Quinazolinone derivative and application thereof in medicine

Abstract

The invention relates to a quinazolinone derivative and application thereof in medicine. Relates to a compound shown in a general formula (I-a) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal of the compound, an intermediate and a pharmaceutical composition of the compound, and application of the compound in preparation of drugs for treating PARP14 related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound described by general formula (I) or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and pharmaceutical compositions thereof, as well as use thereof in preparing drugs for PARP14-related diseases. Background Art

[0002] PARP14 is an interferon-stimulated gene that is overexpressed in multiple tumor types and affects pro-tumor macrophage polarization as well as suppresses anti-tumor inflammatory responses by regulating IFN-γ and IL-4 signaling. PARP14 is a 203 kDa protein with a catalytic domain responsible for the transfer of mono-ADP-ribose to its substrate. In addition to two RNA recognition motifs, PARP14 contains three macrodomains and a WWE domain, which are binding modules for mono- and poly-ADP-ribose, respectively. Catalytic inhibitors of PARP14 have been shown to reverse IL-4-driven pro-tumor gene expression in macrophages. PARP14 is highly expressed in inflammatory disease tissues (but not constitutively in normal tissues), leading to increased primary cytokines (alarmins) and secondary cytokines (Th2 and Th17 cytokines), ultimately leading to increased tissue eosinophils and neutrophils. Targeting these inflammatory pathways with RBN-3143 is expected to have better efficacy than current therapies, such as those that target only a single cytokine such as IL-4, IL-5 and / or IL-13 for asthma treatment.

[0003] The compounds, compositions and methods described herein help to meet the unmet need for the treatment of certain cancers and inflammatory diseases characterized by aberrant expression or activity of PARP14. Summary of the invention

[0004] The present invention aims to provide a novel compound of the general formula (I) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, intermediates and preparation methods thereof, and use thereof in the preparation of drugs for treating diseases associated with abnormal PARP14 expression.

[0005] The compound of the invention has good pharmacokinetic properties and bioavailability, oral properties and good safety.

[0006] The present invention provides a compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds represented by general formula (I) or (II),

[0007]

[0008] In some embodiments, the compound described by general formula (I) is selected from general formula (Ia),

[0009]

[0010] In some embodiments, Ring A is selected from

[0011] or Selected from In some embodiments, Ring A is selected from

[0012]

[0013]

[0014] or Selected from In some embodiments, Ring A is selected from

[0015]

[0016] or Selected from

[0017] In some embodiments, A1 is selected from 5- to 6-membered heterocyclyl, C 4-6 A1 is optionally substituted by 1 to 4 R A1 replace;

[0018] In some embodiments, A1 is selected from thiophenyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, phenyl, The A1 is optionally replaced by 1 to 4 R A1 replace;

[0019] In some embodiments, A2 is selected from a 5-membered heterocyclyl, an 8- to 10-membered heterocyclyl, or a non-aromatic C 5-10 A2 is optionally substituted by 1 to 4 R A2 replace;

[0020] In some embodiments, A2 is selected from 5-membered heteroaryl, 8-10-membered heterocyclyl, non-aromatic C 5-6 A2 is optionally substituted by 1 to 4 R A2 replace;

[0021] In some embodiments, A2 is selected from thiophenyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, benzofuranyl, benzoxazolyl, The A2 is optionally replaced by 1 to 4 R A2 replace;

[0022] In some embodiments, Y1, Y2, and Y3 are each independently selected from N or CR y ;

[0023] In some embodiments, Y1, Y2 are selected from CH, Y3 is selected from CR y ;

[0024] In some embodiments, T1 is selected from N, 15 N or CR t ;

[0025] In some embodiments, T2 is selected from N or 15 N;

[0026] In some embodiments, Z is selected from O or S;

[0027] In some embodiments, R 1 Selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, nonaromatic C 3-12 A carbocyclic group or a non-aromatic 4 to 12-membered heterocyclic group, wherein the aryl, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R 1a replace;

[0028] In some embodiments, R 1 Selected from 1 to 4 R 1a substituted by one of the following groups: phenyl, naphthyl, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 5-12 Cycloalkyl, C 5-12 Spirocycloalkyl, C 5-12 Bridged cycloalkyl, 4- to 7-membered monoheterocycloalkyl, 6- to 12-membered cycloheterocycloalkyl, 6- to 12-membered spiroheterocycloalkyl, 6- to 12-membered bridged heterocycloalkyl;

[0029] In some embodiments, R 1 Selected from 1 to 4 R 1asubstituted by one of the following groups: phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridothiphenyl, pyridooxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidooxazolyl, pyrimidothiazolyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclopropyloxetanyl, cyclopropyl cyclopentyl, cyclopentyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclobutyloxetanyl, cyclobutyltetrahydrofuranyl, cyclobutyltetrahydropyranyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclopentyloxetanyl, cyclopentyltetrahydrofuranyl, cyclopentyltetrahydropyranyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, cyclohexyloxetanyl, cyclohexyltetrahydrofuranyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, cyclohexyloxetanyl, cyclohexyltetrahydrofuranyl, cyclohexyl Tetrahydropyranyl, cyclopropyl spiroazetidinyl, cyclopropyl spiropyrrolidinyl, cyclopropyl spiropiperidinyl, cyclopropyl spirooxetanyl, cyclopropyl spirotetrahydrofuranyl, cyclopropyl spirotetrahydropyranyl, cyclobutyl spiroazetidinyl, cyclobutyl spiropyrrolidinyl, cyclobutyl spiropiperidinyl, cyclobutyl spirooxetanyl, cyclobutyl spirotetrahydrofuranyl, cyclobutyl spirotetrahydropyranyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclopentyl spirooxetanyl, cyclopentyl spirotetrahydrofuranyl, cyclopentyl spirotetrahydropyranyl, cyclohexyl spiro azetidinyl, cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, cyclohexylspiroxetanyl, cyclohexylspirotetrahydrofuranyl, cyclohexylspirotetrahydropyranyl, azacyclohexylspiroazacyclohexyl, azacyclopentylspiroazacyclohexyl, azacyclopentylspiroazacyclopentyl, azacyclohexylazacyclohexyl, azacyclopentylazacyclohexyl, azacyclopentylazacyclohexyl, azacyclopentylazacyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.1]heptanyl, adamantyl,

[0030] In some embodiments, R 1 Selected from 1 to 4 R 1asubstituted by one of the following groups: morpholinyl, azetidinyl, pyrrolidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridothiphenyl, pyridooxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidooxazolyl, pyrimidothiazolyl,

[0031] In some embodiments, R 1 Selected from 1 to 4 R 1a One of the following groups substituted:

[0032] In some embodiments, R 1 is selected from 4 to 7 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by 1 to 4 R 1a replace;

[0033] In some embodiments, R 1 Selected from 1 to 4 R 1a Replaced

[0034] In some embodiments, Selected from

[0035] In some embodiments, L is selected from a bond, -O-, -S-, -NH-, -N(C 1-4 Alkyl)-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene-, -NH-C 1-4 Alkylene-, -N(C 1-4 Alkyl)-C 1-4 Alkylene-, -C 1-4 Alkylene-, said alkylene or alkyl group is optionally substituted by 1 to 4 R k replace;

[0036] In some embodiments, L is selected from a bond, -O-, -S-, -NH-, -OCH2-, -OCH2CH2-, -OCH2CH2CH2-, -NHCH2-, -NHCH2CH2-, -NHCH2CH2-, wherein the -CH2- is optionally replaced by 1 to 4 R k replace;

[0037] In some embodiments, L is selected from -OC 1-4 Alkylene-, said alkylene is optionally substituted by 1 to 4 R k replace;

[0038] In some embodiments, L is selected from -OCH2-;

[0039] In some embodiments, Q is selected from O, NR q , S, S(=O), S(=O)2;

[0040] In some embodiments, Q is selected from O, NH or S;

[0041] In some embodiments, X is selected from O or S;

[0042] In some embodiments, Z1 is selected from NR 5 or 15 NR 5 ;

[0043] In some embodiments, Z2 is selected from N or 15 N; In some embodiments, Ring B is selected from Ring B is selected from C 3-12 Carbocyclyl, 4 to 12 membered heterocyclyl,;

[0044] In some embodiments, Ring B is selected from C 3-12 Cycloalkyl, 4- to 13-membered heterocycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl;

[0045] In some embodiments, Ring B is selected from C 3-7 Monocyclic alkyl, C 3-7 Monocyclic alkenyl, C 5-12 Cycloalkyl, C 5-12 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 4- to 7-membered monoheterocycloalkyl, 4- to 7-membered monoheterocycloalkenyl, 6- to 12-membered cycloheterocycloalkyl, 6- to 12-membered spiroheterocycloalkyl, 6- to 12-membered bridged heterocycloalkyl, benzoC 4-6 Carbocyclic or benzo 4- to 6-membered heterocyclic group;

[0046] In some embodiments, Ring B is selected from C 3-7 Cycloalkyl, C 8-12 Cycloalkyl, C 8-12 Spirocycloalkyl, C 8-12 bridged cycloalkyl, 4- to 7-membered monoheterocycloalkyl, 6- to 12-membered cycloheterocycloalkyl, 6- to 12-membered spiroheterocycloalkyl, 6- to 10-membered bridged heterocycloalkyl, 11- to 13-membered bicyclic heterocycloalkyl, 11- to 13-membered tricyclic heterocycloalkyl, phenyl, naphthyl, 5- to 6-membered heteroaryl, 8- to 10-membered cycloheteroaryl;

[0047] In some embodiments, Ring B is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridothiphenyl, pyridooxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidooxazolyl, pyrimidothiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl , cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylazetidinyl, cyclopropylpiperidinyl, cyclopropyloxetanyl, cyclopropyltetrahydrofuranyl, cyclopropyltetrahydropyranyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclobutyloxetanyl, cyclobutyltetrahydrofuranyl, cyclobutyltetrahydropyranyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclopentyloxetanyl, cyclopentyltetrahydrofuranyl, cyclopentyltetrahydropyranyl, cyclohexylazetidinyl, cyclohexylpyrrolidine cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclopropyl spirooxetanyl, cyclopropyl spirotetrahydrofuranyl, cyclopropyl spirotetrahydropyranyl, cyclobutyl spiroazetidinyl, cyclobutyl spiropyrrolidinyl, cyclobutyl spiropiperidinyl, cyclobutyl spirooxetanyl, cyclobutyl spirotetrahydrofuranyl, cyclobutyl spirotetrahydropyranyl, cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclopentyl spirooxetanyl, cyclopentyl spirotetrahydrofuranyl, cyclopentyl spirotetrahydropyranyl, cyclobutyl spirocyclopropyl, cyclobutyl spirocyclobutyl, cyclopentyl spirocyclopropyl, cyclopentyl ...propyl, cyclopentyl spirocyclobutyl, cyclopentyl spiro cyclohexylspirocyclopentyl, cyclohexylspirocyclopropyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclopentyl, cyclohexylspirocyclohexyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, cyclohexylspirooxetanyl, cyclohexylspirotetrahydrofuranyl, cyclohexylspirotetrahydropyranyl, azacyclohexylspiroazacyclohexyl, azacyclopentylspiroazacyclohexyl, azacyclopentylspiroazacyclohexyl, azacyclopentylspiroazacyclopentyl, azacyclohexylazacyclohexyl, azacyclopentylazacyclohexyl, azacyclopentylazacyclohexyl, azacyclopentylazacyclopentyl, azacyclohexylspirotetrahydropyranyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.1]heptanyl, adamantyl or a radical formed by the following ring:

[0048] In some embodiments, Ring B is selected from And the left side is directly connected to L;

[0049] In some embodiments, Ring B is selected from C 5-12 Bridged cycloalkyl, 4- to 7-membered heterocycloalkyl;

[0050] In some embodiments, Ring B is selected from The left side is connected to L;

[0051] In some embodiments, R 2 Selected from H, -C(=O)R 2a 、-NR 2b C(=O)R 2a 、-S(=O)2R 2a 、-NR 2b S(=O)2R 2a 、-C(=S)R 2a 、-NR 2b C(=S)R 2a , a 5- to 6-membered nitrogen-containing heterocyclic group, wherein the heterocyclic group is optionally substituted by C(═O) or 1 to 3 R 2a replace;

[0052] In some embodiments, R 2 Selected from H, -C(=O)R 2a 、-NR 2b C(=O)R 2a 、-S(=O)2R 2a 、-NR 2b S(=O)2R 2a 、-C(=S)R 2a 、-NR 2b C(=S)R 2a , imidazolyl, oxazolyl, thiazolyl, pyrrolidinyl, imidazolidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, the pyrrolidinyl and imidazolidinyl groups are optionally substituted with C(═O), the imidazolyl, oxazolyl, thiazolyl, pyrrolidinyl, imidazolidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl groups are optionally substituted with 1 to 3 R 2a replace;

[0053] In some embodiments, R 2 Selected from H, -C(=O)R 2a 、-NHC(=O)R 2a 、-S(=O)2R 2a 、-NHS(=O)2R 2a、-C(=S)R 2a 、-NHC(=S)R 2a , a 5- to 6-membered nitrogen-containing heterocyclic group, wherein the heterocyclic group is optionally substituted by C(═O) or 1 to 3 R 2a replace;

[0054] In some embodiments, R 2 Selected from H, -C(=O)R 2a 、-NHC(=O)R 2a 、-S(=O)2R 2a 、-NHS(=O)2R 2a 、-C(=S)R 2a 、-NHC(=S)R 2a , imidazolyl, oxazolyl, thiazolyl, pyrrolidinyl, imidazolidinyl, the pyrrolidinyl, imidazolidinyl are optionally substituted by C (= O), the imidazolyl, oxazolyl, thiazolyl, pyrrolidinyl, imidazolidinyl are optionally substituted by 1 to 3 R 2a replace;

[0055] In some embodiments, R 2 Selected from H.

[0056] In some embodiments, R 2 Selected from -C(=O)R 2a 、-NR 2b C(=O)R 2a ;

[0057] In some embodiments, R 2 Selected from -C(=O)R 2a 、-NHC(=O)R 2a ;

[0058] In some embodiments, Selected from Ring B and R 2 They cannot be connected by nitrogen-nitrogen bonds;

[0059] In some embodiments, Selected from m1 is selected from 0, 1, 2 or 3;

[0060] In some embodiments, R 2a Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkylene-C 3-12 Carbocyclic group, -C 0-4Alkylene-4 to 12-membered heterocyclic group, -C 1-4 Alkylene-NHC(=O)-C 1-4 Alkylene-NR 2aa R 2ab , -C 1-4 Alkylene-C(=O)NR 2aa R 2ab , -C 1-4 Alkylene-NHC(=O)-C 1-6 Alkyl, -C 1-4 Alkylene-SR 2ac , -C 1-4 Alkylene-OR 2ac , -C 1-4 Alkylene-NHC(=NR 2ad )NR 2aa R 2ab , -C 1-4 Alkylene-R 2ae , -C 0-4 Alkylene-C 3-12 Carbocyclyl-R 2ae , -C 0-4 Alkylene-4 to 12 membered heterocyclic group-R 2ae The alkylene group is optionally substituted by NH2, and the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0061] In some embodiments, R 2a Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 6-membered heterocyclic group, -C 1-4 Alkylene-NHC(=O)-C 1-4 Alkylene-NR 2aa R 2ab , -C 1-4 Alkylene-C(=O)NR 2aa R 2ab , -C 1-4 Alkylene-NHC(=O)-C 1-6 Alkyl, -C 1-4 Alkylene-SR 2ac , -C 1-4 Alkylene-OR 2ac , -C 1-4 Alkylene-NHC(=NR 2ad )NR 2aa R 2ab , -C1-4 Alkylene-R 2ae , -C 0-4 Alkylene-C 3-6 Carbocyclyl-R 2ae , -C 0-4 Alkylene-4 to 6 membered heterocyclic group-R 2ae The alkyl, alkenyl, alkynyl, alkylene, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0062] In some embodiments, R 2a Selected from 1 to 4 R k Substituted with one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-NHC(=O)-CH2-NR 2aa R 2ab , -CH2CH2-NHC(=O)-CH2-NR 2aa R 2ab , -CH2CH2CH2-NHC(=O)-CH2-NR 2aa R 2ab , -CH2CH2CH2CH2-NHC(=O)-CH2-NR 2aa R 2ab , -CH2-NHC(=O)-CH2CH2-NR 2aa R 2ab ,-CH2CH2-NHC(=O)-CH2CH2-NR 2aa R 2ab , -CH2CH2CH2-NHC(=O)-CH2CH2-NR 2aa R 2ab , -CH2CH2CH2CH2-NHC(=O)-CH2CH2-NR 2aa R 2ab 、-CH2-C(=O)NR 2aa R 2ab 、-CH2CH2-C(=O)NR 2aa R 2ab 、-CH2CH2CH2-C(=O)NR 2aa R 2ab 、-CH2CH2CH2CH2-C(=O)NR 2aa R 2ab 、-CH2-SR 2ac、-CH2CH2-SR 2ac 、-CH2CH2CH2-SR 2ac 、-CH2CH2CH2CH2-SR 2ac 、-CH2-NHC(=NR 2ad )NR 2aa R 2ab 、-CH2CH2-NHC(=NR 2ad )NR 2aa R 2ab 、-CH2CH2CH2-NHC(=NR 2ad )NR 2aa R 2ab 、-CH2CH2CH2CH2-NHC(=NR 2ad )NR 2aa R 2ab 、-CH2-R 2ae 、-CH2CH2-R 2ae 、-CH2CH2CH2-R 2ae 、-CH2CH2CH2CH2-R 2ae , -cyclopropyl-R 2ae , -cyclobutyl-R 2ae , -cyclopentyl-R 2ae , -cyclohexyl-R 2ae ,-azetidinyl-R 2ae ,-pyrrolidinyl-R 2ae ,-piperidinyl-R 2ae ;

[0063] In some embodiments, R 2a Selected from CF3, CH2CF3, CF2CF3, CH2CF2CF3, CD3, methyl, ethyl, propyl, isopropyl, azetidinyl, pyrrolidinyl, piperidinyl, cyclopropyl, -CH2-cyclopropyl, -CH2-NHC(=O)-CH2-NR 2aa R 2ab 、-CH(NH2)-CH2-SR 2ac 、-CH(NH2)-CH2CH2-SR 2ac 、-CH(NH2)-CH2-C(=O)NR 2aa R 2ab 、-CH(NH2)-CH2CH2-C(=O)NR 2aa R 2ab 、-CH(NH2)-CH2-NHC(=NR 2ad )NR 2aa R 2abb 、-CH(NH2)-CH2CH2-NHC(=NR 2ad )NR2aa R 2ab 、-CH2-R 2ae , -cyclopropyl-R 2ae , -cyclobutyl-R 2ae , -cyclopentyl-R 2ae , -cyclohexyl-R 2ae ,-azetidinyl-R 2ae ,-pyrrolidinyl-R 2ae ,-piperidinyl-R 2ae ;

[0064] In some embodiments, R 2a Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 4 to 12 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 6 R k replace;

[0065] In some embodiments, R 2a Selected from CF3, CH2CF3, CF2CF3, CH2CF2CF3, CD3, methyl, ethyl, propyl, isopropyl, azetidinyl, pyrrolidinyl, piperidinyl, cyclopropyl, -CH2-cyclopropyl;

[0066] In some embodiments, R 2a With R b Direct connection to form C 3-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R s replace;

[0067] In some embodiments, R 2a With R b Direct connection to form C 3-6 Cycloalkyl or 4 to 7 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl optionally substituted by 1 to 4 R s replace;

[0068] In some embodiments, R 2a With R b directly connected to form a 5-membered, 6-membered or 7-membered heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1 to 4 R s replace;

[0069] In some embodiments, R s are each independently selected from H, deuterium, halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkylene-C3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0070] In some embodiments, R s are each independently selected from H, deuterium, halogen, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-4 to 7 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0071] In some embodiments, R s Each is independently selected from H, F, Cl, Br, I, CN, OH, methyl, ethyl;

[0072] In some embodiments, 2 R s Direct connection to form C 3-6 Carbocyclic group or 4 to 7 membered heterocyclic group;

[0073] In some embodiments, 2 R s Direct connection to form C 3-6 Cycloalkyl (e.g. cyclopropyl, cyclobutyl);

[0074] In some embodiments, R 2b Each independently selected from H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0075] In some embodiments, R 2b Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-2 Alkylene-4 to 7 membered heterocycloalkyl, wherein the alkyl, alkylene, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0076] In some embodiments, R 2bEach independently selected from H or optionally 1 to 4 R k substituted with one of the following groups: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl;

[0077] In some embodiments, R 2b are each independently selected from H, deuterium, C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0078] In some embodiments, R 3 , R 4 Each is independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0079] In some embodiments, R 3 , R 4 Each is independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 3-6 carbocyclic group, 4 to 7 membered heterocyclic group, the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0080] In some embodiments, R 3 , R 4 Each is independently selected from H, halogen, CN, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0081] In some embodiments, R 3 , R 4 Each independently selected from H, F, Cl, Br, I, CN, OH, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, wherein the -CH2-, methyl, ethyl, cyclopropyl is optionally substituted by 1 to 4 Rk replace;

[0082] In some embodiments, R 3 , R 4 Each independently selected from H, F or methyl;

[0083] In some embodiments, R 3 With R 4 Direct connection to form C 3-6 carbocyclic or 4 to 7 membered heterocyclic, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0084] In some embodiments, R 3 With R 4 Directly connected to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted by 1 to 4 R k replace;

[0085] In some embodiments, R 2aa , R 2ab , R 2ac , R 2ad , R 5 Each independently selected from H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0086] In some embodiments, R 2aa , R 2ab , R 2ac , R 2ad , R 5 Each independently selected from H, C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0087] In some embodiments, R 2aa , R 2ab , R 2ac , R 2ad Each is independently selected from H, methyl, ethyl, CF3, -CH2-cyclopropyl, cyclopropyl;

[0088] In some embodiments, R 2aa , R2ab , R 2ac , R 2ad Each is independently selected from H, methyl, ethyl;

[0089] In some embodiments, R 2ae Selected from NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -NHC(=O)-C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0090] In some embodiments, R 2ae Selected from NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -NHC(=O)-C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0091] In some embodiments, R 2ae Selected from -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -NHC(=O)-CH3, -NHC(=O)-CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl , -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -CH2-piperazinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-tetrahydropyranyl, the -CH2-, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl are optionally substituted by 1 to 4 R k replace;

[0092] In some embodiments, R 2aeSelected from -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -NHC(=O)-CH3, -NHC(=O)-CH2CH3, cyclopropyl, cyclobutyl;

[0093] In some embodiments, R q , R 5 Each is independently selected from H or methyl;

[0094] In some embodiments, R 5 Selected from H;

[0095] In some embodiments, R a1 , R a2 , R A1 , R A2 , R y , R t , R 1a , R b independently selected from H, deuterium, halogen, OH, =O, CN, NH2, NO2, COOH, CONH2, C 1-6 Alkyl, -C 1-4 Alkylene -OH, -C 1-4 Alkylene-CN, OC 1-6 Alkyl, SC 1-6 Alkyl, -C 1-4 Alkylene-OC 1-6 Alkyl, -C 1-4 Alkylene-SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-10 carbocyclyl, -O-4 to 10 membered heterocyclyl, -NH-C 3-10 Carbocyclic group, -NH-4 to 10-membered heterocyclic group, -SC 3-10 carbocyclic group, -S-4 to 10 membered heterocyclic group, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4 to 10 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0096] In some embodiments, R a1 , R a2 , R A1 , R A2 , R y , R t , R 1a, R b independently selected from H, deuterium, halogen, OH, =O, CN, NH2, NO2, COOH, CONH2, C 1-4 Alkyl, -C 1-4 Alkylene -OH, -C 1-4 Alkylene-CN, OC 1-4 Alkyl, SC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 carbocyclic group, -O-4 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-4 to 6 membered heterocyclic group, -SC 3-6 carbocyclic group, -S-4 to 6-membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-4 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0097] In some embodiments, R a1 , R a2 , R A1 , R A2 , R y , R t , R 1a , R b Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, =O, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, CH2OH, CH2CN, C2H4OH, C2H4CN, -methyl-O-methyl, -ethyl-O-methyl, -methyl-O-ethyl, -methyl-O-cyclopropyl, -cyclopropyl-O-methyl, -CH2-cyclopropyl, wherein the -CH2-, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propynyl, cyclopropyl are optionally substituted by 1 to 4 R k replace;

[0098] In some embodiments, R 1a , R y , R b Each independently selected from H, deuterium, halogen, OH, =O, CN, NH2, C 1-6Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0099] In some embodiments, R y Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, -CH2OCH3, -CH2OH, -CH2CN;

[0100] In some embodiments, R y Selected from H, deuterium, F, Cl, Br, I, CN, OH, CF3, methyl, ethyl;

[0101] In some embodiments, R 1a , R b Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, =O, CF3, methyl, ethyl;

[0102] In some embodiments, R 1a Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, CF3, methyl, ethyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, -CH2OCH3, -CH2OH, -CH2CN;

[0103] In some embodiments, R b Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, =O, CF3, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, -CH2OCH3, -CH2OH, -CH2CN;

[0104] In some embodiments, R a3 Selected from OH;

[0105] In some embodiments, R a4 Selected from halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, OC 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0106] In some embodiments, R a4is selected from F, Cl, Br, I, CN, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propynyl, cyclopropyl is optionally substituted by 1 to 4 R k replace;

[0107] In some embodiments, R a4 Selected from halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, OC 1-4 Alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0108] In some embodiments, R a5 , R a6 Each independently selected from H or C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0109] In some embodiments, R a5 , R a6 Each independently selected from H or C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0110] In some embodiments, R a5 , R a6 Each independently selected from H, methyl or ethyl, wherein the methyl or ethyl is optionally substituted by 1 to 4 R k replace;

[0111] In some embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, NO2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -SC 3-6 carbocyclic group, -S-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0112] In some embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, NO2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -SC 3-6 carbocyclic group, -S-3 to 7 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0113] In some embodiments, R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, NHCH3, N(CH3)2, CONH2, COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0114] In some embodiments, R kEach independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl;

[0115] In some embodiments, n is selected from 1, 2 or 3;

[0116] In some embodiments, m is selected from 0, 1, 2, 3 or 4;

[0117] In some embodiments, p1, p3 are selected from 0, 1;

[0118] In some embodiments, p2 and p4 are each independently selected from 0, 1, 2, 3 or 4;

[0119] Optionally, when Z1 is NH and Z2 is N, X is S.

[0120] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0121]

[0122] R 1 is selected from 4 to 7 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by 1 to 4 R 1a replace;

[0123] L is selected from -OC 1-4 Alkylene-, said alkylene is optionally substituted by 1 to 4 R k replace;

[0124] Ring B is selected from C 5-12 Bridged cycloalkyl, 4- to 7-membered heterocycloalkyl;

[0125] R 2 Selected from -C(=O)R 2a 、-NR 2b C(=O)R 2a ;

[0126] R 2a Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 4 to 12 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 6 R k replace;

[0127] R 2b are each independently selected from H, deuterium, C 1-6Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0128] R 3 , R 4 Each is independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 3-6 carbocyclic group, 4 to 7 membered heterocyclic group, the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0129] Alternatively, R 3 With R 4 Direct connection to form C 3-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0130] R 1a , R y , R b Each independently selected from H, deuterium, halogen, OH, =O, CN, NH2, C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0131] R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, NHCH3, N(CH3)2, CONH2, COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0132] m is selected from 0, 1, 2, 3 or 4.

[0133] As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0134] R 1 Selected from 1 to 4 R 1a Replaced

[0135] L is selected from -OCH2-;

[0136] Ring B is selected from The left side is connected to L;

[0137] R 1a , R b Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, =O, CF3, methyl, ethyl;

[0138] R y Selected from H, deuterium, F, Cl, Br, I, CN, OH, CF3, methyl, ethyl;

[0139] R 2a Selected from CF3, CH2CF3, CF2CF3, CH2CF2CF3, CD3, methyl, ethyl, propyl, isopropyl, azetidinyl, pyrrolidinyl, piperidinyl, cyclopropyl, -CH2-cyclopropyl;

[0140] R 2 Selected from -C(=O)R 2a 、-NHC(=O)R 2a ;

[0141] R 3 , R 4 Each independently selected from H, F or methyl;

[0142] The remaining definitions are the same as those of the first embodiment of the present invention.

[0143] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table S-1.

[0144] Table S-1

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the S-2 structures.

[0152] Table S-2

[0153]

[0154]

[0155]

[0156] The present invention relates to a pharmaceutical composition, comprising the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0157] The present invention relates to use of the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for PARP14-related diseases, preferably tumors and autoimmune diseases.

[0158] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").

[0159] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition. In some embodiments, the mammal of the present invention includes a human.

[0160] "Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition (e.g., tumor) being treated to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg,

[0161] 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25 -500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg,

[0162] 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg , 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200 -400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25 -300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-20 0mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-2 00mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg;

[0163] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-600 mg, 20-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg of a compound of the invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0164] A method for treating a disease in a mammal (e.g., a PARP14-related disease (e.g., a tumor)), comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg.

[0165] A method for treating a disease in a mammal (e.g., a PARP14-related disease (e.g., a tumor)), comprising administering to a subject a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg / day, wherein the daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 1 In some embodiments, the daily dose includes but is not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1500 mg / day, 2000 mg / day.

[0166] The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as that in the above-mentioned pharmaceutical composition.

[0167] The amount of the compound of the invention or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0168] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0169] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0170] "CN" refers to cyano.

[0171] "Halogen" refers to F, Cl, Br or I.

[0172] "Halogen substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substituted" is abbreviated as "halo".

[0173] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0174] "Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)vX-(CH2)vX-(CH2)vH (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, the heteroatom includes but is not limited to N, O or S, and at least one X is selected from a heteroatom, and the N or S in the heteroatom can be oxidized to various oxidation states). The heteroalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0175] "Alkylene" refers to substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon groups, including -(CH2)v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0176] "Heteroalkylene" refers to a substituted or unsubstituted alkylene in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)vX-(CH2)vX-(CH2)v-, v is an integer from 1 to 5, each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.

[0177] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl radical can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc. The cycloalkyl radical can be monovalent, divalent, trivalent, or tetravalent.

[0178] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxadiazole, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazininyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,

[0179]

[0180] The heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

[0181] "Alkenyl" refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2 ... -methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0182] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, 2 to 4 carbon atoms in the backbone, examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentynyl 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl and the like; the alkynyl group may be monovalent, divalent, trivalent or tetravalent.

[0183] "Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0184] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, a 10-15-membered tricyclic ring, or a 12-18-membered quaternary system. The carbocyclyl can be attached to an aromatic ring or a non-aromatic ring, and the ring can be optionally a monocyclic ring, a cyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0185] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The C, N, S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, and can be connected to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

[0186] "Spiro" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called spiro atom), and the number of ring atoms in the spiro system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 selected from N, O or S (=O) n (n is 0, 1 or 2). "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0187] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to selected from N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

[0188] "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0189] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain 0 or more double bonds. Any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12 or 5 to 10.

[0190] Non-limiting examples include Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.

[0191] "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0192] "Carbocyclic", "cyclic carbocyclyl", "carbocyclyl" or "carbocyclyl" refers to a "cyclic" ring system consisting of only carbon atoms.

[0193] "Carbobridged ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" refers to a "bridged ring" wherein the ring system consists of only carbon atoms.

[0194] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle",

[0195] "Heterocyclic ring", "heterocyclic group", "cyclic heterocyclic group" or "cyclic heterocyclic group" refers to a "cyclic ring" containing a heteroatom.

[0196] "Heterospirocycle", "heterospirocyclyl", "spiroheterocyclyl" or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0197] "Heterobridged ring", "heterobridged ring group", "bridged ring heterocyclyl" or "bridged heterocyclyl" refers to a "bridged ring" containing a heteroatom.

[0198] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0199] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, and S on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, n is 1, 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include

[0200] The heteroaryl groups appearing in this article have the same definition as this definition. The heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment site is located on the aromatic ring.

[0201] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2) m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -Alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R c etc., where R b With R c are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R b With R c It can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or paracyclic groups.

[0202] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is selected from any integer between 1 and 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k For example, "1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from..." For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0203] The XY-membered ring (X, Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes X, X+1, X+2, X+3, X+4...Y-membered rings. The ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heterocyclic ring, a heterospirocyclic ring or a heterobridged ring. For example, "4-7-membered heteromonocyclic ring" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterocyclic ring.

[0204] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x , C x+1 , C x+2 , C x+3 , C x+4 …C y A ring of 1-membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example. 3-6 "Cycloalkyl" means C3, C4, C5 or C6 cycloalkyl;

[0205] When a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence. For example It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0206] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0207] "Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

[0208] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0209] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0210] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0211] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0212] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0213] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0214] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0215] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers (such as trans / cis, Z / E), enantiomers, diastereomers and conformational isomers.

[0216] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.

[0217] “IC 50” is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION

[0218] The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0219] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were measured in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometer, the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS);

[0220] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0221] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0222] Thin layer chromatography silica gel plate using Yantai Huanghai HSGF 254 or Qingdao GF 254 Silica gel plate: The silica gel plate used in thin layer chromatography (TLC) has a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification of products is 0.4mm-0.5mm;

[0223] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;

[0224] Boc: tert-butoxycarbonyl;

[0225] Ts: p-toluenesulfonyl;

[0226] Cbz: benzyloxycarbonyl;

[0227] TMS: trimethylsilyl;

[0228] DCM: dichloromethane;

[0229] Lawson's reagent: CAS19172-47-5.

[0230] The compounds of the present application can be prepared by the following synthesis method:

[0231] Synthesis method 1:

[0232]

[0233] The general formula compound (Z-1) and the compound (Z-2) are reacted by substitution to obtain the general formula compound (Z-3);

[0234] The general formula compound (Z-3) and the compound 2,4-dimethoxybenzylamine are reacted by substitution to obtain the general formula compound (Z-4); the general formula compound (Z-4) is de-2,4-dimethoxybenzyl to obtain the general formula compound (Z-5);

[0235] The general formula compound (Z-5) reacts with 2-chloroacetonitrile to obtain a ring-closed general formula compound (Z-6);

[0236] Compound (Z-7) reacts with 4-bromotetrahydropyran to obtain the target compound (Z-8);

[0237] The compound of the general formula (Z-6) reacts with the compound (Z-8) to obtain the compound of the general formula (Z);

[0238] R z1 Selected from Cl, Br, I, OMs, OTs, OTf and other groups.

[0239] The remaining groups have the same definitions as in the specification and claims.

[0240] General synthesis method 2:

[0241]

[0242] The general formula compound (N-1) and the compound (Z-2) are reacted by substitution to obtain the general formula compound (N-3);

[0243] The general formula compound (N-3) and the compound 2,4-dimethoxybenzylamine are reacted by substitution to obtain the general formula compound (N-4); the general formula compound (N-4) is de-2,4-dimethoxybenzyl to obtain the general formula compound (N-5);

[0244] The general formula compound (N-5) reacts with 2-chloroacetonitrile to obtain a ring-closed general formula compound (N-6);

[0245] The compound of the general formula (N-6) reacts with the compound (Z-7) to obtain the compound of the general formula (N);

[0246] R Z1 Selected from Cl, Br, I, OMs, OTs, OTf and other groups.

[0247] The remaining groups have the same definitions as in the specification and claims.

[0248] General synthesis method three:

[0249]

[0250] Ammonium chloride- 15 N reacts with benzoyl chloride to obtain compound M-1;

[0251] Compound M-1 is reduced to obtain compound M-1-1;

[0252] The general formula compound (Z-3) and the compound M-1-1 are subjected to a substitution reaction to obtain the general formula compound (M-2);

[0253] The compound of the general formula (M-2) is debenzylated to obtain the compound of the general formula (M-3);

[0254] The general formula compound (M-3) reacts with 2-chloroacetonitrile to obtain a ring-closed general formula compound (M-4);

[0255] The compound of the general formula (M-4) reacts with the compound (Z-7) to obtain the compound of the general formula (M);

[0256] The remaining groups are as defined above.

[0257] Example 1: Synthesis of Compound 1

[0258]

[0259] Step 1: Synthesis of 1b

[0260] Under nitrogen protection, 1a (1.83 g, 10.0 mmol) was dissolved in 20 mL of dichloromethane, triethylamine (1.52 g, 15.0 mmol) was added, acetyl chloride (1.14 g, 10 mmol) was added dropwise, and the reaction was carried out at room temperature for 3 h. The reaction solution was poured into 100 mL of water and extracted with DCM (30 mL × 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column to obtain 1b (1.4 g, yield: 63.25%).

[0261] Step 2: Synthesis of 1c

[0262] Under nitrogen protection, 1b (1.4 g, 6.22 mmol) was dissolved in 20 mL of tetrahydrofuran, and 2.5 N lithium aluminum tetrahydride tetrahydrofuran solution (5.0 mL, 12.5 mmol) was added dropwise at 0°C, and the reaction was allowed to react at room temperature for 3 h. The reaction solution was poured into 100 mL of water and extracted with DCM (30 mL×2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column to obtain 1c (1.2 g, yield: 97.93%).

[0263] Steps 3 to 7: The synthesis of 1h refers to the synthesis method of patent WO2019126443.

[0264] Step 8: Synthesis of 1j

[0265] Under nitrogen protection, selenium powder (790 mg, 10.0 mmol) was dissolved in 3 mL DMF, sodium hydroxide (400 mg, 10.0 mmol) and hydrazine hydrate (0.36 mL, 7.5 mmol) were added, and 1i (1.98 g, 12.0 mmol) was added after reacting at room temperature for 2 h, and reacted at room temperature for 12 h. The reaction solution was poured into 10 mL of water and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column to obtain 1j (1.4 g, yield: 42.42%).

[0266] Ms m / z(ESI):331.1[M+H] +

[0267] Step 9: 1k synthesis

[0268] Under nitrogen protection, 1j (1.4 g, 4.24 mmol) was dissolved in 10 mL of dry ethanol, and NaBH4 (818 mg, 21.62 mmol) was added at 0°C. The reaction was allowed to react for 1 h at room temperature. The mixture was cooled to 0°C, quenched with 6N aqueous hydrochloric acid, and extracted with DCM (30 mL × 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column to obtain 1k (0.8 g, yield: 57.14%).

[0269] Step 3: Synthesis of Compound 1

[0270] Under nitrogen protection, 1h (81.4 mg, 0.2 mmol) was dissolved in 3 mL of tetrahydrofuran at 0°C, added dropwise to 0.2 mL of 2 mol / L sodium hydroxide solution, and 1k (41.25 mg, 0.25 mmol) was added. The reaction was continued at 0°C for 0.5 h. The reaction solution was poured into 10 mL of water and extracted with EA (30 mL × 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 1 (5 mg, yield: 4.65%).

[0271] Ms m / z(ESI):538.2[M+H] +

[0272] 1H NMR(400MHz,CD3OD)δ6.86(d,1H),6.78(dd,1H),3.90–3.85(m,3H),3.72(s,2H),3.68(s,2H ),3.51–3.43(m,2H),3.40–3.34(m,1H),2.03–1.93(m,8H),1.87(s,3H),1.77–1.67(m,8H).

[0273] Example 2: Synthesis of Compound 2

[0274]

[0275] Under nitrogen protection, intermediate 1 (73.5 mg, 0.2 mmol, reference patent WO 2019126443) was dissolved in 3 mL of tetrahydrofuran at 0 ° C, 0.2 mL of 2 mol / L sodium hydroxide solution was added dropwise, 1k (41.25 mg, 0.25 mmol) was added, and the reaction was carried out at 0 ° C for 0.5 h. The reaction mixture was poured into 10 mL of water and extracted with EA (30 mL × 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 2 (10 mg, yield: 10.1%).

[0276] Ms m / z(ESI):498.1[M+H] +

[0277] 1 H NMR(400MHz,CD3OD)δ6.90(d,1H),6.80(dd,1H),4.58(d,1H),4.02–3.94(m,3H),3.90–3.84(m,2H),3.68(s,2H),3.50–3.41(m,2H),3.39–3.3 3(m,1H),3.22–3.12(m,1H),2.75–2.63(m,1H),2.20–2.07(m,4H),2.04 –1.97(m,2H),1.94–1.85(m,2H),1.81–1.69(m,2H),1.46–1.24(m,2H).

[0278] Example 3: Synthesis of Compound 3

[0279]

[0280] Steps 1 and 2: Synthesis of compound 3c

[0281] Using compound 3a (5.2 g, 26.08 mmol) as the starting material and referring to the synthesis method of reference 10.6023 / cjoc1108121, the target compound 3c (2.0 g, yield: 46.29%) was prepared.

[0282] Step 3: Synthesis of compound 3d

[0283] Under nitrogen protection, compound intermediate 2 (2.0 g, 6.11 mmol) was dissolved in 50 mL N-methylpyrrolidone, compound 3c (2.0 g, 18.51 mmol), potassium carbonate (2.55 g, 18.51 mmol), warmed to 80 ° C, and reacted for 16 h. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 3d (1.0 g, yield: 39.39%).

[0284] Ms m / z(ESI):416.2[M+H] +

[0285] Step 4: Synthesis of compound 3e

[0286] Compound 3d (1.0 g, 2.41 mmol) was dissolved in methanol and Pd / C (0.1 g) was added to the reaction bottle. The hydrogen atmosphere was replaced and the reaction was carried out at room temperature for 2 h. After the reaction was completed, diatomaceous earth was used for filtration and the mixture was concentrated under reduced pressure and column chromatography was performed to obtain compound 3e (0.6 g, yield: 76.60%).

[0287] Ms m / z(ESI):326.2[M+H] +

[0288] Step 5: Synthesis of compound 3f

[0289] Under nitrogen protection, compound 3e (0.6 g, 1.84 mmol) was dissolved in 10 mL of 2N hydrochloric acid 1,4-dioxane solution and chloroacetonitrile (0.27 g, 3.68 mmol), and reacted at 80°C for 2 h. The mixture was concentrated under reduced pressure. The mixture was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 3f (0.3 g, yield: 44.15%).

[0290] Ms m / z(ESI):369.1[M+H] +

[0291] Step 6: Synthesis of compound 3

[0292] Under nitrogen protection, compound 3f (0.3 g, 0.81 mmol) was dissolved in tetrahydrofuran, 1 mL of 2N sodium hydroxide solution was added dropwise to the reaction flask, and intermediate 3 (0.26 g, 1.62 mmol) was reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column to obtain compound 3 (100 mg, yield: 27.25%).

[0293] Ms m / z(ESI):451.2[M+H] +

[0294] 1 H NMR (400MHz, CD3OD) δ6.94–6.90(m,1H),6.85–6.78(m,1H),4.62–4.52(m,1H),4.06–3.94(m,3H),3.94–3.85(m,2H),3.68(d,2H),3.47–3.37 (m,2H),3.23–3.11(m,1H),3.08–2.97(m,1H),2.75–2.63(m,1H),2.21 –2.07(m,4H),1.99–1.84(m,4H),1.64–1.52(m,2H),1.47–1.22(m,2H).

[0295] Example 4: Synthesis of Compound 4

[0296]

[0297] Raw material 4A (100 mg, 0.22 mmol) and Lawesson's reagent (270 mg, 0.66 mmol) were added to dioxane and heated at 100°C for 16 h. Saturated ammonium chloride was added to quench the reaction, and ethyl acetate (10 mL×3) was extracted. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 4 (23 mg, yield: 21.5%).

[0298] Ms m / z(ESI):482.4[M+H] +

[0299] 1H NMR (400MHz, CD3OD) δ6.95–6.91(m,1H),6.87(dd,1H),5.62–5.54(m,1H),4.41–4.32(m,1H),4.05(dd,2H),3.94–3.86(m,2H ),3.72(s,2H),3.50–3.38(m,3H),3.15–2.99(m,2H),2.64(s,3H),2.33–2.21(m,1H),2.01–1.91(m,4H),1.64–1.42(m,4H).

[0300] Example 5: Synthesis of Compound 5

[0301]

[0302] Step 1: Synthesis of compound 5b

[0303] Under nitrogen protection, compound 5a (1.83 g, 10.0 mmol) was dissolved in 20 mL of dichloromethane, triethylamine (1.52 g, 15.0 mmol), and acetyl chloride (1.14 g, 10 mmol) was added dropwise and reacted at room temperature for 3 h. The reaction mixture was poured into 100 mL of water and extracted with DCM (30 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 5b (1.4 g, yield: 63.25%).

[0304] Step 2: Synthesis of compound 5c

[0305] Under nitrogen protection, compound 5b (1.4 g, 6.22 mmol) was dissolved in 20 mL of tetrahydrofuran, and 2.5 N tetrahydrogen lithium aluminum tetrahydrofuran solution (5.0 mL, 12.5 mmol) was added dropwise to a reaction flask at room temperature for 3 h. The reaction mixture was poured into 100 mL of water and extracted with DCM (30 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 5c (1.2 g, yield: 97.93%).

[0306] Ms m / z(ESI):198.1[M+H] +

[0307] Step 3: Synthesis of compound 5d

[0308] Under nitrogen protection, compound 5c (1.2 g, 6.08 mmol) was dissolved in 20 mL of dichloromethane, triethylamine (1.52 g, 15.0 mmol), and methylsulfonyl chloride (1.14 g, 10 mmol) was added dropwise and reacted at room temperature for 3 h. The reaction mixture was poured into 100 mL of water and extracted with DCM (30 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 5d (1.12 g, yield: 70%).

[0309] Step 4: Synthesis of compound 5f

[0310] Under nitrogen protection, compound 5d (1.12 g, 4.07 mmol) was dissolved in 50 mL DMSO, methyl 2,6-difluoro-4-hydroxybenzoate (765 mg, 4.1 mmol), potassium carbonate (1.1 g, 8 mmol), and the temperature was raised to 80 ° C. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 5f (598 mg, yield: 40%).

[0311] Ms m / z(ESI):368.2[M+H] +

[0312] Steps 5 to 8: Synthesis of compound 5

[0313] The target compound 5 (40 mg, 0.081 mmol) was prepared by referring to the synthetic method of compound 3.

[0314] Ms m / z(ESI):491.2[M+H] +

[0315] 1 H NMR(400MHz,CD3OD)δ6.91–6.86(m,1H),6.80(dd,1H),3.94–3.86(m,2H),3.72(s,2H),3.67(d,2H),3.4 7–3.38(m,2H),3.08–2.98(m,1H),2.00–1.90(m,8H),1.86(s,3H),1.74–1.64(m,6H),1.64–1.51(m,2H).

[0316] Biological test cases

[0317] PARP14 ELISA activity test

[0318] The ELISA method was used to test the inhibitory effect of the compounds on the enzyme activity of PARP14. 50 μl of histone (BPS, 52029) was diluted with PBS (Solarbio, P1022) and added to a 384 reaction plate (Greiner, 781074) and coated overnight at 4°C. After washing with PBST (1XPBS + 0.05% Tween-20), 200 μl of Blocking buffer (BPS, 79743) was added and blocked at room temperature for 90 minutes. PARP14 (BPS, 80514) and 5 μl of the test compound and biotin-labeled substrate (BPS, 78371) were added to the 384 reaction plate, and the mixture was diluted in PARP buffer solution (BPS, 80602) and incubated at room temperature for 1 hour. After washing with PBST, 50 μl of horseradish peroxidase-labeled streptavidin (BPS, 80611) was added and incubated at room temperature for 30 minutes. The plate was washed with PBST, and 100 μl of ELISA substrate A and substrate B mixed solution (BPS, 79670) was added. After 10 minutes, the chemiluminescent signal value was read using PHERAstar FSX BMG. IC was calculated using the inhibition-dose (four-parameter) equation in GraphPad Prism 8.0 software. 50 calculate.

[0319] Table 1 PARP14 kinase activity test results

[0320]

[0321]

[0322] Conclusion: The compounds of the present invention, such as the compounds in the examples, have an inhibitory effect on PARP14. Specifically, compounds 1, 3, 4, and 5 have good inhibitory activity on PARP14.

Claims

1. A compound represented by general formula (Ia) or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, R 1 is selected from 4 to 7 membered heterocycloalkyl, the heterocycloalkyl being optionally substituted by 1 to 4 R 1a replace; L is selected from -OC 1-4 Alkylene-, said alkylene is optionally substituted by 1 to 4 R k replace; Ring B is selected from C 5-12 Bridged cycloalkyl, 4- to 7-membered heterocycloalkyl; R 2 Selected from -C(=O)R 2a 、-NR 2b C(=O)R 2a ; R 2a Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic group, 4 to 12 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 6 R k replace; R 2b are each independently selected from H, deuterium, C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace; R 3 , R 4 Each is independently selected from H, halogen, CN, OH, C 1-6 Alkyl, C 3-6 carbocyclic group, 4 to 7 membered heterocyclic group, the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; Alternatively, R 3 With R 4 Direct connection to form C 3-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replace; R 1a , R y , R b Each independently selected from H, deuterium, halogen, OH, =O, CN, NH2, C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace; R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, NHCH3, N(CH3)2, CONH2, COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; m is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 1 Selected from 1 to 4 R 1a Replaced L is selected from -OCH2-; Ring B is selected from The left side is connected to L; R 1a , R b Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, =O, CF3, methyl, ethyl; R y Selected from H, deuterium, F, Cl, Br, I, CN, OH, CF3, methyl, ethyl; R 2a Selected from CF3, CH2CF3, CF2CF3, CH2CF2CF3, CD3, methyl, ethyl, propyl, isopropyl, azetidinyl, pyrrolidinyl, piperidinyl, cyclopropyl, -CH2-cyclopropyl; R 2 Selected from -C(=O)R 2a 、-NHC(=O)R 2a ; R 3 , R 4 Each is independently selected from H, F or methyl.

3. The compound according to claim 1 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: The compound is selected from one of the structures shown in Table S-1.

4. A compound or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: The compound is selected from one of the structures shown in Table S-2.

5. A pharmaceutical composition comprising the compound of any one of claims 1 to 4 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition or pharmaceutical preparation comprising 1-1500 mg of a compound according to any one of claims 1-4 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof and a pharmaceutical excipient.

7. Use of the compound according to any one of claims 1 to 4 or its stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals for the preparation of medicaments for PARP14-related diseases, preferably tumors and autoimmune diseases.

8. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 4 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a PARP14-related disease such as a tumor and an autoimmune disease.

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