nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, and pentadecyl, and one or more methylene groups selected from the nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, and pentadecyl groups are optionally replaced by one or more methylene groups selected from R. 4 The group substitution; the R 4 Each time it appears, it is independently selected from O, C (=O) and NH; Most preferably, the Y is selected from... , , , , , , , , and Where * represents the relationship between Y and R. 2 The connection site.

8. A compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts, characterized in that, The compound is any one of the following: 、 、 、 、 、 、 、 、 、 。 9. A pharmaceutical composition comprising a therapeutically effective amount of the compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts according to any one of claims 1-8, and one or more pharmaceutically acceptable carriers, diluents or excipients.

10. Use of the compound or its stereoisomer, solvate, hydrate, prodrug, stable isotopic derivative, and pharmaceutically acceptable salt according to any one of claims 1-8, or the pharmaceutical composition according to claim 9, characterized in that, Used for preparation: (1) Drugs or PRMT1 degrading agents with PRMT1 degradation activity; (2) Drugs for the treatment or prevention of mammalian diseases associated with abnormal regulation of the PRMT1 protein; Preferably, the disease is selected from tumors, cardiovascular diseases, diabetes, renal failure, asthma, chronic non-obstructive diseases, neurodegenerative diseases, malaria, AIDS, gout, chronic lung diseases, oculopharyngeal muscular dystrophy, cocaine addiction, pulmonary hypertension, amyotrophic lateral sclerosis, and alcoholic cirrhosis. Preferably, the tumor is selected from leukemia, lymphoma, brain cancer, glioblastoma, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, breast cancer, Wilms' tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, gastric cancer, bladder cancer, skin cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, and thyroid cancer; Preferably, the drug having PRMT1 degradation activity is used to treat diseases selected from tumors, cardiovascular diseases, diabetes, renal failure, asthma, chronic non-obstructive diseases, neurodegenerative diseases, malaria, AIDS, gout, chronic lung diseases, oculopharyngeal muscular dystrophy, cocaine addiction, pulmonary hypertension, amyotrophic lateral sclerosis, and alcoholic cirrhosis. Preferably, the tumor is selected from leukemia, lymphoma, brain cancer, glioblastoma, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, breast cancer, Wilms' tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, gastric cancer, bladder cancer, skin cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, and thyroid cancer; Preferably, the PRMT1 degrading agent is used to treat diseases selected from tumors, cardiovascular diseases, diabetes, renal failure, asthma, chronic non-obstructive diseases, neurodegenerative diseases, malaria, AIDS, gout, chronic lung diseases, oculopharyngeal muscular dystrophy, cocaine addiction, pulmonary hypertension, amyotrophic lateral sclerosis, and alcoholic cirrhosis. Preferably, the tumor is selected from leukemia, lymphoma, brain cancer, glioblastoma, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, breast cancer, Wilms' tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, gastric cancer, bladder cancer, skin cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, and thyroid cancer.

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