Alkynyl-containing amide derivative PRMT5 inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a heterocyclic alkynyl-substituted amide derivative as shown in a formula (I), and a preparation method and application of the heterocyclic alkynyl-substituted amide derivative. The invention also relates to a pharmaceutical composition containing the compound as an active ingredient and application of the compound or the pharmaceutical composition in treating and / or preventing related diseases mediated by PRMT5.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a class of acetylene-containing amide derivative PRMT5 inhibitors, their preparation methods, and their applications. Background Technology

[0002] Epigenetics-regulated gene expression plays a vital biological role in protein maturation and cell differentiation, and is crucial in many human diseases. Arginine guanidinomethylation catalyzed by protein arginine methyltransferase (PRMT) is a common post-translational modification in eukaryotic cells, affecting various biological processes such as cell signaling, gene transcription, mRNA translation, DNA recombination, and repair (Cell Mol. Life Sci. 2015.72(11):2041-2059).

[0003] PRMT5 is a member of the PRMT family, and its mediated methylation plays an important role in maintaining normal intracellular homeostasis. However, more and more studies have shown that abnormal expression of PRMT5 is associated with the occurrence of various tumors. It is overexpressed in various tumors and the mechanisms of occurrence differ in different tumors (CellMol.Life Sci.2015.72(11):2041-2059).

[0004] Homozygous deletion of tumor suppressor genes is a key driver of tumorigenesis. The deletion of the tumor suppressor gene CDKN2A, located on human chromosome 9p21, is one of the most frequently mutated genes in tumors, occurring in 15% of cases. Due to its close resemblance to CDKN2A, the methionine phosphorylase gene (MTAP) is frequently deleted in tumors, playing a crucial role in the methionine and adenine rescue pathway (Cell Reports, 2016, 15:574–587). MTAP deletion leads to the accumulation of its substrate, methylthioadenosine (MTA). Because MTA is structurally similar to S-adenosylmethionine (SAM), it selectively competes with SAM for binding to PRMT5, inhibiting some PRMT5 activity and sensitizing further PRMT5 inhibition, i.e., synthetic lethality (Science, 2016, VOL 351 ISSUE 6278:1214-1217).

[0005] However, PRMT5 is a known essential gene. Knockout or siRNA silencing of PRMT5 in normal tissues leads to abnormal physiological functions, such as reduced blood cell counts, infertility, skeletal muscle loss, and myocardial hypertrophy (Journal of Clinical Investigation, 2015, 125(9):3532-44). Currently, none of the PRMT5 inhibitors in the clinical stage can induce synthetic lethality due to MTAP deficiency. Therefore, new strategies are needed to exploit the metabolic vulnerability caused by MTAP deficiency.

[0006] Developing small molecule inhibitors targeting PRMT5·MTA can preferentially act on MTAP-deficient tumor cells. Since normal cells do not lack MTAP and have low MTA concentrations, they do not have a significant inhibitory effect on normal cells, thereby increasing the therapeutic index (AACR Annual Meeting, 2021, Abstract LB003), providing a new strategy for tumor treatment. Summary of the Invention

[0007] The problem the invention aims to solve:

[0008] Although several patent applications for PRMT5 inhibitors have been published, given the huge market demand from MTAP- / - cancer patients and the less-than-ideal clinical efficacy and hematologic toxicity risks of existing PRMT5 inhibitors, new compounds still require further development. Through continuous efforts, the inventors of this application have designed compounds with the structure shown in general formula (I) and discovered that compounds with this structure exhibit excellent PRMT5 inhibitory effects and have great application potential.

[0009] Solution for solving the problem:

[0010] In order to solve the above problems, the inventors of this application have conducted in-depth research and discovered that a class of amide derivatives containing alkyne groups can achieve the desired purpose, resulting in the completion of this invention.

[0011] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0012] The compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof:

[0013]

[0014] in, Selected from single or double bonds;

[0015] X, Y, and Z are independently selected from O, N, S, and CR. 5 ;

[0016] W is selected from CR 6 Or N;

[0017] y = 0, 1, or 2;

[0018] n1 and n2 are selected from 0, 1, and 2; when both n1 and n2 are 0, A does not exist; when n1 and n2 are not both 0, A is selected from CR. 7 R 8 NR 9 Or O;

[0019] Ring M is selected from 6-10 aryl or 5-10 heteroaryl;

[0020] R 4 Selected from H, C 1-6 Alkyl, C 3-6 cycloalkyl;

[0021] R 3 R 5 R 6 R 7 R 8 R 9 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy; wherein, the C 1-6 Alkyl, C 1-6 The alkoxy group is unsubstituted or surrounded by one or more R groups. i Replace; the C 3-6 cycloalkyl, C 3-6 The cycloalkoxy group is unsubstituted or surrounded by one or more R groups. j replace;

[0022] R 1 Selected from C 1-6 Alkyl, C 3-10 cycloalkyl-(C 1-6 alkyl) m -, 4-10 membered heterocyclic group-(C 1-6 alkyl) n -, 5-10 quinone heteroaryl-(C 1-6 alkyl) p -, 5-10 aryl-(C 1-6 alkyl) q -; where n = 0 or 1, m = 0 or 1, p = 0 or 1, q = 0 or 1; the heterocyclic group and the heteroaryl group each contain 1, 2, 3 or 4 heterocyclic atoms selected from O, N or S; wherein, the C 1-6 The alkyl group is unsubstituted or contains one or more R groups. k Replace; the C3-10 The cycloalkyl group is unsubstituted or contains one or more R groups. l Substitution; the 4-10 membered heterocyclic group is unsubstituted or replaced by one or more R groups. m Substitution; the 5-10 aryl and 5-10 heteroaryl groups are unsubstituted or independently substituted by one or more R groups. n replace;

[0023] R 2 Selected from C 3-6 Cycloalkyl, 5-10 aryl, or 5-10 heteroaryl; the C 3-6 Cycloalkyl, 5-10 aryl, or 5-10 heteroaryl unsubstituted or substituted with one or more identical or different R a replace;

[0024] Each R i R j R k R l R m R n Each is independently selected from hydroxyl, deuterium, halogen, cyano, unsubstituted or substituted by one or more C groups selected from halogen, cyano, or hydroxyl. 1-6 Alkyl group, unsubstituted or with one or more radicals selected from halogen, cyano, hydroxyl, -NR'R", C 1-6 alkoxy-substituted C 1-6 Alkoxy, C 3-10 Cycloalkyl, unsubstituted or with one or more C 1-6 Alkyl-substituted 5-10-membered heteroaryl groups, wherein the 5-10-membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N, O, and S; wherein R' and R" are each independently selected from H and C. 1-6 Alkyl, halogenated C 1-6 Alkyl groups, or R' and R" together with the nitrogen atom they are attached to, form 4-8 membered heterocyclic groups, which contain 1, 2, 3 or 4 heteroatoms selected from N, O, and S;

[0025] Each R a Each is independently selected from hydroxyl, deuterium, cyano, halogen, -NR'R", C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group is unsubstituted or has one, two, three, or four groups selected from halogen, hydroxyl, cyano, C... 1-6 Substituents of alkoxy groups; wherein R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6Alkyl groups, or R' and R" together with the nitrogen atom to which they are attached, form 4-8 membered heterocyclic groups, which contain 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

[0026] In some specific implementation schemes, R 1 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl.

[0027] In some specific implementation schemes, R 1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl.

[0028] In some specific implementation schemes, R 1 Selected from methyl, ethyl, cyclopropyl, and cyclobutyl.

[0029] In some specific implementation schemes, R 1 Selected from cyclopropyl and methyl.

[0030] In some specific implementation schemes, R 2 Selected from C 3-5 Cycloalkyl, 5-6-membered heteroaryl, 5-6-membered heteroaryl-5-6-membered heterocyclic, 5-6-membered heteroaryl-5-6-membered heteroaryl, 5-6-membered heteroaryl-phenyl, 5-6-membered heterocyclic-phenyl, which is unsubstituted or surrounded by 1, 2, or 3 identical or different R groups. a Substitution; each of the 5-6 membered heteroaryl and 5-6 membered heterocyclic groups independently contains 1, 2 or 3 heteroatoms selected from N, O or S.

[0031] In some specific implementation schemes, R 2 Selected from cyclopropyl, pyrazolyl, pyridinyl, imidazoleyl, imidazoleyl 5-6-membered heterocyclic alkyl, imidazoleyl 5-6-membered heterocyclic alkenyl, pyrazolyl 5-6-membered heteroaryl, pyridinyl 5-6-membered heterocyclic, and pyridinyl 5-6-membered heteroaryl, wherein it is unsubstituted or is formed by 1, 2, or 3 identical or different R groups. a Substitution; each of the 5-6-membered heteroaryl, 5-6-membered heterocyclic alkyl, 5-6-membered heterocyclic alkenyl, and 5-6-membered heterocyclic groups independently contains 1, 2, or 3 heteroatoms selected from N, O, or S.

[0032] In some specific implementation schemes, R 2 Selected from cyclopropyl, pyrazolyl, pyridyl, piperidinium imidazolyl, pyridinium imidazolyl, pyrazolopyridyl, which are unsubstituted or converted by 1, 2, or 3 identical or different R groups. a replace.

[0033] In some specific implementation schemes, R 2 Selected from cyclopropyl, It is either unsubstituted or replaced by 1, 2, or 3 identical or different Rs. a replace.

[0034] In some specific implementation schemes, each R a Each is independently selected from halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl group.

[0035] In some specific implementation schemes, each R a Each is independently selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkyl group.

[0036] In some specific implementation schemes, each R a Each is independently selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, methoxy, ethoxy, propoxy, and isopropoxy.

[0037] In some specific implementation schemes, each R a Each is independently selected from F, Cl, methyl, -CHF2, and methoxy.

[0038] In some specific implementation schemes, each R a Each is independently selected from halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl.

[0039] In some specific implementation schemes, each R a Each is independently selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl.

[0040] In some specific implementation schemes, each R a Each is independently selected from F, Cl, methyl, -CHF2, methoxy, and cyclopropyl.

[0041] In some specific implementation schemes, R 2 Selected from

[0042] In some specific implementation schemes, R 2 Selected from

[0043]

[0044] In some specific embodiments, ring M is selected from 5-6-membered heteroaryl, phenyl, 8-10-membered heteroaryl, and nayl, wherein the 5-6-membered heteroaryl contains 1, 2, or 3 heteroatoms selected from N, O, and S, and the 8-10-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0045] In some specific embodiments, ring M is selected from 5-6-membered heteroaryl or phenyl, wherein the 5-6-membered heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S.

[0046] In some specific embodiments, ring M is selected from 5-6-membered heteroaryl and phenyl, wherein the 5-6-membered heteroaryl contains 1 or 2 N heteroatoms.

[0047] In some specific embodiments, ring M is selected from pyridyl or phenyl.

[0048] In some specific implementation schemes, A is selected from O.

[0049] In some specific implementation schemes, the structure Selected from

[0050] In some specific implementation schemes, R 3 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkyl group.

[0051] In some specific implementation schemes, R 3 Selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkyl group.

[0052] In some specific implementation schemes, R 3 Selected from H, F, Cl, Br, methyl, ethyl, methoxy, ethoxy.

[0053] In some specific implementation schemes, R 3 Selected from H, Cl, and methyl groups.

[0054] In some specific implementation schemes, R 4 Selected from H.

[0055] In some specific implementation schemes, the structure Selected from:

[0056]

[0057] In some specific implementation schemes, the structure Selected from

[0058] In some specific implementation schemes, the structure Selected from:

[0059]

[0060] In some specific implementations, equation (I) has the structure shown in equation (IA).

[0061]

[0062] Among them, M and R 1 R 2 R 3 R 6 n1 and n2 are defined as described in equation (I).

[0063] In some specific implementation schemes, R 6 Selected from hydrogen, halogens, C 1-6 alkyl.

[0064] In some specific implementation schemes, R 6 Selected from hydrogen, F, Cl, Br, methyl, ethyl, propyl, and isopropyl.

[0065] As an exemplary compound of the present invention, the compound shown in formula (I) is selected from any of the following specific compounds:

[0066]

[0067]

[0068] The term "pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.

[0069] The term "deuterated compound" refers to a compound of the present invention comprising at least one deuterium atom, specifically meaning that one or more hydrogen atoms in the compound of the present invention can be replaced or substituted by a deuterium atom. In some embodiments, the compound comprises two or more deuterium atoms. In some embodiments, the compound comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Methods for synthesizing isotopes into organic compounds are known in the art.

[0070] Preparation method:

[0071] This invention also provides a method for preparing the compound. The preparation of the compound of formula (I) can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered in any way as limiting the scope of the invention. The compound of this invention can also be synthesized by synthetic techniques known to those skilled in the art, or by combining synthetic methods known in the art with the method described in this invention. The product obtained from each reaction step is obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for synthesis can be conventionally synthesized according to literature (such as those provided by Scifinder) or purchased.

[0072] Synthesis process route:

[0073]

[0074] Step 1: Under condensation conditions well known in the art, the compound shown in formula I-2 is treated with the compound shown in I-1 to obtain the compound shown in formula I-3.

[0075] Step 2: Under coupling conditions well-known in the art, using The compound shown in the diagram can be used to treat the compound shown in formula I-3 to obtain the compound shown in formula I.

[0076] Where Q is a halogen, and X, Y, Z, W, A, R 1 R 2 R 3 R 4 The definitions of n1, n2, and ring M are as defined in equation (I) of this paper.

[0077] Pharmaceutical composition:

[0078] The present invention also provides a pharmaceutical composition for treating and / or preventing diseases associated with abnormal PRMT5 expression, the pharmaceutical composition comprising a therapeutic and / or preventive effective amount of the compound as described above or its tautomers, stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, and optionally pharmaceutical excipients.

[0079] In some implementations, the disease associated with abnormal PRMT5 expression is a tumor or cancer.

[0080] In some implementations, the disease associated with abnormal PRMT5 expression refers to a disease associated with abnormal PRMT5 expression and MTAP deficiency.

[0081] In some implementations, the disease associated with abnormal PRMT5 expression refers to tumors or cancers with MTAP deficiency.

[0082] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredient are known, or will be obvious to those skilled in the art according to the disclosure of the present invention. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995), the method for preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents, etc.

[0083] Medical uses:

[0084] The present invention also provides the compounds as described above, or their tautomers, stereoisomers, pharmaceutically acceptable salts or their deuterated compounds, or the pharmaceutical compositions as described above, in the preparation of medicaments for the treatment and / or prevention of diseases associated with abnormal PRMT5 expression.

[0085] In some implementations, the diseases associated with abnormal PRMT5 expression described herein are tumors or cancers.

[0086] In some implementations, the diseases associated with abnormal PRMT5 expression described herein refer to diseases with MTAP deficiency that are associated with abnormal PRMT5 expression.

[0087] In some implementations, the diseases associated with abnormal PRMT5 expression described herein refer to tumors or cancers with MTAP deficiency.

[0088] In this invention, "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect may be preventative based on the complete or partial prevention of the disease or its symptoms; and / or therapeutic based on the partial or complete stabilization or cure of the disease and / or side effects resulting from the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) preventing the disease or symptoms occurring in a patient who has not yet been diagnosed with the disease; (b) suppressing the symptoms of the disease, i.e., preventing its progression; or (c) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0089] In this invention, "subject" and "individual in need" refer to vertebrates. In some embodiments, vertebrates refer to mammals. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In some embodiments, mammals refer to humans.

[0090] In this invention, "effective amount" refers to the amount that effectively achieves the desired therapeutic or preventative effect at the necessary dose and time. The "therapeutic effective amount" of the substance / molecule of this invention may vary depending on factors such as an individual's disease state, age, sex, weight, and the substance / molecule's ability to elicit the desired response in the individual. Therapeutic effective amount also encompasses the amount in which the beneficial therapeutic effect of the substance / molecule outweighs any toxic or harmful consequences. "Preventative effective amount" refers to the amount that effectively achieves the desired preventative effect at the necessary dose and time. Typically, but not necessarily, the preventative effective amount will be lower than the therapeutic effective amount because the preventative dose is administered to the subject before the onset of the disease or in its early stages. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; shrink the tumor volume; inhibit (i.e., slow down, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down, preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent.

[0091] Invention effects:

[0092] The compound represented by formula (I) of the present invention exhibits good PRMT5 inhibitory activity, especially excellent PRMT5 inhibitory activity against MTAP-deficient tumors; and compared with the MTAP wild-type (WT) HCT-116 cell line, the compound provided by the present invention has better selective inhibitory activity against the human MTAP-deficient HCT-116 cell line; and shows excellent plasma exposure, making it suitable as a drug for the treatment and / or prevention of diseases related to this effect. Detailed Implementation

[0093] It should be understood that the terminology used herein is intended to describe specific embodiments and is not intended to be limiting. Furthermore, although any methods, apparatus, and materials similar to or equivalent to those described herein may be used to practice or test the invention, preferred methods, apparatus, and materials are described here.

[0094] The structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker ASCENA-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were expressed in 10⁻¹⁰ increments. -6 (ppm) is given as the unit.

[0095] Reaction monitoring and MS determination were performed using a Thermofisher ESQ (ESI) mass spectrometer.

[0096] The HPLC determination was performed using a Thermo Fisher Scientific U3000 DAD high-performance liquid chromatograph (GL Sciences ODS-HL HP 3μm 3.0*100mm column).

[0097] Thin-layer chromatography (TLC) used Qingdao Ocean GF254 silica gel plates. The silica gel plates used in TLC had a diameter of 0.15–0.2 mm, while the purified products were separated using high-performance thin-layer chromatography (HPLC) preparative plates with a diameter of 0.9–1.0 mm. Column chromatography used Qingdao Ocean 200–300 mesh silica gel as the carrier. The developing solvent systems were A: dichloromethane and methanol; and B: petroleum ether and ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compounds. For medium-pressure preparative liquid chromatography (PLC) purification, a Biotage Isera One preparative PL was used.

[0098] In the following embodiments, unless otherwise specified, all reaction materials can be purchased from suppliers in the SciFinder database. For example, some reagents in the embodiments of this invention were purchased from manufacturers such as Saen Chemical Technology (Shanghai) Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Nanjing Yaoshi Technology Co., Ltd., Jiangsu Aikon Biomedical R&D Co., Ltd., and Shanghai Bid Pharmaceutical Technology Co., Ltd. Furthermore, unless otherwise specified, all raw materials used in the embodiments of this invention are of analytical grade. Unless otherwise specified, all ratios of two liquid substances mentioned herein are volume ratios; all percentages of substances mentioned are mass percentages.

[0099] Example 1: 4-Amino-N-cyclopropyl-7-fluoro-N-((5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (1)

[0100]

[0101] Preparation of 4-amino-N-((5-bromopyridin-2-yl)methyl)-N-cyclopropyl-7-fluoroimidazolo[1,5-a]quinoxaline-8-carboxamide (1c)

[0102] Compound 1a (50 mg, 0.2 mmol, prepared according to WO2024008113A1), N,N-diisopropylethylamine (26 mg, 0.4 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (114 mg, 0.3 mmol) were added to a solution of compound 1b (46 mg, 0.2 mmol, prepared according to WO2024067433A1), N,N-diisopropylethylamine (26 mg, 0.4 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (114 mg, 0.3 mmol). The reaction was carried out at room temperature for 4 hours. After the reaction was complete, water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The solution was then subjected to column chromatography (methanol:dichloromethane = 1:10) to give compound 1c (52 mg). ESI-MS (m / z): 456.8 [M+H] + .

[0103] Preparation of 4-amino-N-cyclopropyl-N-((5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-2-yl)methyl)-7-fluoro-imidazo[1,5-a]quinoxaline-8-carboxamide (1)

[0104] Under nitrogen protection, 4-ethynyl-1-methyl-1H-pyrazole (24 mg, 0.22 mmol), cuprous iodide (4 mg, 0.02 mmol), N,N-diisopropylethylamine (43 mg, 0.33 mmol), and tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) were added sequentially to a solution of compound 1c (52 mg, 0.11 mmol) in N-methylpyrrolidone (2 mL). After addition, the mixture was reacted in a microwave oven at 70 °C for 3 hours. Upon completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The purified compound 1 (12 mg) was obtained by reversed-phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100%–50%:50%). ESI-MS (m / z): 481.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.15(s,1H),8.70(s,1H),8.32(d,J=6.4Hz,1H),8.13(s,1H),7.99–7.90(m,2H),7.74(s,1H),7. 58(s,2H),7.43(d,J=8.0Hz,1H),7.25(d,J=11.2Hz,1H),4.85(s,2H),3.89(s,3H),2.96–2.88(m,1H),0.69–0.36(m,4H).

[0105] Example 2: 4-Amino-7-fluoro-N-methyl-N-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (2)

[0106]

[0107] Preparation of 4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (2b): Compound 1a (50 mg, 0.2 mmol), N,N-diisopropylethylamine (52 mg, 0.4 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (114 mg, 0.3 mmol) were added to a solution of compound 2a (46 mg, 0.2 mmol) in N,N-dimethylformamide (2 mL). After the addition, the mixture was reacted at room temperature for 4 hours. After the reaction was completed, water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation. The mixture was then subjected to column chromatography (methanol:dichloromethane = 1:10) to give compound 2b (55 mg). ESI-MS (m / z): 458.0 [M+H] + .

[0108] Preparation of 4-amino-7-fluoro-N-methyl-N-(6-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (2) under nitrogen protection, 4-ethynyl-1-methyl-1H-pyrazole (26 mg, 0.24 mmol), cuprous iodide (5 mg, 0.02 mmol), N,N-diisopropylethylamine (47 mg, 0.36 mmol) and tetrakis(triphenylphosphine)palladium (15 mg, 0.01 mmol) were added sequentially to a solution of N-methylpyrrolidone (1 mL) of compound 2b (55 mg, 0.12 mmol). After addition, the mixture was reacted in a microwave oven at 70°C for 3 hours. Upon completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The mixture was then purified by reversed-phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100%–50%:50%) to give compound 2 (14 mg). ESI-MS (m / z): 482.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.52–8.28(m,1H),8.10–8.06(m,1H),7.97–7.93(m,1H),7. 71–7.67(m,1H),7.61(s,2H),7.42–7.19(m,2H),7.16–7.08(m,1H),7.04–6.96(m,1H),6.48–6.42 and 5.61–5.54(m,1H),4.92–4.51(m,2H),3.87(s,3H),2.70 and 2.61(s,3H).

[0109] Example 3: (S)-4-amino-7-fluoro-N-methyl-N-(6-(pyridin-3-ylethynyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (3)

[0110]

[0111] Preparation of (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (3b) Synthetic process for preparing compound 3b from compound 1a Reference: Synthetic process for preparing compound 2b from compound 1a ESI-MS (m / z): 458.0 [M+H] + .

[0112] Preparation of (S)-4-amino-7-fluoro-N-methyl-N-(6-(pyridin-3-ylethynyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (3)

[0113] Under nitrogen protection, 3-ethynylpyridine (10.2 mg, 0.10 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (39.9 mg, 0.39 mmol), and tetrakis(triphenylphosphine)palladium (11.4 mg, 0.01 mmol) were added sequentially to a solution of compound 3b (45 mg, 0.10 mmol) in N-methylpyrrolidone (1 mL). After addition, the mixture was reacted in a microwave oven at 80 °C for 4 hours. Upon completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The mixture was purified by reversed-phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100%–50%:50%) to obtain compound 3 (12 mg). ESI-MS (m / z): 479.1 [M+H] +.1H NMR (400MHz, DMSO-d6) δ9.15 (s, 1H), 8.71–8.61 (m, 2H), 8.56–8.29 (m, 1H), 7.96 (d, J = 3.2Hz, 1H), 7.6 2(s,2H),7.58–7.51(m,2H),7.48–7.35(m,1H),7.35–7.22(m,2H),7.17(d,J=18.4Hz,1H),6.52–6.45 and 5.66–5.60(m,1H),4.99–4.56(m,2H),2.72 and 2.63(s,1H).

[0114] Example 4: (S)-4-amino-N-(6-((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzofuran-3-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (4)

[0115]

[0116] Preparation of (S)-4-amino-N-(6-(((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzofuran-3-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (4) under nitrogen protection, 1-cyclopropyl-4-ethynylpyrazole (23.2 mg, 0.18 mmol), cuprous iodide (3.8 mg, 0.02 mmol), triethylamine (35.5 mg, 0.35 mmol) and tetra(triphenylphosphine)palladium (10.1 mg, 0.01 mmol) were added sequentially to a solution of N-methylpyrrolidone (1 mL) of compound 3b (40 mg, 0.09 mmol). After addition, the mixture was reacted in a microwave oven at 80°C for 4 hours. Upon completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The mixture was then purified by reversed-phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100%–50%:50%) to give compound 4 (12 mg). ESI-MS (m / z): 508.1 [M+H] +.1H NMR(400MHz, DMSO-d6)δ9.14(s,1H),8.54–8.28(m,1H),8.17(d,J=4.4Hz,1H),8.00–7.87(m,1H),7.68 (d,J=4.0Hz,1H),7.61(s,2H),7.42–7.19(m,2H),7.13–7.08(m,1H),6.98(d,J=18.0Hz,1H),6.47–6.41 and 5.61–5.53(m,1H),4.91–4.53(m,2H),3.81–3.72(m,1H),2.70 and 2.60(s,3H),1.12–1.04(m,2H),1.03–0.95(m,2H).

[0117] Example 5: 4-amino-N-(5-(((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (5)

[0118]

[0119] Preparation of 3,6-dibromo-2,3-dihydro-1H-inden-1-one (5a): Azobisisobutyronitrile (164 mg, 1 mmol) and NBS (1.78 g, 10 mmol) were added to a solution of 6-bromo-2,3-dihydro-1H-inden-1-one (2.11 g, 10 mmol) in acetonitrile (20 mL). The mixture was stirred at 70 °C for 2 hours. The reaction solution was cooled to room temperature and directly concentrated to obtain a crude product, which was then subjected to column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain 5a (2.05 g).

[0120] Preparation of 6-bromo-3-(methylamino)-2,3-dihydro-1H-inden-1-one (5b): A solution of 5a (1.36 g, 4.69 mmol) in dichloromethane (20 mL) was supplemented with methylamine hydrochloride (950 mg, 14.07 mmol) and triethylamine (950 mg, 9.38 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction solution was directly concentrated to obtain 5b (1.12 g). ESI-MS (m / z): 242.12 [M+H] +

[0121] Preparation of N-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoro-N-methylacetamide (5c): Triethylamine (950 mg, 9.38 mmol) was added to a solution of 5b (1.12 g, 4.69 mmol) in dichloromethane (20 mL). Subsequently, a solution of trifluoroacetic anhydride (1.48 g, 7.04 mmol) in dichloromethane (10 mL) was added to the mixture at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The reaction solution was directly concentrated to obtain a crude product, which was then subjected to column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 5c (800 mg).

[0122] Preparation of N-(6-bromo-2,3-dihydrospiro[indene-1,2'-[1,3]dithionyl]-3-yl)-2,2,2-trifluoro-N-methylacetamide (5d)

[0123] At -15°C, a solution of compound 5c (710 mg, 2.11 mmol) and 1,2-ethylenedithiol (398 mg, 4.22 mmol) in dichloromethane (20 mL) was added to a solution of BF3·Et2O (899 mg, 6.34 mmol). The mixture was stirred at -15°C for 2 hours, then allowed to warm naturally to room temperature and stirred for another 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with 90 mL (30 mL x 3). The organic phase was concentrated to obtain the crude product, which was then subjected to column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain 5d (780 mg).

[0124] Preparation of N-(5-bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoro-N-methylacetamide (5e): Dibromohydantoin (624 mg, 2.18 mmol) was added to a solution of pyridine hydrofluoric acid (824 mg, 5.18 mmol) in dichloromethane (10 mL) under a nitrogen atmosphere at -70 °C. The slurry mixture was stirred at -70 °C for 30 min. Then, a solution of 5e (300 mg, 0.73 mmol) in dichloromethane (10 mL) was added to the mixture. The mixture was stirred at -70 °C for another 1 h, and then at 20 °C for another 3 h. The reaction mixture was quenched with saturated sodium bicarbonate solution at 0 °C and extracted with 90 mL (30 mL x 3). The organic phase was concentrated to obtain the crude product, which was then subjected to column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain 5e (160 mg).

[0125] Preparation of 5-bromo-3,3-difluoro-N-methyl-2,3-dihydro-1H-indene-1-amine (5f): Potassium carbonate (185 mg, 1.34 mmol) was added to a solution of 5e (160 mg, 0.45 mmol) in methanol (5 mL), and the mixture was stirred at 45 °C for 2 hours. The mixture was concentrated to obtain a crude product, which was then subjected to column chromatography (dichloromethane / methanol = 30:1) to obtain 5f (95 mg). ESI-MS (m / z): 261.88 [M+H] +

[0126] Preparation of 4-amino-N-(5-bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (5 g): Compound 5f (50 mg, 0.19 mmol), triethylamine (48.3 mg, 0.48 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (108.8 mg, 0.29 mmol) were added to a solution of compound 1a (47 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL), and the reaction was carried out at 25 °C for 3 h. After the reaction was complete, the reaction solution was cooled to room temperature and poured into ice water, precipitating a solid. The solid was filtered to obtain a crude product, which was then subjected to normal-phase column chromatography (dichloromethane / methanol = 30:1) to give 5 g (56 mg) of the compound. ESI-MS (m / z): 492.03 [M+H] + Preparation of 4-amino-N-(5-(((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-3,3-difluoro-2,3-dihydro-1H-indene-1-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (5): 5 g (56 mg, 0.11 mmol) of the compound was added to a solution of N-methylpyrrolidone (2 mL) containing cuprous iodide (4.4 mg, 0.02 mmol), tetrakis(triphenylphosphine)palladium (13.2 mg, 0.01 mmol), triethylamine (46.2 mg, 0.46 mmol), and 1-cyclopropyl-4-ethynylpyrazole (30.2 mg, 0.23 mmol). After addition, the mixture was microwaved at 80 °C for 4 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Normal-phase column chromatography (methanol / dichloromethane = 10:1) was performed to obtain the crude compound, followed by reverse-phase column chromatography (acetonitrile / 0.05% ammonium bicarbonate solution = 0:100%–45%:55%) to obtain compound 5 (12 mg). ESI-MS (m / z): 542.2 [M+H] +1H NMR (400MHz, DMSO-d6) δ9.21–9.08(m,1H),8.52–8.33(m,1H),8.26–8.18(m,1H),7.95(s,1H ),7.81–7.69(m,3H),7.64–7.56(m,2H),7.53–7.43(m,1H),7.32–7.24(m,1H),6.38–6.29and 5.51–5.42(m,1H),3.82–3.74(m,1H),3.22–2.72(m,2H),2.70and 2.64(s,3H),1.12–1.05(m,2H),1.05–0.96(m,2H).

[0127] Example 6: (S)-4-amino-7-chloro-N-(6-((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (6)

[0128]

[0129] Preparation of (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-7-chloro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (6b): Compound 6a (100 mg, 0.38 mmol) was added to a solution of compound 3a (86.8 mg, 0.38 mmol) in N,N-dimethylformamide (5 mL). (Preparation method refers to WO) 2024 / 032572), triethylamine (96.3 mg, 0.95 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (217 mg, 0.57 mmol) were added and reacted at room temperature for 4 hours. After the reaction was complete, water (20 mL) was added and extracted with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. Column chromatography (methanol:dichloromethane = 1:10) was performed to give compound 6b (96 mg). ESI-MS (m / z): 474.0 [M+H] + .

[0130] Preparation of (S)-4-amino-7-chloro-N-(6-((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (6) under nitrogen protection: 1-cyclopropyl-4-ethynylpyrazole (44.7 mg, 0.34 mmol), cuprous iodide (6.4 mg, 0.03 mmol), triethylamine (68.5 mg, 0.68 mmol) and tetra(triphenylphosphine)palladium (19.6 mg, 0.02 mmol) were added sequentially to a solution of N-methylpyrrolidone (1 mL) of compound 6b (80 mg, 0.17 mmol). After addition, the mixture was reacted in a microwave oven at 80°C for 4 hours. Upon completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The mixture was then purified by reversed-phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100%–50%:50%) to give compound 6 (22 mg). ESI-MS (m / z): 523.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.27–9.03(m,1H),8.60–8.13(m,2H),7.95(s,1H),7.73–7.56(m,3H),7.55–7.23(m,2H),7.23 –7.04(m,1H),7.03–6.92(m,1H),6.55–6.41and5.47–5.38(m,1H),4.90–4.53(m,2H),3.81–3.72(m,1H),2.74–2.69and 2.57–2.53(m,3H),1.11–1.05(m,2H),1.02–0.97(m,2H).

[0131] Biological evaluation

[0132] Experimental Example 1: Inhibitory activity of the compound of the present invention against the proliferation of human colon cancer cells.

[0133] 1. Build MTAP - / - HCT-116 cell line

[0134] HCT-116 colon cancer cell line (Nanjing Kebai) was co-transfected with gene-editing tools CRISPR / Cas9 and sgRNA. MTAP biallelic inactivated MTAP was obtained using Western blotting, Sanger sequencing, and other detection methods. - / - HCT-116 cell line. MTAP - / -The HCT-116 cell line was used for selective screening and evaluation of compounds based on the MTAP deficiency and PRMT5 synergistic mechanism, including symmetric dimethylarginine (SDMA) level assay and cell proliferation assay.

[0135] 2. Cell proliferation

[0136] MTAP was cultured in complete culture medium McCoy's 5A (Gibco, 16600082) / 10% FBS (Gibco, 10099141C) / 1% p / s (Gibco, 15140122). - / - HCT-116 and wild-type HCT-116 cell lines were used to evaluate the effects of compounds on MTAP. - / - The selective inhibition of HCT-116 cell proliferation was enhanced. Day 0, 100 MTAP molecules were added to each well of a 96-well cell culture plate (Corning, 3599). - / - HCT-116 cells or wild-type HCT-116 cells were cultured in a 37°C, 5% CO2 incubator. The compound was serially diluted 3x with DMSO (Sigma, D5879) (starting concentration 20 μM, 3x dilution, for a total of 8 concentration points). On Day 1, the compound was diluted to multiple concentration points and used to treat cells separately, and the cells were cultured for another 10 days at 37°C, 5% CO2. On Day 11, 20 μL of MTS (CellTiter) was added to each well. A Queous One Solution Cell Proliferation Assay (Promega, G3581), after incubation at 37°C and 5% CO2 for 2 hours, readings were taken using Tecan Spark (OD = 490 nM). Data analysis was then performed using GraphPad Prism 8 software, employing the equation "log(inhibitor) vs. normalized response-variable slope" (formula Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)). 50 Data analysis was performed using -X)*HillSlope))) to obtain the IC50 of the compound. 50 Value. Where Y is the inhibition rate, X is the logarithm of the compound concentration, Top refers to the maximum response (inhibition rate at the highest compound concentration), Bottom refers to the baseline response (inhibition rate at zero compound concentration), and Hill Slope refers to the IC50 value. 50 The slope of the curve, IC 50 The concentration of the compound at half-inhibition.

[0137] Table 1IC50 (μM)

[0138]

[0139] Table 1 shows that the compounds provided in this invention have strong inhibitory activity against the proliferation of human MTAP-deficient HCT-116 cell lines. Compounds 1-25 showed IC50 values ​​against human MTAP-deficient HCT-116 cell lines. 50 The values ​​were all less than 0.2 μM. Moreover, compared with the MTAP wild-type (WT) HCT-116 cell line, the compounds provided by this invention have excellent selective inhibitory activity against the human MTAP-deficient HCT-116 cell line. The selective inhibitory activity of compounds 1 to 25 against the human MTAP-deficient HCT-116 cell line was all greater than 40-fold.

[0140] Experimental Example 2: Pharmacokinetic Experiment in Mice

[0141] Experimental materials and methods:

[0142] The experimental animals were healthy adult female BALB / c mice (provided by Beijing Huafukang Biotechnology Co., Ltd. and Sichuan Weitonglihua Laboratory Animal Technology Co., Ltd.);

[0143] BALB / c female mice were administered a single oral gavage dose (10 mg / kg). At 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration, 60 μL of whole blood from the fundus venous plexus of the mice was collected at different time points. The plasma was collected by centrifugation at 4000 rpm for 6 min.

[0144] Sample analysis:

[0145] 10 μL of mouse plasma was collected, and 190 μL of acetonitrile solution containing internal standard was added to precipitate proteins. The mixture was vortexed for 10 min, followed by centrifugation at 4000 rpm for 10 min. The supernatant was collected into a 96-well plate and analyzed by LC-MS / MS (Shimadzu LC-30A, AB API4500). The drug concentration in the plasma of mice at different time points after gavage administration of the compound was determined by LC-MS / MS, and relevant pharmacokinetic parameters were calculated to study the pharmacokinetic behavior of the compound in mice and evaluate its pharmacokinetic characteristics.

[0146] Experimental results:

[0147] Table 2. Pharmacokinetic parameters of the compounds of this invention in mice.

[0148]

[0149] Note: 1. The solvent used is 0.5% MC / 0.2% Tween 80.

[0150] The results showed that the compound of the present invention had excellent high plasma exposure (good AUC, high Cmax) in mouse pharmacokinetics, indicating good drug-like properties.

[0151] Industrial applicability

[0152] The compounds of this invention exhibit excellent PRMT5 inhibitory activity, and compared to the MTAP wild-type (WT) HCT-116 cell line, the compounds provided by this invention have better selective inhibitory activity against the human MTAP-deficient HCT-116 cell line; and show excellent plasma exposure, making them potential drugs for the treatment or prevention of diseases related to this effect.

[0153] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. The compound represented by formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof: in, Selected from single or double bonds; X, Y, and Z are independently selected from O, N, S, and CR. 5 ; W is selected from CR 6 Or N; y = 0, 1, or 2; n1 and n2 are selected from 0, 1, and 2; when both n1 and n2 are 0, A does not exist; when n1 and n2 are not both 0, A is selected from CR. 7 R 8 NR 9 Or O; Ring M is selected from 6-10 aryl or 5-10 heteroaryl; R 4 Selected from H, C 1-6 Alkyl, C 3-6 cycloalkyl; R 3 R 5 R 6 R 7 R 8 R 9 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy; wherein, the C 1-6 Alkyl, C 1-6 The alkoxy group is unsubstituted or surrounded by one or more R groups. i Replace; the C 3-6 cycloalkyl, C 3-6 The cycloalkoxy group is unsubstituted or surrounded by one or more R groups. j replace; R 1 Selected from C 1-6 Alkyl, C 3-10 cycloalkyl-(C 1-6 alkyl) m -, 4-10 membered heterocyclic group-(C 1-6 alkyl) n -, 5-10 quinone heteroaryl-(C 1-6 alkyl) p -, 5-10 aryl-(C 1-6 alkyl) q -; where n = 0 or 1, m = 0 or 1, p = 0 or 1, q = 0 or 1; the heterocyclic group and the heteroaryl group each contain 1, 2, 3 or 4 heterocyclic atoms selected from O, N or S; wherein, the C 1-6 The alkyl group is unsubstituted or contains one or more R groups. k Replace; the C 3-10 The cycloalkyl group is unsubstituted or contains one or more R groups. l Substitution; the 4-10 membered heterocyclic group is unsubstituted or replaced by one or more R groups. m Substitution; the 5-10 aryl and 5-10 heteroaryl groups are unsubstituted or independently substituted by one or more R groups. n replace; R 2 Selected from C 3-6 Cycloalkyl, 5-10 aryl, or 5-10 heteroaryl; the C 3-6 Cycloalkyl, 5-10 aryl, or 5-10 heteroaryl unsubstituted or substituted with one or more identical or different R a replace; Each R i R j R k R l R m R n Each is independently selected from hydroxyl, deuterium, halogen, cyano, unsubstituted or substituted by one or more C groups selected from halogen, cyano, or hydroxyl. 1-6 Alkyl group, unsubstituted or with one or more radicals selected from halogen, cyano, hydroxyl, -NR'R", C 1-6 alkoxy-substituted C 1-6 Alkoxy, C 3-10 Cycloalkyl, unsubstituted or with one or more C 1-6 Alkyl-substituted 5-10-membered heteroaryl groups, wherein the 5-10-membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N, O, and S; wherein R' and R" are each independently selected from H and C. 1-6 Alkyl, halogenated C 1-6 Alkyl groups, or R' and R" together with the nitrogen atom they are attached to, form 4-8 membered heterocyclic groups, which contain 1, 2, 3 or 4 heteroatoms selected from N, O, and S; Each R a Each is independently selected from hydroxyl, deuterium, cyano, halogen, -NR'R", C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl group is unsubstituted or has one, two, three, or four groups selected from halogen, hydroxyl, cyano, C... 1-6 Substituents of alkoxy groups; wherein R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl groups, or R' and R" together with the nitrogen atom to which they are attached, form 4-8 membered heterocyclic groups, which contain 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

2. The compound of claim 1, wherein its tautomers, stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, are characterized in that: R 1 Selected from C 1-6 Alkyl, C 3-8 cycloalkyl; Preferred, R 1 Selected from C 1-4 Alkyl, C 3-6 cycloalkyl; Preferred, R 1 Selected from methyl, ethyl, cyclopropyl, and cyclobutyl; Preferred, R 1 Selected from cyclopropyl and methyl.

3. The compound of claim 1, wherein its tautomers, stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, are characterized in that: R 2 Selected from C 3-5 Cycloalkyl, 5-6-membered heteroaryl, 5-6-membered heteroaryl-5-6-membered heterocyclic, 5-6-membered heteroaryl-5-6-membered heteroaryl, 5-6-membered heteroaryl-phenyl, 5-6-membered heterocyclic-phenyl, which is unsubstituted or surrounded by 1, 2, or 3 identical or different R groups. a Substitution; each of the 5-6 membered heteroaryl and 5-6 membered heterocyclic groups independently contains 1, 2 or 3 heteroatoms selected from N, O or S; Preferred, R 2 Selected from cyclopropyl, pyrazolyl, pyridinyl, imidazoleyl, imidazoleyl 5-6-membered heterocyclic alkyl, imidazoleyl 5-6-membered heterocyclic alkenyl, pyrazolyl 5-6-membered heteroaryl, pyridinyl 5-6-membered heterocyclic, and pyridinyl 5-6-membered heteroaryl, wherein it is unsubstituted or is formed by 1, 2, or 3 identical or different R groups. a Substitution; each of the 5-6-membered heteroaryl, 5-6-membered heterocyclic alkyl, 5-6-membered heterocyclic alkenyl, and 5-6-membered heterocyclic groups independently contains 1, 2, or 3 heteroatoms selected from N, O, or S; Preferred, R 2 Selected from cyclopropyl, pyrazolyl, pyridyl, piperidinium imidazolyl, pyridinium imidazolyl, pyrazolopyridyl, which are unsubstituted or converted by 1, 2, or 3 identical or different R groups. a replace; Preferred, R 2 Selected from cyclopropyl, It is either unsubstituted or replaced by 1, 2, or 3 identical or different Rs. a replace; Preferably, each R a Each is independently selected from halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy; Preferably, each R a Each is independently selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy; Preferably, each R a Each is independently selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, fluoroisopropyl, methoxy, ethoxy, propoxy, and isopropoxy. Preferably, each R a Each is independently selected from F, Cl, methyl, -CHF2, and methoxy; Preferably, each R a Each is independently selected from halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl; Preferably, each R a Each is independently selected from halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 cycloalkyl; Preferably, each R a Each is independently selected from F, Cl, methyl, -CHF2, methoxy, and cyclopropyl; Preferred, R 2 Selected from Preferred, R 2 Selected from 4. The compound of claim 1, wherein its tautomers, stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, are characterized in that: The ring M is selected from 5-6-membered heteroaryl, phenyl, 8-10-membered heteroaryl, and nayl, wherein the 5-6-membered heteroaryl contains 1, 2, or 3 heteroatoms selected from N, O, and S, and the 8-10-membered heteroaryl contains 1, 2, 3, or 4 heteroatoms selected from N, O, and S. Preferably, ring M is selected from 5-6-membered heteroaryl and phenyl, wherein the 5-6-membered heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S; Preferably, ring M is selected from 5-6-membered heteroaryl and phenyl, wherein the 5-6-membered heteroaryl contains 1 or 2 N heteroatoms; Preferably, ring M is selected from pyridyl or phenyl; Preferably, A is selected from O; Preferred structure Selected from Preferred, R 3 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; Preferred, R 3 Selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy; Preferred, R 3 Selected from H, F, Cl, Br, methyl, ethyl, methoxy, ethoxy; Preferred, R 3 Selected from H, Cl, and methyl groups; Preferred, R 4 Selected from H; Preferred structure Selected from: Preferred structure Selected from 5. The compound of claim 1, wherein its tautomers, stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, are characterized in that: structure Selected from:

6. The compound of claim 1, wherein its tautomers, stereoisomers, pharmaceutically acceptable salts, or deuterated compounds thereof, are characterized in that: Equation (I) has the structure shown in equation (IA). Among them, M and R 1 R 2 R 3 R 6 n1 and n2 are each defined as described in equation (I); Preferred, R 6 Selected from hydrogen, halogens, C 1-6 alkyl; Preferred, R 6 Selected from hydrogen, F, Cl, Br, methyl, ethyl, propyl, and isopropyl.

7. The compound according to any one of claims 1-6, wherein its tautomers, stereoisomers, pharmaceutically acceptable salts or deuterated compounds thereof, and the compound represented by formula (I) is selected from:

8. A pharmaceutical composition for treating and / or preventing diseases associated with abnormal PRMT5 expression, characterized in that: The pharmaceutical composition comprises a therapeutic and / or preventative amount of the compound as described in any one of claims 1-7 or its tautomers, stereoisomers, pharmaceutically acceptable salts or their deuterated compounds, and optionally pharmaceutical excipients; Preferably, the disease associated with abnormal PRMT5 expression is a tumor or cancer; Preferably, the diseases associated with abnormal PRMT5 expression refer to diseases with MTAP deficiency that are associated with abnormal PRMT5 expression. Preferably, the disease associated with abnormal PRMT5 expression refers to tumors or cancers with MTAP deficiency.

9. The use of the compound or tautomer, stereoisomer, pharmaceutically acceptable salt or deuterated compound of any one of claims 1-7, or the pharmaceutical composition of claim 8, in the preparation of a medicament for treating and / or preventing diseases associated with abnormal PRMT5 expression; Preferably, the disease associated with abnormal PRMT5 expression is a tumor or cancer; Preferably, the disease associated with abnormal PRMT5 expression refers to a disease with MTAP deficiency that is associated with abnormal PRMT5 expression. Preferably, the disease associated with abnormal PRMT5 expression refers to tumors or cancers with MTAP deficiency.

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