Novel PRMT5 inhibitors and methods of use thereof

Abstract

The present invention describes novel compounds having protein arginine N-methyltransferase 5 (PRMT5) inhibitory activity, as well as methods of their preparation and use. In particular, the present invention describes compounds of Formula (I) and pharmaceutically acceptable salts, hydrates, and solvates thereof, as well as methods of their preparation and use.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and in particular to novel PRMT5 inhibitors and methods of using the same. Background Art

[0002] Epigenetic changes play a crucial role in driving and maintaining the malignant phenotype of tumors. Processes such as DNA methylation, histone acetylation and methylation, noncoding RNA, and post-translational modifications are epigenetic drivers of cancer that are independent of DNA sequence changes. Arginine methylation is an important post-translational modification that influences cell growth, proliferation, apoptosis, angiogenesis, and metastasis by regulating transcription and post-transcriptional RNA processing. There are three types of methylated arginine: ω-NG, N'G-asymmetric dimethylarginine (ADMA) and ω-NG, N'G-symmetric dimethylarginine (SDMA). This modification is catalyzed by the protein arginine methyltransferase (PRMT) family, transferring a methyl group from S-adenosylmethionine (AdoMet) to the arginine side chain of histones and non-histone proteins. Nine PRMT genes have been annotated in the human genome, categorized as type I enzymes (PRMT1, 2, 3, 4, 6, 8), type II enzymes (PRMT5, 9), and type III enzymes (PRMT7). PRMT5 is primarily a type II enzyme, responsible for catalyzing the symmetric dimethylation of arginine. PRMT5 was first discovered in a yeast two-hybrid assay when screening for proteins interacting with Janus kinase 2 (JAK2).

[0003] PRMT5 is a multifunctional transcriptional repressor that forms complexes with various transcription factors, such as BRG1, Hbrm, Blimp1, and Snail. PRMT5 participates in diverse cellular processes, methylating substrates in the cytoplasm and nucleus, including histone H4 residue Arg3 (H4R3) and histone H3 residue Arg8 (H3R8). H4R3 methylation is associated with transcriptional repression, while H3R8 methylation is associated with both transcriptional activation and repression. In addition to directly inducing repressive histone marks, PRMT5's role in gene silencing also involves the formation of a multi-repressor protein complex comprising NuRD components, HDACs, MDB proteins, and DNA methyltransferases. PRMT5 influences substrate specificity by interacting with binding proteins in these complexes. A core component of this protein complex is MEP50, which is essential for PRMT5's enzymatic activity. Studies have shown that PRMT5 can methylate proteins involved in RNA splicing, such as SmD3, which can be used to monitor the chemical activity of PRMT5 within cells.

[0004] PRMT5 plays an important role in tumorigenesis. Studies have found that PRMT5 expression is upregulated in a variety of cancers, including lymphoma, lung cancer, breast cancer, and colorectal cancer. In addition, PRMT5 expression is also upregulated in samples from mantle cell lymphoma (MCL) patients, and knocking out PRMT5 can inhibit MCL cell proliferation, highlighting the importance of PRMT5 in MCL. In melanoma, breast cancer, and lung cancer cell lines, PRMT5 overexpression promotes cell proliferation, while knocking out PRMT5 can inhibit cell proliferation. Therefore, PRMT5 is a potential target for cancer treatment.

[0005] Loss of methylthioadenosine phosphorylase (MTAP) results in a selective cellular dependence on PRMT5 and its binding protein, WDR77. MTAP loss is often due to its proximity to the frequently deleted tumor suppressor gene CDKN2A. MTAP-deficient cells experience elevated levels of methylthioadenosine (MTA), a metabolite cleaved by MTAP. Due to its structural similarity to the intrinsically selective inhibitor S-adenosylmethionine (SAM), elevated MTA levels inhibit SAM binding to PRMT5, thereby inhibiting PRMT5's methyltransferase activity.

[0006] The most significant structural difference between MTAP-deficient and MTAP-wild-type cancer cells is the accumulation of MTA in MTAP-deficient cells, which produces a PRMT5-MTA complex. Inhibitors developed against the PRMT5-MTA complex could selectively target MTAP-deficient cancer cells, minimizing effects on normal cells and significantly improving the therapeutic index. Therefore, identifying and developing small molecules that inhibit PRMT5 activity is an important strategy for treating various PRMT5-related diseases or disorders, especially cancer. Summary of the Invention

[0007] To solve the technical problem of the present invention, the present invention provides a class of compounds with novel structure and potent inhibitory activity against PRMT5.

[0008] Specifically, in one embodiment, the present invention provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, and isotopic derivative thereof.

[0009] Wherein, W1 is N or C; W2 is N or C;

[0010] Where X is CR X or N;

[0011] in, is a single bond or a double bond;

[0012] Among them, R X In each case, independently, C1-C6 alkyl, deuterated C1-C6 alkyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, hydroxy (C1-C6) alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5;

[0013] wherein Ring A is a 3-14 membered saturated or unsaturated monocyclic ring, a 3-14 membered saturated or unsaturated spirocyclic ring, or a 3-14 membered saturated or unsaturated fused ring, and each ring may optionally contain 0, 1 or 2 heteroatoms selected from O, S or N; Wherein, L is -C(O)NR a -、-NR a C(O)-, 5-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-12 membered aryl;

[0014] Wherein, Cy is a 6-12 membered aryl group or a 5-12 membered heteroaryl group;

[0015] Among them, R L and R L’ In each case, each is independently H, D, C1-C6 alkyl;

[0016] Among them, R T and R T’ In each case, each is independently H, D, C1-C6 alkyl;

[0017] Where o is 0, 1 or 2;

[0018] Among them, R a and R b In each case, each independently represents H, D, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, or R a and R b Together with the atoms to which it is attached, it forms a 3-14-membered saturated or unsaturated monocyclic ring, a 3-14-membered saturated or unsaturated spirocyclic ring, or a 3-14-membered saturated or unsaturated fused ring, each of which may optionally contain 0, 1 or 2 heteroatoms selected from O, S or N;

[0019] Wherein, cycloalkyl, heterocycloalkyl, aryl, heteroaryl can be arbitrarily substituted by 0, 1, 2 or 3 substituents, and the substituents are selected from: D, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl (C1-C6 alkyl), hydroxyl (C2-C6 alkenyl), hydroxyl (C2-C6 alkynyl), halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b or -SF5.

[0020] In one embodiment, the compound having the structure of formula (II), or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof:

[0021] Wherein, W1 is N or C; W2 is N or C;

[0022] Where X is CR X or N;

[0023] in, is a single bond or a double bond;

[0024] Y1 is NR Y1 , O, S, Se or CR Y1 R Y1′ ;

[0025] Y2 is NR Y2 , O, S, Se or CR Y2 R Y2’ ;

[0026] Y3 is NR Y3 , O, S, Se or CR Y3 R Y3’ ;

[0027] Among them, R X 、R Y1、R Y1’ 、R Y2 、R Y2’ 、R Y3 and R Y3’ independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy(C1-C6)alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5; Wherein, L is -C(O)NR a -、-NR a C(O)-, 5-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-12 membered aryl;

[0028] Wherein, Cy is a 6-12 membered aryl group or a 5-12 membered heteroaryl group;

[0029] Among them, R L and R L’ In each case, each is independently H, D, C1-C6 alkyl;

[0030] Among them, R T and R T’ In each case, each is independently H, D, C1-C6 alkyl;

[0031] Where o is 0, 1 or 2;

[0032] Among them, R a and R b In each case, each independently represents H, D, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, or R a and R b Together with the atoms to which it is attached, it forms a 3-14-membered saturated or unsaturated monocyclic ring, a 3-14-membered saturated or unsaturated spirocyclic ring, or a 3-14-membered saturated or unsaturated fused ring, each of which may optionally contain 0-2 heteroatoms selected from O, S or N;

[0033] Wherein, cycloalkyl, heterocycloalkyl, aryl, heteroaryl can be arbitrarily substituted by 0, 1, 2 or 3 substituents, and the substituents are selected from: D, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl (C1-C6 alkyl), hydroxyl (C2-C6 alkenyl), hydroxyl (C2-C6 alkynyl), halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b or -SF5.

[0034] In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein X is N. In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein X is CR X , where R X H and D.

[0035] In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein R T and R T’ is independently H or D in each case;

[0036] In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein R L and R L’ is independently H or D in each case;

[0037] In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein L is a 5-12 membered heteroaryl group.

[0038] In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein L is -C(O)NH or -NHC(O)-.

[0039] In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein L is

[0040] in, is a double bond; “*” indicates the binding site with Cy;

[0041] wherein Z1 and Z5 are each independently C or N;

[0042] where Z2 is independently CR in each case Z2 , N, O, S or Se;

[0043] where Z3 is independently CR in each case Z3 , N, O, S or Se;

[0044] where Z4 is independently CR in each case Z4 , N, O, S or Se;

[0045] Among them, R Z2 、R Z3 and R Z4 Each occurrence is independently H, C1-C6 alkyl, haloC1-C6 alkyl, C3-C6 cycloalkyl or halogen.

[0046] In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein L is selected from a group comprising the following structure:

[0047] In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein Cy is a 6-14 membered aryl group or a 5-14 membered heteroaryl group, and the Cy may be arbitrarily substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: D, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl (C1-C6 alkyl), hydroxyl (C2-C6 alkenyl), hydroxyl (C2-C6 alkynyl), halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)Ra 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b or -SF5;

[0048] In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein Cy is selected from ("*" indicates the binding site with L): In addition, Cy can be arbitrarily and independently substituted with 0, 1, 2, 3, 4, 5 or 6 groups selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy (C1-C6 alkyl) or C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, 6-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, wherein C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, 6-10 membered heterocyclic group, C6-C 10 Each ring of the aryl and 5-10 membered heteroaryl groups may be arbitrarily substituted with 0-4 of the following substituents: deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b .

[0049] In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein Cy is selected from ("*" indicates the binding site with L):

[0050] In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein o represents 1. In one embodiment, the compound, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein the compound is selected from the following compounds:

[0051] Unless otherwise expressly stated, the compounds described in the present invention can be interpreted as including, in addition to their specific structures, pharmaceutically acceptable salts, stereoisomers, isotopic variants (such as deuterated compounds), solvates, hydrates, prodrugs and metabolites of the compounds. In other words, pharmaceutically acceptable salts, stereoisomers, isotopic variants (such as deuterated compounds), solvates, hydrates, prodrugs and metabolites of the compounds also fall within the scope of protection of the compounds.

[0052] Preferably, the pharmaceutical composition of the present invention may further comprise a second active substance, wherein the second active substance is an anti-tumor drug, and the anti-tumor drug includes one or more of chemotherapy drugs, tumor targeted therapy drugs, and tumor therapeutic antibody drugs.

[0053] In addition, the present invention also provides a compound of the present invention, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative thereof, and a method for treating a disease by inhibiting the action of PRMT5, preferably the disease is a tumor. definition:

[0054] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight (unbranched) or branched, or cyclic hydrocarbon group, or a combination thereof. It can be saturated, monounsaturated or polyunsaturated, and can include divalent or polyvalent groups, with a specified number of carbon atoms (e.g., C1-C 10 represents one to ten carbon atoms). Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, 2-propenyl, crotyl, 2-(buta-1,3-dienyl), 2-isopentenyl, 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl, 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkyl groups that are limited to hydrocarbon groups are referred to as "homoalkyl". The alkyl group may be optionally substituted with one or more halogen atoms.

[0055] The term "haloalkyl" refers to an alkyl group as defined above wherein one or more hydrogen atoms are replaced by a halogen atom.

[0056] The term "alkylene" by itself or as part of another substituent refers to a divalent radical derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-, -CH2CH2CH(CH2CH2CH3)CH2-. Alkyl (or alkylene) groups typically have from 1 to 24 carbon atoms, and groups having 10 or fewer carbon atoms are preferred herein. "Lower alkyl" or "lower alkylene" refers to shorter chain alkyl or alkylene groups, typically having eight or fewer carbon atoms. The alkylene group may be optionally substituted with one or more halogen atoms.

[0057] The term "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which may be linear or branched, or a combination thereof. Examples of alkynyl include ethynyl, propynyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like. The alkynyl may be optionally substituted with one or more halogen atoms.

[0058] The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbocyclic ring, each having 3 to 10 carbon atoms. A "fused analog" of a cycloalkyl refers to a monocyclic ring fused to an aryl or heteroaryl group, wherein the point of attachment is located on the non-aromatic portion. Examples of cycloalkyls and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, decahydronaphthyl, dihydroindanyl, and the like. The cycloalkyl group may be optionally substituted with one or more halogen atoms. Furthermore, in the context of the present invention, the term "cycloalkyl" includes bridged and spirocyclic ring systems.

[0059] The term "alkoxy" refers to a straight or branched chain alkoxy group having the indicated number of carbon atoms. For example, C 1-6 Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy and the like.

[0060] Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with other terms refers to a stable straight or branched chain hydrocarbon group, or cyclic hydrocarbon group, or combinations thereof, comprising at least one carbon atom and at least one heteroatom selected from O, N, P, Si, and S. The nitrogen, phosphorus, or sulfur atom may optionally be oxidized, and the nitrogen atom may potentially be quaternized. The heteroatom(s) O, N, P, S, and Si may be located at any position within the heteroalkyl group or at the site where the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive. For example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene," by itself or in combination, refers to a divalent radical derived from a heteroalkyl group and includes, but is not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. The heteroatoms in a heteroalkylene group may be located at either or both ends of the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). In addition, for alkoxy and heteroalkoxy linking groups, the way the formula is written does not indicate the orientation of the linking group (e.g., -C(O)OR'- indicates -C(O)OR'- and -R'OC(O)-). As described above, the term "heteroalkyl" includes groups that are attached to the rest of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', ​​NR'R", -OR', -SR', and / or -S02R'. When a reference is made to "heteroalkyl" and a specific heteroalkyl group such as -NR'R" is subsequently listed, it should be understood that the term "heteroalkyl" is different from and is not mutually exclusive of -NR'R". The listing of specific heteroalkyl groups is for clarity of description and is not intended to exclude other heteroalkyl groups such as -NR'R".

[0061] The term "cycloalkoxy" refers to a cyclic alkyl group as above bonded to an oxygen atom, such as cyclopropyloxy.

[0062] The term "haloalkoxy" refers to an alkoxy group as described above in which one or more hydrogen atoms are replaced by a halogen.

[0063] The term "aryl" refers to a monocyclic or bicyclic aromatic group composed solely of carbon atoms. A "fused analog" of an aryl group refers to an aryl group fused to a monocyclic cycloalkyl or heterocyclic group, with the point of attachment being located on the aryl portion. Examples of aryl groups and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, 1,4-benzodioxanyl, and the like.

[0064] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic group containing at least one heteroatom selected from N, O, and S. A "fused analog" of a heteroaryl group refers to a heteroaryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group, with the point of attachment being at the heteroaryl portion. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, furo[2,3-b]pyridinyl, quinolinyl, indolyl, isoquinolinyl, and the like.

[0065] "Substituted or unsubstituted": the defined alkyl, aryl and heteroaryl groups may be unsubstituted or substituted by at least one substituent selected from the group consisting of a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a haloalkoxy group having 1 to 6 carbon atoms, -CN, an alkynyl group having 2 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 ring atoms, a heteroaryl group, an aryl group, an arylalkoxy group having 7 to 10 carbon atoms, an aryloxycarbonyl group, an aminocarbonyl group, a vinyl group having 2 to 5 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an aminosulfonyl group, a sulfonylamino group, a hydroxyl group, -SF5, a hydroxyalkyl group having 1 to 4 carbon atoms, a nitro group, an amino group, a carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 1 to 4 carbon atoms, The present invention also includes but is not limited to alkyl groups, alkyl groups having 1 to 4 carbon atoms, alkylsulfonyl groups having 1 to 4 carbon atoms, acylamino groups having 1 to 4 carbon atoms, acyl(amino)amino groups having 1 to 6 carbon atoms, acyl(amino)amino groups in which the acyl and alkyl moieties each have 1 to 6 carbon atoms, sulfonylamino groups having 1 to 4 carbon atoms, monoalkylamino groups having 1 to 6 carbon atoms or dialkylamino groups having 1 to 6 carbon atoms, monoalkylaminoalkyl groups having 1 to 6 carbon atoms or dialkylaminoalkyl groups having 1 to 6 carbon atoms, aminoalkyl groups having 1 to 4 carbon atoms, monoalkylamino groups having 1 to 6 carbon atoms or dialkylamino groups in which each of the two alkyl moieties has 1 to 6 carbon atoms, arylalkyl groups having 7 to 10 carbon atoms, heteroarylalkyl groups having 1 to 4 carbon atoms in the alkyl moiety, heteroaryloxyalkyl groups having 1 to 4 carbon atoms in the alkoxy moiety, and alkylsulfonylamino groups having 1 to 4 carbon atoms.

[0066] As used herein, the term "heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated, partially saturated, or unsaturated group (but not an aromatic group) having a single ring or fused rings (including bridged and spirocyclic systems) with 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In a fused ring system, one or more rings can be cycloalkyl, aryl, or heteroaryl, as long as the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide N-oxide, sulfinyl, and sulfonyl moieties. Examples of "heterocycle" and its fused analogs include pyrrolidinyl, piperidinyl, pyrazinyl, imidazolidinyl, 2,3-dihydrofuryl(2,3-b)pyridinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolinyl, and the like. The term also includes nonaromatic, partially unsaturated monocyclic rings such as 2- or 4-pyridones or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils).

[0067] As used herein, the term "substituted heterocycloalkyl" or "substituted heterocycle" refers to a heterocycloalkyl group substituted with 1 to 5 (eg, 1 to 3) substituents, wherein the substituents are the same as those defined for substituted cycloalkyl.

[0068] Unless otherwise indicated, the term "halogenated" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. Additionally, the term "haloalkyl" refers to monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C6)alkyl" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0069] "Prodrug" refers to a substance that is converted into the parent drug in the body. In some cases, prodrugs are often used because they are easier to administer than the parent drug. For example, the bioavailability of oral prodrugs may be higher than that of the parent drug. In a pharmaceutical composition, the prodrug may also have a higher solubility than the parent drug. Examples of prodrugs include, but are not limited to, any compound of formula (I) administered in the form of an ester (prodrug) to promote transmembrane transport. This helps to overcome the barrier formed by the cell membrane because the water solubility of the prodrug is not conducive to its transmembrane migration. Once entering the beneficial aqueous environment within the cell, the ester will be metabolically hydrolyzed to the active substance, carboxylic acid. Another example of a prodrug can be a short peptide (polyamino acid) bonded to an acid group, wherein the peptide releases the active portion through metabolism.

[0070] The compounds of formula (I) contain one or more asymmetric centers and may therefore occur as racemates and racemic mixtures, single enantiomers, diastereomers and individual diastereomers. The present invention encompasses all such stereoisomeric forms of the compounds of formula (I).

[0071] Certain compounds described herein contain olefinic double bonds and, unless otherwise indicated, are referred to as E and Z geometric isomers. Certain compounds described herein may contain one or more ring systems and may exist as cis and trans isomers. The present invention is intended to encompass all such cis and trans isomers.

[0072] Certain compounds described herein may have different points of attachment of hydrogen atoms, known as tautomerism. For example, keto-enol tautomerism involves a keto form and its enol form. Individual tautomers as well as mixtures thereof are encompassed by the compounds of the present invention.

[0073] The compounds of the present invention can be separated into diastereomeric pairs of enantiomers, for example, by fractional crystallization from a suitable solvent (e.g., methanol or ethyl acetate or a mixture thereof). The enantiomeric pairs thus obtained can be separated into individual stereoisomers by conventional methods (including the use of optically active amines or acids as resolving agents, or separation on a chiral high performance liquid chromatography column).

[0074] Alternatively, any diastereomer of the compounds described herein can be stereoselectively synthesized using optically pure starting materials or reagents of known configuration.

[0075] Salt and dosage form

[0076] As used herein, the compounds of the present invention should be understood to include pharmaceutically acceptable salts.

[0077] application

[0078] The compounds of the present invention can be used to treat PRMT5-related diseases.

[0079] The compounds of the present invention can be prepared by chemical synthesis, examples of which are shown below. It should be understood that the order of the steps in the methods can be changed, the reagents, solvents and reaction conditions mentioned can be substituted, and the reactive sites can be protected and deprotected if necessary.

[0080] The following abbreviations have the following meanings: -ACN: acetonitrile -EA: ethyl acetate -CDI:N,N'-carbonyldiimidazole -DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene -DIBAL-H: Diisobutylaluminum hydride -DIEA: diisopropylethylamine -DMAP: N,N-dimethylaminopyridine -DME: 1,2-dimethoxyethane -DMF: N,N-dimethylformamide -DMA and DMAc: N,N-dimethylacetamide -DMPE: 1,2-bis(dimethylphosphine)ethane -DMSO: dimethyl sulfoxide -DPPB: 1,4-bis(diphenylphosphino)butane -dppe: 1,2-bis(diphenylphosphino)ethane -dppf: 1,1'-bis(diphenylphosphino)ferrocene -dppm: 1,1-bis(diphenylphosphino)methane -DIAD: diisopropyl azodicarboxylate -EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide -HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate -HMPA: Hexamethylphosphoramide -IPA: Isopropyl alcohol -LDA: lithium diisopropylamide -LHMDS: lithium bis(trimethylsilyl)amide -LAH: lithium aluminum hydride -NCS: N-chlorosuccinimide -NaHMDS: sodium bis(trimethylsilyl)amide -PyBOP: Benzotriazol-1-yl-oxytripyrrolidino hexafluorophosphate -PyBrOP: tripyrrolidinylphosphonium bromide hexafluorophosphate -TDA-I: tris(2-(2-methoxyethoxy)ethyl)amine -DCM: dichloromethane -TEA: triethylamine -TFA: trifluoroacetic acid -THF: Tetrahydrofuran -NMM: N-methylmorpholine -NMP: N-methyl-2-pyrrolidone -PPh3: triphenylphosphine -Rt: Room temperature -PMB: p-methoxybenzyl -Tosmic: p-Toluenesulfonylmethyl isocyanide -(Boc)2O: di-tert-butyl dicarbonate -PE: Petroleum ether -O / n: overnight reaction.

[0081] The following preparations and examples are provided to illustrate the present invention but are not intended to limit the present invention in any way.

[0082] The detailed description of selected embodiments will provide a deeper understanding of the features and advantages of the present invention. As is known to those skilled in the art, the disclosed and claimed subject matter is capable of modifications in various respects, all of which are within the scope of the claims. Therefore, the description is to be regarded as illustrative in nature, not restrictive. The full scope of the present invention is defined in the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1 : Binding mode of Example 14 with the PRMT5-MTA complex (docking score: -11.29)

[0084] Figure 2 : Binding mode of Example 18 with the PRMT5-MTA complex (docking score: -11.19)

[0085] Figure 3 : Binding mode of Example 20 with the PRMT5-MTA complex (docking score: -11.04)

[0086] Figure 4 : Binding mode of Example 22 with the PRMT5-MTA complex (docking score: -10.9)

[0087] Figure 5 : Binding mode of Example 19 with the PRMT5-MTA complex (docking score: -10.89)

[0088] Figure 6 : Binding mode of Example 21 with the PRMT5-MTA complex (docking score: -10.87)

[0089] Figure 7 : Binding mode of Example 16 with the PRMT5-MTA complex (docking score: -10.74)

[0090] Figure 8 : Binding mode of Example 23 with PRMT5-MTA complex (docking score: -10.74)

[0091] In order to better understand the present invention, reference may be made to the following examples, which are intended to illustrate rather than limit the scope of the present invention. Example 1

[0092] The preparation method and steps of Example 1 were adopted, and only the corresponding raw material intermediates were replaced to obtain the following examples: Biological activity detection I. Tumor cell proliferation inhibition assay

[0093] Test 1: Inhibitory activity of compounds on the proliferation of HCT-116MTAP(- / -) deficient cells.

[0094] Materials and cells: HCT-116MTAP(- / -)-deficient cells were purchased from Kangyuan Bochuang (China); RPMI-1640 medium, fetal bovine serum, and penicillin-streptomycin were purchased from Thermo Fisher Scientific (USA); 384-well plates were purchased from PerkinElmer (USA); and the Cell-Titer Glo kit was purchased from Promega (USA).

[0095] Cell culture: HCT116 MTAP(- / -)-deficient cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C and 5% CO2. Only cells in the logarithmic growth phase were used for experiments.

[0096] Cell proliferation inhibition assay: The inhibitory activity of compounds against HCT-116 MTAP(- / -)-deficient cells was assessed using the Cell-Titer Glo assay. Cell concentrations were adjusted, and 40 μl was seeded per well of a 384-well plate. The cells were incubated overnight at 37°C in 5% CO2.

[0097] 40 nL of compound was added to each well at concentrations ranging from 0 to 10,000 nM (starting at 10,000 nM, three-fold dilutions, 10 points) in 0.1% dimethyl sulfoxide. The cell plates were incubated at 37°C, 5% CO₂ for 8 days. Cell viability was then determined by adding 40 μL of Cell-TiterGlo reagent. Results are shown in Table 1.

[0098] Assay 2: Inhibitory activity of compounds on the proliferation of HCT-116 MTAP wild-type cells.

[0099] Materials and cells: HCT-116 MTAP wild-type cells were purchased from Kangyuan Bochuang (China); RPMI-1640 medium, fetal bovine serum, and penicillin-streptomycin were purchased from Thermo Fisher Scientific (USA); 384-well plates were purchased from PerkinElmer (USA); and the Cell-Titer Glo kit was purchased from Promega (USA).

[0100] Cell culture: HCT116 MTAP wild-type cells were cultured in RPMI1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C and 5% CO2. Only cells in the logarithmic growth phase were used for experiments.

[0101] Cell proliferation inhibition assay: The inhibitory activity of compounds against HCT-116 MTAP wild-type cells was assessed using the Cell-Titer Glo assay. Cell concentrations were adjusted, and 40 μl of the compound was seeded into each well of a 384-well plate and incubated overnight at 37°C, 5% CO₂. 40 nl of compound was added to each well at concentrations ranging from 0 to 10,000 nM (starting at 10,000 nM, 3-fold dilutions, 10 points) in the presence of 0.1% dimethyl sulfoxide. The cell plates were incubated at 37°C, 5% CO₂ for 8 days. Cell viability was determined by adding 40 μl of Cell-TiterGlo reagent. Results are shown in Table 1. II. Pharmacokinetic Experiments in Mice

[0102] 1. Test compound

[0103] The compounds used in this experiment are specific examples of the present invention, with reference to the example compounds MRTX1719 and MRTX9786 in Mirat patent WO 2021 / 050915A1.

[0104] 2. Experimental Animals

[0105] ICR male mice, N = 3 / group, were obtained from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd.

[0106] 3. Drug preparation and administration

[0107] For single oral (PO) administration in ICR mice, dissolve the compound in dimethyl sulfoxide, add polyethylene glycol 400 and sterile water, and then add a small amount of 1 mol / L hydrochloric acid to adjust the solution to a clear solution. After fasting overnight, administer the compound by oral gavage at a dose of 10 mg / kg.

[0108] For single intravenous (IV) administration in ICR mice: Dissolve the compound in dimethyl sulfoxide, add polyethylene glycol 400 and sterile water, and then add a small amount of 1 mol / L hydrochloric acid to adjust the solution to a clear solution. After fasting overnight, inject the compound via the tail vein at a dose of 3 mg / kg.

[0109] 4. Sample Collection

[0110] At each time point, approximately 30 μl of blood was collected via the tail vein. Samples were centrifuged at 4°C, 4000 g / min, and 4°C for 5 minutes, using potassium ethylenediaminetetraacetic acid as an anticoagulant, for 1 hour. Blood was collected at 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were stored in a freezer at -20°C.

[0111] Plasma samples (30 μl, 10 μl sample + 20 μl blank plasma) were mixed with 200 μl of glacial acetonitrile containing an internal standard. After vortexing for 30 seconds, the samples were centrifuged at 4000 g / min for 20 minutes. 100 μl of the supernatant was transferred to a 96-well plate, and 200 μl of ultrapure water was added. After vortexing for 30 seconds, 5 μl or 10 μl was injected into the LC-MS / MS for analysis. III. hERG ion channel inhibition experiment

[0112] 1. Test compound

[0113] The compounds used in this experiment are specific examples of the present invention, with reference to the example compounds MRTX1719 and MRTX9786 in Mirat patent WO 2021 / 050915A1.

[0114] 2. Cell Lines and Cell Culture

[0115] The HEK293 cell line stably expressing the hERG ion channel (Cat. No. K1236) was purchased from Invitrogen. The cell line was cultured in a medium containing 85% Dulbecco's modified Eagle's medium, 10% dialyzed fetal bovine serum, 0.1 mM non-essential amino acid solution, 100 U / ml penicillin-streptomycin solution, 25 mM 4-hydroxyethylpiperazineethanesulfonic acid, 5 μg / ml blasticidin, and 400 μg / ml geneticin. When the cell density reached 40% to 80% of the culture dish area, the cells were digested with trypsin and passaged three times a week. Before the experiment, 5×10 5 Cells were cultured at a density of 1 μg / ml and induced for 48 hours with 1 μg / ml doxycycline. Subsequently, the cells were digested and plated onto glass slides for subsequent manual patch clamp experiments.

[0116] 3. Experimental Procedure

[0117] 1) Place the slide containing HEK293 cells in the perfusion chamber on the microscope stage.

[0118] 2) Using an Olympus IX71 or IX73 inverted microscope, use a 10x objective to center the field of view on a suitable cell. Also position the tip of the glass electrode in the center of the field of view. Use the micromanipulator to lower the electrode while adjusting the coarse focus knob to gradually bring the electrode closer to the cell.

[0119] 3) When the electrode is close to the cell, switch to a 40x objective lens for observation. Use the micromanipulator to make fine adjustments to gradually bring the electrode closer to the cell surface.

[0120] 4) Apply negative pressure to form a 1 GΩ seal between the electrode tip and the cell membrane.

[0121] 5) In voltage clamp mode, the instantaneous capacitance current C fast Then, short negative pressure is repeatedly applied to perturb the membrane, ultimately establishing whole-cell recording mode.

[0122] 6) In the -60mV voltage clamp mode, the slow capacitive current C slow , cell membrane capacitance (Cm) and input membrane resistance (Ra) for compensation.

[0123] 7) After the cells stabilize, change the clamping voltage to -90 mV, set the sampling frequency to 20 kHz, and the filtering frequency to 10 kHz. Leakage current detection conditions are a clamping voltage of -80 mV and a duration of 500 ms.

[0124] 8) hERG current measurement method is as follows: apply a 4.8-second depolarization command voltage to depolarize the membrane potential from -80 mV to +30 mV, then immediately apply a 5.2-second repolarization voltage to reduce the membrane potential to -50 mV to eliminate channel inactivation, and observe the hERG tail current. The peak value of the tail current is the hERG current magnitude.

[0125] 9) Continuously record hERG currents induced by the test compound for 120 seconds before administration to assess the stability of hERG currents generated by the test cells. Only cells with acceptable stability can proceed to subsequent compound testing.

[0126] 10) Detect the inhibitory effect of the test compound on hERG current: First, the hERG current measured in the extracellular solution containing 0.1% dimethyl sulfoxide is used as the baseline. After the hERG current remains stable for at least 5 minutes, the solution containing the test compound is perfused around the cells in sequence from low concentration to high concentration. Wait for about 5 minutes after each perfusion to allow the compound to fully act on the cells, and record the hERG current at the same time. After the recorded current stabilizes, record the last 5 hERG current values ​​and take the average as the final current value at a specific concentration. After testing the compound, add 450nM dofetilide to the same cell to completely inhibit its current as a positive control for the cell. At the same time, the positive compound dofetilide is synchronously detected using the same patch clamp system before and after the test drug experiment to ensure the reliability and sensitivity of the entire detection system. The above test steps will be repeated on two separate test cells (n=2).

[0127] 4. Data Analysis

[0128] Data meeting the above criteria will be analyzed using the following steps. Note: Data are exported from PatchMaster software.

[0129] 1) After perfusing the blank solvent or compound gradient solution, obtain five consecutive stable current values ​​and calculate the average value, which is used as the "tail current blank" and "tail current compound" respectively.

[0130] The current inhibition rate was calculated using the following formula:

[0131] Tail current inhibition rate = (1-(tail current compound-tail current positive control) / (tail current blank-tail current positive control)) × 100%

[0132] 2) GraphPad Prism 8.0 software was used to fit the dose-response curve and calculate the IC 50 3) The standard deviation of the three data sets is less than 15 (SD < 15); 4) The widely accepted criteria for evaluating the inhibitory potency of compounds in hERG channel assays are as follows: 1) Low inhibitory efficacy: IC 50 >10μM 2) Moderate inhibitory effect: 1 μM <IC 50 <10 μM 3) High inhibitory efficacy: IC 50 <1 μM

[0133] Data quality control standards

[0134] Only data that meet the following criteria can be analyzed: 1) initial gigaohm sealing resistance greater than 1 GΩ; 2) series resistance less than 15 MΩ, and the series resistance voltage error less than 5 mV; 3) leakage current at the detection voltage less than 50% of the current value under that condition; 4) tail current greater than the plateau current before the prepulse, and the initial tail current value greater than 250 pA; 5) membrane rupture resistance Ra less than 15 MΩ; 6) tail current decay rate per minute less than 2.5%. IV. Docking

[0135] The designed compounds were docked using Glide in the Schrodinger Small Molecule Discovery Suite (March 2022 release). The protein structure (PDB code: 7uoh) was prepared using the protein preparation workflow, retaining the MTA as part of the protein. The docking grid was prepared using the structure containing the parent compound in the presence of MTA. To account for protein flexibility, the van der Waals radius scaling factor was set to 0.9, corresponding to a partial charge cutoff of 0.25. Ligand preparation was performed using Epik (for handling ionization states) and the OPLS4 force field within the virtual screening workflow. By identifying key interactions within the core fused ring, namely, charge interactions between the free amine and Glu444, π-π stacking interactions between the fused ring and Phe327 and Trp579, and additional hydrogen bonding interactions between the pyrazole and Leu312 and the nitrile group and the backbone NH of Phe580, the cocrystallized ligand was successfully reproduced (docking score -12.899). The SP docking protocol was applied within the virtual screening workflow, and hydrogen bonding interactions within the core scaffold were enforced using docking constraints. The docked conformation was then visually inspected. Figure 1-8 Figure 2 is an example of a representative binding mode of the PRMT5-MTA complex, where hydrogen bonding interactions are highlighted with yellow dashed lines.

[0136] Conclusion: As indicated by the docking scores, the compounds described in this invention exhibit excellent binding affinity to the PRMT5-MTA complex. The bound conformation is similar to that of the co-crystallized ligand in the binding pocket, and key interactions are preserved.

[0137] While preferred embodiments have been described above, it will be apparent that modifications may be made by those skilled in the art without departing from the scope of the invention. this Such modifications are considered possible variations within the scope of the present invention.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof: in, W1 is N or C; W2 is N or C; Where X is CR X or N; in, is a single bond or a double bond; Among them, R X In each case, independently, C1-C6 alkyl, deuterated C1-C6 alkyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, hydroxy (C1-C6) alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5; wherein Ring A is a 3-14 membered saturated or unsaturated monocyclic ring, a 3-14 membered saturated or unsaturated spirocyclic ring, or a 3-14 membered saturated or unsaturated fused ring, and each ring may optionally contain 0, 1 or 2 heteroatoms selected from O, S or N; Wherein, L is -C(O)NR a -、-NR a C(O)-, 5-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-12 membered aryl; Wherein, Cy is a 6-12 membered aryl group or a 5-12 membered heteroaryl group; Among them, R L and R L’ In each case, each is independently H, D, C1-C6 alkyl; Among them, R T and R T’ In each case, each is independently H, D, C1-C6 alkyl; Where o is 0, 1 or 2; Among them, R a and R b In each case, each independently represents H, D, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, or R a and R b Together with the atoms to which it is attached, it forms a 3-14-membered saturated or unsaturated monocyclic ring, a 3-14-membered saturated or unsaturated spirocyclic ring, or a 3-14-membered saturated or unsaturated fused ring, each of which may optionally contain 0, 1 or 2 heteroatoms selected from O, S or N; Wherein, cycloalkyl, heterocycloalkyl, aryl, heteroaryl can be arbitrarily substituted by 0, 1, 2 or 3 substituents, and the substituents are selected from: D, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl (C1-C6 alkyl), hydroxyl (C2-C6 alkenyl), hydroxyl (C2-C6 alkynyl), halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b or -SF5.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein: Formula (I) is a compound having the structure of formula (II), or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof: Wherein, W1 is N or C; W2 is N or C; Where X is CR X or N; in, is a single bond or a double bond; Y1 is NR Y1 , O, S, Se or CR Y1 R Y1′ ; Y2 is NR Y2 , O, S, Se or CR Y2 R Y2’ ; Y3 is NR Y3 , O, S, Se or CR Y3 R Y3’ ; Among them, R X 、R Y1 、R Y1’ 、R Y2 、R Y2’ 、R Y3 and R Y3’ independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy(C1-C6)alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5; Wherein, L is -C(O)NR a -、-NR a C(O)-, 5-12 membered heterocyclyl, 5-12 membered heteroaryl, 6-12 membered aryl; Wherein, Cy is a 6-12 membered aryl group or a 5-12 membered heteroaryl group; Among them, R L and R L’ In each case, each is independently H, D, C1-C6 alkyl; Among them, R T and R T’ In each case, each is independently H, D, C1-C6 alkyl; Where o is 0, 1 or 2; Among them, R a and R b In each case, each independently represents H, D, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, or R a and R b The atoms connected thereto form a 3-14 membered saturated or unsaturated monocyclic ring, a 3-14 membered saturated or unsaturated spirocyclic ring, or a 3-14 membered saturated or unsaturated fused ring, each of which may arbitrarily contain 0-2 heteroatoms selected from O, S or N; Wherein, cycloalkyl, heterocycloalkyl, aryl, heteroaryl can be arbitrarily substituted by 0, 1, 2 or 3 substituents, and the substituents are selected from: D, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl (C1-C6 alkyl), hydroxyl (C2-C6 alkenyl), hydroxyl (C2-C6 alkynyl), halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b or -SF5.

3. The compound according to claim 1, or its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein: Ring A is a 4- or 5-membered saturated or unsaturated monocyclic ring, and each ring may optionally contain 0-2 heteroatoms selected from O, S or N.

4. The compound according to claim 1-2, or its pharmaceutical salt, ester, prodrug, stereoisomer or isotopic derivative, wherein: X is N.

5. The compound according to claim 1, or its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein: X is CR X , where R X H and D.

6. The compound according to claim 1-2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R T and R T’ Each occurrence is independently H or D.

7. The compound according to claim 1-2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R L and R L’ is independently H or D in each case; 8. The compound according to claim 1-2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: L is a 5-12 membered heteroaryl group.

9. The compound according to claim 1-2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: L is -C(O)NH or -NHC(O)-.

10. The compound according to claim 1-2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: L is in, is a double bond; "*" indicates the binding site with Cy; wherein Z1 and Z5 are each independently C or N; where Z2 is independently CR in each case Z2 , N, O, S or Se; where Z3 is independently CR in each case Z3 , N, O, S or Se; where Z4 is independently CR in each case Z4 , N, O, S or Se; Among them, R Z2 、R Z3 and R Z4 Each occurrence is independently H, C1-C6 alkyl, haloC1-C6 alkyl, C3-C6 cycloalkyl or halogen.

11. The compound according to claim 1-2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein L is selected from a group comprising the following structure:

12. The compound according to claim 1-2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Cy is a 6-14 membered aryl or 5-14 membered heteroaryl group, and the Cy may be arbitrarily substituted by 0, 1, 2 or 3 substituents selected from the group consisting of: D, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C 1- C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl (C1-C6 alkyl), hydroxyl (C2-C6 alkenyl), hydroxyl (C2-C6 alkynyl), halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、 -OSO3R a 、-NR a R b or -SF5.

13. The compound according to claim 1, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Cy is selected from ("*" indicates the binding site with L): In addition, Cy can be arbitrarily and independently substituted with 0, 1, 2, 3, 4, 5 or 6 groups selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy (C1-C6 alkyl) or C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, 6-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, wherein C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic group, 6-10 membered heterocyclic group, C6-C 10 Each ring of the aryl and 5-10 membered heteroaryl groups may be arbitrarily substituted with 0-4 of the following substituents: deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b .

14. The compound according to claim 1, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Cy is selected from ("*" indicates the binding site with L):

15. The compound according to claim 1, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: o is 1.

16. The compound according to claims 1-15, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein the compound is selected from the following compounds:

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