Fused ring compound, pharmaceutical composition containing same and application of fused ring compound

Abstract

The invention relates to a compound shown in a formula (I), a pharmaceutical composition containing the compound and application of the compound to preparation of a medicine used as a PRMT5 inhibitor.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a fused cyclic compound, a pharmaceutical composition comprising the same, and its use in treating diseases. Background Technology

[0002] Arginine methylation is a type of histone methylation and one of the most common post-translational modifications in mammals, primarily regulated by the PRMT (protein arginine methyltransferase) gene family. PRMTs can transfer the methyl group on S-adenosylmethionine (AdoMet / SAM) to the guanidino nitrogen atom of the arginine side chain in proteins, generating methylated arginine. PRMTs can regulate arginine methylation in various ways and play important roles in biological processes such as gene expression, splicing, and DNA damage repair. Alterations in PRMT enzyme activity, gene mutations, or deletions are often closely related to developmental abnormalities and the occurrence and development of cancer in animals.

[0003] Within the PRMT gene family, PRMT5, as an epigenetic enzyme, participates in numerous physiological processes, including transcriptional regulation, RNA metabolism, ribosome biosynthesis, and cell cycle regulation. In particular, it is upregulated in many cancers such as lymphoma, lung cancer, breast cancer, and ovarian cancer, which is sufficient to prove its important role in tumor formation and development.

[0004] MTAP (methionine phosphorylase) is frequently co-deleted with the commonly found tumor suppressor gene CDKN2A, a phenomenon occurring in 9%–15% of tumors. Other studies have reported that MTAP deficiency leads to the accumulation of intracellular MTA (methionine, an MTAP substrate). Excessive MTA binds to and inhibits some PRMT5 activity, resulting in an MTAP-PRMT5 lethal effect. Currently, several PRMT5 inhibitors are in clinical trials, but most are non-PRMT5·MTA selective, exhibiting poor selectivity for MTAP-deficient tumors and significant toxicity. Summary of the Invention

[0005] This invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound has the structure of formula (I):

[0006] in: Indicates a single bond or a double bond; X is CR X Either N or NH; Y is CR YOr N; Z is CR Z Or N; W is either C or N; R X R Y R Z R 1 R 2 R 3 R 13 Each time it appears, it is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b and -OC 1-6 Alkylene-NR a R b ; Or R 1 and R 2 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10Aromatic rings or 5-14 heterocyclic aromatic rings; R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups; R 8 R 9 R 10 R 11 Each time it appears, it is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and hydroxyl-C 1-6 alkyl; Or R 8 and R 9 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; Or R 9 and R 10 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; A represents O and CR. A1 R A2 or NR N ; R A1 R A2 Each time it appears, it is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, cyclic hydrocarbon group, heterocyclic group, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl; Or R A1 and R A2 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; Or R A1 and R A2 Together with the groups to which it is attached, they optionally constitute C2-6 alkenyl; Or R A1 and R 8 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; R N Selected from H, halogens, -OH, -NH2, -CN, -NO2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, hydroxy-C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 heteroaryl groups; Or R N and R 8 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; R 12 Selected from H, halogens, -OH, -NH2, -CN, and -NO2; Or R 8 and R 12 Together with the single ring containing A that it connects to, they can optionally form a 7-10 bridging heterocyclic group; Or R 10 and R 12 Together with the single ring containing A that it connects to, they can optionally form a 7-10 bridging heterocyclic group; B can be O, CH2, or NH; X1 is either C or N; X2 is either C or N; X3 is either C or N; X4 is either C or N; X5 is either C or N; R 4 R 5 R 6 R 7 Each occurrence is independently selected from the following: non-existent, H, halogen, oxo, -OH, -NH2, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 heteroaryl groups; Or R 4 and R5 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; Or R 5 and R 6 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; The aforementioned alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkyl, heterocyclic, heterocyclic, aryl, aromatic, heteroaryl, heteroaromatic, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -NH2, -CN, -NO2, =CH2, =CF2, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R c -OC(=O)R c -C(=O)OR c -OR c -SR c -S(=O)R c -S(=O)2R c -S(=O)2NR c R d -NR c R d -C(=O)NR c R d -NR c -C(=O)R d -NR c -C(=O)OR d -NR c -S(=O)2-R d -NR c -C(=O)-NR c R d -C 1-6 Alkylene-OR c -C 1-6 Alkylene-NR c R d and -OC 1-6 Alkylene-NR c R dThe alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NR c R d -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, halogenated or unsubstituted C 3-6 Cyclic hydrocarbon group, halogenated or unsubstituted 3-10 membered heterocyclic group, halogenated or unsubstituted C 6-10 aryl, halogen-substituted or unsubstituted 5-14 membered heteroaryl, C 6-12 Aryl groups, -OC 1-6 Alkyl and -C 1-6 Alkylene-OC 1-6 alkyl; R c and R d Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl group, wherein the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and aryl group are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl groups and -C 1-6 Alkylene-OC 1-6 alkyl; m is 0, 1, or 2; p is 0 or 1; n, q, and t are each independently 0 or 1.

[0007] Another aspect of the invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug, and one or more pharmaceutically acceptable carriers.

[0008] Another aspect of the invention provides the use of the compounds of the invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs of the invention, or pharmaceutical compositions of the invention, in the preparation of a medicament used as a PRMT5 inhibitor.

[0009] Another aspect of the invention provides compounds of the invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs of the invention, or pharmaceutical compositions of the invention, which are used as PRMT5 inhibitors.

[0010] Another aspect of the invention provides a method for preventing or treating cancer (preferably MTAP-deficient cancer), the method comprising administering to an individual in need an effective amount of the compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug or pharmaceutical composition of the invention.

[0011] The effects of the invention This application provides compounds for use as PRMT5 inhibitors, which exhibit excellent inhibitory activity against PRMT5 (particularly in MTAP-deficient cells). Furthermore, the compounds of this invention also possess favorable physicochemical properties (e.g., solubility, physical and / or chemical stability), favorable pharmacokinetic properties (e.g., improved bioavailability, good metabolic stability, suitable half-life and duration of action), favorable safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), and are less prone to inducing drug resistance, among other excellent properties. Detailed Implementation

[0012] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0013] definition Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0014] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0015] As used herein, the term "alkylene" means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0016] As used herein, the term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example, 1 to 6 carbon atoms. For example, as used herein, the term "C" is used to refer to... 1-6 "Alkyl" refers to a linear or branched group with 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogens (in which case the group is called "haloalkyl") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0017] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2–6 carbon atoms ("C"). 2-6 The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may exist in pure E (iso-side), pure Z (iso-side), or any mixture thereof. The term "alkenyl" refers to the corresponding divalent group, including, for example, "C..." 2-6 "Ideinyl", "C" 2-4 "Alkenyl", etc., specific examples of which include, but are not limited to: -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, buteneyl, pentenyl, hexeneyl, etc.

[0018] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group comprising one or more triple bonds, preferably having 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents. The term "ynynyl" refers to the corresponding divalent group, including, for example, "C..." 2-8 "Isynyne", "C" 2-6 "Isynyne", "C" 2-4 Examples include, but are not limited to, "ethynyl groups". , , , The alkyne group is optionally substituted by one or more (such as 1 to 3) identical or different substituents.

[0019] As used herein, the term “fused ring” or “dense ring” refers to a ring system formed by two or more ring structures sharing two adjacent atoms.

[0020] As used herein, the term "spiroring" refers to a ring system consisting of two or more ring structures that share a single ring atom.

[0021] As used in this article, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.

[0022] As used herein, the terms “cycloalkylene group,” “cycloalkylene group,” and “hydrocarbon ring” refer to a saturated (i.e., “cycloalkylene group” and “cycloalkylene group”) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring (including spirocyclic, fused (fused) ring, or bridged ring systems) having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6) cyclic carbon atoms, including but not limited to (cycloalkylene group) propyl(ring), (cycloalkylene group) butyl(ring), (cycloalkylene group) pentyl(ring), (cycloalkylene group) hexyl(ring), (cycloalkylene group) heptyl(ring), (cycloalkylene group) octyl(ring), (cycloalkylene group) nonyl(ring), (cycloalkylene group) hexenyl(ring), etc.

[0023] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6"Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) with 3 to 6 cyclic carbon atoms, which is optionally substituted by one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0024] As used herein, the term "heterocyclic group" (or "heterocycle") refers to a saturated or partially unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms and one or more (e.g., one, two, three, or four) heteroatoms selected from O, S, N, and P, and the "heterocyclic group" (or "heterocycle") may contain -C (=O)- as a ring member. The heterocyclic group may be attached to the remainder of the molecule via the carbon atoms and / or heteroatoms (if present). Specifically, 3-10 membered heterocyclic groups are groups having 3-10 carbon atoms and heteroatoms in the ring, such as, but not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolyl, pyrrolidone, imidazoalkyl, pyrazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0025] As used herein, the term "heterocyclic group" (or "heterocycle") encompasses fused ring structures, wherein the connection point between the fused ring structure and other groups can be on any ring within the fused ring structure. Therefore, the heterocyclic groups of the present invention also include, but are not limited to, heterocyclic fused heterocyclic groups, heterocyclic fused cycloalkyl groups, monoheterocyclic fused monoheterocyclic groups, monoheterocyclic fused monocycloalkyl groups, aryl fused heterocyclic groups, and heteroaryl fused heterocyclic groups, such as 3-7 membered (mono)heterocyclic fused 3-7 membered (mono)heterocyclic groups, 3-7 membered (mono)heterocyclic fused (mono)cycloalkyl groups, and 3-7 membered (mono)heterocyclic fused C 4-6 (Mono)cycloalkyl, C 6-10 Aryl 3-7 membered heterocyclic groups and 5-6 membered heteroaryl 3-7 membered heterocyclic groups, examples of which include, but are not limited to, pyrrolidinyl cyclopropyl, cyclopentyl aziridine propyl, pyrrolidinyl cyclobutyl, pyrrolidinyl pyrrolidinyl, pyrrolidinyl piperidinyl, pyrrolidinyl piperazine, and piperidinyl morpholinyl. , or .

[0026] As used herein, the term "heterocyclic group" (or "heterocycle") encompasses both bridged heterocyclic groups (bridged heterocycles) and spirocyclic groups (spirocyclic heterocycles).

[0027] As used herein, the term "bridged heterocycle" refers to a ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and / or sulfur atoms) formed by two rings sharing two non-directly connected ring atoms. This includes, but is not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example... , , , , , , , , , , , , , , , , , , , , , The "nitrogen-bridged heterocycle", "oxygen-bridged heterocycle", and "sulfur-bridged heterocycle" may optionally also contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.

[0028] As used herein, the term "spiroheterocycle" refers to a ring structure consisting of two or more rings sharing a single ring atom and containing one or more heteroatoms (e.g., oxygen, nitrogen, sulfur), including but not limited to 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, and 6-10 membered sulfur-containing spiroheterocycles, etc. , , , , , , , , , , , , , , , , , , and The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", and "sulfur-containing spiroheterocycle" may optionally also contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur. The term "6-10-membered nitrogen-containing spiroheterocycle group" refers to a spiroheterocycle group containing a total of 6-10 ring atoms, of which at least one ring atom is a nitrogen atom.

[0029] As used herein, the terms “(aryl)aryl” and “aromatic ring” refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated π-electron system. For example, as used herein, the term “C…” 6-10 (Asyl) aryl" and "C 6-10 "Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or ()naphthyl (naphthalene ring). The ()aryl and aromatic rings are optionally substituented with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted.

[0030] The term "aralkyl" means an aryl-substituted alkyl group, wherein the aryl group and the alkyl group are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0031] As used herein, the terms “(sub)heteroaryl” and “heteroary ring” refer to monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom that may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused. Specifically, "(hybrid)aryl" or "heteroary ring" is selected from (thienyl)thiophene (ring), (furanyl) (ring), (pyrrolyl) (ring), (oxazolyl) (ring), (thiazolyl) (ring), (imidazolyl) (ring), (pyrazolyl) (ring), (isooxazolyl) (ring), (isothiazolyl) (ring), (oxadiazolyl) (ring), (triazolyl) (ring), (thiadiazolyl) (ring), and their benzo[a] derivatives; or (pyridyl)pyridinyl (ring), (pyridazinyl)pyrimidinyl (ring), (pyrazinyl)pyrazinyl (ring), (triazinyl)pyrazinyl (ring), and their benzo[a] derivatives.

[0032] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0033] As used herein, the term "alkylthio" refers to an alkyl group as defined above, which is attached to a portion of the parent molecule via a sulfur atom. C1-6 Representative examples of alkyl thio groups include, but are not limited to, methyl thio, ethyl thio, tert-butyl thio, and hexyl thio.

[0034] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or partially unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring, and optionally may also contain one or more (e.g., one, two, three, or four) ring members selected from N, O, S, S=O, and S(=O)2; the nitrogen-containing heterocycle is connected to the remainder of the molecule through any ring member. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. Specifically, 3- to 14-membered nitrogen-containing heterocycles are groups having 3 to 14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to ternary nitrogen-containing heterocycles (such as aziridinyl), quaternary nitrogen-containing heterocycles (such as aziridine), pentazolidinyl, pyrrolinyl, pyrrolidone, imidazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolin ...

[0035] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0036] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.

[0037] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0038] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0039] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0040] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0041] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium (D, ...). 2 H), tritium (T), 3 H); carbon isotopes (e.g., ... 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes ... 32 P); and isotopes of sulfur (e.g. 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0042] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0043] Solid lines may be used in this article. ), solid wedge ( ) or virtual wedge ( The carbon-carbon bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) are included at that carbon atom. Solid or imaginary wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0044] Rotation-restricted isomers are compounds that can be isolated into rotation-restricted isomers.

[0045] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0046] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0047] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts for the compounds of the present invention are known to those skilled in the art.

[0048] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the invention may themselves be esters.

[0049] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0050] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0051] This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that readily convert in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (EB Roche, editor, American Pharmaceutical Association). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0052] The scope of this invention also includes polymorphs of the compounds of this invention. "Polymorph" refers to different solid crystalline phases resulting from the presence of two or more different molecular arrangements in the solid state of certain compounds of this invention. Some compounds of this invention may exist in more than one crystal form, and this invention aims to include various crystal forms and mixtures thereof.

[0053] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in *Protective Groups in Organic Chemistry*, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & PGM Wuts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0054] As used herein, the term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0055] compound In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound has the structure of formula (I):

[0056] in: Indicates a single bond or a double bond; X is CR X Either N or NH; Y is CR Y Or N; Z is CR Z Or N; W is either C or N; R X R Y R Z R 1 R 2 R 3 R 13 Each time it appears, it is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a-C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b and -OC 1-6 Alkylene-NR a R b ; Or R 1 and R 2 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups; R 8 R 9 R 10 R 11 Each time it appears, it is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl; Or R 8 and R 9 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; Or R 9 and R 10 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; A represents O and CR. A1 R A2 or NR N ; R A1 R A2 Each time it appears, it is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, cyclic hydrocarbon group, heterocyclic group, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl; Or R A1 and R A2 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; Or R A1 and R A2 Together with the groups to which it is attached, they optionally constitute C 2-6 alkenyl; Or R A1 and R 8 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; R N Selected from H, halogens, -OH, -NH2, -CN, -NO2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, hydroxy-C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 heteroaryl groups; Or R N and R 8 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; R 12 Selected from H, halogens, -OH, -NH2, -CN, and -NO2; Or R 8 and R 12 Together with the single ring containing A that it connects to, they can optionally form a 7-10 bridging heterocyclic group; Or R 10 and R 12 Together with the single ring containing A that it connects to, they can optionally form a 7-10 bridging heterocyclic group; B can be O, CH2, or NH; X1 is either C or N; X2 is either C or N; X3 is either C or N; X4 is either C or N; X5 is either C or N; R 4 R 5 R 6 R 7 Each occurrence is independently selected from the following: non-existent, H, halogen, oxo, -OH, -NH2, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 heteroaryl groups; Or R 4 and R 5 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; Or R 5 and R 6 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; The aforementioned alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkyl, heterocyclic, heterocyclic, aryl, aromatic, heteroaryl, heteroaromatic, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -NH2, -CN, -NO2, =CH2, =CF2, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R c -OC(=O)R c -C(=O)OR c -OR c -SR c -S(=O)R c -S(=O)2R c -S(=O)2NR c R d -NR c R d -C(=O)NR cR d -NR c -C(=O)R d -NR c -C(=O)OR d -NR c -S(=O)2-R d -NR c -C(=O)-NR c R d -C 1-6 Alkylene-OR c -C 1-6 Alkylene-NR c R d and -OC 1-6 Alkylene-NR c R d The alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NR c R d -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, halogenated or unsubstituted C 3-6 Cyclic hydrocarbon group, halogenated or unsubstituted 3-10 membered heterocyclic group, halogenated or unsubstituted C 6-10 aryl, halogen-substituted or unsubstituted 5-14 membered heteroaryl, C 6-12 Aryl groups, -OC 1-6 Alkyl and -C 1-6 Alkylene-OC 1-6 alkyl; R c and R d Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl group, wherein the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and aryl group are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl groups and -C 1-6 Alkylene-OC1-6 alkyl; m is 0, 1, or 2; p is 0 or 1; n, q, and t are each independently 0 or 1.

[0057] In some implementation schemes, R X R Y and R Z Each is independently selected from H, halogen, -CN, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and -O-(C 1-6 alkyl).

[0058] In some implementation schemes, R X R Y and R Z Each is independently selected from H, F, Cl, methyl, trifluoromethyl and methoxy.

[0059] In some implementations, X is CH, C-CH3, or NH.

[0060] In some implementations, Y is CR Y Or N, where R Y Selected from H, halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and -O-(C 1-6 alkyl).

[0061] In some implementation schemes, R Y Selected from H, F, Cl, methyl, trifluoromethyl, and methoxy; In some implementations, Z is CH or N; In some implementations, W is C or N.

[0062] In some implementation schemes, R 1 and R 2 Each is independently selected from H, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups and hydroxyl-C 1-6 alkyl.

[0063] In some implementation schemes, R 1 and R 2 Each is independently selected from H, F, Cl, Br, I, methyl, -CD3, ethyl, cyclopropyl and hydroxymethyl.

[0064] In some implementation schemes, R 1 and R 2 Together with the groups to which it is attached, they optionally constitute C5-6 Hydrocarbon rings, 5-6 membered heterocycles, or 5-6 membered heteroaromatic rings.

[0065] In some implementation schemes, R 1 and R 2 Together with the groups to which they are attached, they optionally constitute , , , , , , , , , , , , , , or .

[0066] In some implementation schemes, R 13 Selected from H, halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and -O-(C 1-6 alkyl).

[0067] In some implementation schemes, R 13 Selected from H, F, Cl, methyl, trifluoromethyl, and methoxy; In some implementations, m is 0 or 1.

[0068] In some implementation schemes, Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0069] In some implementation schemes, R 8 R 9 R 10 R 11 Each time it appears, it is independently selected from H, halogen, -OH, -NH2, C. 1-6 Alkyl and deuterated C 1-6 alkyl.

[0070] In some implementation schemes, R 8 R 9 R 10 R 11 Each time it appears, it is independently selected from H and methyl.

[0071] In some implementation schemes, R 8 and R 9 Together with the groups to which it is attached, they optionally constitute C 3-5 Hydrocarbon rings or 3-6 membered heterocycles.

[0072] In some implementation schemes, R 8 and R 9 Together with the groups to which it is attached, they optionally form a cyclopropane ring.

[0073] In some implementation schemes, R 9 and R 10 Together with the groups to which it is attached, they optionally constitute C 3-5 Hydrocarbon rings or 5-6 membered heteroaromatic rings.

[0074] In some implementation schemes, R 9 and R 10 Together with the groups to which it is attached, they optionally form a cyclobutane ring or .

[0075] In some implementation schemes, R A1 R A2 Each time it appears, it is independently selected from H and C. 1-6 alkyl.

[0076] In some implementation schemes, R A1 R A2 Each time it appears, it is independently selected from H.

[0077] In some implementation schemes, R A1 and R A2 Together with the groups to which they are attached, they optionally form a 4-5 membered heterocycle.

[0078] In some implementation schemes, R A1 and R A2 Together with the groups to which they are attached, they optionally constitute .

[0079] In some implementation schemes, R A1 and R A2 Together with the groups to which it is attached, they optionally constitute C 2-3 Alkenyl group.

[0080] In some implementation schemes, R A1 and R A2Together with the groups to which they are attached, they optionally constitute .

[0081] In some implementation schemes, R A1 and R 8 Together with the groups to which they are attached, they optionally form a 5-6 membered heteroaromatic ring.

[0082] In some implementation schemes, R A1 and R 8 Together with the groups to which they are attached, they optionally form a cyclobutyl group or .

[0083] In some implementation schemes, R N Selected from H, halogens, C 1-6 Alkyl and C 3-6 Cyclic hydrocarbon group.

[0084] In some implementation schemes, R N Selected from cyclopropyl.

[0085] In some implementation schemes, R N and R 8 Together with the groups to which they are attached, they optionally form a 4-5 membered heterocycle.

[0086] In some implementation schemes, R N and R 8 Together with the groups to which they are attached, they optionally constitute .

[0087] In some implementation schemes, R 12 Selected from H and halogens.

[0088] In some implementation schemes, R 12 Selected from H.

[0089] In some implementation schemes, R 8 and R 12 Together with the monocyclic ring containing A that it is connected to, they can optionally form a 7-8 bridging heterocyclic group.

[0090] In some implementation schemes, R 8 and R 12 Together with the single ring containing A that it connects, they can optionally constitute or .

[0091] In some implementation schemes, R 10 and R 12 Together with the monocyclic ring containing A that it is connected to, they can optionally form a 7-8 bridging heterocyclic group.

[0092] In some implementation schemes, R 10 and R12 Together with the single ring containing A that it connects, they can optionally constitute .

[0093] In some implementation schemes, R 4 R 5 R 6 R 7 Each occurrence is independently selected from non-existent, H, halogen, oxidized, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-3 Alkyne group, 6-8 membered heterocyclic group, C 6-10 Aryl and 5-6 quinone heteroaryl groups.

[0094] In some implementation schemes, R 4 R 5 R 6 R 7 Each time it appears, it is independently selected from the following: non-existent, H, Cl, F, Br, oxo, methyl, trifluoromethyl. , , , , , , , and .

[0095] In some implementation schemes, R 4 and R 5 Together with the groups to which they are attached, they optionally form a 5-6 membered heterocycle.

[0096] In some implementation schemes, R 4 and R 5 Together with the groups to which they are attached, they optionally constitute .

[0097] In some implementation schemes, R 5 and R 6 Together with the groups to which they are attached, they optionally form a 5-6 membered heterocycle or a 5-6 membered heteroaromatic ring.

[0098] In some implementation schemes, R 5 and R 6 Together with the groups to which they are attached, they optionally constitute , , , , , , , , , , , , , or .

[0099] In some implementation schemes, Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0100] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound has the structure of formula (II-1), (II-2), (II-3), (IV-1), (IV-2), (IV-3), (III-1), (III-2), (III-3), (V-1), (V-2), (V-3), (VI-1), (VI-2), (VI-3), (VII-1), (VII-2), (VII-3): , , , , , , , , , , , , , , , , , ; Where R Y R 8 R 9 R 10 R 11 A, B, R 5 As defined in this article.

[0101] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein said compound is selected from:

[0102] .

[0103] Pharmaceutical compositions and treatment methods In some embodiments, the present invention provides a pharmaceutical composition comprising a preventatively or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is preferably a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form. In some embodiments, the pharmaceutical composition may also comprise one or more other therapeutic agents.

[0104] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs of the present invention, or pharmaceutical compositions of the present invention, in the preparation of a medicament used as a PRMT5 inhibitor.

[0105] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs of the present invention, or pharmaceutical compositions of the present invention, which are used as PRMT5 inhibitors.

[0106] In some embodiments, the present invention provides a method for preventing or treating cancer (preferably MTAP-deficient cancer), the method comprising administering to an individual in need an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug or pharmaceutical composition of the present invention.

[0107] In some implementations, the cancers include pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck cancer, squamous cell carcinoma of the head and neck, lymphoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, skin cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, and sarcoma.

[0108] In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0109] Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms of such a disease or condition to which such term is applied, or to prevent such a disease or condition or one or more symptoms of such a disease or condition.

[0110] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0111] In another embodiment, the pharmaceutical composition of the present invention may further comprise one or more additional therapeutic or preventative agents.

[0112] Example The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0113] The abbreviations used in this invention have the following meanings:

[0114] Synthesis of intermediate A:

[0115] Step 1: In a nitrogen atmosphere at -78°C o At C, lithium diisopropylamino (63.55 mL, 63.55 mmol) was slowly added dropwise to a tetrahydrofuran (200 mL) solution of compound A-1 (15 g, 63.55 mmol) at -78°C. o React at C for 30 minutes. After 30 minutes, add N,N-dimethylformamide (5.56 g, 76.26 mmol) and react at -78°C. o The reaction proceeded for 2 hours. After the reaction was complete, the reaction solution was quenched with ammonium chloride aqueous solution, and the aqueous phase was extracted three times with ethyl acetate (300 mL). The combined organic phases were washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0% ~ 15%) to obtain compound A-2. LCMS [M+H] + m / z = 264.9, 266.9. Step 2: In a nitrogen atmosphere 0 oAt C, formic acid (5.22 g, 113.64 mmol) and triethylamine (5.74 g, 56.82 mmol) were added dropwise to a 10 mL solution of N,N-dimethylformamide, followed by cyclo(isopropyl)malonide (12.95 g, 113.64 mmol). Finally, A-2 (10 g, 37.88 mmol) was added to the reaction solution, and the mixture was reacted at 80 °C. o The reaction was carried out for 12 hours. After the reaction was complete, the reaction solution was quenched in ice water (50 mL), the pH was adjusted to 2 with hydrochloric acid (1 N), and the aqueous phase was extracted three times with ethyl acetate (100 mL). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50% ~ 100%) to obtain compound A-3. LCMS [MH] - m / z = 307.0, 308.9. Step 3: Dissolve A-3 (7 g, 22.73 mmol) in dichloromethane (70 mL), then add dimethylhydroxylamine hydrochloride (3.33 g, 34.09 mmol), HATU (12.95 g, 34.09 mmol), and N,N-diisopropylethylamine (13.22 g, 102.27 mmol), and heat at 25 °C. o The reaction was carried out at C for 2 hours. After the reaction was complete, water (100 mL) was added, and the mixture was extracted three times with dichloromethane (100 mL). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0% ~ 30%) to give compound A-4, LCMS [M+H]+: m / z = 351.9, 353.9. Step 4: In a nitrogen atmosphere at -78°C o At C, n-butyllithium (8.5 mL, 20.51 mmol) was added dropwise to a tetrahydrofuran solution (60 mL) of A-4 (6 g, 17.09 mmol). The reaction was carried out at -78 °C for 4 hours. After the reaction was complete, the mixture was quenched with an aqueous solution of ammonium chloride (30 mL), extracted three times with ethyl acetate (100 mL), and the combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0% ~ 30%) to give compound A-5. LCMS [M+H]+: m / z = 213.0. Step 5: Sodium borohydride (2.14 g, 56.61 mmol) was slowly added to a methanol solution (40 mL) of A-5 (4 g, 18.87 mmol), and the reaction was carried out at 25 °C for 2 hours. After the reaction was complete, an aqueous solution (50 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound A-6. LCMS [M-OH]+: m / z = 197.0. Step 6: To a 40 mL solution of compound A-6 (4 g, 18.69 mmol) in 1,2-dichloroethane, pyridine p-toluenesulfonate (0.92 g, 1.87 mmol) was added, and the mixture was reacted at 80 °C for 6 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2% ~ 20%) to obtain compound A-7.

[0116] Step 7: Compound A-7 (1 g, 5.10 mmol) was dissolved in dimethyl sulfoxide (10 mL) and water (2 mL), and N-bromosuccinimide (1.35 g, 7.65 mmol) was added. The reaction was carried out at 25 °C for 2 hours. After the reaction was complete, aqueous solution (30 mL) was added, and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with water (30 mL) and saturated brine (30 mL). The reaction solution was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30% ~ 60%) to obtain compound A-8. LCMS [M-OH] + m / z = 274.9, 276.9. Step 8: Compound A-8 (1.01 g, 3.46 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydroxide (166 mg, 4.15 mmol) was added. The reaction was carried out at 25 °C for 2 hours. After the reaction was complete, aqueous solution (30 mL) was added, and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with water (30 mL) and saturated brine (30 mL). The reaction solution was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0% ~ 100%) to obtain compound A-9. LCMS [M+H]+: m / z = 213.0. Step 9: Dissolve compound A-9 (650 mg, 3.07 mmol) in acetonitrile (5 mL), add sulfuric acid (601 mg, 6.13 mmol), and react at 25 °C for 0.5 h. Then add water (1 mL) and react at 80 °C for 2 h. After the reaction is complete, use directly for the next step. LCMS [M+H]+: m / z = 230.0. Step 10: Add saturated sodium bicarbonate solution (5 mL) to the reaction solution from the previous step, then add a THF solution of chloroacetyl chloride (693 mg, 6.14 mmol) (3 mL) and react at 25°C for 1 hour. After the reaction is complete, add aqueous solution (30 mL), extract three times with ethyl acetate (30 mL), combine the organic phases, wash with water (30 mL) and saturated brine (30 mL), and concentrate the reaction solution under reduced pressure to obtain compound A-11. LCMS [M+H]+: m / z = 306.0. Step 11: Under nitrogen atmosphere at 0°C, compound A-11 (500 mg, 1.64 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydride (197 mg, 4.92 mmol, 60%) was added. The reaction was carried out at 25°C for 3 hours. After the reaction was complete, ammonium chloride solution (10 mL) was added, and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with water (30 mL) and saturated brine (30 mL). The reaction solution was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50% ~ 100%) to obtain compound A-12. LCMS [M+H]+: m / z = 270.0. Step 12: Compound A-12 (350 mg, 1.30 mmol), Dppp (422 mg, 1.30 mmol), and rhodium (I) bis(1,5-cyclooctadiene)tetrafluoroborate (59 mg, 0.25 mmol) were dissolved in tetrahydrofuran (5 mL), and styrene silane (421 mg, 3.90 mmol) was added. The reaction was carried out at 50 °C for 3 hours. After the reaction was complete, water (20 mL) was added, and the aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The trifluoroacetate of intermediate A was purified by preparative high-performance liquid chromatography (HPLC) to obtain the racemic cis conformation of intermediate A. LCMS [M+H]+: m / z = 256.0. 1H NMR (400 MHz, CD3OD) δ 7.37 (d, J= 8.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 4.83 (d, J = 4.4 Hz, 1H), 4.74 (dt,J = 7.8, 4.0 Hz, 1H), 3.99 – 3.84 (m, 2H),3.28 – 3.11 (m, 4H). Synthesis of intermediate B:

[0117] Step 1: 0 o At temperature C, TEA (58.71 g, 0.58 mol), compound B-1 (40.0 g, 0.21 mol), and cyclo(isopropyl)malonide (32.52 g, 0.23 mol) were added sequentially to a formic acid (80 mL) solution. The reaction solution was kept at 95 °C. o The reaction was carried out at C for 5 hours. The reaction solution was then cooled to 0°C. o C, add 6M dilute hydrochloric acid (360 mL). Continue at 25°C. o The reaction was carried out at C for 1 hour. After the reaction was completed, the reaction was quenched with H2O (300 mL), extracted with EA (300 mL*3), the organic phase was washed with saturated NaCl solution (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH=20:1) to obtain a yellow oily substance B-2. 1 H NMR (400 MHz, DMSO_d6): δ 12.16 (s, 1H), 7.31-7.28 (m, 2H), 7.08-7.05 (m, 1H), 2.84 (t, J=7.6 Hz, 2H), 2.56-2.50 (m, 2 H). Step 2: Oxaloyl chloride (16.54 g, 0.13 mol) was added to B-2 (25.0 g, 0.11 mol) in 400 mL of DCM and 1 mL of DMF at 0 °C. The mixture was heated to 25 °C under nitrogen protection and stirred for 2 hours. After the reaction was complete, the temperature was lowered to 0 °C, and trifluoromethanesulfonic acid (24.45 g, 0.16 mol) was added. The mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the reaction solution was slowly poured into ice water (300 mL), extracted with DCM (300 mL * 3), and the organic phase was washed with saturated NaCl solution (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to obtain yellow solid B-3.1 H NMR (400 MHz, DMSO_d6): δ 7.63 (s, 1H), 7.59 (d, J=1.6 Hz, 1H), 3.10 (t, J=5.6 Hz, 2H), 2.69-2.66 (m, 2 H). Step 3: Referring to the synthesis method of intermediate A, replace A-5 with B-3 to synthesize intermediate B. LCMS [M+H]+:m / z =256.0. Synthesis of intermediate C:

[0118] Step 1: Dissolve A-1 (2.0 g, 8.44 mmol) and triisopropyl borate (2.38 g, 12.66 mmol) in tetrahydrofuran (40 mL) at -60°C. o Under nitrogen protection, a 2.5 M, 4 mL, 10.13 mmol solution of n-butyllithium tetrahydrofuran was slowly added dropwise. After the addition was complete, the reaction solution was kept at -60°C. o The reaction mixture was subjected to reaction C for 1 hour, then heated to room temperature and stirred for 2 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (40 mL), and the pH was adjusted to approximately 3 with 3N hydrochloric acid aqueous solution. After stirring for 10 minutes, the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give C-1 (1.5 g, 88%). LCMS m / z = 385.0 [2M-H₂O-H] - Step 2: C-1 (930 mg, 4.6 mmol) was dissolved in tetrahydrofuran (18 mL), and 30% hydrogen peroxide solution (9 mL) was slowly added. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction was quenched by slow addition of saturated sodium thiosulfate solution (40 mL) under ice bath conditions, and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 23:2) to obtain C-2 (730 mg, 91%). LCMS m / z = 173.0 [MH] - Step 3: C-2 (730 mg, 4.19 mmol) was dissolved in acetonitrile (10 mL), and a solution of NBS (746 mg, 4.19 mmol) in acetonitrile (2 mL) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (80 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (acetonitrile and 0.1% formic acid aqueous solution) to obtain C-3 (430 mg, 40.5%). LCMS m / z = 250.9 [MH] - Step 4: Dissolve C-3 (350 mg, 1.38 mmol), a mixture of cuprous bromide methyl sulfide (57 mg, 0.28 mmol), and Pd(PPh3)4 (80 mg, 0.07 mmol) in dioxane (8 mL), add C-4 (534 mg, 1.38 mmol), and incubate under nitrogen protection at 100 °C. o The reaction was sealed in tube C for 3 hours. The reaction was quenched with water (80 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 24:1) to give C-5 (175 mg, 47%). LCMS m / z = 270.1 [M+H] + Step 5: Mix C-5 (160 mg, 0.59 mmol) and potassium carbonate (484 mg, 1.49 mmol) in DMA (6 mL) and incubate at 90°C under nitrogen protection. o Stir overnight. Dilute with water (60 mL) and extract with ethyl acetate (3 × 30 mL). Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the crude product by column chromatography (petroleum ether: ethyl acetate = 17:3) to give C-6 (140 mg, 95%). LCMS m / z = 250.1 [M+H] + Step 6: Dissolve C-6 (65 mg, 0.26 mmol) in acetic acid (2 mL), add 10% palladium hydroxide on carbon (90 mg), and heat under hydrogen pressure (50 psi) for 30 minutes. oC. Stir overnight. Filter, and concentrate the filtrate under reduced pressure. Neutralize the crude product with saturated sodium bicarbonate solution (30 mL), and extract with ethyl acetate (3 × 20 mL). Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure to intermediate C (60 mg, 90%). LCMS m / z = 256.1 [M+H] + Example 1:

[0119] Compound A (26 mg, 0.07 mmol, TFA salt), 3-1 (16 mg, 0.07 mmol, Wuxi WuXi AppTec), and NMI (29 mg, 0.35 mmol) were dissolved in DMF (0.5 mL), and TCFH (26 mg, 0.09 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, product 3 was obtained by reversed-phase column chromatography. LCMS m / z [M+H] + = 469.2. 1 HNMR(400 MHz, DMSO-d6) δ 8.81 (d, J = 72.2 Hz, 1H), 7.92 (d,J = 17.3 Hz, 1H),7.33 – 7.26 (m, 1H), 7.22 (d,J = 8.1 Hz, 0.5H), 7.07 (s, 2H), 6.97 (d,J = 8.1Hz, 0.5H), 5.71 (dd,J = 121.0, 3.7 Hz, 1H), 5.38 (dt,J = 6.0, 2.8 Hz, 2H), 5.04 (dt,J = 10.7, 3.6 Hz, 2H), 4.41 (dt,J = 48.8, 3.7 Hz, 1H), 3.79 (t,J =10.8 Hz, 1H), 3.65 – 3.49 (m, 1H), 3.14 – 2.99 (m, 2H), 2.93 – 2.66 (m, 2H). Example 2: Following the synthetic method of compound 3, compounds 1, 2, 4 and 16 were synthesized by condensing the corresponding carboxylic acids with intermediates A, B or C.

[0120] Table 1. Structural and confirmatory data of compounds 1, 2, 4 and 16

[0121] Biological tests Experimental Example 1. Compound Activity Test After preparing a 10 mM stock solution of the compounds with DMSO, nine concentration gradients (starting concentration 10 μM, 1:5 dilution) were prepared using buffer (50 mM Tris-HCl pH 8.5, 5 mM MgCl2, 4 mM DTT, 0.01% Triton X-100, 0.1 M NaCl, 0.5% DMSO), with 5 μL added to each well. SAM, peptides, and MTA were prepared with buffer to final concentrations of 1 μM, 1 μM, and 2 μM, respectively, with a total of 5 µL added to each well. A control group without MTA was also set up. The final concentration of PRMT5 protein was 25 nM, with 5 µL added to each well, and the mixture was incubated at 37°C for 2 h. Subsequently, 2.5 μL of stop buffer A, 2.5 μL of 8X MT assay mixture (final concentration 1X), and a mixture of 24 μg / mL AMP2 / GMP2 antibody (final concentration 3 μg / mL) were added, and the mixture was incubated at room temperature for 1.5 h to detect FP (Ex633, Em 647). Negative control wells (Blank) without protein and positive control wells (DMSO) without the compound were also included. Each experiment was performed in triplicate.

[0122] Data processing: Statistically analyze the values ​​of each group and calculate the inhibition rate using the following formula: Inhibition percentage of compound well (%inh) = [1 - (ave Blank - Cpd well) / (ave Blank - ave DMSO control)] * 100, Note: ave represents the average value, and Cpd represents the value of the compound added to the well; Use GraphPad Prism 7.0 software to plot an S-shaped dose-inhibition rate curve using a nonlinear regression model, fit the curve, and calculate the IC50. 50 value.

[0123] Experimental Example 2. Cell-level Compound Activity Assay Proliferation inhibition The effects of the compounds in this application on human colon cancer cell lines HCT-116 and HCT-116-MTAP were evaluated using CCK8. - / - Antiproliferative activity of (MTAP-deficient) cells. Normally growing cells were digested with trypsin cell digestion solution, centrifuged, counted, and seeded at a suitable cell density into 96-well plates (2000 cells / well), 100 μL per well. The day after cell seeding, different concentrations of the compound were added to each well, with three replicates for each concentration point. A corresponding DMSO negative control group was also included. After 8 days of drug treatment, CCK8 solution was added to each well, and the cells were incubated at 37°C for a period of time (until the OD450 of the solvent group reached above 1.0). The absorbance at 450 nm was read using a microplate reader, and the inhibition rate and EC50 were calculated. 50The values ​​were obtained by fitting using GraphPad Prism 7.0 software.

[0124] Table 2. EC50 of compounds at the cellular level 50 value

[0125] SDMA suppression detection Take HCT-116 and HCT-116-MTAP in the logarithmic growth phase - / - Cells were digested with trypsin-based cell digestion solution, centrifuged, counted, and seeded at a suitable cell density into 96-well plates (2000 cells / well), 100 μL per well, and sealed with PBS. The next day, cells were treated with different concentrations of the compound (starting at 10 μM, 5-fold dilution, 9 concentration gradients). After 96 h, the culture medium was aspirated, and the cells were washed twice with 100 μL of PBS. Cells were then fixed with 4% paraformaldehyde and incubated at room temperature for 20 min. The fixative was discarded, and the cells were washed with PBS. 150 μL of a specific blocking buffer (containing 1% Triton-100) was added to each well, and the cells were blocked at room temperature for 2 h. Excess blocking buffer was washed away with PBS. Anti-SDMA (CST) was diluted 1:2000 with blocking buffer containing 0.033% Triton-100, and a blank control group was included. The cells were incubated overnight at 4°C. On the second day, the antibodies were washed twice with 1X PBST. Anti-rabbit-IgG (H+L) (CST) and DRAQ5 (Thermofisher) were diluted to appropriate concentrations with 0.033% Triton-100 blocking buffer (secondary antibody: 1:2000; DRAQ5: 1:10000) and incubated at room temperature for 2 hours. After washing twice with 1X PBST and once with PBS, fluorescence signals at 700 nm and 800 nm were detected using a Li-COR Odyssey dual-color near-infrared laser imager. The inhibition rate was calculated, and EC50 was... 50 The values ​​were obtained by fitting using GraphPad Prism 7.0 software.

[0126] Table 3. Effects of the detected compounds on SDMA inhibition

[0127] Experimental Example 3. Pharmacokinetic Study of a Compound Mouse pharmacokinetics test Eighteen male Balb / c mice aged 6-8 weeks were randomly divided into two groups (Group IV and Group PO). Group IV mice were administered 5 mg / kg of the corresponding compound via tail vein, while Group PO mice were administered 30 mg / kg of the corresponding compound via gavage. Group IV mice had free access to food and water, while Group PO mice were fasted overnight before administration and fed 4 hours after administration. Throughout the experiment, animals had free access to water. Plasma samples were collected at 0.083 (Group IV only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration. Approximately 100 µL of blood was collected from the orbital sinus into 1.5 mL anticoagulated centrifuge tubes and centrifuged at 8000 rpm at 4ºC for 10 minutes. The supernatant plasma sample was transferred to EP tubes. Plasma samples were stored at -80℃ until analysis. Pharmacokinetic parameters of the drug are calculated based on drug concentration-time data, including peak concentration (Cmax), time to peak concentration (Tmax), clearance (CL), steady-state apparent volume of distribution (Vss), area under the drug-time curve (AUC), elimination half-life (t1 / 2), and bioavailability. Data below the 80% limit of quantitation are not included in the calculation of pharmacokinetic parameters.

[0128] Rat pharmacokinetics test In this experimental example, the pharmacokinetic behavior of the compound was tested in SD rats after intravenous (IV) and oral (PO) administration.

[0129] On the day of administration, the actual body weight of rats was measured and the volume of administration was calculated. Three rats were used in each group, and two tests were conducted for each compound: one group received a single intravenous injection, and the other group received a single gavage administration. Whole blood samples were collected via jugular vein at specified time points (0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration). Immediately after collection, the blood samples were transferred to labeled commercially available sample tubes containing K2-EDTA (0.85–1.15 mg), centrifuged (3200 xg, 4°C, 10 min), and plasma was collected. The plasma was transferred to pre-chilled centrifuge tubes, flash-frozen on dry ice, and then stored at -60°C or lower until LC-MS / MS analysis.

[0130] Plasma concentrations were determined using LC-MS / MS. The plasma drug concentration data were processed using a non-compartmental model with WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. Relevant pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method.

[0131] Experimental Example 4. Pharmacodynamic Study of Compounds Human colorectal cancer HCT-116-MTAP - / -Cells were cultured in vitro in a monolayer using McCoy 5A medium (HyClone) containing 10% fetal bovine serum (BI) and 1% penicillin-streptomycin (Beyotime), in an incubator at 37°C and 5% CO2. Subcultures were performed with trypsin digestion 2-3 times per week. When cell saturation reached 80%-90%, cells were harvested, counted, and seeded. 5 x 10⁶ cells were then cultured in a single layer. 6 0.1 mL HCT-116-MTAP - / - Cells were subcutaneously inoculated into the right posterior dorsal region of each mouse. Around day 15 after inoculation, the average tumor volume reached 172 mm. 3 Animals were randomly assigned to treatment groups (n=6 per group) and a control group. Day 0 was the day of group assignment, and administration began by gavage on day 1. Administered once daily at a volume of 10 mL / kg. The control group received a solvent-based control. Tumor volume was measured 2-3 times per week, and the tumors were weighed and recorded. Physical signs of the mice were observed and recorded daily. At the end of the experiment, the tumors were harvested, weighed, and photographed.

[0132] Formula for calculating tumor volume: Tumor volume (mm) 3 ) = 1 / 2 × (a × b 2 (Note: a represents the major axis and b represents the minor axis) Relative tumor inhibition rate (TGI%) = (1 - tumor weight in treatment group / tumor weight in control group) × 100% Weight change rate (WCR) (%) = (Wt1 - Wt0) / Wt0 × 100%, where Wt0 is the animal's weight at the time of grouping (i.e., day d0), and Wt1 is the animal's weight at each measurement.

[0133] Human non-small cell lung cancer (NCI-H838) cells were cultured in vitro in a monolayer using McCoy 5A medium (HyClone) containing 10% fetal bovine serum (BI) and 1% penicillin-streptomycin (Beyotime), and incubated at 37°C in a 5% CO2 incubator. Cells were passaged using trypsin digestion 2-3 times per week. When cell saturation reached 80%-90%, cells were harvested, counted, and seeded. 5 x 10⁶ cells were then cultured in a single layer. 6 0.1 mL of NCI-H838 cells were subcutaneously inoculated into the right posterior dorsal region of each mouse. Around day 29 after inoculation, the average tumor volume reached 156 mm². 3 Animals were randomly assigned to treatment groups (n=6 per group) and a control group. Day 0 was the day of group assignment, and administration began by gavage on day 1. Administered once daily at a volume of 10 mL / kg. The control group received a solvent-based control. Tumor volume was measured 2-3 times per week, and the tumors were weighed and recorded. Physical signs of the mice were observed and recorded daily. At the end of the experiment, the tumors were harvested, weighed, and photographed.

[0134] Formula for calculating tumor volume: Tumor volume (mm) 3 ) = 1 / 2 × (a × b 2 (Note: a represents the major axis and b represents the minor axis) Relative tumor inhibition rate (TGI%) = (1 - tumor weight in treatment group / tumor weight in control group) × 100% Weight change rate (WCR) (%) = (Wt1 - Wt0) / Wt0 × 100%, where Wt0 is the animal's weight at the time of grouping (i.e., day d0), and Wt1 is the animal's weight at each measurement.

[0135] Experimental Example 5. Effect of Compounds on hERG Potassium Ion Channels HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at 37°C and 5% CO2. Cells were digested with TrypLE™ Express and centrifuged to adjust the cell density to 2 × 10⁻⁶ cells / mL. 6 Cells / mL were prepared and gently mixed on a shaker at room temperature for 15-20 min before patch-clamp assays. The culture medium for the prepared cells was replaced with extracellular fluid. Intracellular and extracellular fluids were aspirated from the liquid pool and added to the intracellular fluid pool and cell / substrate pool of the QPlate chip, respectively. Whole-cell patch-clamp recordings of whole-cell hERG potassium current voltage stimulation were performed, and the data were acquired and stored by Qpatch. The compound was started at 30 μM, diluted 3-fold, and six concentration points were set. Each drug concentration was administered twice, with a duration of at least 5 minutes. The current detected in extracellular fluid without the compound was used as a control group for each cell. Each concentration was measured independently in duplicate using at least two cells. All electrophysiological experiments were performed at room temperature.

[0136] Data analysis first involves standardizing the current and blank control current after each drug concentration. Then, the inhibition rate corresponding to each drug concentration was calculated. Calculate the mean and standard error for each concentration, and calculate the half-inhibitory concentration for each compound: The dose-dependent effect was nonlinearly fitted using the above equation, where Y represents the inhibition rate, C represents the concentration of the test substance, and IC50 is the concentration of the test substance. 50 The half-inhibitory concentration is represented by HillSlope, and the curve fitting and IC50 are shown. 50 The calculations were performed using Graphpad software.

[0137] Experimental Example 6. Study on the inhibitory effect of compounds on human liver microsomal CYP450 enzymes 1) Preparation of buffer solution: 100 mM K-Buffer: Mix 9.5 mL of stock solution A into 40.5 mL of stock solution B, adjust the total volume to 500 mL with ultrapure water, and titrate the buffer to pH 7.4 with KOH or H3PO4.

[0138] Raw material A (1 M potassium dihydrogen phosphate): 136.5 g potassium dihydrogen phosphate in 1 L of water; Stock solution B (1 M potassium dihydrogen phosphate): 174.2 g potassium dihydrogen phosphate in 1 L of water.

[0139] 2) Preparation of the test substance The test sample powder is prepared into a stock solution of a certain concentration using DMSO or other organic solvents, and then further diluted with a suitable organic solvent.

[0140] 3) In vitro incubation The in vitro incubation system for liver microsomes in CYP450 enzyme metabolic phenotype studies involves preparing liver microsomes, supplementing them with redox coenzymes, and then adding enzyme-specific selective inhibitors, and conducting biochemical reactions under conditions simulating physiological temperature and environment.

[0141] 4) Detection of the parent drug or metabolites The concentration of the parent drug or its metabolites in the warm incubation solution was determined by LC-MS / MS, and the IC50 was calculated. 50 value.

[0142] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound has the structure of formula (I): ； in: Indicates a single bond or a double bond; X is CR X Either N or NH; Y is CR Y Or N; Z is CR Z Or N; W is either C or N; R X R Y R Z R 1 R 2 R 3 R 13 Each time it appears, it is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R a -OC(=O)R a -C(=O)OR a -OR a -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b -NR a R b -C(=O)NR a R b -NR a -C(=O)R b -NR a -C(=O)OR b -NR a -S(=O)2-R b -NR a -C(=O)-NR a R b -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR a R b and -OC 1-6 Alkylene-NR a R b ; Or R 1 and R 2 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; R a and R b Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups; R 8 R 9 R 10 R 11 Each time it appears, it is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl; Or R 8 and R 9 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; Or R 9 and R 10 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; A represents O and CR. A1 R A2 or NR N ; R A1 R A2 Each time it appears, it is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, cyclic hydrocarbon group, heterocyclic group, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and hydroxy-C 1-6 alkyl; Or R A1 and R A2 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; Or R A1 and R A2 Together with the groups to which it is attached, they optionally constitute C 2-6 alkenyl; Or R A1 and R 8 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; R N Selected from H, halogens, -OH, -NH2, -CN, -NO2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, hydroxy-C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 heteroaryl groups; Or R N and R 8 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; R 12 Selected from H, halogens, -OH, -NH2, -CN, and -NO2; Or R 8 and R 12 Together with the single ring containing A that it connects to, they can optionally form a 7-10 bridging heterocyclic group; Or R 10 and R 12 Together with the single ring containing A that it connects to, they can optionally form a 7-10 bridging heterocyclic group; B can be O, CH2, or NH; X1 is either C or N; X2 is either C or N; X3 is either C or N; X4 is either C or N; X5 is either C or N; R 4 R 5 R 6 R 7 Each occurrence is independently selected from the following: non-existent, H, halogen, oxo, -OH, -NH2, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 heteroaryl groups; Or R 4 and R 5 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; Or R 5 and R 6 Together with the groups to which it is attached, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 heterocyclic aromatic rings; The aforementioned alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkyl, heterocyclic, heterocyclic, aryl, aromatic, heteroaryl, heteroaromatic, and aralkyl groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -NH2, -CN, -NO2, =CH2, =CF2, C 1-6 Alkyl, C 2-6 alkenyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R c -OC(=O)R c -C(=O)OR c -OR c -SR c -S(=O)R c -S(=O)2R c -S(=O)2NR c R d -NR c R d -C(=O)NR c R d -NR c -C(=O)R d -NR c -C(=O)OR d -NR c -S(=O)2-R d -NR c -C(=O)-NR c R d -C 1-6 Alkylene-OR c -C 1-6 Alkylene-NR c R d and -OC 1-6 Alkylene-NR c R d The alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NR c R d -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, halogenated or unsubstituted C 3-6 Cyclic hydrocarbon group, halogenated or unsubstituted 3-10 membered heterocyclic group, halogenated or unsubstituted C 6-10 aryl, halogen-substituted or unsubstituted 5-14 membered heteroaryl, C 6-12 Aryl groups, -OC 1-6 Alkyl and -C 1-6 Alkylene-OC 1-6 alkyl; R c and R d Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl group, wherein the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and aryl group are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl groups and -C 1-6 Alkylene-OC 1-6 alkyl; m is 0, 1, or 2; p is 0 or 1; n, q, and t are each independently 0 or 1.

2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R X R Y and R Z Each is independently selected from H, halogen, -CN, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and -O-(C 1-6 alkyl); Preferably, R X R Y and R Z Each is independently selected from H, F, Cl, methyl, trifluoromethyl and methoxy.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein: X is CH, C-CH3, or NH; Y is CR Y Or N, where R Y Selected from H, halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and -O-(C 1-6 Alkyl groups, preferably selected from H, F, Cl, methyl, trifluoromethyl, and methoxy groups; Z is CH or N; W can be C or N.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 1 and R 2 Each is independently selected from H, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups and hydroxyl-C 1-6 Alkyl; preferably, R 1 and R 2 Each is independently selected from H, F, Cl, Br, I, methyl, -CD3, ethyl, cyclopropyl, and hydroxymethyl; Or R 1 and R 2 Together with the groups to which it is attached, they optionally constitute C 5-6 Hydrocarbon ring, 5-6 membered heterocyclic ring or 5-6 membered heteroaromatic ring; preferably, R 1 and R 2 Together with the groups to which they are attached, they optionally constitute , , , , , , , , , , , , , , or .

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 13 Selected from H, halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl and -O-(C 1-6 Alkyl groups, preferably selected from H, F, Cl, methyl, trifluoromethyl, and methoxy groups; m is 0 or 1.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein... Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 8 R 9 R 10 R 11 Each time it appears, it is independently selected from H, halogen, -OH, -NH2, C. 1-6 Alkyl and deuterated C 1-6 Alkyl groups, preferably selected from H and methyl groups; Or R 8 and R 9 Together with the groups to which it is attached, they optionally constitute C 3-5 Hydrocarbon ring or 3-6 membered heterocycle; preferably, R 8 and R 9 Together with the groups to which it is attached, they optionally form a cyclopropane ring; Or R 9 and R 10 Together with the groups to which it is attached, they optionally constitute C 3-5 Hydrocarbon ring or 5-6 membered heteroaromatic ring; preferably, R 9 and R 10 Together with the groups to which it is attached, they optionally form a cyclobutane ring or .

8. A compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R A1 R A2 Each time it appears, it is independently selected from H and C. 1-6 Alkyl groups, preferably selected from H; Or R A1 and R A2 Together with the groups to which it is attached, they optionally form a 4-5 membered heterocycle; preferably, R A1 and R A2 Together with the groups to which they are attached, they optionally constitute ; Or R A1 and R A2 Together with the groups to which it is attached, they optionally constitute C 2-3 Alkenyl; preferably, R A1 and R A2 Together with the groups to which they are attached, they optionally constitute ; Or R A1 and R 8 Together with the groups to which it is attached, they optionally form a 5-6 membered heteroaromatic ring; preferably, R A1 and R 8 Together with the groups to which they are attached, they optionally form a cyclobutyl group or ; R N Selected from H, halogens, C 1-6 Alkyl and C 3-6 Cycloalkyl group, preferably selected from cyclopropyl; Or R N and R 8 Together with the groups to which it is attached, they optionally form a 4-5 membered heterocycle; preferably, R N and R 8 Together with the groups to which they are attached, they optionally constitute .

9. A compound of any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 12 Selected from H and halogens, preferably selected from H; Or R 8 and R 12 Together with the monocyclic ring containing A that it is connected to, they optionally constitute a 7-8 bridging heterocyclic group; preferably, R 8 and R 12 Together with the single ring containing A that it connects, they can optionally constitute or ; Or R 10 and R 12 Together with the monocyclic ring containing A that it is connected to, they optionally constitute a 7-8 bridging heterocyclic group; preferably, R 10 and R 12 Together with the single ring containing A that it connects, they can optionally constitute .

10. A compound of any one of claims 1-9 or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 4 R 5 R 6 R 7 Each occurrence is independently selected from non-existent, H, halogen, oxidized, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-3 Alkyne group, 6-8 membered heterocyclic group, C 6-10 Aryl and 5-6-membered heteroaryl groups, preferably selected from those that are absent, H, Cl, F, Br, oxo, methyl, trifluoromethyl, , , , , , , , and ; Or R 4 and R 5 Together with the groups to which it is attached, they optionally form a 5-6 membered heterocycle; preferably, R 4 and R 5 Together with the groups to which they are attached, they optionally constitute ; Or R 5 and R 6 Together with the groups to which it is attached, they optionally form a 5-6 membered heterocycle or a 5-6 membered heteroaromatic ring; preferably, R 5 and R 6 Together with the groups to which they are attached, they optionally constitute , , , , , , , , , , , , , or .

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein... Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

12. A compound of any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein said compound has the following structure: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； Where R Y R 8 R 9 R 10 R 11 A, B, R 5 As defined in any one of claims 1-11.

13. A compound of any one of claims 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, transisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the compound is selected from: ； 。 14. A pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of any one of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug, and a pharmaceutically acceptable carrier.

15. Use of any compound of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug, or the pharmaceutical composition of claim 14, in the preparation of a medicament used as a PRMT5 inhibitor, preferably, the medicament being used for the prevention or treatment of cancer (preferably MTAP-deficient cancers, such as pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck cancer, squamous cell carcinoma of the head and neck, lymphoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, skin cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma).

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