A compound having type i prmt inhibitory activity and uses thereof

Abstract

The present application relates to a kind of compounds with the type I PRMT inhibitory activity shown in formula (I) or its stereoisomer, solvate, hydrate, prodrug, stable isotopic derivative and pharmaceutically acceptable salt: above-mentioned compound greatly improves the PRMTs activity, can be used to treat or prevent the mammalian disease related to PRMTs protein dysregulation.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a compound with type I PRMT inhibitory activity and its applications. Background Technology

[0002] Methylation of arginine in proteins involves an enzymatic reaction catalyzed by arginine methyltransferases (PRMTs), which transfer a methyl group (CH3) from S-adenosyl-L-methionine (SAM) to a guanidino nitrogen atom on the arginine side chain. Nine PRMTs have been previously reported. Based on the reaction products, PRMTs can be classified into three types: Type I PRMTs (PRMT1-4,6,8) can transfer a single methyl group to an arginine residue, converting it to monomethylarginine (MMA), or catalyze a second methyl group to undergo the same guanidino nitrogen addition reaction as the first methylation, generating asymmetric dimethylarginine (Rme2a, ADMA); Type II PRMTs (PRMT5,9) catalyze the formation of symmetric dimethylarginine (Rme2s, SDMA), with the two methyl groups located on the N-terminal axis. ω Up and N ω′ Above; Type III PRMT7 only catalyzes the production of Rme1.

[0003] PRMT4, also known as CARM1 (coactivator-associated arginine methyltransferase 1), is a coactivator of transcription factors found in the cell nucleus and cytoplasm. Numerous studies have confirmed the important role of PRMT4 in various cancers, suggesting that targeting PRMT4 may be an effective therapeutic strategy. PRMT4 has been found to play a carcinogenic role in cancers such as cholangiocarcinoma, lung cancer, liver cancer, gastric cancer, colon cancer, breast cancer, pancreatic cancer, and clear cell renal cell carcinoma. In breast cancer, high expression of PRMT4 promotes cancer cell invasion and metastasis. High expression of PRMT4 in liver cancer cells can affect tumor cell proliferation through pathways such as glycolysis. PRMT4 is primarily responsible for catalyzing the asymmetric dimethylation of arginine and also plays an important role in cardiovascular diseases, diabetes, and kidney disease.

[0004] Currently, the problems of low toxicity and targeting of type I PRMT inhibitors to cancer cells, as well as low selectivity for other PRMT members, remain unresolved. Therefore, there is an urgent need to develop new inhibitors targeting type I PRMT. Summary of the Invention

[0005] The problem the invention aims to solve

[0006] To address the aforementioned problems, this invention provides a compound with type I PRMT inhibitory activity and its application, which significantly improves the inhibitory activity against PRMTs.

[0007] Solution for solving the problem

[0008] To address the aforementioned technical problems, this disclosure provides the following technical solutions:

[0009] This invention provides a compound of formula (I) having type I PRMT inhibitory activity, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof:

[0010]

[0011] Where X is selected from NH, O, S and C=O;

[0012] Y is selected from C=O and CH2;

[0013] R1 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; the substitution is by one or more Q1; wherein each Q1 is independently selected from H, deuterium, alkyl, alkoxy and halogen;

[0014] R2 is selected from

[0015] R3 and R4 are each independently selected from H, substituted or unsubstituted alkyl groups and substituted or unsubstituted cycloalkyl groups, and R3 and R4 are not both methyl; the substitution is by one or more Q2 groups; wherein each Q2 group is independently selected from H, deuterium, cyano, amino, hydroxyl and halogen;

[0016] R5 is selected from H, alkyl, alkylamino, hydroxyl, mercapto, and halogen;

[0017] A1, A2, A3, A4, and A5 are each independently selected from N and CR6;

[0018] B1, B2, B3, B4, and B5 are each independently selected from N and CR7;

[0019] R6 and R7 are each independently selected from H, deuterium, halogens, alkyl groups, and cycloalkyl groups.

[0020] The effects of the invention

[0021] The compounds provided by this invention exhibit inhibitory activity against PRMTs, and significantly improve selective inhibitory activity against types I, II, and III PRMTs. They can be used to prepare drugs or PRMT type I inhibitors that inhibit PRMT type I enzyme activity, and for the treatment or prevention of PRMT-related diseases. Drugs for mammalian diseases related to abnormal regulation of type I proteins, used to treat 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, or alcoholic cirrhosis. Tumors are selected from brain cancer, glioblastoma, leukemia, lymphoma, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, breast cancer, Wilms' tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, gastric cancer, bladder 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, or thyroid cancer. Attached Figure Description

[0022] Figure 1 This is an immunoblot image of PRMT4 expression in tumors after treatment with the compound in Example 32.

[0023] Figure 2 This is a bar chart showing the relative expression levels of PRMT4 in tumors after treatment with the compound in Example 32.

[0024] Figure 3 This is an immunoblot image of PABP1 and ADMA expression in melanoma cell line A375 after treatment with the compound in Example 32.

[0025] Figure 4 This is an immunoblot image showing the expression of PABP1 and ADMA in melanoma cell line A2058 after treatment with the compound in Example 32.

[0026] Figure 5 A comparative diagram showing the size of melanomas in mice after intraperitoneal injection of compound 32 from Example 32.

[0027] Figure 6 Line graph showing the volume inhibition rate of melanoma after intraperitoneal injection of compound 32 in mice.

[0028] Figure 7 Line graph showing the weight inhibition rate of melanoma after intraperitoneal injection of compound 32 in mice.

[0029] Figure 8 Line graph showing the change in body weight of mice after intraperitoneal injection of compound 32 in Example 32.

[0030] Figure 9 This is an immunoblot image showing the expression of ADMA, PABP1, and PABP1me2a in tumor tissue of mice after treatment with the compound of Example 32. Detailed Implementation

[0031] 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.

[0032] This invention provides a compound of formula (I) having type I PRMT inhibitory activity, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof:

[0033]

[0034] Where X is selected from NH, O, S and C=O;

[0035] Y is selected from C=O and CH2;

[0036] R1 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; the substitution is by one or more Q1; wherein each Q1 is independently selected from H, deuterium, alkyl, alkoxy and halogen;

[0037] R2 is selected from

[0038] R3 and R4 are each independently selected from H, substituted or unsubstituted alkyl groups and substituted or unsubstituted cycloalkyl groups, and R3 and R4 are not both methyl; the substitution is by one or more Q2 groups; wherein each Q2 group is independently selected from H, deuterium, cyano, amino, hydroxyl and halogen;

[0039] R5 is selected from H, alkyl, alkylamino, hydroxyl, mercapto, and halogen;

[0040] A1, A2, A3, A4, and A5 are each independently selected from N and CR6;

[0041] B1, B2, B3, B4, and B5 are each independently selected from N and CR7;

[0042] R6 and R7 are each independently selected from H, deuterium, halogens, alkyl groups, and cycloalkyl groups.

[0043] In some embodiments, X is selected from NH, O, S, and C=O.

[0044] In some implementations, X is O or C=O.

[0045] In some implementations, the Y is selected from C=O and CH2.

[0046] In some implementations, Y is CH2.

[0047] In some embodiments, R1 is selected from substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups.

[0048] In some embodiments, R1 is selected from substituted or unsubstituted C. 6-10 Aryl and substituted or unsubstituted 5-10 heteroaryl groups.

[0049] In some embodiments, R1 is selected from substituted or unsubstituted C. 6-10 Aryl groups and substituted or unsubstituted 5-8-membered heteroaryl groups, wherein the heteroaryl group contains 1-4 heteroatoms selected from N, O and S.

[0050] In some embodiments, R1 is selected from substituted or unsubstituted phenyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, thiopheneyl, thiazolyl, benzofuranyl, 1,2,3-triazolyl, and 1,2,4-triazolyl.

[0051] In some embodiments, each Q1 is independently selected from H, deuterium, alkyl, alkoxy, and halogen.

[0052] In some embodiments, each Q1 is independently selected from alkyl groups.

[0053] In some implementations, each Q1 is independently selected from C 1-6 alkyl.

[0054] In some embodiments, each Q1 is independently selected from methyl, ethyl, and propyl.

[0055] In some embodiments, R3 is selected from H, substituted or unsubstituted alkyl groups, and substituted or unsubstituted cycloalkyl groups.

[0056] In some embodiments, R3 is H or substituted or unsubstituted C. 1-6 alkyl.

[0057] In some embodiments, R3 is H, methyl, ethyl, or propyl.

[0058] In some embodiments, the R4 is selected from H, substituted or unsubstituted alkyl groups, and substituted or unsubstituted cycloalkyl groups.

[0059] In some embodiments, R4 is H or substituted or unsubstituted C. 1-6 alkyl.

[0060] In some embodiments, R4 is H, methyl, ethyl, or propyl.

[0061] In some embodiments, each Q2 is independently selected from H, deuterium, cyano, amino, hydroxyl and halogen.

[0062] In some embodiments, each Q2 is independently selected from H, amino, hydroxyl and halogen.

[0063] In some implementations, each Q2 is independently selected from H and halogens.

[0064] In some embodiments, R5 is selected from H, alkyl, alkylamino, hydroxyl, mercapto, and halogen.

[0065] In some embodiments, R5 is H or C. 1-3 Alkyl or hydroxyl.

[0066] In some embodiments, R5 is H or a hydroxyl group.

[0067] In some embodiments, R6 is selected from H, deuterium, halogens, alkyl groups, and cycloalkyl groups.

[0068] In some embodiments, R6 is H, halogen, or C. 1-6 alkyl.

[0069] In some embodiments, R6 is H or a halogen.

[0070] In some embodiments, R7 is selected from H, deuterium, halogens, alkyl groups, and cycloalkyl groups, preferably H, halogens, or C. 1-6 Alkyl, more preferably H or halogen.

[0071] The present invention also provides a compound of formula (I-1) having type I PRMT inhibitory activity, or a stereoisomer thereof, solvate, hydrate, prodrug, stable isotope derivative, or pharmaceutically acceptable salt thereof:

[0072]

[0073] Wherein, R1 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; the substitution is by one or more Q1; wherein each Q1 is independently selected from H, deuterium, alkyl, alkoxy and halogen;

[0074] R2 is selected from

[0075] R3 and R4 are each independently selected from H, substituted or unsubstituted alkyl groups and substituted or unsubstituted cycloalkyl groups, and R3 and R4 are not both methyl; the substitution is by one or more Q2 groups; wherein each Q2 group is independently selected from H, deuterium, cyano, amino, hydroxyl and halogen;

[0076] R5 is selected from H, alkyl, alkylamino, hydroxyl, mercapto, and halogen;

[0077] A1, A2, A3, A4, and A5 are each independently selected from N and CR6;

[0078] B1, B2, B3, B4, and B5 are each independently selected from N and CR7;

[0079] R6 and R7 are each independently selected from H, deuterium, halogens, alkyl groups, and cycloalkyl groups.

[0080] In some embodiments, R1 is selected from substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups.

[0081] In some embodiments, R1 is selected from substituted or unsubstituted C. 6-10 Aryl and substituted or unsubstituted 5-10 heteroaryl groups.

[0082] In some embodiments, R1 is selected from substituted or unsubstituted C. 6-10 Aryl groups and substituted or unsubstituted 5-8-membered heteroaryl groups, wherein the heteroaryl group contains 1-4 heteroatoms selected from N, O and S.

[0083] In some embodiments, R1 is selected from substituted or unsubstituted phenyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, thiopheneyl, thiazolyl, benzofuranyl, 1,2,3-triazolyl, and 1,2,4-triazolyl.

[0084] In some embodiments, each Q1 is independently selected from H, deuterium, alkyl, alkoxy, and halogen.

[0085] In some embodiments, each Q1 is independently selected from alkyl groups.

[0086] In some implementations, each Q1 is independently selected from C 1-6 alkyl.

[0087] In some embodiments, each Q1 is independently selected from methyl, ethyl, and propyl.

[0088] In some embodiments, R3 is selected from H, substituted or unsubstituted alkyl groups, and substituted or unsubstituted cycloalkyl groups.

[0089] In some embodiments, R3 is H or substituted or unsubstituted C. 1-6alkyl.

[0090] In some embodiments, R3 is H, methyl, ethyl, or propyl.

[0091] In some embodiments, the R4 is selected from H, substituted or unsubstituted alkyl groups, and substituted or unsubstituted cycloalkyl groups.

[0092] In some embodiments, R4 is H or substituted or unsubstituted C. 1-6 alkyl.

[0093] In some embodiments, R4 is H, methyl, ethyl, or propyl.

[0094] In some embodiments, each Q2 is independently selected from H, deuterium, cyano, amino, hydroxyl and halogen.

[0095] In some embodiments, each Q2 is independently selected from H, amino, hydroxyl and halogen.

[0096] In some implementations, each Q2 is independently selected from H and halogens.

[0097] In some embodiments, R5 is selected from H, alkyl, alkylamino, hydroxyl, mercapto, and halogen.

[0098] In some embodiments, R5 is H or C. 1-3 Alkyl or hydroxyl.

[0099] In some embodiments, R5 is H or a hydroxyl group.

[0100] In some embodiments, R6 is selected from H, deuterium, halogens, alkyl groups, and cycloalkyl groups.

[0101] In some embodiments, R6 is H, halogen, or C. 1-6 alkyl.

[0102] In some embodiments, R6 is H or a halogen.

[0103] In some embodiments, R7 is selected from H, deuterium, halogens, alkyl groups, and cycloalkyl groups, preferably H, halogens, or C. 1-6 Alkyl, more preferably H or halogen.

[0104] The present invention also provides a compound of formula (I-2) having type I PRMT inhibitory activity, or a stereoisomer thereof, solvate, hydrate, prodrug, stable isotope derivative, or pharmaceutically acceptable salt thereof:

[0105]

[0106] Wherein, R1 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; the substitution is by one or more Q1; wherein each Q1 is independently selected from H, deuterium, alkyl, alkoxy and halogen;

[0107] R2 is selected from

[0108] R3 and R4 are each independently selected from H, substituted or unsubstituted alkyl groups and substituted or unsubstituted cycloalkyl groups, and R3 and R4 are not both methyl; the substitution is by one or more Q2 groups; wherein each Q2 group is independently selected from H, deuterium, cyano, amino, hydroxyl and halogen;

[0109] R5 is selected from H, alkyl, alkylamino, hydroxyl, mercapto, and halogen;

[0110] In some embodiments, R1 is selected from substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups.

[0111] In some embodiments, R1 is selected from substituted or unsubstituted C. 6-10 Aryl and substituted or unsubstituted 5-10 heteroaryl groups.

[0112] In some embodiments, R1 is selected from substituted or unsubstituted C. 6-10 Aryl groups and substituted or unsubstituted 5-8-membered heteroaryl groups, wherein the heteroaryl group contains 1-4 heteroatoms selected from N, O and S.

[0113] In some embodiments, R1 is selected from substituted or unsubstituted phenyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, thiopheneyl, thiazolyl, benzofuranyl, 1,2,3-triazolyl, and 1,2,4-triazolyl.

[0114] In some embodiments, each Q1 is independently selected from H, deuterium, alkyl, alkoxy, and halogen.

[0115] In some embodiments, each Q1 is independently selected from alkyl groups.

[0116] In some implementations, each Q1 is independently selected from C 1-6 alkyl.

[0117] In some embodiments, each Q1 is independently selected from methyl, ethyl, and propyl.

[0118] In some embodiments, R3 is selected from H, substituted or unsubstituted alkyl groups, and substituted or unsubstituted cycloalkyl groups.

[0119] In some embodiments, R3 is H or substituted or unsubstituted C. 1-6 alkyl.

[0120] In some embodiments, R3 is H, methyl, ethyl, or propyl.

[0121] In some embodiments, the R4 is selected from H, substituted or unsubstituted alkyl groups, and substituted or unsubstituted cycloalkyl groups.

[0122] In some embodiments, R4 is H or substituted or unsubstituted C. 1-6 alkyl.

[0123] In some embodiments, R4 is H, methyl, ethyl, or propyl.

[0124] In some embodiments, each Q2 is independently selected from H, deuterium, cyano, amino, hydroxyl, and halogen.

[0125] In some implementations, each Q2 is independently selected from H and halogens.

[0126] In some embodiments, R5 is selected from H, alkyl, alkylamino, hydroxyl, mercapto, and halogen.

[0127] In some embodiments, R5 is H or C. 1-3 Alkyl or hydroxyl.

[0128] In some embodiments, R5 is H or a hydroxyl group.

[0129] In some embodiments, the compound is any of the following:

[0130]

[0131]

[0132]

[0133] The present invention also provides a pharmaceutical composition comprising at least one compound of formula (I) having type I PRMT inhibitory activity as described above, or a stereoisomer thereof, solvate, hydrate, prodrug, stable isotope derivative, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0134] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0135] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of the aforementioned compound based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound.

[0136] 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.

[0137] All compounds involved in this invention, as well as mixtures and compositions comprising compounds of this invention, can be administered to a living organism via any route of administration. Routes of administration may include oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal inhalation, oral inhalation, eye drops, or local or systemic transdermal administration.

[0138] All compounds involved in this invention, as well as mixtures and compositions containing compounds of this invention, can be formulated into single doses, containing the active compounds of this 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.

[0139] 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.

[0140] Depending on the nature and severity of the disease suffered by different individuals, the patient's age, gender, 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 per day, preferably 1-100 mg / kg per day, and can be administered once or multiple times.

[0141] The compound of formula (I) or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or pharmaceutical compositions as described above, having type I PRMT inhibitory activity, provided by the present invention, have any one or more of the following uses:

[0142] (1) Prepare drugs or PRMT type I enzyme inhibitors that inhibit PRMT type I enzyme activity;

[0143] (2) Prepare drugs for the treatment or prevention of mammalian diseases related to abnormal regulation of PRMT type I protein.

[0144] 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, or alcoholic cirrhosis.

[0145] Preferably, the tumor is selected from brain cancer, glioblastoma, leukemia, lymphoma, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, breast cancer, Wilms' tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, gastric cancer, bladder 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, or thyroid cancer.

[0146] Terminology Explanation:

[0147] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between its 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). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl 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 monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0153]

[0154] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon 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, 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:

[0155]

[0156] The term "bridged cycloalkyl" 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 rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0157]

[0158] The cycloalkyl group includes cycloalkyl groups (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

[0159] 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.

[0160] 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 deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0161] 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.

[0162] 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:

[0163]

[0164] 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:

[0165]

[0166] 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:

[0167]

[0168] 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:

[0169] wait.

[0170] 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.

[0171] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl group 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:

[0172]

[0173] The aryl 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.

[0174] The term "heteroaryl" refers to a heteroaryl 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 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 includes heteroaryl groups fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples of heteroaryl groups include:

[0175]

[0176] 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.

[0177] 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".

[0178] The term "halogen" refers alone or in combination to fluorine, chlorine, bromine, or iodine. In particular, it refers to fluorine, chlorine, or bromine.

[0179] The term "hydroxyl group" alone or in combination refers to the -OH group.

[0180] The term "thiol" alone or in combination refers to the group -SH.

[0181] The term "amino" alone or in combination represents primary amino (-NH2), secondary amino (-NH-) or tertiary amino.

[0182] The term "cyano" alone or in combination refers to the group -CN.

[0183] 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).

[0184] In the chemical structure of the compound described in this invention, the bond... No configuration was specified, i.e., key It can be or Or simultaneously include and Two configurations.

[0185] 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.

[0186] The term "isotope derivative" refers to compounds whose structure differs only in the presence of one or more isotope-enriched atoms. For example, compounds with the structure of this invention use "deuterium" or "tritium" instead of hydrogen, or use... 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 14Compounds in which carbon atoms are replaced by C-isotopes are within the scope of this invention. Such compounds can be used as analytical tools or probes in 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 in this invention 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, thus providing certain therapeutic advantages.

[0187] 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 1-6 Alkyl)4 salt.

[0188] The term "solvent" refers to the physical bond between the compound of the present invention and one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonds. In some cases, for example, 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] The following examples further describe the preparation of the compounds and pharmaceutically acceptable salts of the present invention, but these examples are not intended to limit the scope of the present invention.

[0193] Experimental methods in the embodiments of this invention 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.

[0194] Example 1

[0195] Step i:

[0196]

[0197] Starting materials 11-1 (1.0 g, 1.0 equivalent), 11-2 (411 mg, 1.0 equivalent), and potassium carbonate (1.4 g, 3.0 equivalent) were added to DMF and stirred at room temperature for 6 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 680 mg of a white solid product. Yield: 60%.

[0198] Step ii:

[0199]

[0200] In a two-necked flask under nitrogen protection, tetra(triphenylphosphine-palladium) (117 mg, 0.05 equivalent), potassium carbonate (833 mg, 3.0 equivalent), product 11-3 obtained in step i (680 mg, 1.0 equivalent), and 2-bromothiazole (330 mg, 1.0 equivalent) were dissolved in a toluene:ethanol:water solution of 2:1:1. The solution was transferred to a flask and heated at 90°C for 10 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 440 mg of a colorless oily product. Yield: 74%.

[0201] Step iii:

[0202]

[0203] Product 11-4 (210 mg, 1.0 equivalence) obtained in step ii was dissolved in anhydrous dichloromethane. A dichloromethane solution of starting material 11-5 (136 mg, 1.1 equivalence) was added dropwise, followed by two drops of acetic acid. The reaction was carried out at room temperature for half an hour, then sodium triacetoxyborohydride (377 mg, 2.5 equivalence) was added, and the reaction was carried out at room temperature overnight. The reaction system was quenched with water and extracted with dichloromethane. The organic phase was washed with water and saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. 240 mg of a colorless oily product was obtained. Yield: 73%.

[0204] Step iv:

[0205]

[0206] Product 11-6 obtained in step iii was dissolved in saturated ethyl acetate containing hydrogen chloride. The mixture was stirred overnight at room temperature, and a white solid precipitated. The solid was filtered, and the filter cake was washed with ethyl acetate and n-hexane. After drying, 175 mg of the target product was obtained. Yield: 78%.

[0207] Characterization data of compound 1:

[0208] 1 H NMR(400MHz,D2O)δ7.92(d,J=2.6Hz,1H),7.84(d,J=7.9Hz,2H),7.72(d,J=2.7Hz,1H),7.56(d,J=8.0Hz,2H),7.43–7.32(m, 2H),7.07(d,J=8.4Hz,1H),7.03–6.97(m,1H),5.23(s,2H),4.38(s,2H),3.54–3.37(m,2H),3.35–3.26(m,2H),2.79(s,3H).

[0209] 13 C NMR(100MHz,D2O)δ170.00,156.68,140.66,138.56,132.89,132.48,129.01,128.67( 2C),127.46(2C),122.00,121.64,117.07,113.07,69.42,56.03,51.70,40.36,33.84.

[0210] HRMS(ESI): m / z[M-HCl2] + calcd for C 20 H 24N3OS 354.1635, found 354.1641.

[0211] Example 2

[0212] Step i:

[0213]

[0214] Dissolve 210 mg (1.0 equivalent) of starting material 11-4 in anhydrous dichloromethane, add a dichloromethane solution of 147 mg (1.1 equivalent) of starting material 12-5, add two drops of acetic acid, and react at room temperature for half an hour. Add sodium triacetoxyborohydride (377 mg, 2.5 equivalent) and react at room temperature overnight. Quench the reaction system with water and extract with dichloromethane. Wash the organic phase with water and saturated sodium chloride solution. Combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography. 220 mg of a colorless oily product is given. Yield: 66%.

[0215] Step ii:

[0216]

[0217] Product 12-6 obtained in step i was dissolved in saturated ethyl acetate containing hydrogen chloride. The mixture was stirred overnight at room temperature, and a white solid precipitated. The solid was filtered, and the filter cake was washed with ethyl acetate and n-hexane. After drying, 160 mg of the target product was obtained. Yield: 77%.

[0218] Characterization data of compound 2:

[0219] 1 H NMR(400MHz,D2O)δ8.01(d,J=3.7Hz,1H),7.90(d,J=7.9Hz,2H),7.83(d,J=3.7Hz,1H),7.63(d,J=8.0Hz,2H),7.54–7.3 9(m,2H),7.17–7.02(m,2H),5.24(s,2H),4.44(s,2H),3.63–3.45(m,2H),3.46–3.29(m,2H),2.86(s,3H),2.59(s,3H).

[0220] 13 C NMR(100MHz,D2O)δ169.95,156.66,140.87,137.94,132.94,132.55,128.94(2C),128.44 ,127.51(2C),122.24,121.63,116.91,112.88,69.35,55.87,50.53,42.86,40.65,33.16.

[0221] HRMS(ESI): m / z[M-HCl2] + calcd for C 21 H 26 N3OS 368.1791, found 368.1800.

[0222] Example 3-26

[0223] The compounds of Examples 3-26 were prepared using the same or similar methods as those used in Examples 1-2. The structures of the specific compounds are as follows:

[0224]

[0225]

[0226]

[0227]

[0228]

[0229] Example 27

[0230] Step i:

[0231]

[0232] Dissolve 200 mg (1.0 equivalent) of starting material 11-4 in anhydrous dichloromethane, add a dichloromethane solution of 141 mg (1.1 equivalent) of starting material 21-5, add two drops of acetic acid, and react at room temperature for half an hour. Add sodium triacetoxyborohydride (360 mg, 2.5 equivalent) and react at room temperature overnight. Quench the reaction system with water and extract with dichloromethane. Wash the organic phase with water and saturated sodium chloride solution. Combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography. 220 mg of a colorless oily product is given. Yield: 69%.

[0233] Step ii:

[0234]

[0235] Product 21-6 obtained in step i was dissolved in saturated ethyl acetate containing hydrogen chloride. The mixture was stirred overnight at room temperature, and a white solid precipitated. The solid was filtered, and the filter cake was washed with ethyl acetate and n-hexane. After drying, 155 mg of the target product was obtained. Yield: 75%.

[0236] Characterization data of compound 27:

[0237] 1H NMR(400MHz,D2O)δ8.13–8.04(m,1H),7.98–7.85(m,3H),7.64(d,J=8.0Hz,2H),7.54–7.42(m,2H),7.18–6.99(m,2H),5.26(s, 2H),4.54(d,J=12.9Hz,1H),4.27(d,J=13.0Hz,1H),3.40–3.15(m,2H),3.00(t,J=7.8Hz,2H),2.82(s,3H),2.23–2.07(m,2H).

[0238] 13 C NMR(100MHz,D2O)δ170.48,156.55,141.89,136.15,132.91,132.27,128.62(2C),127.72(2C),126.86 ,122.75,121.62,117.52,112.91,69.12,55.51,52.86,40.06,36.49,22.06.HRMS(ESI):m / z[M-HCl2] + calcd for C 21 H 26 N3OS 368.1791, found 368.1795.

[0239] Example 28

[0240] Step i:

[0241]

[0242] Dissolve 600 mg (1.0 equivalent) of starting material 11-4 in anhydrous dichloromethane, add dropwise methylamine methanol solution (27.0–32.0%, 309 mg, ~3 mmol, ~1.5 equivalent), add two drops of acetic acid, react at room temperature for half an hour, add sodium triacetoxyborohydride (1081 mg, 2.5 equivalent), and react at room temperature overnight. Quench the reaction system with water and extract with dichloromethane. Wash the organic phase with water and saturated sodium chloride solution. Combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography. Give 523 mg of colorless oily product. Yield: 83%.

[0243] Step ii:

[0244]

[0245] In a two-necked flask under nitrogen protection, (S)-m-nitrobenzenesulfonic acid glycidyl ester (600 mg, 1.5 equivalents), potassium carbonate (232 mg, 3.5 equivalents), and product 22-5 (150 mg, 1.0 equivalent) obtained in step i were dissolved in acetonitrile solution and heated at 70°C for 10 hours. The reaction system was cooled and extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 120 mg of a colorless oily product. Yield: 69%.

[0246] Step iii:

[0247]

[0248] The product 22-6 (120 mg, 1.0 equivalent) obtained in step ii was dissolved in anhydrous dichloromethane, and a methylamine methanol solution was added dropwise. The mixture was then sealed and reacted for 16 hours. The solution was concentrated under reduced pressure and purified by column chromatography. 70 mg of a pale yellow oily product was obtained. Yield: 53%.

[0249] Characterization data of compound 28:

[0250] 1 H NMR (400MHz, CDCl3) δ7.98 (d, J=7.9Hz, 2H), 7.87 (d, J=3.3Hz, 1H), 7.50 (d, J= 8.0Hz,2H),7.33(d,J=3.2Hz,1H),7.31–7.27(m,1H),7.26–7.17(m,1H),6.99– 6.88(m,2H),5.15(s,2H),3.89–3.81(m,1H),3.77(d,J=13.1Hz,1H),3.53(d,J =13.1Hz,1H),2.64–2.45(m,4H),2.42–2.39(m,1H),2.39(s,3H),2.27(s,3H).

[0251] 13 C NMR (100MHz, CDCl3) δ167.97,156.81,143.76,139.03,133.24,131.20,128.67,127.81(2C),126.89,126 .87(2C),120.90,118.96,112.16,69.71,65.71,61.31,56.75,55.47,42.61,35.82.HRMS(ESI):m / z[M+H] + calcd for C 22 H 28 N3O2S 398.1897, found 398.1867.

[0252] Examples 29-37

[0253] Compounds of Examples 29-37 were prepared using a method similar to that of Example 28, and the structures of the specific compounds are as follows:

[0254]

[0255]

[0256] Example 38: AlphaLISA In Vitro Activity Assay

[0257] After serial dilution of the compounds, 100 nmL of each solution was transferred to the reaction plate along with the DMSO group and the positive control group (SAH). 5 μL of enzyme solution (PRMT1, PRMT4) 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 dim 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. (In the table, +++++ indicates IC50). 50 <5nM; ++++ means 5nM≤IC 50 <10nM; +++ means 10nM≤IC 50 <100nM; ++ indicates 100nM ≤ IC 50 <1μM; + indicates 1μM≤IC 50 <20μM; - indicates 20μM≤IC 50 )

[0258] Table 1. Results of AlphaLISA in vitro activity assays in Examples 1-37

[0259]

[0260]

[0261]

[0262] Example 39

[0263] This embodiment uses melanoma cell lines A375, A2058, HCT116 (colon cancer cells), MCF-7 (breast cancer cells), and T47D (human breast cancer cells) as cell models to examine the IC50 (increase response rate) of compounds on the proliferation inhibition of these cells. 50 .

[0264] First, cells were cultured in DMEM medium supplemented with 10% fetal bovine serum. After cell counting, 1000-3000 cells / 100 μl were seeded in 96-well plates, and the compound was administered simultaneously, with a two-fold serial dilution starting at 100 μM. Cell proliferation was assessed using the CCK8 assay 4-6 days after administration, with the commercially available compound GSK3368715 (a type I PRMT inhibitor that has undergone FDA Phase I clinical trials) serving as the control group. A graph was plotted with cell viability on the ordinate and drug concentration on the x-axis, and the IC50 of the compound for inhibiting cell proliferation in each cell line was calculated. 50 The results are shown in Table 2. (++++ in the table indicates IC) 50 <1μM; +++ indicates IC 50 =1-5μM;++ indicates IC 50 =5-20μM; + indicates IC 50 =20-50μM; - indicates IC 50 >50μM)

[0265] The cell viability (%) is calculated as follows:

[0266] Survival rate (%) = (OD of drug administration well - OD of blank well) / (OD of control well - OD of blank well) × 100.

[0267] Table 2 Results of tumor cell viability assay

[0268]

[0269]

[0270] " / " indicates that the compound was not tested.

[0271] The results showed that the compounds in the examples effectively inhibited the proliferation of the aforementioned tumor cells.

[0272] Example 40

[0273] This embodiment analyzes the intracellular protein thermostability of the compound from Example 32, demonstrating that the structure of the series of compounds of this invention, represented by this compound, effectively binds to the PRMT4 target protein.

[0274] After treating A375 tumor cells with 5 μM of the compound from Example 32 for 4 hours, the cell lysate supernatant was collected and subjected to a temperature gradient heating, followed by a PRMT4 protein immunoblotting assay and calculation of the grayscale value (e.g., ...). Figure 1 and Figure 2 (As shown). The results indicate that the compound in Example 32 can enhance the protein thermostability of PRMT4 in a concentration-dependent manner, suggesting that the compound can enter cells and bind directly to PRMT4.

[0275] Example 41

[0276] In this example, after treating melanoma cell line A375 cells with the compound of Example 32 for 96 hours, the results showed that the compound of Example 32 reduced the levels of asymmetric dimethylPABP1 and global ADMA in a dose-dependent manner. Figure 3 Furthermore, in the melanoma cell line A2058, the compound of Example 32 also reduced the level of asymmetric dimethylated-PABP1 in a concentration-dependent manner. Figure 4 The above results confirm that the compound of Example 32 can affect the asymmetric dimethylation level of PRMT4 substrates in the cellular environment by inhibiting the methyltransferase activity of PRMT4.

[0277] Example 42

[0278] To investigate the in vivo antitumor effect of the compound from Example 32, a nude mouse xenograft model of human A375 melanoma cells was constructed in this example. The animals were intraperitoneally injected with compound from Example 32 at 10 mg / kg / day and 25 mg / kg / day for 14 consecutive days. Figures 5 to 7 As shown, the compound in Example 32 significantly inhibited tumor growth in vivo, with tumor growth inhibition rates (TGI) of 63% (25 mg / kg) and 55% (10 mg / kg), respectively. Furthermore, no significant change in mouse body weight was observed during the experimental observation period compared to the control group, and no significant toxicity was detected. Figure 8 The levels of ADMA, PABP1, and PABP1me2a in tumor tissue were assessed using Western blotting. The results showed a significant decrease in asymmetric dimethylation, consistent with findings from cell studies. Figure 9 This indicates that the compound inhibits tumor growth by suppressing the activity of target proteins and reducing methylation levels.

[0279] 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 formula (I-1) having type I PRMT inhibitory activity, or a pharmaceutically acceptable salt thereof: ， in, R1 is selected from substituted or unsubstituted C. 6-10 Aryl and substituted or unsubstituted 5-10-membered heteroaryl groups; said substitution is by one or more Q1s; wherein each Q1 is independently selected from H, methyl, ethyl and propyl; R2 is selected from and ; R3 and R4 are each independently selected from H, methyl, ethyl, and propyl, and R3 and R4 are not simultaneously methyl; the substitution is by one or more Q2s; wherein each Q2 is independently selected from H and halogens; R5 is selected from H and hydroxyl groups; A1, A2, A3, A4, and A5 are each independently selected from CR6; B1, B2, B3, B4 and B5 are each independently selected from CR7; R6 and R7 are each independently selected from H and halogens.

2. The compound of formula (I-1) having type I PRMT inhibitory activity according to claim 1, characterized in that: The compound has the structure of formula (I-2). ， Wherein, R1 and R2 are as defined in claim 1.

3. The compound of formula (I-1) having type I PRMT inhibitory activity according to claim 1, characterized in that: R1 is selected from substituted or unsubstituted C. 6-10 Aryl groups and substituted or unsubstituted 5-8-membered heteroaryl groups, wherein the heteroaryl group contains 1-4 heteroatoms selected from N, O and S.

4. The compound of formula (I-1) having type I PRMT inhibitory activity according to claim 3, characterized in that: R1 is selected from substituted or unsubstituted phenyl, pyridinyl, pyrimidinyl, pyridazinyl, furanyl, thiopheneyl, thiazolyl, benzofuranyl, 1,2,3-triazolyl, and 1,2,4-triazolyl.

5. The compound of formula (I-1) having type I PRMT inhibitory activity according to any one of claims 1-4, characterized in that: The compound is any one of the following: 。 6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a compound of formula (I-1) having type I PRMT inhibitory activity as described in any one of claims 1-5, or a pharmaceutically acceptable salt thereof.

7. Use of a compound of formula (I-1) having type I PRMT inhibitory activity as described in any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6, characterized in that, Used for preparation: (1) Drugs that inhibit the activity of PRMT type I enzyme or PRMT type I inhibitors; (2) Drugs for the treatment or prevention of mammalian diseases associated with abnormal regulation of PRMT type I protein.

8. The use according to claim 7, characterized in that, The diseases mentioned are 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.

9. The use according to claim 8, characterized in that, The tumors are selected from brain cancer, glioblastoma, leukemia, lymphoma, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, breast cancer, Wilms' tumor, Ewing sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, gastric cancer, bladder 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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