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WO2024251205A1 - Quinazolinone derivative and medical use thereof - Google Patents

Quinazolinone derivative and medical use thereof Download PDF

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Publication number
WO2024251205A1
WO2024251205A1 PCT/CN2024/097795 CN2024097795W WO2024251205A1 WO 2024251205 A1 WO2024251205 A1 WO 2024251205A1 CN 2024097795 W CN2024097795 W CN 2024097795W WO 2024251205 A1 WO2024251205 A1 WO 2024251205A1
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WO
WIPO (PCT)
Prior art keywords
alkylene
nhc
alkyl
membered
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
PCT/CN2024/097795
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French (fr)
Chinese (zh)
Inventor
张晨
何平
宣兆利
廖鹏飞
宁文涛
王乐
李瑶
严庞科
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tibet Haisco Pharmaceutical Co Ltd
Original Assignee
Tibet Haisco Pharmaceutical Co Ltd
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Publication of WO2024251205A1 publication Critical patent/WO2024251205A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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.
  • 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- ⁇ 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.
  • PARP14 contains three macrodomains and a WE 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.
  • alarmins primary cytokines
  • Th2 and Th17 cytokines secondary cytokines
  • Targeting these inflammatory pathways with PARP14 inhibitors is expected to have better efficacy than current therapies, such as those that target only single cytokines such as IL-4, IL-5 and/or IL-13 for asthma treatment.
  • 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.
  • the object of the present invention is to provide a novel compound of the general formula (I) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods thereof, and their use in the preparation of drugs for treating diseases associated with abnormal PARP14 expression.
  • the compound of the invention has good pharmacokinetic properties and bioavailability, oral properties and good safety.
  • 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),
  • the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia), (Ib), (Ic), (Id), (Ie), (If),
  • the compound represented by general formula (I) is selected from the compounds represented by general formula (Ih) and (II),
  • the compound represented by general formula (I) is selected from the compound represented by general formula (IJ),
  • Selected from m1 is selected from 0, 1, 2 or 3;
  • Y 1 , Y 2 , and Y 3 are each independently selected from N or CR y ;
  • Y 1 , Y 2 are selected from CH, and Y 3 is selected from CR y ;
  • Y 1 is selected from N
  • Y 2 is selected from CH
  • Y 3 is selected from CR y ;
  • R 1 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, non-aromatic C 3-12 carbocyclyl, or non-aromatic 4 to 12 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with 1 to 4 R 1a ;
  • R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, 5 to 6 membered heteroaryl, 8 to 10 membered cycloheteroaryl, C 3-7 monocycloalkyl, C 4-7 monocycloalkenyl, 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;
  • R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridothiphenyl, pyridooxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidooxazolyl, pyrimidothiazolyl,
  • R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a :
  • R 1 is selected from R 1A or R 1A optionally substituted with 1 to 4 R 1A
  • R 1A is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted with 1 to 4 R 1a ;
  • R 1A is selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, or 8- to 10-membered heteroaryl, wherein the phenyl, naphthyl, or heteroaryl is optionally substituted with 1 to 4 R 1a ;
  • R 1A is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridothiphenyl, pyridooxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidooxazolyl, pyrimidothiazolyl, pyrimi
  • R 1A is selected from one of the following groups optionally substituted with 1 to 4 R 1a :
  • L is selected from a bond, -O-, -S-, -NH-, -N(C 1-4 alkyl)-, -OC 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 being optionally substituted with 1 to 4 R k ;
  • L is selected from a bond, -O-, -S-, -NH-, -OCH2- , -OCH2CH2-, -OCH2CH2CH2- , -NHCH2- , -NHCH2CH2-, -NHCH2CH2- , -NHCH2CH2CH2- , said -CH2- being optionally substituted with 1 to 4 Rk ;
  • L is selected from -OCH 2 -;
  • Ring B is selected from C 3-7 cycloalkyl, C 8-12 cycloalkyl, 4 to 10 membered heterocycloalkyl, 11 to 13 membered heterocycloalkyl, 11 to 13 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl;
  • 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 10 membered benzoheterocycloalkyl, 6 to 10 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 benzoheterocycloaryl, benzo7 to 9 membered heterocycloalkyl, 5 to 6 membered heteroaryl and 7 to 9 membered heterocycloalkyl;
  • ring B is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridothiphenyl, pyridooxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidooxazolyl, pyrimidothiazolyl, Cyclopropyl, cyclobutyl, cyclopent
  • Ring B is selected from or ring B 1 , and the left side is directly connected to L;
  • Ring B is selected from or ring B 1 , and the left side is directly connected to L;
  • Ring B 1 is selected from C 8-12 cycloalkyl 11 to 13 membered heterocyclyl or 11 to 13 membered heterocycloalkyl;
  • Ring B1 is selected from
  • R2 is selected from or R 2A ;
  • R 2a is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-12 carbocyclyl, -C 0-4 alkylene-4 to 12 membered heterocyclyl, -C 1-6 alkylene-NHC( ⁇ O)-C 1-6 alkylene-NR 2aa R 2ab , -C 1-6 alkylene-C( ⁇ O)NR 2aa R 2ab , -C 1-4 alkylene-NR 2aa C( ⁇ O)R 2ab , -C 1-6 alkylene-N(C 1-6 alkylene)R 2aa , -C 1-6 alkylene-SR 2ac , -C 1-6 alkylene-NHC( ⁇ NR 2ad )NR 2aa R 2ab , -C 1-6 alkylene-R 2ae , -C 1-6 alkylene- -C 0-6 alky
  • R 2a is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-4 to 6 membered heterocyclyl, -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-NR 2aa C( ⁇ O)R 2ab , -C 1-4 alkylene-N(C 1-4 alkylene)R 2aa , -C 1-4 alkylene-SR 2ac , -C 1-4 alkylene-NHC( ⁇ NR 2ad )NR 2aa R 2ab , -C 1-6 alkylene-R 2ae , -C 1-4 alkylene- 0-4 alkylene-C
  • R 2A is selected from
  • R 2B is selected from
  • R 2C is selected from
  • R 3B is selected from
  • Q is selected from O, NR q , S, S( ⁇ O), S( ⁇ O) 2 ;
  • Q is selected from O, NH or S
  • Q 1 is selected from O or NH
  • R 3 and R 4 are each 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 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 3 and R 4 are each 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 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 3 and R 4 are directly linked to form a C 3-6 carbocyclyl or a 4- to 7-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, CN, OH, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl, wherein the -CH 2 -, methyl, ethyl, cyclopropyl are optionally substituted with 1 to 4 R k ;
  • R 3 and R 4 are directly connected to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with 1 to 4 R k ;
  • R 3 and R 4 are each independently selected from H, F or methyl
  • R q , R 5 are each independently selected from H or methyl
  • R 5 is selected from H
  • R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocyclyl, and -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 2aa , R 2ab , R 2ac , R 2ad are each independently selected from H, methyl, ethyl, CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
  • R 2aa , R 2ab , R 2ac , and R 2ad are each independently selected from H, methyl, and ethyl;
  • R 2ae is 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 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 2ae is 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 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 2ae is selected from -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -NHC( ⁇ O)-CH 3 , -NHC( ⁇ O)-CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -pipe
  • R y , R 1a , and R b are each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, ⁇ O, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, and —CH 2 -cyclopropyl, wherein the —CH 2 -, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propynyl, and cyclopropyl are optionally substituted with 1 to 4 R k ;
  • each R y is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH 2 -cyclopropyl, -CH 2 OCH 3 , -CH 2 OH, -CH 2 CN;
  • R y is selected from F, Cl, Br, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;
  • each R 1a is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH 2 -cyclopropyl, -CH 2 OCH 3 , -CH 2 OH, -CH 2 CN;
  • R b is selected from H, deuterium, halogen, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;
  • R b1 is selected from -CH 2 OH, -CH 2 -OCH 3 , -CH 2 CN;
  • n is selected from 1, 2 or 3;
  • m is selected from 0, 1, 2, 3 or 4.
  • Y 1 , Y 2 , and Y 3 are each independently selected from N or CR y ;
  • R 1 is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, non-aromatic C 3-12 carbocyclyl or non-aromatic 4- to 12-membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R 1a ;
  • L is selected from a bond, -O-, -S-, -NH-, -N(C 1-4 alkyl)-, -OC 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 is optionally substituted by 1 to 4 R k ;
  • Ring B is selected from C 3-7 cycloalkyl, C 8-12 cycloalkyl, 4- to 10-membered heterocycloalkyl, 11- to 13-membered heterocycloalkyl, 11- to 13-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;
  • R 2a is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-12 carbocyclyl, -C 0-4 alkylene-4 to 12-membered heterocyclyl, -C 1-6 alkylene-NHC( ⁇ O)-C 1-6 alkylene-NR 2aa R 2ab , -C 1-6 alkylene-C( ⁇ O)NR 2aa R 2ab , -C 1-4 alkylene-NR 2aa C( ⁇ O)R 2ab , -C 1-6 alkylene-N(C 1-6 alkylene)R 2aa , -C 1-6 alkylene-SR 2ac , -C 1-6 alkylene-NHC( ⁇ NR 2ad )NR 2aa R 2ab , -C 1-6 alkylene-R 2ae , -C 0-6 alkylene-C 3-12 carbocycl
  • Q is selected from O, NR q , S, S( ⁇ O), S( ⁇ O) 2 ;
  • R 3 and R 4 are each 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 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 3 and R 4 are directly linked to form a C 3-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;
  • R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocyclyl, and -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 2ae is 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 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R y , R 1a , R b are independently selected from H, deuterium, halogen, OH, ⁇ O, CN, NH 2 , NO 2 , COOH, CONH 2 , 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 3-10 carbocyclyl, —O-4 to 10 membered heterocyclyl, —NH-C 3-10 carbocyclyl, —NH-4 to 10 membered heterocyclyl, —SC 3-10 carbocyclyl, —S-4 to 10 membered heterocyclyl, —C 0-4 alkylene-C 3-10 carbocyclyl, —C 0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycl
  • n is selected from 1, 2 or 3;
  • n is selected from 0, 1, 2, 3 or 4;
  • R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, 5 to 6 membered heteroaryl, 8 to 10 membered cycloheteroaryl, C 3-7 monocycloalkyl, C 4-7 monocycloalkenyl, 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;
  • Ring B is selected from C3-7 cycloalkyl, C8-12 cycloalkyl, C8-12 spirocycloalkyl, C8-12 bridged cycloalkyl, 4 to 7 membered monoheterocycloalkyl, 6 to 10 membered cycloheterocycloalkyl, 6 to 10 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, benzoC7-9cycloalkyl , benzo7 to 9 membered heterocycloalkyl, 5 to 6 membered heteroaryl andC7-9cycloalkyl , 5 to 6 membered heteroaryl and7 to 9 membered heterocycloalkyl;
  • R 2a is selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-4 to 6 membered heterocyclyl, -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-NR 2aa C( ⁇ O)R 2ab , -C 1-4 alkylene-N(C 1-4 alkylene)R 2aa , -C 1-4 alkylene-SR 2ac , -C 1-4 alkylene-NHC( ⁇ NR 2ad )NR 2aa R 2ab , -C 1-4 alkylene-R 2ae , -C 0-4 alkylene-C 3-6 carbocycl
  • R 3 and R 4 are each 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 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 3 and R 4 are directly linked to form a C 3-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;
  • R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocyclyl, and -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R 2ae is 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 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • R y , R 1a , and R b are independently selected from H, deuterium, halogen, OH, ⁇ O, CN, NH 2 , NO 2 , COOH, CONH 2 , C 1-4 alkyl, OC 1-4 alkyl, 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 carbocyclyl, -O-4 to 6-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-4 to 6-membered heterocyclyl, -SC 3-6 carbocyclyl, -S-4 to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbo
  • R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : 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, Cyclopropy
  • Ring B is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyrazolyl, imidazolyl, pyridofuranyl, pyridothiphenyl, pyridoxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidoxazolyl, pyrimidothiazolyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohex
  • R 2aa , R 2ab , R 2ac , R 2ad are each independently selected from H, methyl, ethyl, CF 3 , -CH 2 -cyclopropyl, cyclopropyl;
  • R q , R 5 are each independently selected from H or methyl
  • R y , R 1a , and R b are each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, ⁇ O, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, and —CH 2 -cyclopropyl, wherein the —CH 2 -, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propynyl, and cyclopropyl are optionally substituted by 1 to 4 R k ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, CN, OH, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl, wherein the -CH 2 -, methyl, ethyl, cyclopropyl is optionally substituted by 1 to 4 R k ;
  • R 3 and R 4 are directly linked to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted by 1 to 4 R k ;
  • L is selected from a bond, -O-, -S-, -NH-, -OCH2- , -OCH2CH2- , -OCH2CH2CH2- , -NHCH2-, -NHCH2CH2-, -NHCH2CH2- , -NHCH2CH2CH2- , said -CH2- being optionally substituted with 1 to 4 Rk ;
  • Q is selected from O, NH or S
  • R 3 and R 4 are each independently selected from H, F or methyl
  • R5 is selected from H
  • R 1 is selected from one of the following groups optionally substituted by 1 to 4 R 1a :
  • R 2aa , R 2ab , R 2ac , and R 2ad are each independently selected from H, methyl, and ethyl;
  • R b1 is selected from -CH 2 OH, -CH 2 -OCH 3 , -CH 2 CN;
  • the compound represented by the general formula (I) is selected from the compounds represented by the general formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If),
  • R 1A is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted by 1 to 4 R 1a ;
  • Q 1 is selected from O or NH
  • Ring B1 is selected from C8-12 cycloalkyl, 11 to 13 membered heterocyclyl or 11 to 13 membered heterocycloalkyl;
  • n 1;
  • p is selected from 2 or 3;
  • R 2A is selected from
  • Ring B 1 is selected from
  • R 1A is selected from one of the following groups optionally substituted with 1 to 4 R 1a : 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,
  • L is selected from -OCH 2 -;
  • R 2 is selected from or R 2A ;
  • R 1 is selected from R 1A or R 1A optionally substituted by 1 to 4 R 1A
  • Ring B is selected from or ring B 1 , and the left side is directly connected to L;
  • the compound represented by the general formula (I) is selected from the compounds represented by the general formula (Ih) and (II),
  • Ring B2 is selected from C8-12 bridged cycloalkyl or 6 to 10 membered spiro heterocycloalkyl, preferably, Ring B2 is selected from The left side is connected to the methylene group;
  • R b is selected from H, deuterium, halogen, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;
  • R y is selected from F, Cl, Br, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;
  • R 2B is selected from
  • R 2C is selected from
  • the compound represented by the general formula (I) is selected from the compounds represented by the general formula (IJ),
  • R y is selected from F, Cl, Br, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;
  • R 3B is selected from
  • R b is selected from H, deuterium, halogen, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;
  • the present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table S.
  • 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.
  • the present invention relates to use of the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of drugs for PARP14-related diseases, preferably tumors, atopic dermatitis and autoimmune diseases.
  • 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").
  • 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.
  • the mammal of the present invention includes a human.
  • an "effective amount” or “therapeutically effective amount” as used herein refers to administering a sufficient amount of the compound disclosed herein to alleviate to some extent one or more symptoms of the disease or condition being treated (e.g., tumors, atopic dermatitis, and autoimmune diseases).
  • the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired effect of a biological system.
  • an "effective amount” for therapeutic uses is the amount of a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms.
  • 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, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 5-5 00mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg
  • 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.
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a compound of the present invention 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, atopic dermatitis).
  • a method for treating a disease in a mammal comprising administering a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof to a subject at a daily dose of 1-1500 mg/day
  • 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, 100-800 mg/day , 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include but are 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
  • 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.
  • 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.
  • 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 other
  • the isotopes of carbon include 12 C, 13 C and 14 C
  • the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen) and tritium (T, also called super tritium)
  • the isotopes of oxygen include 16 O, 17 O and 18 O
  • the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S
  • the isotopes of nitrogen include 14 N and 15 N
  • the isotopes of fluorine include 17 F and 19 F
  • the isotopes of chlorine include 35 Cl and 37 Cl
  • the isotopes of bromine include 79 Br and 81 Br.
  • CN refers to cyano
  • Halogen refers to F, Cl, Br or I.
  • 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”.
  • 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.
  • Heteroalkyl refers to a substituted or unsubstituted alkyl 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.
  • Alkylene refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.
  • 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-(CH 2 )vX-(CH 2 )vX-(CH 2 )v-(CH 2 )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.
  • 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.
  • 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,
  • the heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
  • Alkenyl refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a main chain including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms.
  • alkenyl groups include but are not limited to 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-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
  • 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
  • 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.
  • 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.
  • 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, te
  • Spiro or “spirocyclic group” refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom).
  • "Spirocycle” or “spirocyclyl” can be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10.
  • Non-limiting examples include: "Bicyclic" or "bicyclic group” can be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” wherein the ring system consists of only carbon atoms.
  • Carbocyclic refers to a “cyclic” ring system consisting of only carbon atoms.
  • Carbobridged ring refers to a “bridged ring” wherein the ring system consists of only carbon atoms.
  • Heteromonocycle refers to a monocyclic ring system of "heterocyclyl” or “heterocycle”,
  • Heterocyclic ring refers to a "cyclo" containing a heteroatom.
  • Heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • Heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • 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.
  • heteroaryl examples 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
  • 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.
  • X-Y membered rings (X, Y are integers, and 3 ⁇ X ⁇ Y, X ⁇ Y ⁇ 20 are selected from any integer between 4 and 20) include X, X+1, X+2, X+3, X+4....Y membered rings.
  • Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings or heterobridged rings.
  • 4--7 membered heteromonocyclic rings refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings
  • 5--10 membered heterocyclic rings refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings
  • Cxy carbocycle (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, cyclic carbocycle or bridged carbocycle) includes Cx , Cx +1 , Cx+2 , Cx +3 , Cx +4 ...
  • Cy -membered ring (x is an integer, and 3 ⁇ x ⁇ y, y is selected from any integer between 4 and 20), for example.
  • C3-6 cycloalkyl refers to C3 , C4 , C5 or C6 cycloalkyl;
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • 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.
  • 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
  • connection directions include connection from left to right and from right to left in reading order, for example, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.
  • 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.
  • “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.
  • “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.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • 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.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism.
  • the prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the modified compounds, which can be removed by conventional manipulation or in vivo to obtain the parent compound.
  • the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
  • 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.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
  • Stepoisomers 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.
  • 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.
  • IC50 is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • Boc tert-butoxycarbonyl
  • Ts p-toluenesulfonyl
  • DIPEA CAS: 7087-68-5;
  • HATU CAS: 148893-10-1;
  • LAH CAS: 16853-85-3;
  • Dess-Martin oxide CAS: 87413-09-0.
  • the compounds of the present application can be prepared by the following synthesis method:
  • the compound (Z-4) is subjected to removal of 2,4-dimethoxybenzyl to obtain the compound (Z-5);
  • the compound of the general formula (Z-6) reacts with the compound (Z-7) to obtain the compound of the general formula (Z);
  • R z1 is selected from Cl, Br, I, OMs, OTs, OTf and the like.
  • compound 2b (synthetic route according to document WO2022206795) (1.5 g, 7.50 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 Na 2 SO 4 , filtered and concentrated in vacuo.
  • the residue was purified by silica gel column to obtain compound 2c (2.0 g, yield: 71.94%)
  • compound 2d (1.20 g, 3.24 mmol) was dissolved in 50 mL of N-methylpyrrolidone, 2,4-dimethoxybenzylamine (0.82 g, 4.86 mmol), potassium carbonate (0.90 g, 6.48 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 Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 2e (1.2 g, yield: 71.56%).
  • compound 2e (1.20 g, 2.32 mmol) was dissolved in 10 mL of dichloromethane and 2 mL of trifluoroacetic acid, triethylsilane (0.54 g, 4.64 mmol), and reacted at room temperature for 2 h. Vacuum concentration was performed. 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 2f (0.6 g, yield: 70.43%).
  • compound 2f (0.6 g, 1.63 mmol) was dissolved in 10 mL 2N hydrochloric acid 1,4-dioxane solution, chloroacetonitrile (0.24 g, 3.26 mmol), reacted at 80 ° C for 2 h, and concentrated under reduced pressure. Dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column to obtain compound 2g (0.2 g, yield: 29.83%)
  • compound 2g (0.2g, 0.49mmol) was dissolved in tetrahydrofuran, 1mL of 2N sodium hydroxide solution was added dropwise to the reaction flask, and intermediate 1 (0.16g, 0.98mmol) was reacted at room temperature for 2h. The residue was concentrated under reduced pressure and purified by silica gel column to obtain compound 2 (25mg, yield: 10.41%).
  • compound 3b (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 to the reaction bottle at 0°C 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 Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 3b (1.2 g, yield: 97.93%).
  • compound 4d (0.70 g, 1.43 mmol) was dissolved in 10 mL of dichloromethane and 2 mL of trifluoroacetic acid, triethylsilane (0.54 g, 4.64 mmol), and reacted at room temperature for 2 h. Vacuum concentration was performed. Dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 4e (0.25 g, yield: 51.47%)
  • compound 5b (4.5 g, 15.23 mmol) was dissolved in acetonitrile (30 mL) and water (3 mL), trifluoroacetic acid (40.26 mmol, 3 mL) was added, and the reaction was allowed to proceed at room temperature for one hour.
  • the pH of the reaction solution was adjusted to 7-8 with sodium bicarbonate aqueous solution, poured into 100 mL of water and extracted with ethyl acetate (30 mL ⁇ 2).
  • the combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude product of compound 5c, which was directly used in the next step.
  • compound 5c (4 g, 14.22 mmol) was dissolved in methanol (20 mL), and then sodium borohydride (800 mg, 21.21 mmol) was slowly added at 0°C and reacted at 0°C for one hour.
  • the pH of the reaction solution was adjusted to 6-7 with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate (30 mL ⁇ 2).
  • the combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by silica gel column to obtain compound 5d (3.5 g, 86.85%).
  • compound 10b (4.0 g, 13.94 mmol) was dissolved in 100 mL of tetrahydrofuran, and 2.5 M LAH (13.94 mL, 34.85 mmol) was added dropwise to the reaction bottle at 0°C, and the reaction was carried out at room temperature for 3 h.
  • the reaction mixture was poured into 100 mL of water and extracted with DCM (100 mL ⁇ 2).
  • the combined organic phase was washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • the residue was purified by silica gel column to obtain compound 10c (3.0 g, yield: 83.11%).
  • compound 10d (3.0 g, 8.90 mmol) was dissolved in 30 mL of dichloromethane, and 10 mL of 4N HCl in 1,4-dioxane was added dropwise, and the mixture was reacted at room temperature for 1 h. The reaction mixture was concentrated in vacuo to obtain compound 10e, which was used directly in the next step (3.0 g, crude product).
  • compound 10f (1.0 g, 3.58 mmol) was dissolved in 10 mL DMSO, methyl 2,6-difluoro-4-hydroxybenzoate (1.01 g, 5.37 mmol), potassium carbonate (1.38 g, 10 mmol), microwave heated to 120 ° C, and reacted for 2 h.
  • the reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (30 mL ⁇ 2).
  • the combined organic phase was washed with brine (20 mL ⁇ 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • the residue was purified by silica gel column to obtain compound 10g (0.3 g, yield: 20.94%).
  • compound 10h (0.25 g, 0.48 mmol) was dissolved in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid, triethylsilane (0.11 g, 0.96 mmol) was added, and the reaction was carried out at room temperature for 2 h. Vacuum concentration was performed. The product 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 10i (0.15 g, yield: 84.46%).
  • compound 10i (0.15 g, 0.41 mmol) was dissolved in 5 mL 2N hydrochloric acid 1,4-dioxane solution and chloroacetonitrile (0.06 g, 0.82 mmol) and reacted at 80 °C for 2 h. Concentrated in vacuo. Dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column to obtain compound 10j (0.10 g, yield: 59.69%).
  • compound 10j (0.10 g, 0.24 mmol) was dissolved in tetrahydrofuran, 1 mL of 2N sodium hydroxide solution was added dropwise to the reaction flask, intermediate 1 (0.08 g, 0.48 mmol) was added, and the mixture 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 10 (50 mg, yield: 41.68%).
  • 1,1-Dibromo-3,3,3-trifluoroacetone (4.98 g, 18.49 mmol) was placed in a 250 mL single-mouth bottle, 30 mL of water and sodium acetate (1.89 g, 23.09 mmol) were added, and the temperature was raised to 90 °C for 1 hour. After cooling to room temperature, 60 mL of methanol, 11C (3.02 g, 15.39 mmol) and concentrated aqueous ammonia (15 mL) were added in sequence, and the temperature was raised to 90 °C for 2 hours. After cooling to room temperature, the reaction solution was poured into 200 mL of water, filtered, and the filter cake was washed with water (2 ⁇ 10 mL). The filter cake was dried under reduced pressure to obtain 11D (2.9 g, yield: 62%).
  • 11D (2.0 g, 6.62 mmol) was dissolved in 30 mL DMF at room temperature, and isopropyl iodide (4.50 g, 26.48 mmol) and cesium carbonate (6.47 g, 19.86 mmol) were added in sequence, and the temperature was raised to 90°C for overnight reaction. After cooling to room temperature, water and ethyl acetate were added for extraction, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 11E (1.2 g, yield: 52%).
  • 11D (5.0 g, 16.54 mmol) was dissolved in 30 mL DMF at room temperature, iodomethane (10.78 g, 33.10 mmol) and cesium carbonate (3.52 g, 24.74 mmol) were added in sequence, and the temperature was raised to 80 °C for 16 hours.
  • the reaction solution was cooled to room temperature, water (30 mL) was added, and it was extracted twice with ethyl acetate (30 mL ⁇ 2), and the organic phases were combined.
  • compound 14a (5 g, 27.29 mmol) was dissolved in 20 mL of tetrahydrofuran, and 2.5 N tetrahydrogen lithium aluminum tetrahydrofuran solution (10.0 mL, 255.6 mmol) was added dropwise to the reaction bottle at 0°C. After the addition, the reaction was allowed to react 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), then dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 14b (3 g, yield: 70.83%).
  • the organic phases were combined, and the organic phases were washed twice with water (20 mL ⁇ 2) and once with a saturated aqueous solution of NaCl (20 mL ⁇ 1) in sequence, and then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain the target compound 15e (0.30 g, yield 58.50%).
  • 16b (1.4 g, 6.27 mmol) was dissolved in 35 mL of toluene, and methyl 2,6-difluoro-4-hydroxybenzoate (1.42 g, 7.52 mmol) and cyanomethylenetri-n-butylphosphine (4.54 g, 18.81 mmol) were added in sequence, and the mixture was reacted at 100°C for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain the target compound 16c (1 g, yield 40.54%).
  • 16e (0.3 g, 0.77 mmol) was dissolved in 6 mL 1,4-dioxane, and chloroacetonitrile (170 mg, 2.31 mmol) and dioxane hydrochloride solution (0.5 mL, 4 mol/L) were added in sequence, and the mixture was reacted at 80°C for 4 hours.
  • the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was chromatographed on a silica gel column to obtain compound 16f (0.3 g, yield 89.99%).
  • 16f (0.3 g, 0.69 mmol) was dissolved in 4 mL of tetrahydrofuran, and intermediate 1 (0.44 g, 2.76 mmol) and sodium hydroxide solution (0.5 mL, 3N) were added in sequence, and the mixture was reacted at room temperature for 3 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was chromatographed on a silica gel column to obtain compound 16 (42 mg, yield 11.78%).
  • the ELISA method was used to test the inhibitory effect of compounds on the enzyme activity of PARP14.
  • 50 ⁇ L 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 ⁇ L of Blocking buffer (BPS, 79743) was added and blocked at room temperature for 90 minutes.
  • the compounds of the present invention have an inhibitory effect on PARP14.
  • compounds 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15 and 16 have good inhibitory activity on PARP14.
  • mice Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, 6 SD rats/compound were randomly divided into groups according to body weight. The rats were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.2% Tween 80 + 99.8% 0.5% MC.
  • DMA dimethylacetamide
  • Solutol polyethylene glycol-15-hydroxystearate
  • Saline physiological saline
  • 0.5% MC 0.5% aqueous solution of methylcellulose.
  • the compounds of the present invention have good pharmacokinetic properties in rats. Specifically, compound 3 has better oral absorption performance and/or lower clearance rate in rats.
  • mice Male BALB/c mice, 20-25 g, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, six BALB/c mice were randomly divided into groups according to their body weight. They were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.2% Tween 80 + 99.8% 0.5% MC.
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic properties in mice.
  • mice Male beagle dogs, about 8-11 kg, 5-6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.
  • Test method On the test day, 5-6 beagle dogs/compound were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours one day before administration, and food was given 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.2% Tween 80 + 99.8% 0.5% MC.
  • the compounds of the present invention such as the compounds in the examples, have good oral absorption properties in beagle dogs.
  • mice Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.
  • Test method On the test day, 4-6 monkeys/compound were randomly divided into groups according to body weight. The monkeys were fasted but not watered for 14-18 hours one day before administration and were fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.2% Tween 80 + 99.8% 0.5% MC.
  • DMA dimethylacetamide
  • Solutol polyethylene glycol-15-hydroxystearate
  • Saline physiological saline
  • 0.5% MC 0.5% aqueous solution of methylcellulose.
  • 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube.
  • the blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.
  • the blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h.
  • all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.
  • the compounds of the present invention such as the compounds in the examples, have good oral absorption properties in monkeys.
  • the experiment used a monolayer of Caco-2 cells and three parallel incubations were performed in a 96-well Transwell plate.
  • a transport buffer solution (HBSS, 10mM HEPES, pH 7.4 ⁇ 0.05) containing the compound of the present invention (5 ⁇ M) was added to the dosing port hole on the apical side or the basolateral side.
  • a transport buffer solution containing DMSO was added to the corresponding receiving port hole.
  • the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate. Subsequently, acetonitrile containing an internal standard was added to precipitate the protein.
  • the samples were analyzed using LC MS/MS and the concentrations of the compounds of the present invention and the control compounds were determined.
  • the concentration data were used to calculate the apparent permeability coefficients for transport from the apical side to the basolateral side of the monolayer cells and from the basolateral side to the apical side, thereby calculating the efflux rate.
  • the integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.
  • the compounds of the present invention have good Caco2 permeability. Compared with the control compound 1, for example, compound 3 has better permeability and lower efflux rate.
  • liver microsomes from five species including humans, dogs, rats and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.
  • test substance was incubated with microsomal proteins and coenzyme NADPH. After a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS/MS. T 1/2 was calculated by the ln value of the drug residual rate in the incubation system and the incubation time, and the liver microsomal intrinsic clearance CLint(mic) and liver intrinsic clearance CLint(Liver) were further calculated.
  • the compounds of the present invention such as the compounds in the examples, have good metabolic stability in liver microsomes.

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Abstract

The present invention relates to a compound as represented by general formula (I) or a stereoisomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, and an intermediate and a pharmaceutical composition thereof, and the use thereof in the preparation of a drug for PARP14-related diseases.

Description

一种喹唑啉酮衍生物及其在医药上的应用A quinazolinone derivative and its application in medicine 技术领域Technical Field

本发明涉及一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体及药物组合物，以及用于制备PARP14相关疾病的药物中的用途。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.

背景技术Background Art

PARP14是一种干扰素刺激的基因，在多种肿瘤类型中过度表达，通过调节IFN-γ和IL-4信号传导影响促肿瘤巨噬细胞极化以及抑制抗肿瘤炎症反应。PARP14是一种203kDa蛋白，具有一个催化结构域，负责将单ADP-核糖转移到其底物上。除了两个RNA识别基序之外，PARP14还包含三个宏结构域和一个WWE结构域，它们分别是单ADP-核糖和多聚ADP-核糖的结合模块。PARP14的催化抑制剂已被证明可逆转巨噬细胞中IL-4驱动的促肿瘤基因表达，PARP14在炎症性疾病组织中高表达(而不是在正常组织中组成型)，导致一级细胞因子(alarmins)和二级细胞因子(Th2和Th17细胞因子)增加，最终导致组织嗜酸性粒细胞和中性粒细胞增加。用PARP14抑制剂靶向减少这些炎症通路预计会比目前的疗法有更好的疗效，例如那些仅针对单一细胞因子如IL-4、IL-5和/或IL-13的哮喘治疗。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 PARP14 inhibitors is expected to have better efficacy than current therapies, such as those that target only single cytokines such as IL-4, IL-5 and/or IL-13 for asthma treatment.

本文描述的化合物、组合物和方法有助于满足以PARP14的异常表达或活性为特征的某些癌症和炎性病的治疗需求。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.

发明内容Summary of the invention

本发明的目的是提供一种结构新颖的通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗与PARP14表达异常相关的疾病药物中的应用。The object of the present invention is to provide a novel compound of the general formula (I) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods thereof, and their use in the preparation of drugs for treating diseases associated with abnormal PARP14 expression.

本发明化合物具有良好的药代性能和生物利用度、具有口服性能和良好的安全性。The compound of the invention has good pharmacokinetic properties and bioavailability, oral properties and good safety.

本发明提供一种化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，化合物选自通式(I)所示的化合物，
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),

在一些实施方案中，通式(I)所示化合物选自通式(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)所示化合物，
In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia), (Ib), (Ic), (Id), (Ie), (If),

在一些实施方案中，通式(I)所示化合物选自通式(I-h)、(I-I)所示化合物，
In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (Ih) and (II),

在一些实施方案中，通式(I)所示化合物选自通式(I-J)所示化合物，
In some embodiments, the compound represented by general formula (I) is selected from the compound represented by general formula (IJ),

在一些实施方案中，选自 In some embodiments, Selected from

在一些实施方案中，选自m1选自0、1、2或3；In some embodiments, Selected from m1 is selected from 0, 1, 2 or 3;

在一些实施方案中，Y1、Y2、Y3各自独立地选自N或CRy；In some embodiments, Y 1 , Y 2 , and Y 3 are each independently selected from N or CR y ;

在一些实施方案中，Y1、Y2选自CH，Y3选自CRy；In some embodiments, Y 1 , Y 2 are selected from CH, and Y 3 is selected from CR y ;

在一些实施方案中，Y1选自N，Y2选自CH，Y3选自CRy；In some embodiments, Y 1 is selected from N, Y 2 is selected from CH, and Y 3 is selected from CR y ;

在一些实施方案中，R1选自C6-10芳基、5至10元杂芳基、非芳香的C3-12碳环基或者非芳香的4至12元杂环基，所述的芳基、杂芳基、碳环基或杂环基任选被1至4个R1a取代；In some embodiments, R 1 is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, non-aromatic C 3-12 carbocyclyl, or non-aromatic 4 to 12 membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl, or heterocyclyl is optionally substituted with 1 to 4 R 1a ;

在一些实施方案中，R1选自任选被1至4个R1a取代的如下基团之一：苯基、萘基、5至6元杂芳基、8至10元并环杂芳基、C3-7单环烷基、C4-7单环烯基、C5-12并环烷基、C5-12螺环烷基、C5-12桥环烷基、4至7元单杂环烷基、6至12元并杂环烷基、6至12元螺杂环烷基、6至12元桥杂环烷基；In some embodiments, R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, 5 to 6 membered heteroaryl, 8 to 10 membered cycloheteroaryl, C 3-7 monocycloalkyl, C 4-7 monocycloalkenyl, 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;

在一些实施方案中，R1选自任选被1至4个R1a取代的如下基团之一：苯基、萘基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、异喹唑啉基、吡啶并吡唑基、吡啶并咪唑基、吡啶并呋喃基、吡啶并噻吩基、吡啶并噁唑基、吡啶并噻唑基、嘧啶并吡唑基、嘧啶并咪唑基、嘧啶并呋喃基、嘧啶并噻吩基、嘧啶并噁唑基、嘧啶并噻唑基、环丙基、环丁基、环戊基、环己基、环己烯基、苯基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丙基并氧杂环丁基、环丙基并四氢呋喃基、环丙基并四氢吡喃基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环丁基并氧杂环丁基、环丁基并四氢呋喃基、环丁基并四氢吡喃基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环戊基并氧杂环丁基、环戊基并四氢呋喃基、环戊基并四氢吡喃基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、环己基并氧杂环丁基、环己基并四氢呋喃基、环己基并四氢吡喃基、环丙基螺氮杂环丁基、环丙基螺吡咯烷基、环丙基螺哌啶基、环丙基螺氧杂环丁基、环丙基螺四氢呋喃基、环丙基螺四氢吡喃基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环丁基螺氧杂环丁基、环丁基螺四氢呋喃基、环丁 基螺四氢吡喃基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环戊基螺氧杂环丁基、环戊基螺四氢呋喃基、环戊基螺四氢吡喃基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、环己基螺氧杂环丁基、环己基螺四氢呋喃基、环己基螺四氢吡喃基、氮杂环己基螺氮杂环己基、氮杂环戊基螺氮杂环己基、氮杂环戊基螺氮杂环戊基、氮杂环己基并氮杂环己基、氮杂环戊基并氮杂环己基、氮杂环戊基并氮杂环戊基、双环[1.1.1]戊烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.1.1]庚烷基、金刚烷基、 In some embodiments, R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, 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, cyclopropyltetrahydrofuranyl, cyclopropyltetrahydropyranyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclobutyloxetanyl, cyclobutyl cyclobutyltetrahydropyranyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclopentyloxetanyl, cyclopentyltetrahydrofuranyl, cyclopentyltetrahydropyranyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, cyclohexyloxetanyl, cyclohexyltetrahydrofuranyl, cyclohexyltetrahydropyranyl, cyclopropylspiroazetidinyl, cyclopropylspiropyrrolidinyl, cyclopropylspiropiperidinyl, cyclopropylspirooxetanyl, cyclopropylspirotetrahydrofuranyl, cyclopropylspirotetrahydropyranyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidinyl, cyclobutylspiropiperidinyl, cyclobutylspirooxetanyl, cyclobutylspirotetrahydrofuranyl, cyclobutyl cyclopentylspirotetrahydropyranyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidinyl, cyclopentylspiropiperidinyl, cyclopentylspirooxetanyl, cyclopentylspirotetrahydrofuranyl, cyclopentylspirotetrahydropyranyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, cyclohexylspirooxetanyl, cyclohexylspirotetrahydrofuranyl, cyclohexylspirotetrahydropyranyl, azacyclohexylspiroazacyclohexyl, azacyclopentylspiroazacyclohexyl, azacyclopentylspiroazacyclohexyl, azacyclopentylspiroazacyclopentyl, azacyclohexyl and azacyclohexyl, azacyclopentyl and azacyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.1]heptanyl, adamantyl,

在一些实施方案中，R1选自任选被1至4个R1a取代的如下基团之一： In some embodiments, R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a :

在一些实施方案中，R1选自R1A或任选被1至4个R1a取代的 In some embodiments, R 1 is selected from R 1A or R 1A optionally substituted with 1 to 4 R 1A

在一些实施方案中，R1A选自C6-10芳基、5至10元杂芳基，所述的芳基或杂芳基任选被1至4个R1a取代；In some embodiments, R 1A is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted with 1 to 4 R 1a ;

在一些实施方案中，R1A选自苯基、萘基、5至6元杂芳基或8至10元杂芳基，所述的苯基、萘基、或杂芳基任选被1至4个R1a取代；In some embodiments, R 1A is selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, or 8- to 10-membered heteroaryl, wherein the phenyl, naphthyl, or heteroaryl is optionally substituted with 1 to 4 R 1a ;

在一些实施方案中，R1A选自任选被1至4个R1a取代的如下基团之一：苯基、萘基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、异喹唑啉基、吡啶并吡唑基、吡啶并咪唑基、吡啶并呋喃基、吡啶并噻吩基、吡啶并噁唑基、吡啶并噻唑基、嘧啶并吡唑基、嘧啶并咪唑基、嘧啶并呋喃基、嘧啶并噻吩基、嘧啶并噁唑基、嘧啶并噻唑基、 In some embodiments, R 1A is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyridoimidazolyl, pyridofuranyl, pyridothiphenyl, pyridooxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidooxazolyl, pyrimidothiazolyl,

在一些实施方案中，R1A选自任选被1至4个R1a取代的如下基团之一： In some embodiments, R 1A is selected from one of the following groups optionally substituted with 1 to 4 R 1a :

在一些实施方案中，L选自键、-O-、-S-、-NH-、-N(C1-4烷基)-、-O-C1-4亚烷基-、-NH-C1-4亚烷基-、-N(C1-4烷基)-C1-4亚烷基-、-C1-4亚烷基-，所说的亚烷基或烷基任选被1至4个Rk取代；In some embodiments, L is selected from a bond, -O-, -S-, -NH-, -N(C 1-4 alkyl)-, -OC 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 being optionally substituted with 1 to 4 R k ;

在一些实施方案中，L选自键、-O-、-S-、-NH-、-OCH2-、-OCH2CH2-、-OCH2CH2CH2-、-NHCH2-、-NHCH2CH2-、-NHCH2CH2CH2-，所述的-CH2-任选被1至4个Rk取代； In some embodiments, L is selected from a bond, -O-, -S-, -NH-, -OCH2- , -OCH2CH2-, -OCH2CH2CH2- , -NHCH2- , -NHCH2CH2-, -NHCH2CH2- , -NHCH2CH2CH2- , said -CH2- being optionally substituted with 1 to 4 Rk ;

在一些实施方案中，L选自-OCH2-；In some embodiments, L is selected from -OCH 2 -;

在一些实施方案中，环B选自C3-7环烷基、C8-12环烷基、4至10元杂环烷基、11至13元杂环烷基、11至13元杂环基、C6-10芳基、5至10元杂芳基；In some embodiments, Ring B is selected from C 3-7 cycloalkyl, C 8-12 cycloalkyl, 4 to 10 membered heterocycloalkyl, 11 to 13 membered heterocycloalkyl, 11 to 13 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl;

在一些实施方案中，环B选自C3-7环烷基、C8-12并环烷基、C8-12螺环烷基、C8-12桥环烷基、 4至7元单杂环烷基、6至10元并杂环烷基、6至10元螺杂环烷基、6至10元桥杂环烷基、11至13元二环杂环烷基、11至13元三环杂环烷基、苯基、萘基、5至6元杂芳基、8至10元并环杂芳基、苯并C7-9环烷基、苯并7至9元杂环烷基、5至6元杂芳基并C7-9环烷基、5至6元杂芳基并7至9元杂环烷基；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 10 membered benzoheterocycloalkyl, 6 to 10 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 benzoheterocycloaryl, benzo7 to 9 membered heterocycloalkyl, 5 to 6 membered heteroaryl and 7 to 9 membered heterocycloalkyl;

在一些实施方案中，环B选自苯基、萘基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、异喹唑啉基、吡啶并吡唑基、吡啶并咪唑基、吡啶并呋喃基、吡啶并噻吩基、吡啶并噁唑基、吡啶并噻唑基、嘧啶并吡唑基、嘧啶并咪唑基、嘧啶并呋喃基、嘧啶并噻吩基、嘧啶并噁唑基、嘧啶并噻唑基、环丙基、环丁基、环戊基、环己基、环己烯基、苯基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丙基并氧杂环丁基、环丙基并四氢呋喃基、环丙基并四氢吡喃基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环丁基并氧杂环丁基、环丁基并四氢呋喃基、环丁基并四氢吡喃基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环戊基并氧杂环丁基、环戊基并四氢呋喃基、环戊基并四氢吡喃基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、环己基并氧杂环丁基、环己基并四氢呋喃基、环己基并四氢吡喃基、环丙基螺氮杂环丁基、环丙基螺吡咯烷基、环丙基螺哌啶基、环丙基螺氧杂环丁基、环丙基螺四氢呋喃基、环丙基螺四氢吡喃基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环丁基螺氧杂环丁基、环丁基螺四氢呋喃基、环丁基螺四氢吡喃基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环戊基螺氧杂环丁基、环戊基螺四氢呋喃基、环戊基螺四氢吡喃基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、环己基螺氧杂环丁基、环己基螺四氢呋喃基、环己基螺四氢吡喃基、氮杂环己基螺氮杂环己基、氮杂环戊基螺氮杂环己基、氮杂环戊基螺氮杂环戊基、氮杂环己基并氮杂环己基、氮杂环戊基并氮杂环己基、氮杂环戊基并氮杂环戊基、氮杂环己基螺四氢吡喃基、双环[1.1.1]戊烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.1.1]庚烷基、金刚烷基、 In some embodiments, ring B is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, 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, cyclopropyltetra ... cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclopropyloxetanyl, cyclopropyltetrahydrofuranyl, cyclopropylcyclopropyl furanyl, cyclopropyltetrahydropyranyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclobutyloxetanyl, cyclobutyltetrahydrofuranyl, cyclobutyltetrahydropyranyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclopentyloxetanyl, cyclopentyltetrahydrofuranyl, cyclopentyltetrahydropyranyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, cyclohexyloxetanyl, cyclohexyltetrahydrofuranyl, cyclohexyltetrahydropyranyl, 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 spiroazetidinyl, cyclohexyl cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, cyclohexylspiroxetanyl, cyclohexylspirotetrahydrofuranyl, cyclohexylspirotetrahydropyranyl, azacyclohexylspiroazacyclohexyl, 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,

在一些实施方案中，环B选自 或环B1，且左侧与L直接连接；In some embodiments, Ring B is selected from or ring B 1 , and the left side is directly connected to L;

在一些实施方案中，环B选自或环B1，且左侧与L直接连接；In some embodiments, Ring B is selected from or ring B 1 , and the left side is directly connected to L;

在一些实施方案中，环B1选自C8-12环烷基11至13元杂环基或11至13元杂环烷基；In some embodiments, Ring B 1 is selected from C 8-12 cycloalkyl 11 to 13 membered heterocyclyl or 11 to 13 membered heterocycloalkyl;

在一些实施方案中，环B1选自 In some embodiments, Ring B1 is selected from

在一些实施方案中，环B2选自C8-12桥环烷基或6至10元螺杂环烷基，优选地，环B2选自左侧与亚甲基相连；在一些实施方案中，R2选自H、-C(＝O)R2a、-NHC(＝O)R2a、-N(C1-6烷基)C(＝O)R2a、--S(＝O)2R2a、-NHS(＝O)2R2a、-C(＝S)R2a、-NHC(＝S)R2a、NHR2a、5至10元杂芳基、5至10元含内酰胺的杂环烷基、5至10元含脲基的杂环烷基，所述杂芳基、杂环烷基、烷基任选进一步被1至4个选自氘、卤素、OH、NH2、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6卤代烯基、C2-6炔基、C2-6卤代炔基的取代基取代；In some embodiments, ring B2 is selected from C8-12 bridged cycloalkyl or 6 to 10 membered spiroheterocycloalkyl, preferably, ring B2 is selected from The left side is connected to a methylene group; in some embodiments, R 2 is selected from H, -C(=O)R 2a , -NHC(=O)R 2a , -N(C 1-6 alkyl)C(=O)R 2a , --S(=O) 2 R 2a , -NHS(=O) 2 R 2a , -C(=S)R 2a , -NHC(=S)R 2a , NHR 2a , 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl containing lactam, 5- to 10-membered heterocycloalkyl containing urea, wherein the heteroaryl, heterocycloalkyl, alkyl is optionally further substituted by 1 to 4 members selected from deuterium, halogen, OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl , C 2-6 alkynyl, C 2-6 haloalkynyl substituents;

在一些实施方案中，R2选自H、-C(＝O)R2a、-NHC(＝O)R2a、-N(C1-4烷基)C(＝O)R2a、-S(＝O)2R2a、-NHS(＝O)2R2a、-C(＝S)R2a、-NHC(＝S)R2a、NHR2a、5至7元杂芳基、5至7元含内酰胺的杂环烷基、5至7元含脲基的杂环烷基，所述杂芳基、杂环烷基、烷基任选进一步被1至4个选自氘、卤素、OH、NH2、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C2-4卤代炔基的取代基取代；In some embodiments, R 2 is selected from H, -C(＝O)R 2a , -NHC(＝O)R 2a , -N(C 1-4 alkyl)C(＝O)R 2a , -S(＝O) 2 R 2a , -NHS(＝O) 2 R 2a , -C(＝S)R 2a , -NHC(＝S)R 2a , NHR 2a , 5- to 7-membered heteroaryl, 5- to 7-membered heterocycloalkyl containing lactam, 5- to 7-membered heterocycloalkyl containing urea, wherein the heteroaryl, heterocycloalkyl, alkyl is optionally further substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl;

在一些实施方案中，R2选自H、-C(＝O)R2a、-NHC(＝O)R2a、-N(CH3)C(＝O)R2a、-N(CH2CH3)C(＝O)R2a、-S(＝O)2R2a、-NHS(＝O)2R2a、-C(＝S)R2a、-NHC(＝S)R2a、NHR2a、5元杂芳基、6元杂芳基、5元含内酰胺的杂环烷基、6元含内酰胺的杂环烷基、7元含内酰胺的杂环烷基、咪唑烷酮基、四氢-2-嘧啶酮，所述CH3、CH2、杂芳基、杂环烷基、咪唑烷酮基、四氢-2-嘧啶酮任选进一步被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、 CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代；In some embodiments, R 2 is selected from H, -C(=O)R 2a , -NHC(=O)R 2a , -N(CH 3 )C(=O)R 2a , -N(CH 2 CH 3 )C(=O)R 2a , -S(=O) 2 R 2a , -NHS(=O) 2 R 2a , -C(=S)R 2a , -NHC(=S)R 2a , NHR 2a , 5-membered heteroaryl, 6-membered heteroaryl, 5-membered lactam-containing heterocycloalkyl, 6-membered lactam-containing heterocycloalkyl, 7-membered lactam-containing heterocycloalkyl, imidazolidinone, tetrahydro-2-pyrimidinone, and the CH 3 , CH 2 , heteroaryl, heterocycloalkyl, imidazolidinone, tetrahydro-2-pyrimidinone, optionally further substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, Substitution with CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl;

在一些实施方案中，R2选自H、-C(＝O)R2a、-NHC(＝O)R2a、-N(CH3)C(＝O)R2a、-N(CH2CH3)C(＝O)R2a、-S(＝O)2R2a、-NHS(＝O)2R2a、-C(＝S)R2a、-NHC(＝S)R2a、NHR2a、吡咯基、吡唑基、咪唑基、噁唑基、噁二唑基、三唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、所述CH2、CH3、吡咯基、吡唑基、咪唑基、噁唑基、噁二唑基、三唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、任选进一步被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代；In some embodiments, R 2 is selected from H, -C(=O)R 2a , -NHC(=O)R 2a , -N(CH 3 )C(=O)R 2a , -N(CH 2 CH 3 )C(=O)R 2a , -S(=O) 2 R 2a , -NHS(=O) 2 R 2a , -C(=S)R 2a , -NHC(=S)R 2a , NHR 2a , pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, The CH 2 , CH 3 , pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl;

在一些实施方案中，R2选自 或R2A；In some embodiments, R2 is selected from or R 2A ;

在一些实施方案中，R2a选自C1-6烷基、C2-6烯基、C2-6炔基、-C0-4亚烷基-C3-12碳环基、-C0-4亚烷基-4至12元杂环基、-C1-6亚烷基-NHC(＝O)-C1-6亚烷基-NR2aaR2ab、-C1-6亚烷基-C(＝O)NR2aaR2ab、-C1-4亚烷基-NR2aaC(＝O)R2ab、-C1-6亚烷基-N(C1-6亚烷基)R2aa、-C1-6亚烷基-SR2ac、-C1-6亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C1-6亚烷基-R2ae、-C0-6亚烷基-C3-12碳环基-R2ae、-C0-6亚烷基-4至12元杂环基-R2ae，优选为C1-6烷基、C2-6烯基、C2-6炔基、-C0-4亚烷基-C3-12碳环基、-C0-4亚烷基-4至12元杂环基、-C1-4亚烷基-NHC(＝O)-C1-4亚烷基-NR2aaR2ab、-C1-4亚烷基-C(＝O)NR2aaR2ab、-C1-4亚烷基-SR2ac、-C1-4亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C1-4亚烷基-R2ae、-C0-4亚烷基-C3-12碳环基-R2ae、-C0-4亚烷基-4至12元杂环基-R2ae，所述烷基、亚烷基任选被NH2取代，优选为1至3个NH2取代，所述的烷基、烯基、炔基、亚烷基、碳环基、杂环基任选被1至4个Rk取代；In some embodiments, R 2a is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-12 carbocyclyl, -C 0-4 alkylene-4 to 12 membered heterocyclyl, -C 1-6 alkylene-NHC(═O)-C 1-6 alkylene-NR 2aa R 2ab , -C 1-6 alkylene-C(═O)NR 2aa R 2ab , -C 1-4 alkylene-NR 2aa C(═O)R 2ab , -C 1-6 alkylene-N(C 1-6 alkylene)R 2aa , -C 1-6 alkylene-SR 2ac , -C 1-6 alkylene-NHC(═NR 2ad )NR 2aa R 2ab , -C 1-6 alkylene-R 2ae , -C 1-6 alkylene- -C 0-6 alkylene-C 3-12 carbocyclyl-R 2ae , -C 0-6 alkylene-4 to 12-membered heterocyclyl-R 2ae , preferably C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-12 carbocyclyl, -C 0-4 alkylene-4 to 12-membered heterocyclyl, -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-SR 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, -C 0-4 alkylene-4 to 12 - membered heterocyclyl, 3-12 carbocyclyl-R 2ae , -C 0-4 alkylene-4 to 12 membered heterocyclyl-R 2ae , the alkyl and alkylene groups are optionally substituted by NH 2 , preferably 1 to 3 NH 2 , and the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl and heterocyclyl groups are optionally substituted by 1 to 4 R k ;

在一些实施方案中，R2a选自C1-6烷基、C2-6烯基、C2-6炔基、-C0-4亚烷基-C3-12碳环基、-C0-4亚烷基-4至12元杂环基、-C1-4亚烷基-NHC(＝O)-C1-4亚烷基-NR2aaR2ab、-C1-4亚烷基-C(＝O)NR2aaR2ab、-C1-4亚烷基-SR2ac、-C1-4亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C1-4亚烷基-R2ae、-C0-4 亚烷基-C3-12碳环基-R2ae、-C0-4亚烷基-4至12元杂环基-R2ae，所述亚烷基任选被NH2取代，所述的烷基、烯基、炔基、亚烷基、碳环基、杂环基任选被1至4个Rk取代；In some embodiments, R 2a is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-12 carbocyclyl, -C 0-4 alkylene-4 to 12 membered heterocyclyl, -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-SR 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 heterocyclyl-R 2ae , wherein the alkylene is optionally substituted by NH 2 , and the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R k ;

在一些实施方案中，R2a选自C1-4烷基、C2-4烯基、C2-4炔基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-4至6元杂环基、-C1-4亚烷基-NHC(＝O)-C1-4亚烷基-NR2aaR2ab、-C1-4亚烷基-C(＝O)NR2aaR2ab、-C1-4亚烷基-NR2aaC(＝O)R2ab、-C1-4亚烷基-N(C1-4亚烷基)R2aa、-C1-4亚烷基-SR2ac、-C1-4亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C1-6亚烷基-R2ae、-C0-4亚烷基-C3-6碳环基-R2ae、-C0-4亚烷基-4至6元杂环基-R2ae，所述亚烷基、烷基任选被1至3个NH2取代，所述的烷基、烯基、炔基、亚烷基、碳环基、杂环基任选被1至4个Rk取代；In some embodiments, R 2a is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-4 to 6 membered heterocyclyl, -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-NR 2aa C(═O)R 2ab , -C 1-4 alkylene-N(C 1-4 alkylene)R 2aa , -C 1-4 alkylene-SR 2ac , -C 1-4 alkylene-NHC(═NR 2ad )NR 2aa R 2ab , -C 1-6 alkylene-R 2ae , -C 1-4 alkylene- 0-4 alkylene-C 3-6 carbocyclyl-R 2ae , -C 0-4 alkylene-4 to 6 membered heterocyclyl-R 2ae , wherein the alkylene and alkyl groups are optionally substituted by 1 to 3 NH 2 , and the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl and heterocyclyl groups are optionally substituted by 1 to 4 R k ;

在一些实施方案中，R2a选自任选被1至4个Rk取代的如下基团之一：甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-吡咯烷基、-CH2-哌啶基、-CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2CH2CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2CH2CH2CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2CH2CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2CH2CH2CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2-C(＝O)NR2aaR2ab、-CH2CH2-C(＝O)NR2aaR2ab、-CH2CH2CH2-C(＝O)NR2aaR2ab、-CH2CH2CH2CH2-C(＝O)NR2aaR2ab、-CH2-SR2ac、-CH2CH2-SR2ac、-CH2CH2CH2-SR2ac、-CH2CH2CH2CH2-SR2ac、-CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2-R2ae、-CH2CH2-R2ae、-CH2CH2CH2-R2ae、-CH2CH2CH2CH2-R2ae、-CH2CH2CH2CH2CH2-R2ae、-CH2-NR2aaC(＝O)R2ab、-CH2CH2CH2CH2-NR2aaC(＝O)R2ab、-CH2-N(甲基)R2aa、-CH2CH2-NR2aaC(＝O)R2ab、-CH2CH2CH2-NR2aaC(＝O)R2ab、-CH2CH2CH2CH2-N(甲基)R2aa-、-CH2CH2CH2-N(甲基)R2aa、-CH2CH2-N(甲基)R2aa、-CH2CH2CH2-N(乙基)R2aa、-CH2CH2CH2CH2-N(乙基)R2aa-、-CH2CH2-N(乙基)R2aa、-CH2-N(乙基)R2aa、-环丙基-R2ae、-环丁基-R2ae、-环戊基-R2ae、-环己基-R2ae、-氮杂环丁基-R2ae、-吡咯烷基-R2ae、-哌啶基-R2ae，所述的CH2、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基任选被1至3个NH2取代；In some embodiments, R 2a is selected from one of the following groups optionally substituted with 1 to 4 R k : methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 -NHC(＝O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 -NHC(＝O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(＝O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 CH 2 -NHC(=O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 -C(=O)NR 2aa R 2ab , -CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH 2 CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH 2 CH 2 CH 2 CH -CH 2 ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ -NHC(=NR 2ad )NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(=NR 2ad )NR 2aa R 2ab , -CH 2 CH 2 CH 2 CH 2 -NHC(=NR 2ad )NR 2aa R 2ab , -CH 2 -R 2ae , -CH 2 CH 2 -R 2ae , -CH 2 CH 2 CH2 - R2ae -CH 2 CH 2 CH 2 -R 2ae , -CH 2 CH 2 CH 2 CH 2 -R 2ae , -CH 2 -NR 2aa C(═O)R 2ab , -CH 2 CH 2 CH 2 CH 2 -NR 2aa C(═O)R 2ab , -CH 2 -N(methyl)R 2aa , -CH 2 CH 2 -NR 2aa C(═O)R 2ab , -CH 2 CH 2 -NR 2aa C(═O)R 2ab , -CH 2 CH 2 CH 2 -NR 2aa C(═O)R 2ab , -CH 2 CH 2 CH 2 -N(methyl)R 2aa -, -CH 2 CH 2 CH 2 -N(methyl)R 2aa , -CH 2 CH 2 -N(methyl)R 2aa , -CH 2 CH 2 -N (ethyl)R -Cyclopropyl -R 2ae , -cyclobutyl - R 2ae , -cyclopentyl - R 2ae , -cyclohexyl - R 2ae , -azetidinyl-R 2ae , -pyrrolidinyl-R 2ae , -piperidinyl-R 2ae , wherein the CH 2 , methyl, ethyl , propyl , isopropyl, butyl, isobutyl and sec- butyl are optionally substituted by 1 to 3 NH 2 ;

在一些实施方案中，R2a选自甲基、乙基、氮杂环丁基、吡咯烷基、哌啶基、-CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH(NH2)-CH2-SR2ac、-CH(NH2)-CH2CH2-SR2ac、-CH(NH2)-CH2-C(＝O)NR2aaR2ab、-CH(NH2)-CH2CH2-C(＝O)NR2aaR2ab、-CH(NH2)-CH2-NHC(＝NR2ad)NR2aaR2abb、-CH(NH2)-CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2-R2ae、-CH2CH2CH2-R2ae、-CH(NH2)-CH2CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2-R2ae、-CH2CH2-R2ae、-CH2CH2CH2CH2-R2ae、-CH2CH2CH2CH2CH2-R2ae、-CH(NH2)CH2CH2CH2CH2-R2ae、-环丙基-R2ae、-环丁基-R2ae、-环戊基-R2ae、-环己基-R2ae、-氮杂环丁基-R2ae、-吡咯烷基-R2ae、-哌啶基-R2ae，所述的甲基或乙基任选被1个NH2取代；In some embodiments, R 2a is selected from methyl, ethyl, azetidinyl, pyrrolidinyl, piperidinyl, -CH 2 -NHC(=O)-CH 2 -NR 2aa R 2ab , -CH(NH 2 )-CH 2 -SR 2ac , -CH(NH 2 )-CH 2 CH 2 -SR 2ac , -CH(NH 2 )-CH 2 -C(=O)NR 2aa R 2ab , -CH(NH 2 )-CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH(NH 2 )-CH 2 -NHC(=NR 2ad )NR 2aa R 2abb , -CH(NH 2 )-CH 2 CH 2 -NHC(=NR 2ad )NR 2aa R 2ab , -CH 2 -R 2ae , -CH 2 CH 2 CH2 - R2ae , -CH( NH2 ) -CH2CH2CH2 - NHC (＝ NR2ad ) NR2aaR2ab , -CH2 - R2ae , -CH2CH2- R2ae , -CH2CH2CH2CH2 - R2ae , -CH2CH2CH2CH2CH2-R2ae , -CH ( NH2 )CH2CH2CH2CH2 - R2ae , -cyclopropyl -R2ae , -cyclobutyl - R2ae , -cyclopentyl-R2ae, -cyclohexyl-R2ae, -azetidinyl-R2ae , -pyrrolidinyl - R2ae , -piperidinyl - R2ae , the methyl or ethyl group is optionally substituted by one NH2 ;

在一些实施方案中，R2A选自-C(＝S)R2a、-NHC(＝S)R2a、-C(＝O)R2af、-NHC(＝O)R2af；In some embodiments, R 2A is selected from -C(=S)R 2a , -NHC(=S)R 2a , -C(=O)R 2af , -NHC(=O)R 2af ;

在一些实施方案中，R2A选自 In some embodiments, R 2A is selected from

在一些实施方案中，R2B选自-C(＝O)C1-3烷基、-NHC(＝O)-C1-3烷基、-NHC(＝O)-C3-6环烷基、-N(C1-2烷基)C(＝O)-C1-3烷基、-N(C1-2烷基)C(＝O)-C3-6环烷基、5至6元杂芳基、5至6元含内酰胺的杂环烷基，所述R2B任选进一步被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代；In some embodiments, R 2B is selected from -C(＝O)C 1-3 alkyl, -NHC(＝O)-C 1-3 alkyl, -NHC(＝O)-C 3-6 cycloalkyl, -N(C 1-2 alkyl)C(＝O)-C 1-3 alkyl, -N(C 1-2 alkyl)C(＝O)-C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered lactam-containing heterocycloalkyl, said R 2B is optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl;

优选地，R2B选自-C(＝O)-甲基、-C(＝O)-乙基、-NHC(＝O)-甲基、-NHC(＝O)-乙基、-NHC(＝O)-环丙基、-NHC(＝O)-环丁基、-NHC(＝O)-环戊基、-NHC(＝O)-环己基、-N(CH3)C(＝O)-甲基、-N(CH3)C(＝O)-环丙基、吡咯基、吡唑基、咪唑基、噁唑基、噁二唑基、三唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基，所述R2B任选进一步被1至4个选自氘、F、Cl、Br、I、甲基、乙基、CF3、CHF2、CH2F的取代基取代；Preferably, R 2B is selected from -C(=O)-methyl, -C(=O)-ethyl, -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl, -NHC(=O)-cyclohexyl, -N(CH 3 )C(=O)-methyl, -N(CH 3 )C(=O)-cyclopropyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, said R 2B is optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, methyl, ethyl, CF 3 , CHF 2 , CH 2 F;

更优选地，R2B选自 More preferably, R 2B is selected from

在一些实施方案中，R2C选自-C(＝S)C1-3烷基、-C(＝O)N(C1-3烷基)2、-C(＝O)-C1-4亚烷基-NHC(＝NH)NH2、-C(＝O)-C1-4亚烷基-C(＝O)NH2、-C(＝O)-C1-4亚烷基-NHC(＝O)C1-3烷基，所述亚烷基任选被NH2取代，所述烷基、亚烷基任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代；In some embodiments, R 2C is selected from -C(＝S)C 1-3 alkyl, -C(＝O)N(C 1-3 alkyl) 2 , -C(＝O)-C 1-4 alkylene-NHC(＝NH)NH 2 , -C(＝O)-C 1-4 alkylene-C(＝O)NH 2 , -C(＝O)-C 1-4 alkylene-NHC(＝O)C 1-3 alkyl, the alkylene is optionally substituted with NH 2 , the alkyl and alkylene are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl;

优选地，R2C选自-C(＝S)-甲基、-C(＝S)-乙基、-C(＝O)N(甲基)2、-C(＝O)N(乙基)2、-C(＝O)-CH2CH2CH2CH2-NHC(＝NH)NH2、-C(＝O)-CH2CH2CH2-NHC(＝NH)NH2、 -C(＝O)-CH2CH2-NHC(＝NH)NH2、-C(＝O)-CH2CH2CH2CH2-C(＝O)NH2、-C(＝O)-CH2CH2CH2-C(＝O)NH2、-C(＝O)-CH2CH2-C(＝O)NH2、-C(＝O)-CH2CH2CH2CH2-NHC(＝O)-甲基、-C(＝O)-CH2CH2CH2CH2-NHC(＝O)-乙基、-C(＝O)-CH2CH2CH2-NHC(＝O)-甲基、-C(＝O)-CH2CH2CH2-NHC(＝O)-乙基、-C(＝O)-CH2CH2-NHC(＝O)-甲基、-C(＝O)-CH2CH2-NHC(＝O)-乙基，所述CH2任选被NH2取代，所述甲基、乙基、CH2任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代；Preferably, R 2C is selected from -C(＝S)-methyl, -C(＝S)-ethyl, -C(＝O)N(methyl) 2 , -C(＝O)N(ethyl) 2 , -C(＝O)-CH 2 CH 2 CH 2 -NHC (＝NH)NH 2 , -C(＝O)-CH 2 CH 2 CH 2 -NHC(＝NH)NH 2 , -C(=O)-CH 2 CH 2 -NHC(=NH)NH 2 , -C(=O)-CH 2 CH 2 CH 2 CH 2 -C(=O)NH 2 , -C(=O)-CH 2 CH 2 CH 2 -C(=O)NH 2 , -C(=O)-CH 2 CH 2 -C(=O)NH 2 , -C(=O)-CH 2 CH 2 CH 2 CH 2 -NHC(=O)-methyl, -C(=O)-CH 2 CH 2 CH 2 CH 2 -NHC(=O)-ethyl, -C(=O)-CH 2 CH 2 CH 2 -NHC(=O)-methyl, -C(=O)-CH 2 CH 2 CH 2 -NHC(=O)-ethyl, -C(=O)-CH 2 CH 2 -NHC(=O)-methyl, -C(=O)-CH 2 CH 2 -NHC(=O)-ethyl, the CH 2 is optionally substituted by NH 2 , the methyl, ethyl, CH 2 is optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl;

更优选地，R2C选自 More preferably, R 2C is selected from

在一些实施方案中，R3B选自-NHC(＝O)-C1-3烷基、-NHC(＝O)-C3-6环烷基、-N(C1-2烷基)C(＝O)-C1-3烷基、5至6元杂芳基、5至6元含内酰胺的杂环烷基，所述R2B任选进一步被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代；In some embodiments, R 3B is selected from -NHC(=O)-C 1-3 alkyl, -NHC(=O)-C 3-6 cycloalkyl, -N(C 1-2 alkyl)C(=O)-C 1-3 alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered lactam-containing heterocycloalkyl, said R 2B is optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl;

优选地，R3B选自-NHC(＝O)-甲基、-NHC(＝O)-乙基、-NHC(＝O)-环丙基、-NHC(＝O)-环丁基、-NHC(＝O)-环戊基、-NHC(＝O)-环己基、-N(CH3)C(＝O)-甲基、-N(CH3)C(＝O)-环丙基、 吡咯基、吡唑基、咪唑基、噁唑基、噁二唑基、三唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基，所述R2B任选进一步被1至4个选自氘、F、Cl、Br、I、甲基、乙基、CF3、CHF2、CH2F的取代基取代；Preferably, R 3B is selected from -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl, -NHC(=O)-cyclohexyl, -N(CH 3 )C(=O)-methyl, -N(CH 3 )C(=O)-cyclopropyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, said R 2B is optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, methyl, ethyl, CF 3 , CHF 2 , CH 2 F;

更优选地，R3B选自 More preferably, R 3B is selected from

在一些实施方案中，R2af选自-C1-4亚烷基-NHC(＝O)-C1-4亚烷基-NR2aaR2ab、-C1-4亚烷基-C(＝O)NR2aaR2ab、-C1-4亚烷基-SR2ac、-C1-4亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C1-4亚烷基-R2ae、-C0-4亚烷基-C3-12碳环基-R2ae、-C0-4亚烷基-4至12元杂环基-R2ae，所述亚烷基任选被NH2取代，所述的烷基、亚烷基、碳环基、杂环基任选被1至4个Rk取代；In some embodiments, R 2af is selected from -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-SR 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 heterocyclyl-R 2ae , the alkylene is optionally substituted with NH 2 , and the alkyl, alkylene, carbocyclyl and heterocyclyl are optionally substituted with 1 to 4 R k ;

在一些实施方案中，R2af选自-CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2CH2CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2CH2CH2CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2CH2CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2CH2CH2CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2-C(＝O)NR2aaR2ab、-CH2CH2-C(＝O)NR2aaR2ab、-CH2CH2CH2-C(＝O)NR2aaR2ab、-CH2CH2CH2CH2-C(＝O)NR2aaR2ab、-CH2-SR2ac、-CH2CH2-SR2ac、 -CH2CH2CH2-SR2ac、-CH2CH2CH2CH2-SR2ac、-CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2-R2ae、-CH2CH2-R2ae、-CH2CH2CH2-R2ae、-CH2CH2CH2CH2-R2ae、-环丙基-R2ae、-环丁基-R2ae、-环戊基-R2ae、-环己基-R2ae、-氮杂环丁基-R2ae、-吡咯烷基-R2ae、-哌啶基-R2ae，所述的CH2任选被NH2取代；In some embodiments, R 2af is selected from the group consisting of -CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 -NHC(＝O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 -NHC(＝O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 -NHC(＝O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 -NHC(＝O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 -NHC(＝O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(＝O)-CH 2 CH 2 -NR 2aa R 2ab 2 -NHC(=O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 -C(=O)NR 2aa R 2ab , -CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH 2 CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH 2 CH 2 CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH 2 -SR 2ac , -CH 2 CH 2 -SR 2ac , -CH 2 CH 2 CH 2 -SR 2ac , -CH 2 CH 2 CH 2 CH 2 -SR 2ac , -CH 2 -NHC(=NR 2ad )NR 2aa R 2ab , -CH 2 CH 2 -NHC(=NR 2ad )NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(=NR 2ad )NR 2aa R 2ab , -CH 2 CH 2 CH 2 CH 2 -NHC (＝NR 2ad )NR 2aa R 2ab , -CH 2 -R 2ae , -CH 2 CH 2 -R 2ae , -CH 2 CH 2 CH 2 -R 2ae , -CH 2 CH 2 CH 2 CH 2 -R 2ae , -cyclopropyl-R 2ae , -cyclobutyl-R 2ae , -cyclopentyl-R 2ae , -cyclohexyl-R 2ae , -azetidinyl-R 2ae , -pyrrolidinyl-R 2ae , -piperidinyl-R 2ae , wherein CH 2 is optionally substituted by NH 2 ;

在一些实施方案中，Q选自O、NRq、S、S(＝O)、S(＝O)2；In some embodiments, Q is selected from O, NR q , S, S(═O), S(═O) 2 ;

在一些实施方案中，Q选自O、NH或S；In some embodiments, Q is selected from O, NH or S;

在一些实施方案中，Q1选自O或NH；In some embodiments, Q 1 is selected from O or NH;

在一些实施方案中，R3、R4各自独立地选自H、卤素、CN、OH、C1-6烷基、C2-6烯基、C2-6炔基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-4至7元杂环基，所述的烷基、烯基、炔基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；In some embodiments, R 3 and R 4 are each 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 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;

在一些实施方案中，R3、R4各自独立地选自H、卤素、CN、OH、C1-4烷基、C2-4烯基、C2-4炔基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至7元杂环基，所述的烷基、烯基、炔基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；In some embodiments, R 3 and R 4 are each 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 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;

在一些实施方案中，R3与R4直接连接形成C3-6碳环基或4至7元杂环基，所述的碳环基或杂环基任选被1至4个Rk取代；In some embodiments, R 3 and R 4 are directly linked to form a C 3-6 carbocyclyl or a 4- to 7-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;

在一些实施方案中，R3、R4各自独立地选自H、F、Cl、Br、I、CN、OH、甲基、乙基、环丙基、-CH2-环丙基，所述的-CH2-、甲基、乙基、环丙基任选被1至4个Rk取代；In some embodiments, R 3 and R 4 are each independently selected from H, F, Cl, Br, I, CN, OH, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl, wherein the -CH 2 -, methyl, ethyl, cyclopropyl are optionally substituted with 1 to 4 R k ;

在一些实施方案中，R3与R4直接连接形成环丙基、环丁基、环戊基或环己基，所述的环丙基、环丁基、环戊基或环己基任选被1至4个Rk取代；In some embodiments, R 3 and R 4 are directly connected to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with 1 to 4 R k ;

在一些实施方案中，R3、R4各自独立地选自H、F或甲基；In some embodiments, R 3 and R 4 are each independently selected from H, F or methyl;

在一些实施方案中，Rq、R5各自独立地选自H或甲基；In some embodiments, R q , R 5 are each independently selected from H or methyl;

在一些实施方案中，R5选自H；In some embodiments, R 5 is selected from H;

在一些实施方案中，R2aa、R2ab、R2ac、R2ad、Rq、R5各自独立地选自H、C1-6烷基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-4至7元杂环基，所述的烷基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；In some embodiments, R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocyclyl, and -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;

在一些实施方案中，R2aa、R2ab、R2ac、R2ad、Rq、R5各自独立地选自H、C1-4烷基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至7元杂环基，所述的烷基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；In some embodiments, R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;

在一些实施方案中，R2aa、R2ab、R2ac、R2ad各自独立地选自H、甲基、乙基、CF3、-CH2-环丙基、环丙基；In some embodiments, R 2aa , R 2ab , R 2ac , R 2ad are each independently selected from H, methyl, ethyl, CF 3 , -CH 2 -cyclopropyl, cyclopropyl;

在一些实施方案中，R2aa、R2ab、R2ac、R2ad各自独立地选自H、甲基、乙基；In some embodiments, R 2aa , R 2ab , R 2ac , and R 2ad are each independently selected from H, methyl, and ethyl;

在一些实施方案中，R2ae选自NHC1-6烷基、N(C1-6烷基)2、-NHC(＝O)-C1-6烷基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-4至7元杂环基，所述的烷基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；In some embodiments, R 2ae is 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 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;

在一些实施方案中，R2ae选自NHC1-4烷基、N(C1-4烷基)2、-NHC(＝O)-C1-4烷基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至7元杂环基，所述的烷基、亚烷基、碳环基或杂环基任选被1至4个Rk取代； In some embodiments, R 2ae is 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 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;

在一些实施方案中，R2ae选自-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH2CH3)2、-NHC(＝O)-CH3、-NHC(＝O)-CH2CH3、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、哌嗪基、氧杂环丁基、四氢呋喃基、四氢吡喃基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-吡咯烷基、-CH2-哌啶基、-CH2-吗啉基、-CH2-哌嗪基、-CH2-氧杂环丁基、-CH2-四氢呋喃基、-CH2-四氢吡喃基，所述的-CH2-、甲基、乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、哌嗪基、氧杂环丁基、四氢呋喃基、四氢吡喃基任选被1至4个Rk取代；In some embodiments, R 2ae is selected from -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -NHC(═O)-CH 3 , -NHC(═O)-CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -morpholinyl, -CH 2 -piperazinyl, -CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 - 2 -tetrahydropyranyl, wherein the -CH2- , methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 Rk ;

在一些实施方案中，R2ae选自-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH2CH3)2、-NHC(＝O)-CH3、-NHC(＝O)-CH2CH3、环丙基、环丁基；In some embodiments, R 2ae is selected from -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -NHC(=O)-CH 3 , -NHC(=O)-CH 2 CH 3 , cyclopropyl, cyclobutyl;

在一些实施方案中，Ry、R1a、Rb自独立地选自H、氘、卤素、OH、＝O、CN、NH2、NO2、COOH、CONH2、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、NHC1-6烷基、N(C1-6烷基)2、-O-C3-10碳环基、-O-4至10元杂环基、-NH-C3-10碳环基、-NH-4至10元杂环基、-S-C3-10碳环基、-S-4至10元杂环基、-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-4至10元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；In some embodiments, R y , R 1a , and R b are independently selected from H, deuterium, halogen, OH, ＝O, CN, NH 2 , NO 2 , COOH, CONH 2 , 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 3-10 carbocyclyl, -O-4 to 10 membered heterocyclyl, -NH-C 3-10 carbocyclyl, -NH-4 to 10 membered heterocyclyl, -SC 3-10 carbocyclyl, -S-4 to 10 membered heterocyclyl, -C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 -alkylene-4 to 10-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;

在一些实施方案中，Ry、R1a、Rb自独立地选自H、氘、卤素、OH、＝O、CN、NH2、NO2、COOH、CONH2、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-O-C3-6碳环基、-O-4至6元杂环基、-NH-C3-6碳环基、-NH-4至6元杂环基、-S-C3-6碳环基、-S-4至6元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至6元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；In some embodiments, R y , R 1a , R b are independently selected from H, deuterium, halogen, OH, ＝O, CN, NH 2 , NO 2 , COOH, CONH 2 , C 1-4 alkyl, OC 1-4 alkyl, 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 carbocyclyl, -O-4 to 6 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-4 to 6 membered heterocyclyl, -SC 3-6 carbocyclyl, -S-4 to 6 membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;

在一些实施方案中，Ry、R1a、Rb各自独立地选自H、氘、F、Cl、Br、I、CN、OH、＝O、甲基、乙基、乙烯基、乙炔基、丙炔基、甲氧基、乙氧基、环丙基、-CH2-环丙基，所述的-CH2-、甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、丙炔基、环丙基任选被1至4个Rk取代；In some embodiments, R y , R 1a , and R b are each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, ═O, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, and —CH 2 -cyclopropyl, wherein the —CH 2 -, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propynyl, and cyclopropyl are optionally substituted with 1 to 4 R k ;

在一些实施方案中，Ry各自独立地选自H、氘、F、Cl、Br、I、CN、OH、甲基、乙基、乙烯基、乙炔基、丙炔基、甲氧基、乙氧基、环丙基、-CH2-环丙基、-CH2OCH3、-CH2OH、-CH2CN；In some embodiments, each R y is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH 2 -cyclopropyl, -CH 2 OCH 3 , -CH 2 OH, -CH 2 CN;

在一些实施方案中，Ry选自F、Cl、Br、甲基、CF3、CHF2、CH2F、CD3、CHD2、CH2D；In some embodiments, R y is selected from F, Cl, Br, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;

在一些实施方案中，R1a各自独立地选自H、氘、F、Cl、Br、I、CN、OH、甲基、乙基、乙烯基、乙炔基、丙炔基、甲氧基、乙氧基、环丙基、-CH2-环丙基、-CH2OCH3、-CH2OH、-CH2CN；In some embodiments, each R 1a is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH 2 -cyclopropyl, -CH 2 OCH 3 , -CH 2 OH, -CH 2 CN;

在一些实施方案中，Rb各自独立地选自H、氘、F、Cl、Br、I、CN、OH、＝O、甲基、乙基、乙烯基、乙炔基、丙炔基、甲氧基、乙氧基、环丙基、-CH2-环丙基、-CH2OCH3、-CH2OH、-CH2CN；In some embodiments, each R b is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, =0, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH 2 -cyclopropyl, -CH 2 OCH 3 , -CH 2 OH, -CH 2 CN;

在一些实施方案中，Rb选自H、氘、卤素、甲基、CF3、CHF2、CH2F、CD3、CHD2、CH2D；In some embodiments, R b is selected from H, deuterium, halogen, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;

任选地，当n选自1，Q选自S、S(＝O)、S(＝O)2，环B选自C3-7环烷基、4至10元杂环烷基、C6-10芳基、5至10元杂芳基，R1选自任选被1至4个R1a取代的非芳香的C3-12碳环基或者非芳香的4至12元杂环基时，满足如下条件之一：1)R2选自-C(＝O)R2a、-NHC(＝O)R2a、-N(C1-6烷基)C(＝O)R2a、-S(＝O)2R2a，R2a选自-C1-4亚烷基-NHC(＝O)-C1-4亚烷基-NR2aaR2ab、-C1-4亚烷基-C(＝O)NR2aaR2ab、-C1-4亚烷基-SR2ac、-C1-4亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C0-4亚烷基-C3-12碳环基-R2ae、-C0-4亚烷基-4至12元杂环基-R2ae，所述的亚烷基、碳环基、杂环基任选被1至4个Rk取代；2)R2选自-C(＝S)R2a、-NHC(＝S)R2a；3)m选自1、2、3或4，至少有1个Rb为Rb1，Rb1选自C1-6烷基，所述烷基被1个选自氘、OH、＝O、CN、C1-6烷氧基的取代基所取代，所述烷基 进一步任选被1至3个Rk取代；Optionally, when n is selected from 1, Q is selected from S, S(=O), S(=O) 2 , Ring B is selected from C 3-7 cycloalkyl, 4 to 10 membered heterocycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, R 1 is selected from a non-aromatic C 3-12 carbocyclic group or a non-aromatic 4 to 12 membered heterocyclic group optionally substituted by 1 to 4 R 1a , one of the following conditions is satisfied: 1) R 2 is selected from -C(=O)R 2a , -NHC(=O)R 2a , -N(C 1-6 alkyl)C(=O)R 2a , -S(=O) 2 R 2a , R 2a is selected from -C 1-4 alkylene-NHC(=O)-C 1-4 alkylene-NR 2aa R 2ab , -C 1-4 alkylene-C(=O)NR 2aa R 2ab , 1-4 alkylene-SR 2ac , -C 1-4 alkylene-NHC(＝NR 2ad )NR 2aa R 2ab , -C 0-4 alkylene-C 3-12 carbocyclyl-R 2ae , -C 0-4 alkylene-4 to 12 membered heterocyclyl-R 2ae , wherein the alkylene, carbocyclyl and heterocyclyl are optionally substituted by 1 to 4 R k ; 2) R 2 is selected from -C(＝S)R 2a , -NHC(＝S)R 2a ; 3) m is selected from 1, 2, 3 or 4, at least one R b is R b1 , R b1 is selected from C 1-6 alkyl, the alkyl is substituted by one substituent selected from deuterium, OH, ＝O, CN, C 1-6 alkoxy, the alkyl is further optionally substituted with 1 to 3 R k ;

在一些实施方案中，Rb1选自C1-6烷基，所述烷基被1个选自氘、OH、＝O、CN、C1-6烷氧基的取代基所取代，所述烷基进一步任选被1至3个Rk取代；In some embodiments, R b1 is selected from C 1-6 alkyl, the alkyl being substituted with 1 substituent selected from deuterium, OH, =O, CN, C 1-6 alkoxy, the alkyl being further optionally substituted with 1 to 3 R k ;

在一些实施方案中，Rb1选自甲基、乙基、丙基、异丙基，所述的甲基、乙基、丙基、异丙基被1个选自氘、OH、＝O、CN、甲氧基、乙氧基的取代基所取代，所述的甲基、乙基、丙基、异丙基进一步任选被1至3个Rk取代；In some embodiments, R b1 is selected from methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is substituted with one substituent selected from deuterium, OH, =O, CN, methoxy, ethoxy, and the methyl, ethyl, propyl, isopropyl is further optionally substituted with 1 to 3 R k ;

在一些实施方案中，Rb1选自-CH2OH、-CH2-OCH3、-CH2CN；In some embodiments, R b1 is selected from -CH 2 OH, -CH 2 -OCH 3 , -CH 2 CN;

在一些实施方案中，Rk各自独立的选自氘、卤素、OH、＝O、CN、NO2、COOH、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、-O-C3-6碳环基、-O-3至7元杂环基、-NH-C3-6碳环、-NH-3至7元杂环基、-S-C3-6碳环基、-S-3至7元杂环基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-3至7元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-6烷基、C1-6烷氧基的取代基所取代；In some embodiments, each R k is independently selected from deuterium, halogen, OH, =O, CN, NO 2 , COOH, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -SC 3-6 carbocyclyl, -S-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3 to 7 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy;

在一些实施方案中，Rk各自独立的选自氘、卤素、OH、＝O、CN、NO2、COOH、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、-O-C3-6碳环基、-O-3至7元杂环基、-NH-C3-6碳环、-NH-3至7元杂环基、-S-C3-6碳环基、-S-3至7元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-3至7元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；In some embodiments, each R k is independently selected from deuterium, halogen, OH, =O, CN, NO 2 , COOH, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -SC 3-6 carbocyclyl, -S-3 to 7 membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-3 to 7 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy;

在一些实施方案中，Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基，所述的甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基任选被1至4个选自氘、F、Cl、Br、I、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；In some embodiments, each R k is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, 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 with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy;

在一些实施方案中，Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基；In some embodiments, each R k is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl;

在一些实施方案中，n选自1、2或3；In some embodiments, n is selected from 1, 2 or 3;

在一些实施方案中，m选自0、1、2、3或4。In some embodiments, m is selected from 0, 1, 2, 3 or 4.

作为本发明的第一种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
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,

Y1、Y2、Y3各自独立地选自N或CRy；Y 1 , Y 2 , and Y 3 are each independently selected from N or CR y ;

R1选自C6-10芳基、5至10元杂芳基、非芳香的C3-12碳环基或者非芳香的4至12元杂环基，所述的芳基、杂芳基、碳环基或杂环基任选被1至4个R1a取代；R 1 is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, non-aromatic C 3-12 carbocyclyl or non-aromatic 4- to 12-membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R 1a ;

L选自键、-O-、-S-、-NH-、-N(C1-4烷基)-、-O-C1-4亚烷基-、-NH-C1-4亚烷基-、-N(C1-4烷基)-C1-4 亚烷基-、-C1-4亚烷基-，所说的亚烷基或烷基任选被1至4个Rk取代；L is selected from a bond, -O-, -S-, -NH-, -N(C 1-4 alkyl)-, -OC 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 is optionally substituted by 1 to 4 R k ;

环B选自C3-7环烷基、C8-12环烷基、4至10元杂环烷基、11至13元杂环烷基、11至13元杂环基、C6-10芳基、5至10元杂芳基；Ring B is selected from C 3-7 cycloalkyl, C 8-12 cycloalkyl, 4- to 10-membered heterocycloalkyl, 11- to 13-membered heterocycloalkyl, 11- to 13-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

R2选自H、-C(＝O)R2a、-NHC(＝O)R2a、-N(C1-6烷基)C(＝O)R2a、-S(＝O)2R2a、-NHS(＝O)2R2a、-C(＝S)R2a、-NHC(＝S)R2a、NHR2a、5至10元杂芳基、5至10元含内酰胺的杂环烷基、5至10元含脲基的杂环烷基，所述杂芳基、杂环烷基、烷基任选进一步被1至4个选自氘、卤素、OH、NH2、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6卤代烯基、C2-6炔基、C2-6卤代炔基的取代基取代；R 2 is selected from H, -C(＝O)R 2a , -NHC(＝O)R 2a , -N(C 1-6 alkyl)C(＝O)R 2a , -S(＝O) 2 R 2a , -NHS(＝O) 2 R 2a , -C(＝S)R 2a , -NHC(＝S)R 2a , NHR 2a , 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl containing lactam, 5- to 10-membered heterocycloalkyl containing urea, wherein the heteroaryl, heterocycloalkyl, alkyl is optionally further substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl;

R2a选自C1-6烷基、C2-6烯基、C2-6炔基、-C0-4亚烷基-C3-12碳环基、-C0-4亚烷基-4至12元杂环基、-C1-6亚烷基-NHC(＝O)-C1-6亚烷基-NR2aaR2ab、-C1-6亚烷基-C(＝O)NR2aaR2ab、-C1-4亚烷基-NR2aaC(＝O)R2ab、-C1-6亚烷基-N(C1-6亚烷基)R2aa、-C1-6亚烷基-SR2ac、-C1-6亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C1-6亚烷基-R2ae、-C0-6亚烷基-C3-12碳环基-R2ae、-C0-6亚烷基-4至12元杂环基-R2ae，所述亚烷基或烷基任选被1至3个NH2取代，所述的烷基、烯基、炔基、亚烷基、碳环基、杂环基任选被1至4个Rk取代；R 2a is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-12 carbocyclyl, -C 0-4 alkylene-4 to 12-membered heterocyclyl, -C 1-6 alkylene-NHC(═O)-C 1-6 alkylene-NR 2aa R 2ab , -C 1-6 alkylene-C(═O)NR 2aa R 2ab , -C 1-4 alkylene-NR 2aa C(═O)R 2ab , -C 1-6 alkylene-N(C 1-6 alkylene)R 2aa , -C 1-6 alkylene-SR 2ac , -C 1-6 alkylene-NHC(═NR 2ad )NR 2aa R 2ab , -C 1-6 alkylene-R 2ae , -C 0-6 alkylene-C 3-12 carbocyclyl-R 2ae , -C 0-6 alkylene-4 to 12 membered heterocyclyl-R 2ae , the alkylene or alkyl group is optionally substituted by 1 to 3 NH 2 , and the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R k ;

Q选自O、NRq、S、S(＝O)、S(＝O)2；Q is selected from O, NR q , S, S(═O), S(═O) 2 ;

R3、R4各自独立地选自H、卤素、CN、OH、C1-6烷基、C2-6烯基、C2-6炔基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-4至7元杂环基，所述的烷基、烯基、炔基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；R 3 and R 4 are each 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 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;

作为选择，R3与R4直接连接形成C3-6碳环基或4至7元杂环基，所述的碳环基或杂环基任选被1至4个Rk取代；Alternatively, R 3 and R 4 are directly linked to form a C 3-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;

R2aa、R2ab、R2ac、R2ad、Rq、R5各自独立地选自H、C1-6烷基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-4至7元杂环基，所述的烷基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocyclyl, and -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;

R2ae选自NHC1-6烷基、N(C1-6烷基)2、-NHC(＝O)-C1-6烷基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-4至7元杂环基，所述的烷基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；R 2ae is 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 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;

Ry、R1a、Rb自独立地选自H、氘、卤素、OH、＝O、CN、NH2、NO2、COOH、CONH2、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、NHC1-6烷基、N(C1-6烷基)2、-O-C3-10碳环基、-O-4至10元杂环基、-NH-C3-10碳环基、-NH-4至10元杂环基、-S-C3-10碳环基、-S-4至10元杂环基、-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-4至10元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；R y , R 1a , R b are independently selected from H, deuterium, halogen, OH, ═O, CN, NH 2 , NO 2 , COOH, CONH 2 , 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 3-10 carbocyclyl, —O-4 to 10 membered heterocyclyl, —NH-C 3-10 carbocyclyl, —NH-4 to 10 membered heterocyclyl, —SC 3-10 carbocyclyl, —S-4 to 10 membered heterocyclyl, —C 0-4 alkylene-C 3-10 carbocyclyl, —C 0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k replaces;

Rk各自独立的选自氘、卤素、OH、＝O、CN、NO2、COOH、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、-O-C3-6碳环基、-O-3至7元杂环基、-NH-C3-6碳环、-NH-3至7元杂环基、-S-C3-6碳环基、-S-3至7元杂环基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-3至7元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-6烷基、C1-6烷氧基的取代基所取代；R k is each independently selected from deuterium, halogen, OH, =O, CN, NO 2 , COOH, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -SC 3-6 carbocyclyl, -S-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3 to 7 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy;

n选自1、2或3；n is selected from 1, 2 or 3;

m选自0、1、2、3或4；m is selected from 0, 1, 2, 3 or 4;

条件是当n选自1，Q选自S、S(＝O)、S(＝O)2，环B选自C3-7环烷基、4至10元杂环烷基、C6-10芳基、5至10元杂芳基，R1选自任选被1至4个R1a取代的非芳香的C3-12碳环基或者非芳香的4至12元杂环基时，满足如下条件之一：1)R2选自-C(＝O)R2a、-NHC(＝O)R2a、-N(C1-6烷 基)C(＝O)R2a、-S(＝O)2R2a，R2a选自-C1-4亚烷基-NHC(＝O)-C1-4亚烷基-NR2aaR2ab、-C1-4亚烷基-C(＝O)NR2aaR2ab、-C1-6亚烷基-NR2aaC(＝O)R2ab、-C1-6亚烷基-N(C1-6亚烷基)R2aa、-C1-6亚烷基-R2ae、-C1-4亚烷基-SR2ac、-C1-4亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C0-4亚烷基-C3-12碳环基-R2ae、-C0-4亚烷基-4至12元杂环基-R2ae，所述亚烷基任选被1个NH2取代，所述的亚烷基、碳环基、杂环基任选被1至4个Rk取代；2)R2选自-C(＝S)R2a、-NHC(＝S)R2a；3)m选自1、2、3或4，至少有1个Rb为Rb1，Rb1选自C1-6烷基，所述烷基被1个选自氘、OH、＝O、CN、C1-6烷氧基的取代基所取代，所述烷基进一步任选被1至3个Rk取代。The condition is that when n is selected from 1, Q is selected from S, S(=O), S(=O) 2 , Ring B is selected from C 3-7 cycloalkyl, 4 to 10 membered heterocycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, R 1 is selected from a non-aromatic C 3-12 carbocyclic group or a non-aromatic 4 to 12 membered heterocyclic group optionally substituted by 1 to 4 R 1a , one of the following conditions is satisfied: 1) R 2 is selected from -C(=O)R 2a , -NHC(=O)R 2a , -N(C 1-6 alkane) R 2a is selected from -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 1-6 alkylene-NR 2aa C(=O)R 2ab , -C 1-6 alkylene-N(C 1-6 alkylene)R 2aa , -C 1-6 alkylene-R 2ae , -C 1-4 alkylene-SR 2ac , -C 1-4 alkylene-NHC(=NR 2ad ) NR 2aa R 2ab , -C 0-4 alkylene-C 3-12 carbocyclyl-R 2ae , -C 0-4 alkylene-4 to 12 membered heterocyclyl -R 2ae , the alkylene is optionally substituted by 1 NH 2 , and the alkylene, carbocyclyl and heterocyclyl are optionally substituted by 1 to 4 R k ; 2) R 2 is selected from -C(＝S)R 2a , -NHC(＝S)R 2a ; 3) m is selected from 1, 2, 3 or 4, at least 1 R b is R b1 , R b1 is selected from C 1-6 alkyl, the alkyl is substituted by 1 substituent selected from deuterium, OH, ＝O, CN, C 1-6 alkoxy, and the alkyl is further optionally substituted by 1 to 3 R k .

作为本发明的第二种实施方案，上述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，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,

R1选自任选被1至4个R1a取代的如下基团之一：苯基、萘基、5至6元杂芳基、8至10元并环杂芳基、C3-7单环烷基、C4-7单环烯基、C5-12并环烷基、C5-12螺环烷基、C5-12桥环烷基、4至7元单杂环烷基、6至12元并杂环烷基、6至12元螺杂环烷基、6至12元桥杂环烷基；R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, 5 to 6 membered heteroaryl, 8 to 10 membered cycloheteroaryl, C 3-7 monocycloalkyl, C 4-7 monocycloalkenyl, 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;

环B选自C3-7环烷基、C8-12并环烷基、C8-12螺环烷基、C8-12桥环烷基、4至7元单杂环烷基、6至10元并杂环烷基、6至10元螺杂环烷基、6至10元桥杂环烷基、11至13元二环杂环烷基、11至13元三环杂环烷基、苯基、萘基、5至6元杂芳基、8至10元并环杂芳基、苯并C7-9环烷基、苯并7至9元杂环烷基、5至6元杂芳基并C7-9环烷基、5至6元杂芳基并7至9元杂环烷基；Ring B is selected from C3-7 cycloalkyl, C8-12 cycloalkyl, C8-12 spirocycloalkyl, C8-12 bridged cycloalkyl, 4 to 7 membered monoheterocycloalkyl, 6 to 10 membered cycloheterocycloalkyl, 6 to 10 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, benzoC7-9cycloalkyl , benzo7 to 9 membered heterocycloalkyl, 5 to 6 membered heteroaryl andC7-9cycloalkyl , 5 to 6 membered heteroaryl and7 to 9 membered heterocycloalkyl;

R2选自H、-C(＝O)R2a、-NHC(＝O)R2a、-N(C1-4烷基)C(＝O)R2a、-S(＝O)2R2a、-NHS(＝O)2R2a、-C(＝S)R2a、-NHC(＝S)R2a、NHR2a、5至7元杂芳基、5至7元含内酰胺的杂环烷基、5至7元含脲基的杂环烷基，所述烷基、杂芳基、杂环烷基任选进一步被1至4个选自氘、卤素、OH、NH2、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C2-4卤代炔基的取代基取代； R2 is selected from H, -C(=O) R2a , -NHC(=O) R2a , -N( C1-4 alkyl)C(=O) R2a , -S(=O) 2R2a , -NHS(=O) 2R2a , -C(= S ) R2a , -NHC(=S) R2a , NHR2a , 5- to 7-membered heteroaryl, 5- to 7-membered heterocycloalkyl containing lactam, 5- to 7-membered heterocycloalkyl containing urea, wherein the alkyl, heteroaryl, heterocycloalkyl is optionally further substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2 , C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, C2-4 haloalkynyl ;

R2a选自C1-4烷基、C2-4烯基、C2-4炔基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-4至6元杂环基、-C1-4亚烷基-NHC(＝O)-C1-4亚烷基-NR2aaR2ab、-C1-4亚烷基-C(＝O)NR2aaR2ab、-C1-4亚烷基-NR2aaC(＝O)R2ab、-C1-4亚烷基-N(C1-4亚烷基)R2aa、-C1-4亚烷基-SR2ac、-C1-4亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C1-4亚烷基-R2ae、-C0-4亚烷基-C3-6碳环基-R2ae、-C0-4亚烷基-4至6元杂环基-R2ae，所述烷基、亚烷基任选被1至3个NH2取代，所述的烷基、烯基、炔基、亚烷基、碳环基、杂环基任选被1至4个Rk取代；R 2a is selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-4 to 6 membered heterocyclyl, -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-NR 2aa C(═O)R 2ab , -C 1-4 alkylene-N(C 1-4 alkylene)R 2aa , -C 1-4 alkylene-SR 2ac , -C 1-4 alkylene-NHC(═NR 2ad )NR 2aa R 2ab , -C 1-4 alkylene-R 2ae , -C 0-4 alkylene-C 3-6 carbocyclyl-R 2ae , -C 0-4 alkylene-4 to 6 membered heterocyclyl-R 2ae , wherein the alkyl and alkylene groups are optionally substituted by 1 to 3 NH 2 , and the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl and heterocyclyl groups are optionally substituted by 1 to 4 R k ;

R3、R4各自独立地选自H、卤素、CN、OH、C1-4烷基、C2-4烯基、C2-4炔基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至7元杂环基，所述的烷基、烯基、炔基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；R 3 and R 4 are each 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 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;

作为选择，R3与R4直接连接形成C3-6碳环基或4至7元杂环基，所述的碳环基或杂环基任选被1至4个Rk取代；Alternatively, R 3 and R 4 are directly linked to form a C 3-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;

R2aa、R2ab、R2ac、R2ad、Rq、R5各自独立地选自H、C1-4烷基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至7元杂环基，所述的烷基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocyclyl, and -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;

R2ae选自NHC1-4烷基、N(C1-4烷基)2、-NHC(＝O)-C1-4烷基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至7元杂环基，所述的烷基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；R 2ae is 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 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;

Ry、R1a、Rb自独立地选自H、氘、卤素、OH、＝O、CN、NH2、NO2、COOH、CONH2、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-O-C3-6碳环基、 -O-4至6元杂环基、-NH-C3-6碳环基、-NH-4至6元杂环基、-S-C3-6碳环基、-S-4至6元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至6元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；R y , R 1a , and R b are independently selected from H, deuterium, halogen, OH, ═O, CN, NH 2 , NO 2 , COOH, CONH 2 , C 1-4 alkyl, OC 1-4 alkyl, 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 carbocyclyl, -O-4 to 6-membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-4 to 6-membered heterocyclyl, -SC 3-6 carbocyclyl, -S-4 to 6-membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6-membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;

Rk各自独立的选自氘、卤素、OH、＝O、CN、NO2、COOH、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、-O-C3-6碳环基、-O-3至7元杂环基、-NH-C3-6碳环、-NH-3至7元杂环基、-S-C3-6碳环基、-S-3至7元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-3至7元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；R k is each independently selected from deuterium, halogen, OH, =O, CN, NO 2 , COOH, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -SC 3-6 carbocyclyl, -S-3 to 7 membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-3 to 7 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy;

其余定义与本发明第一种实施方案相同。The remaining definitions are the same as those of the first embodiment of the present invention.

作为本发明的第三种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a third 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,

R1选自任选被1至4个R1a取代的如下基团之一：苯基、萘基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、异喹唑啉基、吡啶并吡唑基、吡啶并咪唑基、吡啶并呋喃基、吡啶并噻吩基、吡啶并噁唑基、吡啶并噻唑基、嘧啶并吡唑基、嘧啶并咪唑基、嘧啶并呋喃基、嘧啶并噻吩基、嘧啶并噁唑基、嘧啶并噻唑基、环丙基、环丁基、环戊基、环己基、环己烯基、苯基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丙基并氧杂环丁基、环丙基并四氢呋喃基、环丙基并四氢吡喃基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环丁基并氧杂环丁基、环丁基并四氢呋喃基、环丁基并四氢吡喃基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环戊基并氧杂环丁基、环戊基并四氢呋喃基、环戊基并四氢吡喃基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、环己基并氧杂环丁基、环己基并四氢呋喃基、环己基并四氢吡喃基、环丙基螺氮杂环丁基、环丙基螺吡咯烷基、环丙基螺哌啶基、环丙基螺氧杂环丁基、环丙基螺四氢呋喃基、环丙基螺四氢吡喃基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环丁基螺氧杂环丁基、环丁基螺四氢呋喃基、环丁基螺四氢吡喃基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环戊基螺氧杂环丁基、环戊基螺四氢呋喃基、环戊基螺四氢吡喃基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、环己基螺氧杂环丁基、环己基螺四氢呋喃基、环己基螺四氢吡喃基、氮杂环己基螺氮杂环己基、氮杂环戊基螺氮杂环己基、氮杂环戊基螺氮杂环戊基、氮杂环己基并氮杂环己基、氮杂环戊基并氮杂环己基、氮杂环戊基并氮杂环戊基、双环[1.1.1]戊烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.1.1]庚烷基、金刚烷基、 R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : 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,

环B选自苯基、萘基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、异喹唑啉基、吡啶并吡唑基、吡 啶并咪唑基、吡啶并呋喃基、吡啶并噻吩基、吡啶并噁唑基、吡啶并噻唑基、嘧啶并吡唑基、嘧啶并咪唑基、嘧啶并呋喃基、嘧啶并噻吩基、嘧啶并噁唑基、嘧啶并噻唑基、 环丙基、环丁基、环戊基、环己基、环己烯基、苯基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丙基并氧杂环丁基、环丙基并四氢呋喃基、环丙基并四氢吡喃基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环丁基并氧杂环丁基、环丁基并四氢呋喃基、环丁基并四氢吡喃基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环戊基并氧杂环丁基、环戊基并四氢呋喃基、环戊基并四氢吡喃基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、环己基并氧杂环丁基、环己基并四氢呋喃基、环己基并四氢吡喃基、环丙基螺氮杂环丁基、环丙基螺吡咯烷基、环丙基螺哌啶基、环丙基螺氧杂环丁基、环丙基螺四氢呋喃基、环丙基螺四氢吡喃基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环丁基螺氧杂环丁基、环丁基螺四氢呋喃基、环丁基螺四氢吡喃基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环戊基螺氧杂环丁基、环戊基螺四氢呋喃基、环戊基螺四氢吡喃基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、环己基螺氧杂环丁基、环己基螺四氢呋喃基、环己基螺四氢吡喃基、氮杂环己基螺氮杂环己基、氮杂环戊基螺氮杂环己基、氮杂环戊基螺氮杂环戊基、氮杂环己基并氮杂环己基、氮杂环戊基并氮杂环己基、氮杂环戊基并氮杂环戊基、氮杂环己基螺四氢吡喃基、双环[1.1.1]戊烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.1.1]庚烷基、金刚烷基、 Ring B is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, isoquinazolinyl, pyridopyrazolyl, pyrazolyl, imidazolyl, pyridofuranyl, pyridothiphenyl, pyridoxazolyl, pyridothiazolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrimidofuranyl, pyrimidothiphenyl, pyrimidoxazolyl, 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, cyclopropyltetra ... cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclopropyloxetanyl, cyclopropyltetrahydrofuranyl, cyclopropylcyclopropyl furanyl, cyclopropyltetrahydropyranyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclobutyloxetanyl, cyclobutyltetrahydrofuranyl, cyclobutyltetrahydropyranyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclopentyloxetanyl, cyclopentyltetrahydrofuranyl, cyclopentyltetrahydropyranyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, cyclohexyloxetanyl, cyclohexyltetrahydrofuranyl, cyclohexyltetrahydropyranyl, 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 spiroazetidinyl, cyclohexyl cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, cyclohexylspiroxetanyl, cyclohexylspirotetrahydrofuranyl, cyclohexylspirotetrahydropyranyl, azacyclohexylspiroazacyclohexyl, 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,

R2选自H、-C(＝O)R2a、-NHC(＝O)R2a、-N(CH3)C(＝O)R2a、-N(CH2CH3)C(＝O)R2a、-S(＝O)2R2a、-NHS(＝O)2R2a、-C(＝S)R2a、-NHC(＝S)R2a、NHR2a、5元杂芳基、6元杂芳基、5元含内酰胺的杂环烷基、6元含内酰胺的杂环烷基、7元含内酰胺的杂环烷基、咪唑烷酮基、四氢-2-嘧啶酮，所述CH3、CH2、杂芳基、杂环烷基、咪唑烷酮基、四氢-2-嘧啶酮任选进一步被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代； R2 is selected from H, -C(=O) R2a , -NHC(=O) R2a , -N ( CH3 )C(=O) R2a , -N( CH2CH3 )C(=O) R2a , -S(=O )2R2a , -NHS(= O ) 2R2a , -C(=S) R2a , -NHC(=S) R2a , NHR2a , 5-membered heteroaryl, 6-membered heteroaryl, 5-membered lactam-containing heterocycloalkyl, 6-membered lactam-containing heterocycloalkyl, 7-membered lactam-containing heterocycloalkyl, imidazolidinone, tetrahydro-2-pyrimidinone, wherein CH3 , CH2 , heteroaryl, heterocycloalkyl, imidazolidinone, tetrahydro-2-pyrimidinone is optionally further substituted by 1 to 4 atoms selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl substituents;

R2a选自任选被1至4个Rk取代的如下基团之一：甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-吡咯烷基、-CH2- 哌啶基、-CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2CH2CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2CH2CH2CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2CH2CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2CH2CH2CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2-C(＝O)NR2aaR2ab、-CH2CH2-C(＝O)NR2aaR2ab、-CH2CH2CH2-C(＝O)NR2aaR2ab、-CH2CH2CH2CH2-C(＝O)NR2aaR2ab、-CH2-SR2ac、-CH2CH2-SR2ac、-CH2CH2CH2-SR2ac、-CH2CH2CH2CH2-SR2ac、-CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2-R2ae、-CH2CH2-R2ae、-CH2CH2CH2-R2ae、-CH2CH2CH2CH2-R2ae、-CH2CH2CH2CH2CH2-R2ae、-CH2-NR2aaC(＝O)R2ab、-CH2CH2CH2CH2-NR2aaC(＝O)R2ab、-CH2-N(甲基)R2aa、-CH2CH2-NR2aaC(＝O)R2ab、-CH2CH2CH2-NR2aaC(＝O)R2ab、-CH2CH2CH2CH2-N(甲基)R2aa-、-CH2CH2CH2-N(甲基)R2aa、-CH2CH2-N(甲基)R2aa、-CH2CH2CH2-N(乙基)R2aa、-CH2CH2CH2CH2-N(乙基)R2aa-、-CH2CH2-N(乙基)R2aa、-CH2-N(乙基)R2aa、-环丙基-R2ae、-环丁基-R2ae、-环戊基-R2ae、-环己基-R2ae、-氮杂环丁基-R2ae、-吡咯烷基-R2ae、-哌啶基-R2ae，所述的、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、CH2任选被1至3个NH2取代；R 2a is selected from one of the following groups optionally substituted with 1 to 4 R k : methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 - Piperidinyl, -CH 2 -NHC(=O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 -NHC(=O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(=O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 CH 2 -NHC(=O)-CH 2 -NR 2aa R 2ab , -CH 2 -NHC(＝O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 -NHC(＝O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(＝O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 CH 2 -NHC(=O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 -C(=O)NR 2aa R 2ab , -CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH 2 CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH 2 CH 2 CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH 2 -SR 2ac , -CH 2 CH 2 -SR 2ac , -CH 2 CH 2 CH 2 -SR 2ac , -CH 2 CH 2 CH 2 CH 2 -SR 2ac , -CH 2 -NHC(=NR 2ad )NR 2aa R 2ab , -CH 2 CH 2 -NHC(=NR 2ad )NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC (＝NR 2ad )NR 2aa R 2ab , -CH 2 CH 2 CH 2 CH 2 -NHC (＝NR 2ad )NR 2aa R 2ab , -CH 2 -R 2ae , -CH 2 CH 2 -R 2ae , -CH 2 CH 2 CH 2 -R 2ae , -CH 2 CH 2 CH 2 CH 2 -R 2ae , -CH 2 CH 2 CH 2 CH 2 CH 2 -R 2ae , -CH 2 -NR 2aa C(＝O)R 2ab , -CH 2 CH 2 CH 2 CH 2 -NR 2aa C(＝O)R 2ab , -CH 2 -N(methyl)R 2aa , -CH 2 CH 2 -NR 2aa C(＝O)R 2ab -CH2CH2CH2 - NR2aaC (＝O ) R2ab , -CH2CH2CH2CH2-N(methyl ) R2aa- , -CH2CH2CH2 - N (methyl) R2aa , -CH2CH2- N (methyl ) R2aa , -CH2CH2CH2 -N(methyl) R2aa , -CH2CH2CH2-N(ethyl) R2aa , -CH2CH2CH2CH2 - N (ethyl) R2aa- , -CH2CH2 -N(ethyl) R2aa , -CH2 -N(ethyl) R2aa , -cyclopropyl- R2ae , -cyclobutyl- R2ae , -cyclopentyl - R2ae , -cyclohexyl - R2ae , -azetidinyl- R2ae , -pyrrolidinyl - R2ae , -piperidinyl-R 2ae , wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, CH 2 is optionally substituted by 1 to 3 NH 2 ;

R2aa、R2ab、R2ac、R2ad各自独立地选自H、甲基、乙基、CF3、-CH2-环丙基、环丙基；R 2aa , R 2ab , R 2ac , R 2ad are each independently selected from H, methyl, ethyl, CF 3 , -CH 2 -cyclopropyl, cyclopropyl;

R2ae选自-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH2CH3)2、-NHC(＝O)-CH3、-NHC(＝O)-CH2CH3、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、哌嗪基、氧杂环丁基、四氢呋喃基、四氢吡喃基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-吡咯烷基、-CH2-哌啶基、-CH2-吗啉基、-CH2-哌嗪基、-CH2-氧杂环丁基、-CH2-四氢呋喃基、-CH2-四氢吡喃基，所述的-CH2-、甲基、乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、哌嗪基、氧杂环丁基、四氢呋喃基、四氢吡喃基吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、任选被1至4个Rk取代； R2ae is selected from the group consisting of -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, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, -CH2 -cyclopropyl, -CH2 -cyclobutyl, -CH2 -cyclopentyl, -CH2 -cyclohexyl, -CH2 -azetidinyl, -CH2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -morpholinyl, -CH 2 -piperazinyl, -CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 -tetrahydropyranyl, wherein -CH 2 -, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranylpyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, are optionally substituted with 1 to 4 R k ;

Rq、R5各自独立地选自H或甲基；R q , R 5 are each independently selected from H or methyl;

Ry、R1a、Rb各自独立地选自H、氘、F、Cl、Br、I、CN、OH、＝O、甲基、乙基、乙烯基、乙炔基、丙炔基、甲氧基、乙氧基、环丙基、-CH2-环丙基，所述的-CH2-、甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、丙炔基、环丙基任选被1至4个Rk取代；R y , R 1a , and R b are each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, ═O, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, and —CH 2 -cyclopropyl, wherein the —CH 2 -, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propynyl, and cyclopropyl are optionally substituted by 1 to 4 R k ;

Rb1选自甲基、乙基、丙基、异丙基，所述的甲基、乙基、丙基、异丙基被1个选自氘、OH、＝O、CN、甲氧基、乙氧基的取代基所取代，所述的甲基、乙基、丙基、异丙基进一步任选被1至3个Rk取代；R b1 is selected from methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is substituted by one substituent selected from deuterium, OH, =O, CN, methoxy, ethoxy, and the methyl, ethyl, propyl, isopropyl is further optionally substituted by 1 to 3 R k ;

R3、R4各自独立地选自H、F、Cl、Br、I、CN、OH、甲基、乙基、环丙基、-CH2-环丙基，所述的-CH2-、甲基、乙基、环丙基任选被1至4个Rk取代；R 3 and R 4 are each independently selected from H, F, Cl, Br, I, CN, OH, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl, wherein the -CH 2 -, methyl, ethyl, cyclopropyl is optionally substituted by 1 to 4 R k ;

作为选择，R3与R4直接连接形成环丙基、环丁基、环戊基或环己基，所述的环丙基、环丁基、环戊基或环己基任选被1至4个Rk取代；Alternatively, R 3 and R 4 are directly linked to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted by 1 to 4 R k ;

Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、 氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基，所述的甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基任选被1至4个选自氘、F、Cl、Br、I、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；R k is each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, 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 with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2 , C1-4 alkyl, C1-4 alkoxy;

其余定义与本发明第一种或第二种实施方案相同。The remaining definitions are the same as those of the first or second embodiment of the present invention.

作为本发明的第四种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a fourth 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,

L选自键、-O-、-S-、-NH-、-OCH2-、-OCH2CH2-、-OCH2CH2CH2-、-NHCH2-、-NHCH2CH2-、-NHCH2CH2CH2-，所述的-CH2-任选被1至4个Rk取代；L is selected from a bond, -O-, -S-, -NH-, -OCH2- , -OCH2CH2- , -OCH2CH2CH2- , -NHCH2-, -NHCH2CH2-, -NHCH2CH2- , -NHCH2CH2CH2- , said -CH2- being optionally substituted with 1 to 4 Rk ;

Q选自O、NH或S；Q is selected from O, NH or S;

R3、R4各自独立地选自H、F或甲基；R 3 and R 4 are each independently selected from H, F or methyl;

R5选自H； R5 is selected from H;

R1选自任选被1至4个R1a取代的如下基团之一： R 1 is selected from one of the following groups optionally substituted by 1 to 4 R 1a :

R2选自H、-C(＝O)R2a、-NHC(＝O)R2a、-N(CH3)C(＝O)R2a、-N(CH2CH3)C(＝O)R2a、-S(＝O)2R2a、-NHS(＝O)2R2a、-C(＝S)R2a、-NHC(＝S)R2a、NHR2a、吡咯基、吡唑基、咪唑基、噁唑基、噁二唑基、三唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、所述CH3、CH2、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、任选进一步被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代； R2 is selected from H, -C(=O) R2a , -NHC(=O) R2a , -N ( CH3 )C(=O) R2a , -N ( CH2CH3 )C(=O) R2a , -S(=O) 2R2a , -NHS(=O) 2R2a , -C(=S) R2a , -NHC(=S) R2a , NHR2a, pyrrolyl, pyrazolyl , imidazolyl, oxazolyl , oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, The CH 3 , CH 2 , pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl;

R2a选自甲基、乙基、氮杂环丁基、吡咯烷基、哌啶基、-CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH(NH2)-CH2-SR2ac、-CH(NH2)-CH2CH2-SR2ac、-CH(NH2)-CH2-C(＝O)NR2aaR2ab、-CH(NH2)-CH2CH2-C(＝O)NR2aaR2ab、-CH(NH2)-CH2-NHC(＝NR2ad)NR2aaR2abb、-CH(NH2)-CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2-R2ae、-CH2CH2CH2-R2ae、-CH(NH2)-CH2CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2-R2ae、-CH2CH2-R2ae、-CH2CH2CH2CH2-R2ae、-CH2CH2CH2CH2CH2-R2ae、-CH(NH2)CH2CH2CH2CH2-R2ae、-环丙基-R2ae、-环丁基-R2ae、-环戊基-R2ae、-环己基-R2ae、-氮杂环丁基-R2ae、-吡咯烷基-R2ae、-哌啶基-R2ae，所述的甲基或乙基任选被1个NH2取代；R 2a is selected from methyl, ethyl, azetidinyl, pyrrolidinyl, piperidinyl, -CH 2 -NHC(=O)-CH 2 -NR 2aa R 2ab , -CH(NH 2 )-CH 2 -SR 2ac , -CH(NH 2 )-CH 2 CH 2 -SR 2ac , -CH(NH 2 )-CH 2 -C(=O)NR 2aa R 2ab , -CH(NH 2 )-CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH(NH 2 )-CH 2 -NHC(=NR 2ad )NR 2aa R 2abb , -CH(NH 2 )-CH 2 CH 2 -NHC(=NR 2ad )NR 2aa R 2ab , -CH 2 -R 2ae , -CH 2 CH 2 CH 2 -R 2ae , -CH(NH 2 )-CH 2 CH 2 CH 2 -NHC(＝NR 2ad )NR 2aa R 2ab , -CH 2 -R 2ae , -CH 2 CH 2 -R 2ae , -CH 2 CH 2 CH 2 CH 2 -R 2ae , -CH 2 CH 2 CH 2 CH 2 -R 2ae , -CH(NH 2 )CH 2 CH 2 CH 2 CH 2 -R 2ae , -cyclopropyl-R 2ae , -cyclobutyl-R 2ae , -cyclopentyl-R 2ae , -cyclohexyl-R 2ae , -azetidinyl-R 2ae , -pyrrolidinyl-R 2ae , -piperidinyl-R 2ae , the methyl or ethyl group is optionally substituted by one NH 2 ;

R2aa、R2ab、R2ac、R2ad各自独立地选自H、甲基、乙基；R 2aa , R 2ab , R 2ac , and R 2ad are each independently selected from H, methyl, and ethyl;

R2ae选自-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH2CH3)2、-NHC(＝O)-CH3、-NHC(＝O)-CH2CH3、 环丙基、环丁基、吡唑基、咪唑基；R 2ae is selected from -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -NHC(=O)-CH 3 , -NHC(=O)-CH 2 CH 3 , Cyclopropyl, cyclobutyl, pyrazolyl, imidazolyl;

Rb1选自-CH2OH、-CH2-OCH3、-CH2CN；R b1 is selected from -CH 2 OH, -CH 2 -OCH 3 , -CH 2 CN;

Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基；R k is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl;

其余定义与本发明第一种、第二种或第三种实施方案相同。The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

作为本发明的第五种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a fifth 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,

通式(I)所示化合物选自通式(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)所示化合物，
The compound represented by the general formula (I) is selected from the compounds represented by the general formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If),

R2A选自-C(＝S)R2a、-NHC(＝S)R2a、-C(＝O)R2af、-NHC(＝O)R2af；R 2A is selected from -C(=S)R 2a , -NHC(=S)R 2a , -C(=O)R 2af , -NHC(=O)R 2af ;

R2af选自-C1-4亚烷基-NHC(＝O)-C1-4亚烷基-NR2aaR2ab、-C1-4亚烷基-C(＝O)NR2aaR2ab、-C1-4亚烷基-SR2ac、-C1-4亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C1-4亚烷基-R2ae、-C0-4亚烷基-C3-12碳环基-R2ae、-C0-4亚烷基-4至12元杂环基-R2ae，所述亚烷基任选被NH2取代，所述的烷基、亚烷基、碳环基、杂环基任选被1至4个Rk取代；R 2af is selected from -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-SR 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 heterocyclyl-R 2ae , the alkylene is optionally substituted by NH 2 , and the alkyl, alkylene, carbocyclyl and heterocyclyl are optionally substituted by 1 to 4 R k ;

R1A选自C6-10芳基、5至10元杂芳基，所述的芳基或杂芳基任选被1至4个R1a取代；R 1A is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted by 1 to 4 R 1a ;

Q1选自O或NH；Q 1 is selected from O or NH;

环B1选自C8-12环烷基、11至13元杂环基或11至13元杂环烷基；Ring B1 is selected from C8-12 cycloalkyl, 11 to 13 membered heterocyclyl or 11 to 13 membered heterocycloalkyl;

m1选自0、1、2或3；m1 is selected from 0, 1, 2 or 3;

p选自2或3；p is selected from 2 or 3;

其余定义与本发明第一种、第二种、第三种或第四种实施方案相同。The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

作为本发明的第六种实施方案，上述通式(I-a)、(I-b)、(I-c)、(I-d)、(I-e)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a sixth embodiment of the present invention, the compounds represented by the above general formula (I-a), (I-b), (I-c), (I-d), (I-e) or their stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

R2A选自 R 2A is selected from

环B1选自 Ring B 1 is selected from

R1A选自任选被1至4个R1a取代的如下基团之一：苯基、萘基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、异喹唑啉基、吡啶并吡唑基、吡啶并咪唑基、吡啶并呋喃基、吡啶并噻吩基、吡啶并噁唑基、吡啶并噻唑基、嘧啶并吡唑基、嘧啶并咪唑基、嘧啶并呋喃基、嘧啶并噻吩基、嘧啶并噁唑基、嘧啶并噻唑基、 R 1A is selected from one of the following groups optionally substituted with 1 to 4 R 1a : 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,

其余定义与本发明第一种、第二种、第三种、第四种、第五种实施方案相同。The remaining definitions are the same as those of the first, second, third, fourth and fifth embodiments of the present invention.

作为本发明的第七种实施方案，上述通式(I-a)、(I-b)、(I-c)、(I-d)、(I-e)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a seventh embodiment of the present invention, the compounds represented by the above general formula (I-a), (I-b), (I-c), (I-d), (I-e) or their stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

L选自-OCH2-；L is selected from -OCH 2 -;

R2选自 或R2A；R 2 is selected from or R 2A ;

R1选自R1A或任选被1至4个R1a取代的 R 1 is selected from R 1A or R 1A optionally substituted by 1 to 4 R 1A

环B选自或环B1，且左侧与L直接连接；Ring B is selected from or ring B 1 , and the left side is directly connected to L;

其余定义与本发明第一种、第二种、第三种、第四种、第五种或第六种实施方案相同。The remaining definitions are the same as those of the first, second, third, fourth, fifth or sixth embodiment of the present invention.

作为本发明的第八种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As an eighth 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,

通式(I)所示化合物选自通式(I-h)、(I-I)所示化合物，
The compound represented by the general formula (I) is selected from the compounds represented by the general formula (Ih) and (II),

环B2选自C8-12桥环烷基或6至10元螺杂环烷基，优选地，环B2选自 左侧与亚甲基相连；Ring B2 is selected from C8-12 bridged cycloalkyl or 6 to 10 membered spiro heterocycloalkyl, preferably, Ring B2 is selected from The left side is connected to the methylene group;

Rb选自H、氘、卤素、甲基、CF3、CHF2、CH2F、CD3、CHD2、CH2D；R b is selected from H, deuterium, halogen, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;

Ry选自F、Cl、Br、甲基、CF3、CHF2、CH2F、CD3、CHD2、CH2D；R y is selected from F, Cl, Br, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;

R2B选自-C(＝O)C1-3烷基、-NHC(＝O)-C1-3烷基、-NHC(＝O)-C3-6环烷基、-N(C1-2烷基)C(＝O)-C1-3烷基、-N(C1-2烷基)C(＝O)-C3-6环烷基、5至6元杂芳基、5至6元含内酰胺的杂环烷基，所述R2B任选进一步被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代；R 2B is selected from -C(＝O)C 1-3 alkyl, -NHC(＝O)-C 1-3 alkyl, -NHC(＝O)-C 3-6 cycloalkyl, -N(C 1-2 alkyl)C(＝O)-C 1-3 alkyl, -N(C 1-2 alkyl)C(＝O)-C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered lactam-containing heterocycloalkyl, said R 2B is optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl;

优选地，R2B选自-C(＝O)-甲基、-C(＝O)-乙基、-NHC(＝O)-甲基、-NHC(＝O)-乙基、-NHC(＝O)- 环丙基、-NHC(＝O)-环丁基、-NHC(＝O)-环戊基、-NHC(＝O)-环己基、-N(CH3)C(＝O)-甲基、-N(CH3)C(＝O)-环丙基、吡咯基、吡唑基、咪唑基、噁唑基、噁二唑基、三唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基，所述R2B任选进一步被1至4个选自氘、F、Cl、Br、I、甲基、乙基、CF3、CHF2、CH2F的取代基取代；Preferably, R2B is selected from -C(=O)-methyl, -C(=O)-ethyl, -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)- Cyclopropyl, -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl, -NHC(=O)-cyclohexyl, -N(CH 3 )C(=O)-methyl, -N(CH 3 )C(=O)-cyclopropyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, said R 2B is optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, methyl, ethyl, CF 3 , CHF 2 , CH 2 F;

更优选地，R2B选自 More preferably, R 2B is selected from

R2C选自-C(＝S)C1-3烷基、-C(＝O)N(C1-3烷基)2、-C(＝O)-C1-4亚烷基-NHC(＝NH)NH2、-C(＝O)-C1-4亚烷基-C(＝O)NH2、-C(＝O)-C1-4亚烷基-NHC(＝O)C1-3烷基，所述亚烷基任选被NH2取代，所述烷基、亚烷基任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代； R2C is selected from -C(＝S) C1-3alkyl , -C(＝O)N( C1-3alkyl ) 2 , -C(＝O)-C1-4alkylene-NHC(＝ NH ) NH2 , -C(＝O)-C1-4alkylene- C (＝O) NH2 , -C(＝O)-C1-4alkylene- NHC (＝O) C1-3alkyl , the alkylene is optionally substituted with NH2 , the alkyl and alkylene are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF3 , CHF2 , CH2F , vinyl, ethynyl;

优选地，R2C选自-C(＝S)-甲基、-C(＝S)-乙基、-C(＝O)N(甲基)2、-C(＝O)N(乙基)2、-C(＝O)-CH2CH2CH2CH2-NHC(＝NH)NH2、-C(＝O)-CH2CH2CH2-NHC(＝NH)NH2、-C(＝O)-CH2CH2-NHC(＝NH)NH2、-C(＝O)-CH2CH2CH2CH2-C(＝O)NH2、-C(＝O)-CH2CH2CH2-C(＝O)NH2、-C(＝O)-CH2CH2-C(＝O)NH2、-C(＝O)-CH2CH2CH2CH2-NHC(＝O)-甲基、-C(＝O)-CH2CH2CH2CH2-NHC(＝O)-乙基、-C(＝O)-CH2CH2CH2-NHC(＝O)-甲基、-C(＝O)-CH2CH2CH2-NHC(＝O)-乙基、-C(＝O)-CH2CH2-NHC(＝O)-甲基、-C(＝O)-CH2CH2-NHC(＝O)-乙基，所述CH2任选被NH2取代，所述甲基、乙基、CH2任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代；Preferably, R2C is selected from -C(＝S)-methyl, -C(＝S)-ethyl, -C(＝O)N( methyl ) 2 , -C(＝ O )N(ethyl) 2 , -C(＝O) -CH2CH2CH2CH2 -NHC(＝NH)NH2, -C(＝O ) -CH2CH2CH2- NHC (＝NH) NH2 , -C (＝O)-CH2CH2CH2 -NHC (＝ NH ) NH2 , -C(＝O) -CH2CH2CH2 -NHC(＝ NH ) NH2 , -C(＝O ) -CH2CH2CH2CH2-NHC(＝ NH ) NH2 , -C(＝O)-CH2CH2CH2CH2 - C(＝O)NH2, -C(＝O) -CH2CH2CH2CH2 - C(＝O) NH2 , -C (＝O)-CH2CH2CH2-C(＝O) NH2 , -C (＝ O )-CH2CH2CH2-C(＝O) NH2 , -C (＝O) -CH2CH2CH2CH2 -NHC(＝O)-methyl, -C(＝O ) -CH2CH2CH2CH2- NHC (＝O) -ethyl , -C(＝O)-CH2CH2CH2 - NHC(＝O)-methyl, -C (＝ O ) -CH2CH2CH2 - NHC (＝O)-ethyl, -C(＝ O ) -CH2CH2 -NHC(＝O) -methyl, -C(＝O) -CH2CH2 -NHC (＝O)-ethyl, said CH2 is optionally substituted with NH2 , and said methyl, ethyl, CH2 is optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, OH, NH2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF3 , CHF2 , CH2F , vinyl, ethynyl;

更优选地，R2C选自 More preferably, R 2C is selected from

其余定义与本发明第一种、第二种、第三种、第四种、第五种、第六种或第七种实施方案相同。The remaining definitions are the same as those of the first, second, third, fourth, fifth, sixth or seventh embodiment of the present invention.

作为本发明的第九种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As a ninth 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,

通式(I)所示化合物选自通式(I-J)所示化合物，
The compound represented by the general formula (I) is selected from the compounds represented by the general formula (IJ),

Ry选自F、Cl、Br、甲基、CF3、CHF2、CH2F、CD3、CHD2、CH2D；R y is selected from F, Cl, Br, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;

R3B选自-NHC(＝O)-C1-3烷基、-NHC(＝O)-C3-6环烷基、-N(C1-2烷基)C(＝O)-C1-3烷基、5至6元杂芳基、5至6元含内酰胺的杂环烷基，所述R2B任选进一步被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代；R 3B is selected from -NHC(=O)-C 1-3 alkyl, -NHC(=O)-C 3-6 cycloalkyl, -N(C 1-2 alkyl)C(=O)-C 1-3 alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered lactam-containing heterocycloalkyl, said R 2B is optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl;

优选地，R3B选自-NHC(＝O)-甲基、-NHC(＝O)-乙基、-NHC(＝O)-环丙基、-NHC(＝O)-环丁基、-NHC(＝O)-环戊基、-NHC(＝O)-环己基、-N(CH3)C(＝O)-甲基、-N(CH3)C(＝O)-环丙基、 吡咯基、吡唑基、咪唑基、噁唑基、噁二唑基、三唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基，所述R2B任选进一步被1至4个选自氘、F、Cl、Br、I、甲基、乙基、CF3、CHF2、CH2F的取代基取代；Preferably, R 3B is selected from -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl, -NHC(=O)-cyclohexyl, -N(CH 3 )C(=O)-methyl, -N(CH 3 )C(=O)-cyclopropyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, said R 2B is optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, methyl, ethyl, CF 3 , CHF 2 , CH 2 F;

更优选地，R3B选自 More preferably, R 3B is selected from

Rb选自H、氘、卤素、甲基、CF3、CHF2、CH2F、CD3、CHD2、CH2D；R b is selected from H, deuterium, halogen, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D;

其余定义与本发明第一种、第二种、第三种、第四种、第五种、第六种、第七种或第八种实施方案相同。The remaining definitions are the same as those of the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment of the present invention.

本发明涉及一种下述化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自表S结构之一。The present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table S.

表S


Table S


本发明涉及一种药物组合物，包括本发明上述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。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.

本发明涉及一种本发明上述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备PARP14相关疾病药物中的应用，优选肿瘤、特应性皮炎和自身免疫性疾病。The present invention relates to use of the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of drugs for PARP14-related diseases, preferably tumors, atopic dermatitis and autoimmune diseases.

本发明涉及一种药物组合物或药物制剂，所述的药物组合物或药物制剂包含治疗有效量的本发明所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和药用赋型剂。该药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。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").

本发明还提供一种用于治疗哺乳动物的疾病的方法，其包括向所述哺乳动物给予治疗有效量的本发明所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或药物组合物。一些实施方案中，本发明中所述哺乳动物包括人。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.

本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物，其将在某种程度上缓解所治疗的疾病或病症(例如肿瘤、特应性皮炎和自身免疫性疾病)的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物系统的任何其它希望 改变。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的化合物的量。治疗有效量的实例包括但不限于1-1500mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、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、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、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg；The term "effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of the compound disclosed herein to alleviate to some extent one or more symptoms of the disease or condition being treated (e.g., tumors, atopic dermatitis, and autoimmune diseases). In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired effect of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound disclosed herein that is 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, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 5-5 00mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 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, 250-400m g, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-30 0mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200m g, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg;

在一些实施方案中，该药物组合物包括但不限于1-1500mg、1-600mg、20-400mg、25-200mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、300mg的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。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.

一种治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选1-1500mg，所述的疾病优选PARP14相关疾病(如肿瘤、特应性皮炎)。A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention 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, atopic dermatitis).

一种治疗哺乳动物的疾病的方法，所述方法包括，将药物本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶以1-1500mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于10-1500mg/天、10-800mg/天、25-800mg/天、50-800mg/天、100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些实施方案中，日剂量包括但不限于10mg/天、20mg/天、25mg/天、50mg/天、100mg/天、125mg/天、150mg/天、200mg/天、400mg/天、600mg/天、800mg/天、1500mg/天、2000mg/天。A method for treating a disease in a mammal, the method comprising administering a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof to a subject at a daily dose of 1-1500 mg/day, 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, 100-800 mg/day , 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include but are 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.

本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的组合物，该试剂盒包含本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，本发明化合物的或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶量与上述药物组合物中其量相同。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.

本发明中本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量在每种情况下以游离碱的形式换算。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.

除非另有说明，在说明书和权利要求书中使用的术语具有下述含义。Unless otherwise stated, the terms used in the specification and claims have the following meanings.

本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它 们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。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 other The isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen) and tritium (T, also called super tritium), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.

“CN”是指氰基。"CN" refers to cyano.

“卤素”是指F、Cl、Br或I。"Halogen" refers to F, Cl, Br or I.

“卤素取代的”是指F、Cl、Br或I取代，包括但不限于1至10个选自F、Cl、Br或I的取代基所取代，1至6个选自F、Cl、Br或I的取代基所取代，1至4个选自F、Cl、Br或I的取代基所取代。“卤素取代的”简称为“卤代”。"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".

“烷基”是指取代的或者未取代的直链或支链饱和脂肪族烃基，包括但不限于1至20个碳原子的烷基、1至8个碳原子的烷基、1至6个碳原子的烷基、1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；烷基可以是一价、二价、三价或四价。"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.

“杂烷基”指取代的或者未取代的烷基中的1个或多个(包括但不限于2、3、4、5或6个)碳原子被杂原子(包括但不限于N、O或S)替换。非限制性实施例包括-X-(CH2)v-X-(CH2)v-X-(CH2)v-H(v为1至5的整数，X各自独立的选自键或杂原子，杂原子包括但不限于N、O或S，且至少有1个X选自杂原子，且杂原子中的N或S可被氧化成各种氧化态)。杂烷基可以是一价、二价、三价或四价。"Heteroalkyl" refers to a substituted or unsubstituted alkyl 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.

“亚烷基”是指取代的或者未取代的直链和支链的二价饱和烃基，包括-(CH2)v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等。"Alkylene" refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.

“亚杂烷基”是指取代的或者未取代的亚烷基中的1个或多个(包括但不限于2、3、4、5或6个)碳原子被杂原子(包括但不限于N、O或S)替换。非限制性实施例包括-X-(CH2)v-X-(CH2)v-X-(CH2)v-，v为1至5的整数，X各自独立的选自键、N、O或S，且至少有1个X选自N、O或S。"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-(CH 2 )vX-(CH 2 )vX-(CH 2 )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.

“环烷基”是指取代的或者未取代的饱和的碳环烃基，通常有3至12个碳原子，环烷基可以是单环、并环、桥环和螺环。非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环丁基并环丁基、环丁基螺环丁基、金刚烷等。环烷基可以是一价、二价、三价或四价。"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.

“杂环烷基”是指取代的或者未取代的饱和的含有杂原子的环烃基，包括但不限于3至12个原子、3至8个原子，包含1至3个选自N、O或S的杂原子，杂环烷基的环上的C、N、S可被氧化成各种氧化态。杂环烷基可以是单环、并环、桥环和螺环。杂环烷基可以连接在杂原子或者碳原子上，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢-2H-吡喃基、二氧戊环基、二氧六环基、吡咯烷基、哌啶基、咪唑烷基、噁唑烷基、噁嗪烷基、吗啉基、六氢嘧啶基、哌嗪基、杂环烷基可以是一价、二价、三价或四价。"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, The heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

“烯基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括但不限于2至10个、2至6个或2至4个碳原子，烯基实施例包括但 不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；烯基可以是一价、二价、三价或四价。"Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a main chain including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include but are not limited to 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-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.

“炔基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，主链包括2至10个碳原子，包括但不限于在主链上有2至6个碳原子，主链上有2至4个碳原子，炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基等；炔基可以是一价、二价、三价或四价。"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.

“烷氧基”是指取代的或者未取代的-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。"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.

“碳环基”或“碳环”是指取代的或未取代的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环、10至15元三环、12至18元四元体系，碳环基可以连接在芳香环上或者非芳香环上，环任选为单环、并环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环、萘环、 “碳环基”或“碳环”可以是一价、二价、三价或四价。"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.

“杂环基”或“杂环”是指取代的或未取代的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环、12至18元四元体系，且包含1个或多个(包括但不限于2、3、4或5个)个选自N、O或S的杂原子，杂环基的环中选择性取代的C、N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接在芳香环上或者非芳香环上，杂环基任选为单环、桥环、并环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并咪唑基、苯并噻唑基、苯并噁唑基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基、 “杂环基”或“杂环”可以是一价、二价、三价或四价。"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.

“螺环”或“螺环基”是指取代的或未取代的单环之间共用一个原子(称螺原子)的多环基团，螺环体系中环原子的个数包括但不限于含有5至20个、6至14个、6至12个、6至10个，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且任选可以含有0至5个选自N、O或S(＝O)n(n为0、1或2)的杂原子。“螺环”或“螺环基”可以是一价、二价、三价或四价。"Spiro" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom). The number of ring atoms in the spirocyclic 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 may optionally contain 0 to 5 heteroatoms selected from N, O or S(=O) n (n is 0, 1 or 2). "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

“并环”或“并环基”是指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环基团，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个杂原子或含有杂原子的基团(包括但不限于选自N、S(＝O)n或O，n为0、1或2)。并环体系中环原子的个数包括但不限于5至20个，5至14个，5至12个，5至10个。非限定性实例包括： “并环”或“并环基”可以是一价、二价、三价或四价。"Cyclic" or "Cyclic radical" 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 cyclic 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 cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

“桥环”或“桥环基”是指取代的或未取代的含有任意两个不直接连接的原子的多环基团，可以含有0个或多个双键，桥环体系中的任意环可以含0至5个选自杂原子或含有杂原子的基团(包括但不限于N、S(＝O)n或O，其中n为0、1、2)。环原子个数包括但不限于5至20个、5至14个、5至12个或5至10个。非限定性实例包括 立方烷、金刚烷。“桥环”或“桥环基”可以是一价、二价、三价或四价。"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. Non-limiting examples include Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.

“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”是指环体系仅有碳原子组成的“螺环”。"Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”是指环体系仅有碳原子组成的“并环”。"Carbocyclic", "cyclic carbocyclyl", "carbocyclyl" or "carbocyclyl" refers to a "cyclic" ring system consisting of only carbon atoms.

“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”是指环体系仅有碳原子组成的“桥环”。"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.

“杂单环”、“单环杂环基”或“杂单环基”是指单环体系的“杂环基”或“杂环”，"Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle",

“杂并环”、“杂并环基”“并环杂环基”或“并杂环基”是指含有杂原子的“并环”。"Heterocyclic ring", "heterocyclic group", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

“杂螺环”、“杂螺环基”、“螺环杂环基”或“螺杂环基”是指含有杂原子的“螺环”。"Heterospirocycle", "heterospirocyclyl", "spiroheterocyclyl" or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

“杂桥环”、“杂桥环基”、“桥环杂环基”或“桥杂环基”是指含有杂原子的“桥环”。"Heterobridged ring", "heterobridged ring group", "bridged ring heterocyclyl" or "bridged heterocyclyl" refers to a "bridged ring" containing a heteroatom.

“芳基”或“芳环”是指取代的或者未取代的具有单环或稠合环的芳香族烃基，芳香环中环原子个数包括但不限于6至18、6至12或6至10个碳原子。芳基环可以稠合于饱和或不饱和的碳环，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含苯环、萘环、“芳基”或“芳环”可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于芳基环上。"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.

“杂芳基”或“杂芳环”是指取代或未取代的芳香族烃基，且含有1至5个杂原子或含有杂原子的基团(包括但不限于N、O或S(＝O)n，n为0、1、2)，杂芳香环中环原子个数包括但不限于5至15、5至10或5至6个。环上的原子C、N、S任选被氧化(即C(＝O)、NO、S(＝O)n，n为1、2)，杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并吡唑基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、吡啶酮基等。所述杂芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含 本文中出现的杂芳基，其定义与本定义一致。杂芳基可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于具有芳香性的环上。"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 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.

“取代”或“取代的”是指被1个或多个(包括但不限于2、3、4或5个)取代基所取代，取代基包括但不限于H、F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可 形成五或六元环烷基或杂环基，Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。"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, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring group, spirocyclyl, cyclocyclyl, 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 ) mS (=O) nR 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, silyl or -NR b R c , wherein R b and R c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an alternative, R b and R c can be To form a five- or six-membered cycloalkyl or heterocyclic group, Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, spirocyclic group or cyclocyclic group.

“1至X个选自…..取代基所取代”是指被1、2、3….X个选自…..取代基所取代，X选自1至10之间的任意整数。如“1至4个Rk取代”是指被1、2、3或4个Rk取代。如“1至5个选自…..取代基所取代”是指被1、2、3、4或5个选自…..取代基所取代。如“杂桥环任选被1至4个选自H或F的取代基所取代”是指杂桥环任选被1、2、3或4个选自H或F的取代基所取代。"1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from...", X is selected from any integer between 1 and 10. For example, "1 to 4 R k substituted" means substituted 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.

X-Y元的环(X、Y为整数，且3≤X＜Y，X＜Y≤20选自4至20之间的任意整数)包括了X、X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环，“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。X-Y membered rings (X, Y are integers, and 3≤X＜Y, X＜Y≤20 are selected from any integer between 4 and 20) include X, X+1, X+2, X+3, X+4….Y membered rings. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings or heterobridged rings. For example, "4-7 membered heteromonocyclic rings" refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings, and "5-10 membered heterocyclic rings" refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings.

Cx-y碳环(包括芳基、环烷基、单环碳环、螺环碳环、并环碳环或桥环碳环)包括了Cx、Cx+1、Cx+2、Cx+3、Cx+4….Cy元的环(x为整数，且3≤x＜y，y选自4至20之间的任意整数)，例如。如C3-6环烷基”是指C3、C4、C5或C6环烷基； Cxy carbocycle (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, cyclic carbocycle or bridged carbocycle) includes Cx , Cx +1 , Cx+2 , Cx +3 , Cx +4 ... Cy -membered ring (x is an integer, and 3≤x＜y, y is selected from any integer between 4 and 20), for example. For example, " C3-6 cycloalkyl" refers to C3 , C4 , C5 or C6 cycloalkyl;

当某一个基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团连接。当该化学键的连接方式是不定位的，且可连接位点存在氢原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。例如表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括这4种连接方式，即使-N-上画出了H原子，也包括了例如表示该哌啶基上的R基团可以位于C上，可以位于N上，至少包括了 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

当所列举的连接基团没有指明其连接方向时，其连接方向包括了从左向右和从右向左的读取顺序的方向进行连接，例如A-L-B，L选自-M-W-时，包括了A-M-W-B和A-W-M-B。When the listed connecting 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, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.

“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"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.

“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"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.

“药物组合物”是指一种或多种本发明所述化合物、或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"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.

“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。"Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"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.

“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发 明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。"Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the modified compounds, which can be removed by conventional manipulation or in vivo to obtain the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。"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.

“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。"Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体(如trans/cis,Z/E)、对映异构体、非对映异构体和构象异构体。"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.

“互变异构体”是指分子中某一原子在两个位置迅速移动而产生的官能团异构体，如酮式-烯醇式异构和酰胺-亚胺醇式异构等。"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.

“IC50”是对指定的生物过程(或该过程中的某个组分比如酶、受体、细胞等)抑制一半时所需的药物或者抑制剂的浓度。" IC50 " is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.

具体实施方式DETAILED DESCRIPTION

以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。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.

化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the solvent, and tetramethylsilane (TMS) as the internal standard;

MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);

薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;

Boc：叔丁氧基羰基；Boc: tert-butoxycarbonyl;

Ts：对甲苯磺酰基；Ts: p-toluenesulfonyl;

Cbz：苄氧羰基；Cbz: benzyloxycarbonyl;

TMS：三甲基硅基；TMS: trimethylsilyl;

劳森试剂：CAS:19172-47-5；Lawson's reagent: CAS: 19172-47-5;

DIPEA：CAS:7087-68-5；DIPEA: CAS: 7087-68-5;

HATU：CAS:148893-10-1；HATU: CAS: 148893-10-1;

LDA：CAS:4111-54-0；LDA: CAS: 4111-54-0;

LAH：CAS:16853-85-3；LAH: CAS: 16853-85-3;

戴斯-马丁氧化剂：CAS:87413-09-0。Dess-Martin oxide: CAS: 87413-09-0.

本申请化合物可以通过如下合成方法制备得到：The compounds of the present application can be prepared by the following synthesis method:

合成方法一：
Synthesis method 1:

通式化合物(Z-1)与化合物(Z-2)通过取代反应得到通式化合物(Z-3)；The general formula compound (Z-1) and the compound (Z-2) are reacted by substitution to obtain the general formula compound (Z-3);

通式化合物(Z-3)与化合物2,4-二甲氧基苄胺通过取代反应得到通式化合物(Z-4)；The general formula compound (Z-3) and the compound 2,4-dimethoxybenzylamine are reacted by substitution to obtain the general formula compound (Z-4);

通式化合物(Z-4)脱除2,4-二甲氧基苄基得到通式化合物(Z-5)；The compound (Z-4) is subjected to removal of 2,4-dimethoxybenzyl to obtain the compound (Z-5);

通式化合物(Z-5)与2-氯乙腈反应得到关环的通式化合物(Z-6)；The general formula compound (Z-5) reacts with 2-chloroacetonitrile to obtain a ring-closed general formula compound (Z-6);

通式化合物(Z-6)与化合物(Z-7)反应得到通式化合物(Z)；The compound of the general formula (Z-6) reacts with the compound (Z-7) to obtain the compound of the general formula (Z);

Rz1选自Cl，Br，I，OMs，OTs，OTf等基团。R z1 is selected from Cl, Br, I, OMs, OTs, OTf and the like.

其余基团的定义与说明书和权利要求书中的定义相同。The remaining groups have the same definitions as in the specification and claims.

实施例1：化合物1的合成
Example 1: Synthesis of Compound 1

第一步：化合物1b的合成Step 1: Synthesis of compound 1b

将化合物1a(合成路线按照文献WO 2019126443)(2.50g，7.71mmol)，2-氯丙腈(1.57g,17.50mmol)溶解在2N的盐酸-1,4-二氧六环溶液(11mL，25.00mmol)中，将混合液在80℃下加热2小时。将反应混合物倒入100mL水中并用DCM:MeOH＝20:1(10mL×2)萃取。合并的有机相用盐水(30mL)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱分离纯化获得化合物1b(0.9g，产率：30.57％)Compound 1a (synthetic route according to document WO 2019126443) (2.50 g, 7.71 mmol) and 2-chloropropionitrile (1.57 g, 17.50 mmol) were dissolved in 2N hydrochloric acid-1,4-dioxane solution (11 mL, 25.00 mmol), and the mixture was heated at 80 ° C for 2 hours. The reaction mixture was poured into 100 mL of water and extracted with DCM: MeOH = 20: 1 (10 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was separated and purified by silica gel column to obtain compound 1b (0.9 g, yield: 30.57%)

Ms m/z(ESI):382.0[M+H]+ Ms m/z(ESI):382.0[M+H] +

第二步：化合物1的合成Step 2: Synthesis of compound 1

在氮气保护下，将化合物1b(0.9g，2.36mmol)、2N的氢氧化钠溶液(2.7mL，9.46mol)和中间体1(合成路线按照文献WO 2019126443)(0.45g，2.83mmo)溶解在四氢呋喃(10mL)中，室温反应3h。将反应混合物倒入100mL水中并用DCM:MeOH＝20:1(10mL×2)萃取。合并的有机相用盐水(30mL)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱(DCM:MeOH＝20:1)纯化获得化合物1(0.6g，产率：54.84％)Under nitrogen protection, compound 1b (0.9 g, 2.36 mmol), 2N sodium hydroxide solution (2.7 mL, 9.46 mol) and intermediate 1 (synthetic route according to document WO 2019126443) (0.45 g, 2.83 mmol) were dissolved in tetrahydrofuran (10 mL) and reacted at room temperature for 3 h. The reaction mixture was poured into 100 mL of water and extracted with DCM: MeOH = 20: 1 (10 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH = 20: 1) to obtain compound 1 (0.6 g, yield: 54.84%)

Ms m/z(ESI):464.2[M+H]+ Ms m/z(ESI):464.2[M+H] +

1H NMR(400MHz,CD3OD)δ6.94-6.90(m,1H),6.89-6.82(m,1H),4.63-4.53(m,1H),4.06-3.86(m,5H),3.48-3.38(m,2H),3.23-3.11(m,1H),3.07-2.90(m,5H),2.75-2.63(m,1H),2.21-2.07(m,4H),2.00-1.83(m,4H),1.63-1.50(m,2H),1.47-1.36(m,1H),1.36-1.22(m,2H). 1 H NMR (400MHz, CD 3 OD)δ6.94-6.90(m,1H),6.89-6.82(m,1H),4.63-4.53(m,1H),4.06-3.86(m,5H),3.48-3.38(m,2H),3.23 -3.11(m,1H),3.07-2 .90(m,5H),2.75-2.63(m,1H),2.21-2.07(m,4H),2.00-1.83(m,4H),1.63-1.50(m,2H),1.47-1.36(m, 1H),1.36-1.22(m,2H).

实施例2：化合物2的合成
Example 2: Synthesis of Compound 2

第一步：化合物2c的合成Step 1: Synthesis of compound 2c

在氮气保护下，将化合物2b(合成路线按照文献WO2022206795)(1.5g，7.50mmol)溶解在20mL二氯甲烷中，三乙胺(1.52g，15.0mmol)，滴加甲基磺酰氯(1.14g，10mmol)室温反应3h。将反应混合物倒入100mL水中并用DCM(30mL×2)萃取。合并的有机相用盐水(30mL)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物2c(2.0g，产率：71.94％)Under nitrogen protection, compound 2b (synthetic route according to document WO2022206795) (1.5 g, 7.50 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 Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 2c (2.0 g, yield: 71.94%)

Ms m/z(ESI):279.1[M+H]+ Ms m/z(ESI):279.1[M+H] +

第二步：化合物2d的合成Step 2: Synthesis of compound 2d

在氮气保护下，将化合物2c(2.78g，10.0mmol)溶解在50mL DMSO中，2,6-二氟-4-羟基苯甲酸甲酯(1.88g，10.0mmol)，碳酸钾(2.76g，20.0mmol)，升温至80℃，反应16h。将反应混合物倒入100mL水中并用乙酸乙酯(100mL×2)萃取。合并的有机相用盐水(100mL×2)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物2d(1.5g，产率：40.54％)Under nitrogen protection, compound 2c (2.78 g, 10.0 mmol) was dissolved in 50 mL DMSO, methyl 2,6-difluoro-4-hydroxybenzoate (1.88 g, 10.0 mmol), potassium carbonate (2.76 g, 20.0 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 Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 2d (1.5 g, yield: 40.54%)

Ms m/z(ESI):371.1[M+H]+ Ms m/z(ESI):371.1[M+H] +

第三步：化合物2e的合成Step 3: Synthesis of compound 2e

在氮气保护下，将化合物2d(1.20g，3.24mmol)溶解在50mL N-甲基吡咯烷酮中，2,4-二甲氧基苯甲胺(0.82g，4.86mmol)，碳酸钾(0.90g，6.48mmol)，升温至80℃，反应16h。将反应混合物倒入100mL水中并用乙酸乙酯(100mL×2)萃取。合并的有机相用盐水(100mL×2)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物2e(1.2g，产率：71.56％)。Under nitrogen protection, compound 2d (1.20 g, 3.24 mmol) was dissolved in 50 mL of N-methylpyrrolidone, 2,4-dimethoxybenzylamine (0.82 g, 4.86 mmol), potassium carbonate (0.90 g, 6.48 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 Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 2e (1.2 g, yield: 71.56%).

第四步：化合物2f的合成Step 4: Synthesis of compound 2f

在氮气保护下，将化合物2e(1.20g，2.32mmol)溶解在10mL二氯甲烷和2mL三氟乙酸中，三乙基硅烷(0.54g，4.64mmol)，室温反应2h。真空浓缩。二氯甲烷溶解，饱和碳酸氢钠溶液洗涤，有机相无水硫酸钠干燥，减压浓缩，残余物通过硅胶柱纯化获得化合物2f(0.6g，产率：70.43％)。Under nitrogen protection, compound 2e (1.20 g, 2.32 mmol) was dissolved in 10 mL of dichloromethane and 2 mL of trifluoroacetic acid, triethylsilane (0.54 g, 4.64 mmol), and reacted at room temperature for 2 h. Vacuum concentration was performed. 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 2f (0.6 g, yield: 70.43%).

第五步：化合物2g的合成 Step 5: Synthesis of compound 2g

在氮气保护下，将化合物2f(0.6g，1.63mmol)溶解在10mL 2N的盐酸1,4-二氧六环溶液中，氯乙腈(0.24g，3.26mmol)，80℃反应2h，减压浓缩。二氯甲烷溶解，饱和碳酸氢钠溶液洗涤，有机相无水硫酸钠干燥，减压浓缩，残余物通过硅胶柱纯化获得化合物2g(0.2g，产率：29.83％)Under nitrogen protection, compound 2f (0.6 g, 1.63 mmol) was dissolved in 10 mL 2N hydrochloric acid 1,4-dioxane solution, chloroacetonitrile (0.24 g, 3.26 mmol), reacted at 80 ° C for 2 h, and concentrated under reduced pressure. Dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column to obtain compound 2g (0.2 g, yield: 29.83%)

Ms m/z(ESI):411.1[M+H]+ Ms m/z(ESI):411.1[M+H] +

第六步：化合物2的合成Step 6: Synthesis of Compound 2

在氮气保护下，将化合物2g(0.2g，0.49mmol)溶解在四氢呋喃中，2N氢氧化钠溶液1mL滴加到反应瓶中，中间体1(0.16g，0.98mmol)室温反应2h。减压浓缩，残余物通过硅胶柱纯化获得化合物2(25mg，产率：10.41％)Under nitrogen protection, compound 2g (0.2g, 0.49mmol) was dissolved in tetrahydrofuran, 1mL of 2N sodium hydroxide solution was added dropwise to the reaction flask, and intermediate 1 (0.16g, 0.98mmol) was reacted at room temperature for 2h. The residue was concentrated under reduced pressure and purified by silica gel column to obtain compound 2 (25mg, yield: 10.41%).

Ms m/z(ESI):493.3[M+H]+ Ms m/z(ESI):493.3[M+H] +

1H NMR(400MHz,CD3OD)δ6.95-6.89(m,1H),6.81(dd,1H),4.61-4.49(m,1H),4.10-3.96(m,3H),3.94-3.85(m,2H),3.68(s,2H),3.47-3.32(m,4H),3.19-2.97(m,2H),2.78-2.66(m,1H),2.41(s,6H),2.21-2.08(m,1H),1.99-1.85(m,4H),1.65-1.51(m,2H),1.47-1.37(m,1H),1.37-1.24(m,1H). 1 H NMR (400MHz, CD 3 OD)δ6.95-6.89(m,1H),6.81(dd,1H),4.61-4.49(m,1H),4.10-3.96(m,3H),3.94-3.85(m,2H),3.68(s ,2H),3.47-3.32(m,4H),3.19-2.9 7(m,2H),2.78-2.66(m,1H),2.41(s,6H),2.21-2.08(m,1H),1.99-1.85(m,4H),1.65-1.51(m,2H), 1.47-1.37(m,1H),1.37-1.24(m,1H).

实施例3：化合物3的合成
Example 3: Synthesis of Compound 3

第一步：化合物3b的合成Step 1: Synthesis of compound 3b

在氮气保护下，将化合物3a(1.83g，10.0mmol)溶解在20mL二氯甲烷中，三乙胺(1.52g，15.0mmol)，滴加乙酰氯(1.14g，10mmol)室温反应3h。将反应混合物倒入100mL水中并用DCM(30mL×2)萃取。合并的有机相用盐水(30mL)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物3b(1.4g，产率：63.25％)Under nitrogen protection, compound 3a (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 Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 3b (1.4 g, yield: 63.25%)

第二步：化合物3b的合成Step 2: Synthesis of compound 3b

在氮气保护下，将化合物3b(1.4g，6.22mmol)溶解在20mL四氢呋喃中，0℃，2.5N四氢锂铝的四氢呋喃溶液(5.0mL，12.5mmol)，滴加到反应瓶中室温反应3h。将反应混合物倒入100mL水中并用DCM(30mL×2)萃取。合并的有机相用盐水(30mL)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物3b(1.2g，产率：97.93％)。Under nitrogen protection, compound 3b (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 to the reaction bottle at 0°C 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 Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 3b (1.2 g, yield: 97.93%).

第三步到第八步：化合物3的合成 Steps 3 to 8: Synthesis of Compound 3

将化合物3c(1.2g，6.09mmol)参照化合物2的合成，制得化合物3(10mg)Compound 3c (1.2 g, 6.09 mmol) was synthesized according to the method of compound 2 to obtain compound 3 (10 mg).

Ms m/z(ESI):490.3[M+H]+ Ms m/z(ESI):490.3[M+H] +

1H NMR(400MHz,CD3OD)δ6.90-6.86(m,1H),6.82-6.74(m,1H),3.94-3.86(m,2H),3.72(s,2H),3.69-3.64(m,2H),3.47-3.38(m,2H),3.08-2.98(m,1H),2.00-1.90(m,8H),1.86(s,3H),1.73-1.64(m,6H),1.63-1.51(m,2H). 1 H NMR (400MHz, CD 3 OD)δ6.90-6.86(m,1H),6.82-6.74(m,1H),3.94-3.86(m,2H),3.72(s,2H),3.69-3.64(m,2H),3.47-3 .38(m,2H),3.08-2.98(m,1H),2.00-1.90(m,8H),1.86(s,3H),1.73-1.64(m,6H),1.63-1.51(m,2H) .

实施例4：化合物4的合成
Example 4: Synthesis of Compound 4

第一步：化合物4b的合成Step 1: Synthesis of compound 4b

在氮气保护下，将化合物4a(2.0g，8.51mmol)和劳森试剂(4.12g，10.21mmol)溶解在甲苯中，升温至100℃，继续搅拌2h，减压浓缩，残余物经柱层析得化合物4b(1.20g，产率：56.17％)Under nitrogen protection, compound 4a (2.0 g, 8.51 mmol) and Lawesson's reagent (4.12 g, 10.21 mmol) were dissolved in toluene, heated to 100°C, stirred for 2 h, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 4b (1.20 g, yield: 56.17%).

Ms m/z(ESI):252.1[M+H]+ Ms m/z(ESI):252.1[M+H] +

第二步：化合物4c的合成Step 2: Synthesis of compound 4c

在氮气保护下，将化合物4b(1.20g，4.78mmol)溶解在50mL DMSO中，2,6-二氟-4-羟基苯甲酸甲酯(1.17g，6.21mmol)，碳酸钾(1.65g，11.95mmol)，升温至80℃，反应16h。冷却至室温，将反应混合物倒入100mL水中并用乙酸乙酯(100mL×2)萃取。合并的有机相用饱和食盐水(100mL×2)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物4c(1.20g，产率：73.17％)Under nitrogen protection, compound 4b (1.20 g, 4.78 mmol) was dissolved in 50 mL DMSO, methyl 2,6-difluoro-4-hydroxybenzoate (1.17 g, 6.21 mmol), potassium carbonate (1.65 g, 11.95 mmol), and the temperature was raised to 80 ° C. The reaction mixture was reacted for 16 h. After cooling to room temperature, 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 saturated brine (100 mL × 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 4c (1.20 g, yield: 73.17%)

Ms m/z(ESI):344.1[M+H]+ Ms m/z(ESI):344.1[M+H] +

第三步：化合物4d的合成Step 3: Synthesis of compound 4d

在氮气保护下，将化合物4c(1.2g，3.50mmol)溶解在50mL N-甲基吡咯烷酮中，然后加入2,4-二甲氧基苯甲胺(0.82g，4.86mmol)，碳酸钾(0.90g，6.48mmol)，升温至80℃，反应16h。冷却至室温，将反应混合物倒入100mL水中并用乙酸乙酯(100mL×2)萃取。合并的有机相用饱和食盐水(100mL×2)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物4d(1.0g，产率：70.01％)Under nitrogen protection, compound 4c (1.2 g, 3.50 mmol) was dissolved in 50 mL of N-methylpyrrolidone, and then 2,4-dimethoxybenzylamine (0.82 g, 4.86 mmol) and potassium carbonate (0.90 g, 6.48 mmol) were added, the temperature was raised to 80 ° C, and the reaction was carried out for 16 h. After cooling to room temperature, 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 saturated brine (100 mL × 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 4d (1.0 g, yield: 70.01%)

第四步：化合物4e的合成Step 4: Synthesis of compound 4e

在氮气保护下，将化合物4d(0.70g，1.43mmol)溶解在10mL二氯甲烷和2mL三氟乙酸中，三乙基硅烷(0.54g，4.64mmol)，室温反应2h。真空浓缩。二氯甲烷溶解，饱和碳酸氢钠溶液洗涤，有机相无水硫酸钠干燥，过滤，减压浓缩，残余物通过硅胶柱纯化获得化合物4e(0.25g，产率：51.47％)Under nitrogen protection, compound 4d (0.70 g, 1.43 mmol) was dissolved in 10 mL of dichloromethane and 2 mL of trifluoroacetic acid, triethylsilane (0.54 g, 4.64 mmol), and reacted at room temperature for 2 h. Vacuum concentration was performed. Dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 4e (0.25 g, yield: 51.47%)

Ms m/z(ESI):341.1[M+H]+ Ms m/z(ESI):341.1[M+H] +

第五步：化合物4f的合成Step 5: Synthesis of compound 4f

在氮气保护下，将化合物4e(50mg，0.15mmol)溶解在2mL 2N的盐酸1,4-二氧六环溶液中，加入氯乙腈(22.5mg，0.30mmol)，80℃反应10min。冷却至室温，真空浓缩。二氯甲烷溶解，饱和碳酸氢钠溶液洗涤，有机相无水硫酸钠干燥，过滤，减压浓缩，残余物通过硅胶柱纯化获得化合物4f(50mg，产率：88.77％)Under nitrogen protection, compound 4e (50 mg, 0.15 mmol) was dissolved in 2 mL 2N hydrochloric acid 1,4-dioxane solution, chloroacetonitrile (22.5 mg, 0.30 mmol) was added, and the reaction was carried out at 80 ° C for 10 min. Cooled to room temperature and concentrated in vacuo. Dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 4f (50 mg, yield: 88.77%)

Ms m/z(ESI):384.1[M+H]+ Ms m/z(ESI):384.1[M+H] +

第六步：化合物4的合成Step 6: Synthesis of compound 4

在氮气保护下，将化合物4f(50mg，0.13mmol)溶解在四氢呋喃中，2N氢氧化钠溶液1mL滴加到反应瓶中，中间体1(60mg，0.26mmol)室温反应2h。减压浓缩，残余物通过硅胶柱纯化获得化合物4(5mg，产率：8.27％)Under nitrogen protection, compound 4f (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran, 1 mL of 2N sodium hydroxide solution was added dropwise to the reaction flask, and intermediate 1 (60 mg, 0.26 mmol) was reacted at room temperature for 2 h. The residue was concentrated under reduced pressure and purified by silica gel column to obtain compound 4 (5 mg, yield: 8.27%).

Ms m/z(ESI):466.1[M+H]+ Ms m/z(ESI):466.1[M+H] +

1H NMR(400MHz,CD3OD)δ6.91(d,1H),6.79(dd,1H),5.62-5.54(m,1H),4.42-4.32(m,1H),4.06-3.98(m,2H),3.95-3.87(m,2H),3.67(s,2H),3.47-3.39(m,2H),3.39-3.33(m,1H),3.16-2.97(m,2H),2.64(s,3H),2.34-2.21(m,1H),2.07-1.90(m,4H),1.66-1.42(m,4H). 1 H NMR (400MHz, CD 3 OD)δ6.91(d,1H),6.79(dd,1H),5.62-5.54(m,1H),4.42-4.32(m,1H),4.06-3.98(m,2H),3.95-3.87(m ,2H),3.67(s,2H),3. 47-3.39(m,2H),3.39-3.33(m,1H),3.16-2.97(m,2H),2.64(s,3H),2.34-2.21(m,1H),2.07-1.90(m,4H ),1.66-1.42(m,4H).

实施例5：化合物5的合成
Example 5: Synthesis of Compound 5

第一步：化合物5b的合成Step 1: Synthesis of compound 5b

在氮气保护下，将(甲氧基甲基)三苯基溴化膦(11.49g，37.4mmoL)溶于超干四氢呋喃(50mL)溶液中，随后于-78℃下缓缓加入二(三甲基硅基)氨基锂(37.4mmoL，7mL)，反应30min后加入化合物5a(5g，18.70mmoL)，随后继续反应两个小时。将反应混合物倒入100mL水中并用乙酸乙酯(30mL×2)萃取。合并的有机相用盐水(30mL)洗涤，用无水硫酸钠干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物5b(4.5g，产率：81.46％)。Under nitrogen protection, (methoxymethyl) triphenylphosphine bromide (11.49 g, 37.4 mmol) was dissolved in ultra-dry tetrahydrofuran (50 mL) solution, followed by the slow addition of di(trimethylsilyl) lithium amide (37.4 mmol, 7 mL) at -78 ° C. After reacting for 30 min, compound 5a (5 g, 18.70 mmol) was added, followed by the continued reaction for two hours. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 5b (4.5 g, yield: 81.46%).

Ms m/z(ESI):240.4[M+H]+ Ms m/z(ESI):240.4[M+H] +

第二步：化合物5c的合成Step 2: Synthesis of compound 5c

在氮气保护下，将化合物5b(4.5g，15.23mmoL)溶于乙腈(30mL)和水(3mL)中，加入三氟乙酸(40.26mmoL，3mL)，室温下反应一个小时。用碳酸氢钠水溶液将反应液pH调至7～8，倒入100mL水中并用乙酸乙酯(30mL×2)萃取。合并的有机相用盐水(30mL)洗涤，用无水硫酸钠干燥，过滤并真空浓缩获得化合物5c的粗产物，直接用于下一步反应。Under nitrogen protection, compound 5b (4.5 g, 15.23 mmol) was dissolved in acetonitrile (30 mL) and water (3 mL), trifluoroacetic acid (40.26 mmol, 3 mL) was added, and the reaction was allowed to proceed at room temperature for one hour. The pH of the reaction solution was adjusted to 7-8 with sodium bicarbonate aqueous solution, poured into 100 mL of water and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude product of compound 5c, which was directly used in the next step.

Ms m/z(ESI):226.2[M+H]+ Ms m/z(ESI):226.2[M+H] +

第三步：化合物5d的合成Step 3: Synthesis of compound 5d

在氮气保护下，将化合物5c(4g，14.22mmoL)溶于甲醇(20mL)中，随后于0℃下缓慢加入硼氢化钠(800mg，21.21mmoL)，0℃反应一个小时。用1N盐酸水溶液将反应液pH调至6～7，并用乙酸乙酯(30mL×2)萃取。合并的有机相用盐水(30mL)洗涤，用无水硫酸钠干燥，过滤并真空浓缩，硅胶柱纯化获得化合物5d(3.5g，86.85％)。Under nitrogen protection, compound 5c (4 g, 14.22 mmol) was dissolved in methanol (20 mL), and then sodium borohydride (800 mg, 21.21 mmol) was slowly added at 0°C and reacted at 0°C for one hour. The pH of the reaction solution was adjusted to 6-7 with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by silica gel column to obtain compound 5d (3.5 g, 86.85%).

Ms m/z(ESI):228.2[M+H]+ Ms m/z(ESI):228.2[M+H] +

第四步到第五步：化合物5f的合成Step 4 to Step 5: Synthesis of Compound 5f

将化合物5d按照化合物3的第三步到第四步的合成方法，得到化合物5f(4.1g，86.02％)。Compound 5d was synthesized according to the third step to the fourth step of compound 3 to obtain compound 5f (4.1 g, 86.02%).

Ms m/z(ESI):398.5[M+H]+ Ms m/z(ESI):398.5[M+H] +

第六步：化合物5g的合成Step 6: Synthesis of compound 5g

将化合物5f(200mg，0.44mmoL)溶于二氯甲烷(5mL)中，再加入盐酸-1，4二氧六环溶液(5mL)，室温下反应一小时。反应液减压浓缩得到化合物5g的盐酸盐粗品，直接用于下一步反应。Compound 5f (200 mg, 0.44 mmol) was dissolved in dichloromethane (5 mL), and then hydrochloric acid-1,4-dioxane solution (5 mL) was added and reacted at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain the crude hydrochloride of compound 5g, which was directly used in the next step.

第七步：化合物5h的合成Step 7: Synthesis of compound 5h

将化合物5g的盐酸盐粗品(200mg，0.57mmoL)溶于二氯甲烷(8mL)中，加入三乙胺(150mg，1.44mmoL),搅拌均匀后于0℃下滴加乙酸酐(70mg，0.68mmoL),滴加完毕后撤去冰浴，室温下反应三个小时。将反应液倒入100mL水中并用乙酸乙酯(30mL×2)萃取。合并的有机相用盐水(30mL)洗涤，用无水Na2SO4干燥，过滤并真空浓缩，硅胶柱纯化获得化合物5h(180mg，79.86％)。The crude hydrochloride of compound 5g (200 mg, 0.57 mmol) was dissolved in dichloromethane (8 mL), triethylamine (150 mg, 1.44 mmol) was added, and acetic anhydride (70 mg, 0.68 mmol) was added dropwise at 0°C after stirring. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for three hours. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo, and purified by silica gel column to obtain compound 5h (180 mg, 79.86%).

Ms m/z(ESI):396.4[M+H]+ Ms m/z(ESI):396.4[M+H] +

第八步到第十一步：化合物5的合成Step 8 to Step 11: Synthesis of Compound 5

将化合物5h(180mg，0.46mmol)按照化合物3的第五步到第八步合成路线，纯化获得化合物5(15mg)。Compound 5h (180 mg, 0.46 mmol) was purified according to the fifth to eighth steps of the synthetic route of compound 3 to obtain compound 5 (15 mg).

1H NMR(400MHz,CD3OD)δ6.92(d,1H),6.82(dd,1H),3.97(d,2H),3.94-3.87(m,2H),3.82-3.67(m,2H),3.59-3.38(m,6H),3.09-2.99(m,1H),2.11-2.06(m,3H),2.00-1.90(m,2H),1.88-1.69(m,5H),1.66-1.53(m,4H),1.46-1.20(m,6H). 1 H NMR (400MHz, CD 3 OD)δ6.92(d,1H),6.82(dd,1H),3.97(d,2H),3.94-3.87(m,2H),3.82-3.67(m,2H),3.59-3.38(m,6H ),3.09- 2.99(m,1H),2.11-2.06(m,3H),2.00-1.90(m,2H),1.88-1.69(m,5H),1.66-1.53(m,4H),1.46-1.20(m,6H ).

Ms m/z(ESI):518.2[M+H]+ Ms m/z(ESI):518.2[M+H] +

实施例6：化合物6的合成
Example 6: Synthesis of Compound 6

第一步到第六步：化合物6g的合成Steps 1 to 6: Synthesis of compound 6g

以化合物6a为起始原料，参照化合物2合成，制得化合物6g(1g)。Compound 6g (1 g) was prepared by using compound 6a as the starting material and synthesizing the same with reference to compound 2.

Ms m/z(ESI):542.6[M+H]+ Ms m/z(ESI):542.6[M+H] +

第七步：化合物6h的合成Step 7: Synthesis of compound 6h

将化合物6g(200mg，0.37mmoL)溶于乙腈(5mL)中，再加入三甲基碘硅烷(178mg，0.89mmoL)，室温下反应1小时。加入1N盐酸水溶液(5mL)，继续搅拌10分钟。反应液减压浓缩，加入30mL水中并用乙酸乙酯(30mL×2)萃取，然后将水相冻干，得到化合物6h的盐酸盐粗品，直接用于下一步反应。Compound 6g (200 mg, 0.37 mmol) was dissolved in acetonitrile (5 mL), and trimethylsilyl iodide (178 mg, 0.89 mmol) was added, and the mixture was reacted at room temperature for 1 hour. 1N aqueous hydrochloric acid solution (5 mL) was added, and stirring was continued for 10 minutes. The reaction solution was concentrated under reduced pressure, added to 30 mL of water, and extracted with ethyl acetate (30 mL × 2), and then the aqueous phase was freeze-dried to obtain the crude hydrochloride of compound 6h, which was directly used in the next step.

Ms m/z(ESI):408.5[M+H]+ Ms m/z(ESI):408.5[M+H] +

第八步：化合物6的合成Step 8: Synthesis of Compound 6

将化合物6h的盐酸盐粗品(100mg，0.25mmol)溶于二氯甲烷(10mL)中，加入N-乙酰甘氨酸(35mg，0.30mmol),HATU(114mg，0.30mmoL),DIPEA(97mg，0.75mmoL)，室温下反应三个小时。将反应液倒入100mL水中并用乙酸乙酯(30mL×2)萃取。合并的有机相用盐水(30mL)洗涤，用无水Na2SO4干燥，过滤并真空浓缩，硅胶柱纯化获得化合物6(25mg，19.68％)。The crude hydrochloride of compound 6h (100 mg, 0.25 mmol) was dissolved in dichloromethane (10 mL), and N-acetylglycine (35 mg, 0.30 mmol), HATU (114 mg, 0.30 mmoL), and DIPEA (97 mg, 0.75 mmoL) were added and reacted at room temperature for three hours. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo, and purified by silica gel column to obtain compound 6 (25 mg, 19.68%).

Ms m/z(ESI):507.1[M+H]+ Ms m/z(ESI):507.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ7.97-7.85(m,1H),6.97-6.83(m,2H),6.09-5.69(m,1H)；4.45-4.32(m,1H),4.05-3.77(m,7H),3.66-3.59(m,2H),3.37-3.27(m,2H),3.11-2.96(m,2H),2.69-2.56(m,1H),2.11-1.98(m,1H),1.93-1.74(m,7H),1.51-1.38(m,2H),1.33-1.07(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ7.97-7.85(m,1H),6.97-6.83(m,2H),6.09-5.69(m,1H);4.45-4.32(m,1H),4.05-3.77(m,7H),3.66- 3.59(m,2H),3.37-3. 27(m,2H),3.11-2.96(m,2H),2.69-2.56(m,1H),2.11-1.98(m,1H),1.93-1.74(m,7H),1.51-1.38(m,2H ),1.33-1.07(m,2H).

实施例7：化合物7的合成
Example 7: Synthesis of Compound 7

第一步：化合物7a的合成Step 1: Synthesis of compound 7a

以化合物6h的盐酸盐粗品(100mg，0.25mmol)参照化合物6的第八步的合成路线，纯化获得化合物7a(115mg，73.99％)。The crude hydrochloride of compound 6h (100 mg, 0.25 mmol) was purified according to the synthesis route of compound 6 in step 8 to obtain compound 7a (115 mg, 73.99%).

Ms m/z(ESI):622.5[M+H]+ Ms m/z(ESI):622.5[M+H] +

第二步：化合物7的合成Step 2: Synthesis of compound 7

将化合物7a(115mg，0.18mmol)溶于二氯甲烷(5mL)中，再加入盐酸-1，4二氧六环溶液(5mL)，室温下反应一小时。反应液减压浓缩，硅胶柱纯化获得化合物7(10mg，10.61％)。Compound 7a (115 mg, 0.18 mmol) was dissolved in dichloromethane (5 mL), and then hydrochloric acid-1,4-dioxane solution (5 mL) was added and reacted at room temperature for one hour. The reaction solution was concentrated under reduced pressure and purified by silica gel column to obtain compound 7 (10 mg, 10.61%).

Ms m/z(ESI):522.8[M+H]+ Ms m/z(ESI):522.8[M+H] +

1H NMR(400MHz,CD3OD)δ6.95-6.90(m,1H),6.86-6.78(m,1H),4.74-4.66(m,1H),4.63-4.51(m,1H),4.07-3.98(m,2H),3.98-3.86(m,3H),3.70-3.65(m,2H),3.47-3.37(m,2H),3.28-3.17(m,1H),3.08-2.99(m,1H),2.87-2.75(m,2H),2.73-2.58(m,1H),2.25-2.13(m,1H),2.06-1.89(m,4H),1.64-1.52(m,2H),1.50-1.27(m,2H). 1 H NMR (400 MHz, CD 3 OD)δ6.95-6.90(m,1H),6.86-6.78(m,1H),4.74-4.66(m,1H),4.63-4.51(m,1 H),4.07-3.98(m,2H),3.98-3.86(m,3H),3.70-3.65(m,2H),3.47-3.37(m,2H ),3.28-3.17(m,1H),3.08-2.99(m,1H),2.87-2.75(m,2H),2.73-2.58(m,1H) ,2.25-2.13(m,1H),2.06-1.89(m,4H),1.64-1.52(m,2H),1.50-1.27(m,2H).

实施例8：化合物8的合成
Example 8: Synthesis of Compound 8

第一步到第二步：化合物8的合成Step 1 to Step 2: Synthesis of Compound 8

将化合物6h的盐酸盐粗品(100mg，0.25mmoL)，参照化合物7合成路线，纯化获得化合物8(20mg，15.35％)。The crude hydrochloride of compound 6h (100 mg, 0.25 mmol) was purified according to the synthetic route of compound 7 to obtain compound 8 (20 mg, 15.35%).

Ms m/z(ESI):564.9[M+H]+ Ms m/z(ESI):564.9[M+H] +

1H NMR(400MHz,CD3OD)δ6.95-6.90(m,1H),6.85-6.76(m,1H),4.65-4.44(m,2H),4.09-3.85(m,5H),3.71-3.65(m,2H),3.46-3.38(m,2H),3.30-3.19(m,3H),3.08-2.97(m,1H),2.89-2.75(m,1H),2.26-2.14(m,1H),2.08-1.81(m,6H),1.80-1.65(m,2H),1.64-1.51(m,2H),1.50-1.23(m,2H). 1 H NMR (400MHz, CD 3 OD)δ6.95-6.90(m,1H),6.85-6.76(m,1H),4.65-4.44(m,2H),4.09-3.85(m,5H),3.71-3.65(m,2H),3.46 -3.38(m,2H),3.30-3.19(m,3H ),3.08-2.97(m,1H),2.89-2.75(m,1H),2.26-2.14(m,1H),2.08-1.81(m,6H),1.80-1.65(m,2H),1.64-1.51 (m,2H),1.50-1.23(m,2H).

实施例9：化合物9的合成
Example 9: Synthesis of Compound 9

以化合物9a为起始原料，参照化合物2合成，制得化合物9(10mg)Compound 9 (10 mg) was prepared by using compound 9a as the starting material and synthesizing with reference to compound 2.

1H NMR(400MHz,CD3OD)δ6.93(d,1H),6.82(dd,1H),4.61-4.51(m,1H),4.10-3.97(m,3H),3.94-3.86(m,2H),3.69(s,2H),3.47-3.38(m,2H),3.21-3.10(m,1H),3.09-2.99(m,1H),2.98-2.83(m,4H),2.81-2.70(m,1H),2.24-2.09(m,1H),2.00-1.88(m,4H),1.64-1.53(m,2H),1.51-1.42(m,1H),1.39-1.27(m,3H),1.24-1.14(m,6H). 1 H NMR (400 MHz, CD 3 OD)δ6.93(d,1H),6.82(dd,1H),4.61-4.51(m,1H),4.10-3.97(m,3H),3.94-3 .86(m,2H),3.69(s,2H),3.47-3.38(m,2H),3.21-3.10(m,1H),3.09-2.99(m,1 H),2.98-2.83(m,4H),2.81-2.70(m,1H),2.24-2.09(m,1H),2.00-1.88(m,4H ),1.64-1.53(m,2H),1.51-1.42(m,1H),1.39-1.27(m,3H),1.24-1.14(m,6H).

Ms m/z(ESI):521.4[M+H]+ Ms m/z(ESI):521.4[M+H] +

实施例10：化合物10的合成
Example 10: Synthesis of Compound 10

第一步：化合物10b的合成Step 1: Synthesis of compound 10b

在氮气保护下，将化合物10a(5g，20.57mmol)溶解在100mL四氢呋喃中，降温至-78℃，滴加LDA(20.6mL，51.43mmol)，继续搅拌1h，滴加溴甲基甲醚(3.86g，30.86mmol)在-40℃反应3h。加水100mL淬灭，并用EA(100mL×2)萃取。合并的有机相用盐水(100mL)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物10b(4.0g，产率：67.73％)。Under nitrogen protection, compound 10a (5 g, 20.57 mmol) was dissolved in 100 mL of tetrahydrofuran, cooled to -78 °C, LDA (20.6 mL, 51.43 mmol) was added dropwise, and stirring was continued for 1 h. Bromomethyl methyl ether (3.86 g, 30.86 mmol) was added dropwise and reacted at -40 °C for 3 h. 100 mL of water was added to quench, and extracted with EA (100 mL×2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 10b (4.0 g, yield: 67.73%).

Ms m/z(ESI):288.1[M+H]+ Ms m/z(ESI):288.1[M+H] +

第二步：化合物10c的合成Step 2: Synthesis of compound 10c

在氮气保护下，将化合物10b(4.0g，13.94mmol)溶解在100mL四氢呋喃中，0℃下将2.5M LAH(13.94mL，34.85mmol)滴加到反应瓶中，室温反应3h。将反应混合物倒入100mL水中并用DCM(100mL×2)萃取。合并的有机相用盐水(100mL)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物10c(3.0g，产率：83.11％)。Under nitrogen protection, compound 10b (4.0 g, 13.94 mmol) was dissolved in 100 mL of tetrahydrofuran, and 2.5 M LAH (13.94 mL, 34.85 mmol) was added dropwise to the reaction bottle at 0°C, and the reaction was carried out at room temperature for 3 h. The reaction mixture was poured into 100 mL of water and extracted with DCM (100 mL×2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 10c (3.0 g, yield: 83.11%).

Ms m/z(ESI):260.1[M+H]+ Ms m/z(ESI):260.1[M+H] +

第三步：化合物10d的合成Step 3: Synthesis of compound 10d

在氮气保护下，将化合物10c(3.0g，11.57mmol)溶解在50mL二氯甲烷中，三乙胺(2.92g，28.93mmol)，滴加甲基磺酰氯(1.98g，17.35mmol)室温反应3h。将反应混合物倒入100mL水中并用DCM(100mL×2)萃取。合并的有机相用盐水(100mL)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物10d(3.0g，产率：76.85％)。Under nitrogen protection, compound 10c (3.0 g, 11.57 mmol) was dissolved in 50 mL of dichloromethane, triethylamine (2.92 g, 28.93 mmol), and methylsulfonyl chloride (1.98 g, 17.35 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 (100 mL×2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 10d (3.0 g, yield: 76.85%).

第四步：化合物10e的合成Step 4: Synthesis of compound 10e

在氮气保护下，将化合物10d(3.0g，8.90mmol)溶解在30mL二氯甲烷中，滴加10mL4N HCl的1,4-二氧六环溶液，室温反应1h。将反应混合物真空浓缩得化合物10e,直接用于下一步(3.0g,粗品)。 Under nitrogen protection, compound 10d (3.0 g, 8.90 mmol) was dissolved in 30 mL of dichloromethane, and 10 mL of 4N HCl in 1,4-dioxane was added dropwise, and the mixture was reacted at room temperature for 1 h. The reaction mixture was concentrated in vacuo to obtain compound 10e, which was used directly in the next step (3.0 g, crude product).

第五步：化合物10f的合成Step 5: Synthesis of compound 10f

在氮气保护下，将化合物10e(2.0g)溶解在20mL二氯甲烷中，三乙胺(1.52g，15.0mmol)，滴加乙酰氯(1.14g，10mmol)室温反应3h。将反应混合物倒入100mL水中并用DCM(30mL×2)萃取。合并的有机相用盐水(30mL)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物10f(1.0g，四、五两步产率：60.39％)。Under nitrogen protection, compound 10e (2.0 g) 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 Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 10f (1.0 g, yield of the fourth and fifth steps: 60.39%).

Ms m/z(ESI):280.1[M+H]+ Ms m/z(ESI):280.1[M+H] +

第六步：化合物10g的合成Step 6: Synthesis of compound 10g

在氮气保护下，将化合物10f(1.0g，3.58mmol)溶解在10mL DMSO中，2,6-二氟-4-羟基苯甲酸甲酯(1.01g，5.37mmol)，碳酸钾(1.38g，10mmol)，微波升温至120℃，反应2h。将反应混合物倒入30mL水中并用乙酸乙酯(30mL×2)萃取。合并的有机相用盐水(20mL×2)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物10g(0.3g，产率：20.94％)。Under nitrogen protection, compound 10f (1.0 g, 3.58 mmol) was dissolved in 10 mL DMSO, methyl 2,6-difluoro-4-hydroxybenzoate (1.01 g, 5.37 mmol), potassium carbonate (1.38 g, 10 mmol), microwave heated to 120 ° C, and reacted for 2 h. The reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 10g (0.3 g, yield: 20.94%).

Ms m/z(ESI):372.1[M+H]+ Ms m/z(ESI):372.1[M+H] +

第七步：化合物10h的合成Step 7: Synthesis of compound 10h

在氮气保护下，将化合物10g(0.30g，0.81mmol)溶解在5mL N-甲基吡咯烷酮中，加入2,4-二甲氧基苯甲胺(0.21g，1.21mmol)，碳酸钾(0.33g，2.42mmol)，升温至80℃，反应16h。将反应混合物倒入10mL水中并用乙酸乙酯(10mL×2)萃取。合并的有机相用盐水(10mL×2)洗涤，用无水Na2SO4干燥，过滤并真空浓缩。残余物通过硅胶柱纯化获得化合物10h(0.25g，产率：59.68％)。Under nitrogen protection, compound 10g (0.30g, 0.81mmol) was dissolved in 5mL N-methylpyrrolidone, 2,4-dimethoxybenzylamine (0.21g, 1.21mmol), potassium carbonate (0.33g, 2.42mmol) were added, the temperature was raised to 80°C, and the reaction was carried out for 16h. The reaction mixture was poured into 10mL of water and extracted with ethyl acetate (10mL×2). The combined organic phase was washed with brine (10mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column to obtain compound 10h (0.25g, yield: 59.68%).

第八步：化合物10i的合成Step 8: Synthesis of compound 10i

在氮气保护下，将化合物10h(0.25g，0.48mmol)溶解在5mL二氯甲烷和1mL三氟乙酸中，加入三乙基硅烷(0.11g，0.96mmol)，室温反应2h。真空浓缩。二氯甲烷溶解，饱和碳酸氢钠溶液洗涤，有机相无水硫酸钠干燥，减压浓缩，残余物通过硅胶柱纯化获得化合物10i(0.15g，产率：84.46％)。Under nitrogen protection, compound 10h (0.25 g, 0.48 mmol) was dissolved in 5 mL of dichloromethane and 1 mL of trifluoroacetic acid, triethylsilane (0.11 g, 0.96 mmol) was added, and the reaction was carried out at room temperature for 2 h. Vacuum concentration was performed. The product 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 10i (0.15 g, yield: 84.46%).

第九步：化合物10j的合成Step 9: Synthesis of compound 10j

在氮气保护下，将化合物10i(0.15g，0.41mmol)溶解在5mL 2N的盐酸1,4-二氧六环溶液中，氯乙腈(0.06g，0.82mmol)，80℃反应2h。真空浓缩。二氯甲烷溶解，饱和碳酸氢钠溶液洗涤，有机相无水硫酸钠干燥，减压浓缩，残余物通过硅胶柱纯化获得化合物10j(0.10g，产率：59.69％)。Under nitrogen protection, compound 10i (0.15 g, 0.41 mmol) was dissolved in 5 mL 2N hydrochloric acid 1,4-dioxane solution and chloroacetonitrile (0.06 g, 0.82 mmol) and reacted at 80 °C for 2 h. Concentrated in vacuo. Dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column to obtain compound 10j (0.10 g, yield: 59.69%).

Ms m/z(ESI):412.1[M+H]+ Ms m/z(ESI):412.1[M+H] +

第十步：化合物10的合成Step 10: Synthesis of compound 10

在氮气保护下，将化合物10j(0.10g，0.24mmol)溶解在四氢呋喃中，2N氢氧化钠溶液1mL滴加到反应瓶中，加入中间体1(0.08g,0.48mmol)，室温反应2h。减压浓缩，残余物通过硅胶柱纯化获得化合物10(50mg，产率：41.68％)。Under nitrogen protection, compound 10j (0.10 g, 0.24 mmol) was dissolved in tetrahydrofuran, 1 mL of 2N sodium hydroxide solution was added dropwise to the reaction flask, intermediate 1 (0.08 g, 0.48 mmol) was added, and the mixture 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 10 (50 mg, yield: 41.68%).

Ms m/z(ESI):494.4[M+H]+ Ms m/z(ESI):494.4[M+H] +

1H NMR(400MHz,CD3OD)δ6.96(d,1H),6.84(dd,1H),4.06(s,2H),3.95-3.85(m,2H),3.72-3.65(m,2H),3.60-3.53(m,3H),3.46(s,2H),3.43(d,1H),3.33(s,3H),3.09-2.99(m,1H),2.11(s,3H),1.99-1.90(m,2H),1.77-1.63(m,4H),1.61-1.42(m,4H). 1 H NMR (400MHz, CD 3 OD)δ6.96(d,1H),6.84(dd,1H),4.06(s,2H),3.95-3.85(m,2H),3.72-3.65(m,2H),3.60-3.53(m,3H ),3.46(s,2H), 3.43(d,1H),3.33(s,3H),3.09-2.99(m,1H),2.11(s,3H),1.99-1.90(m,2H),1.77-1.63(m,4H),1.61- 1.42(m,4H).

实施例11：化合物11的制备
Example 11: Preparation of Compound 11

第一步：11B的制备Step 1: Preparation of 11B

将4-(甲氧羰基)双环[2.2.2]辛烷-1-羧酸11A(5g,23.58mmol)溶于THF(60mL)中，0℃下缓慢滴加硼烷四氢呋喃溶液(47mL,1M)，加完升至室温反应16小时。0℃下加入甲醇淬灭，减压浓缩，残留物用硅胶柱层析纯化得到11B(3.8g,收率：81％)。4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 11A (5 g, 23.58 mmol) was dissolved in THF (60 mL), and borane tetrahydrofuran solution (47 mL, 1 M) was slowly added dropwise at 0°C, and the mixture was heated to room temperature for 16 hours. Methanol was added at 0°C to quench the mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 11B (3.8 g, yield: 81%).

第二步：11C的制备Step 2: Preparation of 11C

将11B(3.8g,19.16mmol)溶于DCM(100mL)中，0℃下分批加入戴斯-马丁氧化剂(16.25g,38.32mmol)，升至室温反应3小时。减压浓缩，残留物用硅胶柱层析纯化得到11C(3.02g,收率：80％)。11B (3.8 g, 19.16 mmol) was dissolved in DCM (100 mL), and Dess-Martin periodinane (16.25 g, 38.32 mmol) was added in batches at 0°C, and the mixture was heated to room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 11C (3.02 g, yield: 80%).

第三步：11D的制备Step 3: Preparation of 11D

将1,1-二溴-3,3,3-三氟丙酮(4.98g,18.49mmol)置于250mL单口瓶中，加入30mL水和醋酸钠(1.89g,23.09mmol)，升温至90℃反应1小时。冷却至室温，依次加入60mL甲醇、11C(3.02g,15.39mmol)和浓氨水(15mL)，升温至90℃继续反应2小时。冷却至室温，将反应液倒入200mL水中，过滤，滤饼用水(2×10mL)洗涤，滤饼减压干燥得到11D(2.9g,收率：62％)。1,1-Dibromo-3,3,3-trifluoroacetone (4.98 g, 18.49 mmol) was placed in a 250 mL single-mouth bottle, 30 mL of water and sodium acetate (1.89 g, 23.09 mmol) were added, and the temperature was raised to 90 °C for 1 hour. After cooling to room temperature, 60 mL of methanol, 11C (3.02 g, 15.39 mmol) and concentrated aqueous ammonia (15 mL) were added in sequence, and the temperature was raised to 90 °C for 2 hours. After cooling to room temperature, the reaction solution was poured into 200 mL of water, filtered, and the filter cake was washed with water (2×10 mL). The filter cake was dried under reduced pressure to obtain 11D (2.9 g, yield: 62%).

LCMS m/z＝303.1[M+H]+ LCMS m/z＝303.1[M+H] +

第四步：11E的制备Step 4: Preparation of 11E

室温下将11D(2.0g,6.62mmol)溶于30mL DMF中，依次加入异丙基碘(4.50g,26.48mmol)和碳酸铯(6.47g,19.86mmol)，升温至90℃反应过夜。冷却至室温，加入水和乙酸乙酯萃取，有机层用饱和食盐水洗涤，用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析纯化得到11E(1.2g,收率：52％)。11D (2.0 g, 6.62 mmol) was dissolved in 30 mL DMF at room temperature, and isopropyl iodide (4.50 g, 26.48 mmol) and cesium carbonate (6.47 g, 19.86 mmol) were added in sequence, and the temperature was raised to 90°C for overnight reaction. After cooling to room temperature, water and ethyl acetate were added for extraction, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 11E (1.2 g, yield: 52%).

LCMS m/z＝345.2[M+H]+ LCMS m/z＝345.2[M+H] +

第五步：11F的制备Step 5: Preparation of 11F

将11E(1.2g,3.48mmol)溶于20mL THF中，加入硼氢化锂(0.38g,17.40mmol)，升温至60℃搅拌2小时。冷却至室温，加入饱和氯化铵水溶液淬灭反应，加入水和乙酸乙酯萃取，有机层用无水硫酸钠干燥，减压浓缩，得到11F(0.9g,收率：81％)。 11E (1.2 g, 3.48 mmol) was dissolved in 20 mL THF, lithium borohydride (0.38 g, 17.40 mmol) was added, and the temperature was raised to 60°C and stirred for 2 hours. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and water and ethyl acetate were added for extraction. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 11F (0.9 g, yield: 81%).

LCMS m/z＝317.2[M+H]+ LCMS m/z＝317.2[M+H] +

第六步：11G的制备Step 6: Preparation of 11G

将11F(5g,15.80mmol)溶解于甲苯(40mL)中，依次加入2,6-二氟-4-羟基苯甲酸甲酯(2.97g,15.80mmol)，氰基亚甲基三正丁基膦(11.44g,47.40mmol)，氮气氛围下，100℃反应16小时。反应液冷却至室温，减压浓缩除去反应溶剂，残余物用硅胶柱层析，即得目标化合物11G(2.8g，产率36.43％)。11F (5 g, 15.80 mmol) was dissolved in toluene (40 mL), and methyl 2,6-difluoro-4-hydroxybenzoate (2.97 g, 15.80 mmol) and cyanomethylene tri-n-butylphosphine (11.44 g, 47.40 mmol) were added in sequence, and the mixture was reacted at 100°C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was chromatographed on a silica gel column to obtain the target compound 11G (2.8 g, yield 36.43%).

LCMS m/z＝487.4[M+H]+ LCMS m/z＝487.4[M+H] +

第七步：11H的制备Step 7: Preparation of 11H

将11G(2.8g,5.76mmol)溶解于N-甲基吡咯烷酮(15mL)，依次加入2,4-二甲氧基苄胺(1.93g,11.54mmol)、无水碳酸钾(1.59g,11.60mmol)，80℃反应16小时。反应液冷却至室温，加入水(20mL)，用乙酸乙酯(20mL×2)萃取两次，合并有机相，有机相依次用水(20mL×2)洗两次、饱和NaCl的水溶液(20mL×1)洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残余物用硅胶柱层析得到11H(2.33g，产率63.84％)。11G (2.8 g, 5.76 mmol) was dissolved in N-methylpyrrolidone (15 mL), and 2,4-dimethoxybenzylamine (1.93 g, 11.54 mmol) and anhydrous potassium carbonate (1.59 g, 11.60 mmol) were added in sequence, and the mixture was reacted at 80°C for 16 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL × 2). The organic phases were combined, and the organic phases were washed twice with water (20 mL × 2) and once with a saturated aqueous solution of NaCl (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain 11H (2.33 g, yield 63.84%).

LCMS m/z＝634.0[M+H]+ LCMS m/z＝634.0[M+H] +

第八步：11I的制备Step 8: Preparation of 11I

将11H(0.7g,1.1mmol)溶解于二氯甲烷(10mL)，依次加入三乙基硅烷(0.26g,2.2mmol)、三氟乙酸(1mL)，室温下反应16小时。减压浓缩除去反应溶剂，残余物用硅胶柱层析得到11I(0.53g，产率99.65％)。11H (0.7 g, 1.1 mmol) was dissolved in dichloromethane (10 mL), triethylsilane (0.26 g, 2.2 mmol) and trifluoroacetic acid (1 mL) were added in sequence, and the mixture was reacted at room temperature for 16 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 11I (0.53 g, yield 99.65%).

LCMS m/z＝484.0[M+H]+ LCMS m/z＝484.0[M+H] +

第九步：11J的制备Step 9: Preparation of 11J

将11I(0.53g,1.1mmol)溶解于1,4-二氧六环(8mL)，依次加入氯乙腈(0.24g,3.16mmol)、盐酸二氧六环溶液(0.5mL，4mol/L)，80℃反应4小时。反应液冷却至室温，减压浓缩除去反应溶剂，残余物用硅胶柱层析得到11J(0.34g，产率58.66％)。11I (0.53 g, 1.1 mmol) was dissolved in 1,4-dioxane (8 mL), and chloroacetonitrile (0.24 g, 3.16 mmol) and dioxane hydrochloride solution (0.5 mL, 4 mol/L) were added in sequence, and the mixture was reacted at 80°C for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was purified by silica gel column chromatography to obtain 11J (0.34 g, yield 58.66%).

LCMS m/z＝527.0[M+H]+ LCMS m/z＝527.0[M+H] +

第十步：化合物11的制备Step 10: Preparation of compound 11

将11J(0.2g,0.38mmol)溶解于四氢呋喃(6mL)，依次加入中间体1(0.12g,0.75mmol)、氢氧化钠溶液(0.5mL，3N),室温下反应3小时。减压浓缩除去反应溶剂，残余物用硅胶柱层析得到化合物11(40mg，产率18.59％)。11J (0.2 g, 0.38 mmol) was dissolved in tetrahydrofuran (6 mL), and intermediate 1 (0.12 g, 0.75 mmol) and sodium hydroxide solution (0.5 mL, 3N) were added in sequence, and the mixture was reacted at room temperature for 3 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 11 (40 mg, yield 18.59%).

LCMS m/z＝609.2[M+H]+ LCMS m/z＝609.2[M+H] +

1H NMR(400MHz,CD3OD)δ7.66(d,1H),6.92(d,1H),6.83(dd,1H),5.01-4.93(m,1H),3.95-3.88(m,2H),3.80(s,2H),3.69(s,2H),3.51-3.39(m,2H),3.10-3.00(m,1H),2.14-2.06(m,6H),2.00-1.91(m,2H),1.80-1.71(m,6H),1.68-1.52(m,2H),1.47(d,6H). 1 H NMR (400MHz, CD 3 OD)δ7.66(d,1H),6.92(d,1H),6.83(dd,1H),5.01-4.93(m,1H),3.95-3.88(m,2H),3.80(s,2H), 3.69(s,2H),3.51-3. 39(m,2H),3.10-3.00(m,1H),2.14-2.06(m,6H),2.00-1.91(m,2H),1.80-1.71(m,6H),1.68-1.52(m,2H ),1.47(d,6H).

实施例12：化合物12的制备
Example 12: Preparation of Compound 12

第一步：12B的制备Step 1: Preparation of 12B

室温下将11D(5.0g，16.54mmol)溶于30mL DMF中，依次加入碘甲烷(10.78g，33.10mmol)和碳酸铯(3.52g，24.74mmol)，升温至80℃反应16小时。反应液冷却至室温，加入水(30mL)，用乙酸乙酯(30mL×2)萃取两次，合并有机相，有机相依次用水(30mL×2)洗两次、饱和NaCl的水溶液(30mL×1)洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残余物用硅胶柱层析得到12B(3.7g,收率：70.72％)。11D (5.0 g, 16.54 mmol) was dissolved in 30 mL DMF at room temperature, iodomethane (10.78 g, 33.10 mmol) and cesium carbonate (3.52 g, 24.74 mmol) were added in sequence, and the temperature was raised to 80 °C for 16 hours. The reaction solution was cooled to room temperature, water (30 mL) was added, and it was extracted twice with ethyl acetate (30 mL × 2), and the organic phases were combined. The organic phases were washed twice with water (30 mL × 2) and once with a saturated NaCl aqueous solution (30 mL × 1), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain 12B (3.7 g, yield: 70.72%).

LCMS m/z＝317.0[M+H]+ LCMS m/z＝317.0[M+H] +

第二步：12C的制备Step 2: Preparation of 12C

将12B(3.7g,11.70mmol)溶解于四氢呋喃(30mL)中，加入硼氢化锂(1.28g,58.68mmol)，60℃反应4小时。反应液冷却至室温，将反应冷却至室温，缓慢加入饱和氯化铵水溶液(20mL)，并用乙酸乙酯2(30mL×2)萃取两次，合并乙酸乙酯层，乙酸乙酯层用无水硫酸钠干燥，过滤，滤液减压浓缩后得到12C(2.88g,收率：85.38％)。12B (3.7 g, 11.70 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium borohydride (1.28 g, 58.68 mmol) was added, and the mixture was reacted at 60°C for 4 hours. The reaction solution was cooled to room temperature, and a saturated aqueous ammonium chloride solution (20 mL) was slowly added, and the mixture was extracted twice with ethyl acetate 2 (30 mL×2). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 12C (2.88 g, yield: 85.38%).

LCMS m/z＝289.1[M+H]+ LCMS m/z＝289.1[M+H] +

第三步：12D的制备Step 3: Preparation of 12D

将12C(2.88g,9.99mmol)溶解于甲苯(15mL)中，依次加入2,6-二氟-4-羟基苯甲酸甲酯(1.88g,9.99mmol)，氰基亚甲基三正丁基膦(7.23g,29.97mmol)，氮气氛围下，100℃反应16小时。反应液冷却至室温，减压浓缩除去反应溶剂，残余物用硅胶柱层析，即得目标化合物12D(2.27g，产率49.57％)。12C (2.88 g, 9.99 mmol) was dissolved in toluene (15 mL), and methyl 2,6-difluoro-4-hydroxybenzoate (1.88 g, 9.99 mmol) and cyanomethylenetri-n-butylphosphine (7.23 g, 29.97 mmol) were added in sequence, and the mixture was reacted at 100°C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was chromatographed on a silica gel column to obtain the target compound 12D (2.27 g, yield 49.57%).

LCMS m/z＝459.3[M+H]+ LCMS m/z＝459.3[M+H] +

第四步：12E的制备Step 4: Preparation of 12E

将12D(2.1g,4.58mmol)溶解于N-甲基吡咯烷酮(15mL)，依次加入2,4-二甲氧基苄胺(1.15g,6.84mmol)、无水碳酸钾(1.27g,9.19mmol)，80℃反应16小时。反应液冷却至室温，加入水(20mL)，用乙酸乙酯(20mL×2)萃取两次，合并有机相，有机相依次用水(20mL×2)洗两次、饱和NaCl的水溶液(20mL×1)洗一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残余物用硅胶柱层析得到12E(1.31g，产率47.23％)。12D (2.1 g, 4.58 mmol) was dissolved in N-methylpyrrolidone (15 mL), and 2,4-dimethoxybenzylamine (1.15 g, 6.84 mmol) and anhydrous potassium carbonate (1.27 g, 9.19 mmol) were added in sequence, and the mixture was reacted at 80°C for 16 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL × 2). The organic phases were combined, and the organic phases were washed twice with water (20 mL × 2) and once with a saturated aqueous solution of NaCl (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 12E (1.31 g, yield 47.23%).

第五步：12F的制备 Step 5: Preparation of 12F

将12E(0.75g,1.24mmol)溶解于二氯甲烷(10mL)，依次加入三乙基硅烷(0.29g,2.49mmol)、三氟乙酸(0.5mL)，室温下反应16小时。减压浓缩除去反应溶剂，残余物用硅胶柱层析得到12F(0.36g，产率63.74％)。12E (0.75 g, 1.24 mmol) was dissolved in dichloromethane (10 mL), triethylsilane (0.29 g, 2.49 mmol) and trifluoroacetic acid (0.5 mL) were added in sequence, and the mixture was reacted at room temperature for 16 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 12F (0.36 g, yield 63.74%).

LCMS m/z＝456.1[M+H]+ LCMS m/z＝456.1[M+H] +

第五步：12G的制备Step 5: Preparation of 12G

将12F(0.31g,0.68mmol)溶解于1,4-二氧六环(4mL)，依次加入氯乙腈(0.5mL)、盐酸二氧六环溶液(1mL，4mol/L)，80℃反应2小时。反应液冷却至室温，减压浓缩除去反应溶剂，残余物用硅胶柱层析得到12G(0.2g，产率58.95％)。12F (0.31 g, 0.68 mmol) was dissolved in 1,4-dioxane (4 mL), and chloroacetonitrile (0.5 mL) and dioxane hydrochloride solution (1 mL, 4 mol/L) were added in sequence, and the mixture was reacted at 80°C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was purified by silica gel column chromatography to obtain 12G (0.2 g, yield 58.95%).

LCMS m/z＝499.1[M+H]+ LCMS m/z＝499.1[M+H] +

第六步：化合物12的制备Step 6: Preparation of compound 12

将12G(0.2g,0.4mmol)溶解于四氢呋喃(5mL)，依次加入中间体1(0.096g,0.6mmol)、氢氧化钠溶液(0.5mL，3N),室温下反应2小时。减压浓缩除去反应溶剂，残余物用硅胶柱层析得到化合物12(30mg，产率12.92％)。12G (0.2 g, 0.4 mmol) was dissolved in tetrahydrofuran (5 mL), and intermediate 1 (0.096 g, 0.6 mmol) and sodium hydroxide solution (0.5 mL, 3 N) were added in sequence, and the mixture was reacted at room temperature for 2 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 12 (30 mg, yield 12.92%).

LCMS m/z＝581.4[M+H]+ LCMS m/z＝581.4[M+H] +

1H NMR(400MHz,CD3OD)δ7.41(d,1H),6.92(d,1H),6.82(dd,1H),3.94-3.87(m,2H),3.85(s,3H),3.80(s,2H),3.69(s,2H),3.48-3.39(m,2H),3.09-3.00(m,1H),2.13-2.07(m,6H),2.00-1.92(m,2H),1.78-1.71(m,6H),1.64-1.53(m,2H). 1 H NMR (400MHz, CD 3 OD)δ7.41(d,1H),6.92(d,1H),6.82(dd,1H),3.94-3.87(m,2H),3.85(s,3H),3.80(s,2H),3.69( s,2H),3.48 -3.39(m,2H),3.09-3.00(m,1H),2.13-2.07(m,6H),2.00-1.92(m,2H),1.78-1.71(m,6H),1.64-1.53(m, 2H).

实施例13：化合物13的制备
Example 13: Preparation of Compound 13

第一步：化合物13b的合成Step 1: Synthesis of compound 13b

将13a(2g,9.00mmol)(合成参考专利WO2020168148)溶解于甲苯(40mL)中，依次加入2,6-二氟-4-羟基苯甲酸甲酯(2.54g,13.5mmol)，氰基亚甲基三正丁基膦(27g,6.52mmol)，氮气氛围下，100℃反应16小时。反应液冷却至室温，减压浓缩除去反应溶剂，残余物用硅胶柱层析，即得目标化合物13b(1.3g，产率36.82％)。13a (2 g, 9.00 mmol) (synthesis reference patent WO2020168148) was dissolved in toluene (40 mL), and methyl 2,6-difluoro-4-hydroxybenzoate (2.54 g, 13.5 mmol) and cyanomethylenetri-n-butylphosphine (27 g, 6.52 mmol) were added in sequence, and reacted at 100 ° C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was chromatographed on a silica gel column to obtain the target compound 13b (1.3 g, yield 36.82%).

LCMS m/z＝393.4[M+H]+ LCMS m/z＝393.4[M+H] +

第二步：化合物13的合成Step 2: Synthesis of compound 13

化合物13c至化合物13的合成参照化合物2第三步到第六步的合成路线，得到化合物13(30mg)。The synthesis of compound 13c to compound 13 followed the synthetic route of step 3 to step 6 of compound 2 to obtain compound 13 (30 mg).

LCMS m/z＝515.3[M+H]+ LCMS m/z＝515.3[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),6.91-6.82(m,2H),3.85-3.77(m,4H),3.61(s,2H),3.37-3.30(m,2H),3.11-3.00(m,1H),2.30(s,3H),1.98-1.83(m,8H),1.69-1.59(m,6H), 1.52-1.39(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ12.13(s,1H),6.91-6.82(m,2H),3.85-3.77(m,4H),3.61(s,2H),3.37-3.30 (m,2H),3.11-3.00(m,1H),2.30(s,3H),1.98-1.83(m,8H),1.69-1.59(m,6H), 1.52-1.39(m,2H).

实施例14：化合物14的制备
Example 14: Preparation of Compound 14

第一步：化合物14b的合成Step 1: Synthesis of compound 14b

在氮气保护下，将化合物14a(5g，27.29mmol)溶解在20mL四氢呋喃中，0℃下将2.5N四氢锂铝的四氢呋喃溶液(10.0mL，255.6mmol)滴加到反应瓶中，加完后，室温反应3h。将反应混合物倒入100mL水中并用DCM(30mL×2)萃取。合并的有机相用盐水(30mL)洗涤，然后用无水Na2SO4干燥，过滤并减压浓缩。残余物通过硅胶柱纯化获得化合物14b(3g，产率：70.83％)。Under nitrogen protection, compound 14a (5 g, 27.29 mmol) was dissolved in 20 mL of tetrahydrofuran, and 2.5 N tetrahydrogen lithium aluminum tetrahydrofuran solution (10.0 mL, 255.6 mmol) was added dropwise to the reaction bottle at 0°C. After the addition, the reaction was allowed to react 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), then dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 14b (3 g, yield: 70.83%).

LCMS m/z＝156.4[M+H]+ LCMS m/z＝156.4[M+H] +

第二步：化合物14c的合成Step 2: Synthesis of compound 14c

冰浴条件下，将化合物14b(3g，19.32mmol)溶解于30mL二氯甲烷中，加入三乙胺(8mL，57.96mmol)，搅拌五分钟后向反应液中缓缓加入氯甲酸苄酯(8mL，57.96mmol)，十分钟后升至室温过夜反应。将反应混合物倒入100mL水中并用DCM(30mL×2)萃取。合并的有机相用盐水(30mL)洗涤，随后用无水Na2SO4干燥，过滤并减压浓缩。残余物通过硅胶柱纯化获得化合物14c(1.9g，产率：33.98％)。Under ice bath conditions, compound 14b (3 g, 19.32 mmol) was dissolved in 30 mL of dichloromethane, triethylamine (8 mL, 57.96 mmol) was added, and benzyl chloroformate (8 mL, 57.96 mmol) was slowly added to the reaction solution after stirring for five minutes. After ten minutes, the temperature was raised to room temperature for overnight reaction. 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), then dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column to obtain compound 14c (1.9 g, yield: 33.98%).

LCMS m/z＝290.4[M+H]+ LCMS m/z＝290.4[M+H] +

第三步：化合物14d的合成Step 3: Synthesis of compound 14d

将14c(1.9g,6.57mmol)溶解于甲苯(30mL)中，依次加入2,6-二氟-4-羟基苯甲酸甲酯(1.85g,9.86mmol)，氰基亚甲基三正丁基膦(6.34g,26.28mmol)，氮气氛围下，100℃反应16小时。反应液冷却至室温，减压浓缩除去反应溶剂，残余物用硅胶柱层析，即得目标化合物14d(1.2g，产率39.78％)。14c (1.9 g, 6.57 mmol) was dissolved in toluene (30 mL), and methyl 2,6-difluoro-4-hydroxybenzoate (1.85 g, 9.86 mmol) and cyanomethylenetri-n-butylphosphine (6.34 g, 26.28 mmol) were added in sequence, and the mixture was reacted at 100°C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was chromatographed on a silica gel column to obtain the target compound 14d (1.2 g, yield 39.78%).

LCMS m/z＝460.4[M+H]+ LCMS m/z＝460.4[M+H] +

第四至九步：化合物14的合成Steps 4 to 9: Synthesis of compound 14

化合物14e至化合物14的合成参照化合物6第三步到第八步的合成路线，得到化合物14(20mg)。The synthesis of compound 14e to compound 14 followed the synthetic route of step 3 to step 8 of compound 6 to obtain compound 14 (20 mg).

LCMS m/z＝516.1[M+H]+ LCMS m/z＝516.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),7.52(s,1H),6.88-6.81(m,2H),3.85-3.77(m, 2H),3.73(s,2H),3.61(s,2H),3.36-3.29(m,2H),3.10-2.99(m,1H),1.92-1.78(m,8H),1.61-1.51(m,7H),1.50-1.38(m,2H),0.62-0.51(m,4H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.11(s,1H),7.52(s,1H),6.88-6.81(m,2H),3.85-3.77(m, 2H),3.73(s,2H),3.61(s,2H),3.36-3.29(m,2H),3.10-2.99(m,1H),1.9 2-1.78(m,8H),1.61-1.51(m,7H),1.50-1.38(m,2H),0.62-0.51(m,4H).

实施例15：化合物15的制备
Example 15: Preparation of Compound 15

第一步：15a的制备Step 1: Preparation of 15a

将14a(6g,32.88mmol)溶解于50mL二氯甲烷中，加入三乙胺(6.6g,65.76mmol)，0℃下缓慢滴加乙酰氯(2.88g,36.12mmol)，滴完后室温反应2小时。反应液减压浓缩后残余物用硅胶色谱柱柱层析即得15a(3g，收率：40.45％)。14a (6 g, 32.88 mmol) was dissolved in 50 mL of dichloromethane, triethylamine (6.6 g, 65.76 mmol) was added, and acetyl chloride (2.88 g, 36.12 mmol) was slowly added dropwise at 0°C, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain 15a (3 g, yield: 40.45%).

LCMS m/z＝226.1[M+H]+ LCMS m/z＝226.1[M+H] +

第二步：15b的制备Step 2: Preparation of 15b

将15a(3g,13.32mmol)溶解于20mL N,N-二甲基甲酰胺中，0℃分批加入氢化钠(0.48g,19.98mmol)，0℃下反应30min，缓慢滴入碘甲烷(2.84g,19.98mmol)，滴完后60℃反应16小时。冷却至室温，反应液中加入水(25mL)，并用乙酸乙酯(25mL×2)萃取，合并乙酸乙酯层，乙酸乙酯层依次用水(25mL×2)，饱和NaCl的水溶液(25mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残余物用硅胶色谱柱柱层析即得化合物15b(2.8g，产率87.86％)。15a (3 g, 13.32 mmol) was dissolved in 20 mL N,N-dimethylformamide, sodium hydride (0.48 g, 19.98 mmol) was added in batches at 0°C, reacted at 0°C for 30 min, iodomethane (2.84 g, 19.98 mmol) was slowly added dropwise, and reacted at 60°C for 16 hours after the addition was complete. After cooling to room temperature, water (25 mL) was added to the reaction solution, and extracted with ethyl acetate (25 mL × 2), the ethyl acetate layers were combined, and the ethyl acetate layers were washed with water (25 mL × 2) and saturated NaCl aqueous solution (25 mL) in turn, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain compound 15b (2.8 g, yield 87.86%).

LCMS m/z＝240.2[M+H]+ LCMS m/z＝240.2[M+H] +

第三步：15c的制备Step 3: Preparation of 15c

将15b(1.5g,13.32mmol)溶解于10mL四氢呋喃中，0℃分批加入硼氢化锂(0.27g,12.54mmol)，室温反应16小时。反应液减压浓缩后残余物用硅胶色谱柱柱层析即得化合物15c(0.75g，产率56.63％)。15b (1.5 g, 13.32 mmol) was dissolved in 10 mL of tetrahydrofuran, and lithium borohydride (0.27 g, 12.54 mmol) was added in batches at 0°C, and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain compound 15c (0.75 g, yield 56.63%).

LCMS m/z＝212.1[M+H]+ LCMS m/z＝212.1[M+H] +

第四步：15d的制备Step 4: Preparation of 15d

将15c(0.75g,3.53mmol)溶解于15mL甲苯中，依次加入2,6-二氟-4-羟基苯甲酸甲酯(0.86g,4.59mmol)，氰基亚甲基三正丁基膦(2.56g,10.59mmol)，氮气氛围下，100℃反应16小时。冷却至室温，减压浓缩后残余物用硅胶色谱柱柱层析即得目标化合物15d(0.37g，产率24.46％)。15c (0.75 g, 3.53 mmol) was dissolved in 15 mL of toluene, and methyl 2,6-difluoro-4-hydroxybenzoate (0.86 g, 4.59 mmol) and cyanomethylenetri-n-butylphosphine (2.56 g, 10.59 mmol) were added in sequence, and the mixture was reacted at 100°C for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain the target compound 15d (0.37 g, yield 24.46%).

LCMS m/z＝382.2[M+H]+ LCMS m/z＝382.2[M+H] +

第五步：15e的制备Step 5: Preparation of 15e

将15d(0.37g,0.97mmol)溶解于N-甲基吡咯烷酮(8mL)，依次加入2,4-二甲氧基苄胺(0.32g,1.94mmol)，无水碳酸钾(0.27g,1.94mmol)，80℃反应16小时。反应液冷却至室温，加入水(20mL)，用乙酸乙酯(20mL×2)萃取两次，合并有机相，有机相依次用水(20mL×2)洗两次、饱和NaCl的水溶液(20mL×1)洗一次，然后有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残余物用硅胶色谱柱柱层析得目标化合物15e(0.30g，产率58.50％)。 15d (0.37 g, 0.97 mmol) was dissolved in N-methylpyrrolidone (8 mL), and 2,4-dimethoxybenzylamine (0.32 g, 1.94 mmol) and anhydrous potassium carbonate (0.27 g, 1.94 mmol) were added in sequence, and the mixture was reacted at 80°C for 16 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL×2). The organic phases were combined, and the organic phases were washed twice with water (20 mL×2) and once with a saturated aqueous solution of NaCl (20 mL×1) in sequence, and then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain the target compound 15e (0.30 g, yield 58.50%).

LCMS m/z＝529.4[M+H]+ LCMS m/z＝529.4[M+H] +

第六步：15f的制备Step 6: Preparation of 15f

将15e(0.3g,0.57mmol)溶解于二氯甲烷(10mL)，依次加入三乙基硅烷(0.13g,1.14mmol)，三氟乙酸(1mL)，室温下反应16小时。减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析即得化合物15f(0.184g，产率85.67％)。15e (0.3 g, 0.57 mmol) was dissolved in dichloromethane (10 mL), and triethylsilane (0.13 g, 1.14 mmol) and trifluoroacetic acid (1 mL) were added in sequence, and the reaction was carried out at room temperature for 16 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was chromatographed on a silica gel column to obtain compound 15f (0.184 g, yield 85.67%).

LCMS m/z＝379.2[M+H]+ LCMS m/z＝379.2[M+H] +

第七步：15g的制备Step 7: Preparation of 15g

将15f(0.53g,0.49mmol)溶解于4mL 1,4-二氧六环中，依次加入氯乙腈(74mg,0.98mmol)、盐酸二氧六环溶液(0.5mL，4mol/L)，80℃反应4小时。反应液冷却至室温，减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析得到化合物15g(0.14g，产率68.25％)。15f (0.53 g, 0.49 mmol) was dissolved in 4 mL 1,4-dioxane, and chloroacetonitrile (74 mg, 0.98 mmol) and dioxane hydrochloride solution (0.5 mL, 4 mol/L) were added in sequence, and the mixture was reacted at 80°C for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was chromatographed on a silica gel column to obtain compound 15g (0.14 g, yield 68.25%).

LCMS m/z＝422.2[M+H]+ LCMS m/z＝422.2[M+H] +

第八步：化合物15的制备Step 8: Preparation of compound 15

将15g(0.14g,0.33mmol)溶解于6mL四氢呋喃中，依次加入中间体1(0.16g,0.99mmol)、氢氧化钠溶液(0.5mL，3N)，室温下反应3小时。减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析得到化合物15(22mg，产率13.16％)。15g (0.14g, 0.33mmol) was dissolved in 6mL tetrahydrofuran, and intermediate 1 (0.16g, 0.99mmol) and sodium hydroxide solution (0.5mL, 3N) were added in sequence, and the mixture was reacted at room temperature for 3 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was chromatographed on a silica gel column to obtain compound 15 (22mg, yield 13.16%).

LCMS m/z＝504.8[M+H]+ LCMS m/z＝504.8[M+H] +

1H NMR(400MHz,CD3OD)δ6.89(d,1H),6.80(dd,1H),3.94-3.86(m,2H),3.72(s,2H),3.67(s,2H),3.46-3.38(m,2H),3.08-2.98(m,1H),2.95(s,3H),2.19-2.11(m,6H),2.07(s,3H),1.98-1.90(m,2H),1.74-1.66(m,6H),1.63-1.51(m,2H). 1 H NMR (400MHz, CD 3 OD)δ6.89(d,1H),6.80(dd,1H),3.94-3.86(m,2H),3.72(s,2H),3.67(s,2H),3.46-3.38(m,2H), 3.08-2.98( m,1H),2.95(s,3H),2.19-2.11(m,6H),2.07(s,3H),1.98-1.90(m,2H),1.74-1.66(m,6H),1.63-1.51( m,2H).

实施例16：化合物16的制备
Example 16: Preparation of Compound 16

第一步：16a的制备Step 1: Preparation of 16a

将14a(8g,43.66mmol)溶解于50mL二氯甲烷中，加入三乙胺(9.72g,96.05mmol)，0℃下缓慢滴加4-溴丁基氯酸(17g,91.69mmol)，滴完后继续反应1小时，然后升至室温反应3小时。加水稀释,DCM萃取三次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经柱层析纯化得产物16a(8.458g，收率：77.09％)。14a (8 g, 43.66 mmol) was dissolved in 50 mL of dichloromethane, triethylamine (9.72 g, 96.05 mmol) was added, and 4-bromobutyl chloroacetic acid (17 g, 91.69 mmol) was slowly added dropwise at 0°C. After the addition was complete, the reaction was continued for 1 hour, and then the temperature was raised to room temperature for 3 hours. The mixture was diluted with water, extracted with DCM three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product 16a (8.458 g, yield: 77.09%).

LCMS m/z＝252.2[M+H]+ LCMS m/z＝252.2[M+H] +

第二步：16b的制备Step 2: Preparation of 16b

将16a(4.3g,17.11mmol)溶解于100mL THF中，置换氮气保护，0℃加入氢化锂铝(2.5Nin THF)(13.68mL,34.22mmol,2.5N in THF)，反应3h。反应液中加入饱和氯化铵溶液稀释(125mL)，并用乙酸乙酯(50mL×3)萃取，合并乙酸乙酯层，乙酸乙酯层依次用水(25mL×2)，饱和NaCl的水溶液(25mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残余物用硅胶色谱柱柱 层析即得化合物16b(1.4g，产率36.64％)。16a (4.3 g, 17.11 mmol) was dissolved in 100 mL THF, replaced with nitrogen protection, and lithium aluminum hydride (2.5 N in THF) (13.68 mL, 34.22 mmol, 2.5 N in THF) was added at 0 ° C and reacted for 3 h. Saturated ammonium chloride solution (125 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (50 mL × 3). The ethyl acetate layer was combined, and the ethyl acetate layer was washed with water (25 mL × 2) and saturated NaCl aqueous solution (25 mL) in turn. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed on a silica gel column. Compound 16b (1.4 g, yield 36.64%) was obtained by chromatography.

LCMS m/z＝224.2[M+H]+ LCMS m/z＝224.2[M+H] +

第三步：16c的制备Step 3: Preparation of 16c

将16b(1.4g,6.27mmol)溶解于35mL甲苯中，依次加入2,6-二氟-4-羟基苯甲酸甲酯(1.42g,7.52mmol)，氰基亚甲基三正丁基膦(4.54g,18.81mmol)，氮气氛围下，100℃反应16小时。冷却至室温，减压浓缩后残余物用硅胶色谱柱柱层析即得目标化合物16c(1g，产率40.54％)。16b (1.4 g, 6.27 mmol) was dissolved in 35 mL of toluene, and methyl 2,6-difluoro-4-hydroxybenzoate (1.42 g, 7.52 mmol) and cyanomethylenetri-n-butylphosphine (4.54 g, 18.81 mmol) were added in sequence, and the mixture was reacted at 100°C for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain the target compound 16c (1 g, yield 40.54%).

LCMS m/z＝394.2[M+H]+ LCMS m/z＝394.2[M+H] +

第四步：16d的制备Step 4: Preparation of 16d

将16c(0.6g,1.53mmol)溶解于N-甲基吡咯烷酮(8mL)，依次加入2,4-二甲氧基苄胺(0.38g,2.29mmol)，无水碳酸铯(0.75g,2.29mmol)，80℃反应16小时。反应液冷却至室温，加入水(20mL)，用乙酸乙酯(20mL×2)萃取两次，合并有机相，有机相依次用水(20mL×2)洗两次、饱和NaCl的水溶液(20mL×1)洗一次，然后有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后残余物用硅胶色谱柱柱层析得化合物16d(0.429g，产率52.03％)。16c (0.6 g, 1.53 mmol) was dissolved in N-methylpyrrolidone (8 mL), and 2,4-dimethoxybenzylamine (0.38 g, 2.29 mmol) and anhydrous cesium carbonate (0.75 g, 2.29 mmol) were added in sequence, and the mixture was reacted at 80°C for 16 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL × 2). The organic phases were combined, and the organic phases were washed twice with water (20 mL × 2) and once with a saturated aqueous solution of NaCl (20 mL × 1). The organic phase was then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain compound 16d (0.429 g, yield 52.03%).

LCMS m/z＝541.4[M+H]+ LCMS m/z＝541.4[M+H] +

第五步：16e的制备Step 5: Preparation of 16e

将16d(0.429g,0.79mmol)溶解于二氯甲烷(10mL)，依次加入三乙基硅烷(0.28g,2.37mmol)，三氟乙酸(0.27g,2.37mmol)，室温下反应3小时。减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析即得化合物16e(0.3g，产率96.83％)。16d (0.429 g, 0.79 mmol) was dissolved in dichloromethane (10 mL), triethylsilane (0.28 g, 2.37 mmol) and trifluoroacetic acid (0.27 g, 2.37 mmol) were added in sequence, and the mixture was reacted at room temperature for 3 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was chromatographed on a silica gel column to obtain compound 16e (0.3 g, yield 96.83%).

LCMS m/z＝391.3[M+H]+ LCMS m/z＝391.3[M+H] +

第六步：16f的制备Step 6: Preparation of 16f

将16e(0.3g,0.77mmol)溶解于6mL 1,4-二氧六环中，依次加入氯乙腈(170mg,2.31mmol)、盐酸二氧六环溶液(0.5mL，4mol/L)，80℃反应4小时。反应液冷却至室温，减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析得到化合物16f(0.3g，产率89.99％)。16e (0.3 g, 0.77 mmol) was dissolved in 6 mL 1,4-dioxane, and chloroacetonitrile (170 mg, 2.31 mmol) and dioxane hydrochloride solution (0.5 mL, 4 mol/L) were added in sequence, and the mixture was reacted at 80°C for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and the residue was chromatographed on a silica gel column to obtain compound 16f (0.3 g, yield 89.99%).

LCMS m/z＝434.2[M+H]+ LCMS m/z＝434.2[M+H] +

第七步：化合物16的制备Step 7: Preparation of compound 16

将16f(0.3g,0.69mmol)溶解于4mL四氢呋喃中，依次加入中间体1(0.44g,2.76mmol)、氢氧化钠溶液(0.5mL，3N)，室温下反应3小时。减压浓缩除去反应溶剂，残余物用硅胶色谱柱柱层析得到化合物16(42mg，产率11.78％)。16f (0.3 g, 0.69 mmol) was dissolved in 4 mL of tetrahydrofuran, and intermediate 1 (0.44 g, 2.76 mmol) and sodium hydroxide solution (0.5 mL, 3N) were added in sequence, and the mixture was reacted at room temperature for 3 hours. The reaction solvent was removed by concentration under reduced pressure, and the residue was chromatographed on a silica gel column to obtain compound 16 (42 mg, yield 11.78%).

LCMS m/z＝516.4[M+H]+ LCMS m/z＝516.4[M+H] +

1H NMR(400MHz,CD3OD)δ6.89(d,1H),6.80(dd,1H),3.94-3.85(m,2H),3.72(s,2H),3.67(s,2H),3.47-3.38(m,2H),3.36-3.25(m,2H),3.08-2.99(m,1H),2.01-1.90(m,8H),1.75-1.64(m,6H),1.63-1.49(m,2H),0.79-0.72(m,2H),0.70-0.62(m,2H). 1 H NMR (400MHz, CD 3 OD)δ6.89(d,1H),6.80(dd,1H),3.94-3.85(m,2H),3.72(s,2H),3.67(s,2H),3.47-3.38(m,2H), 3.36-3.25(m,2H) ,3.08-2.99(m,1H),2.01-1.90(m,8H),1.75-1.64(m,6H),1.63-1.49(m,2H),0.79-0.72(m,2H),0.70-0.62( m,2H).

对照化合物1：
Control compound 1:

生物测试例Biological test cases

PARP14 ELISA活性测试实验PARP14 ELISA activity test

用ELISA方法测试化合物对PARP14的酶活性抑制实验。将50微升组蛋白(BPS,52029)用PBS(Solarbio，P1022)稀释后添加到384反应板(Greiner,781074)上4℃包被过夜。PBST(1XPBS+0.05％Tween-20)清洗后，添加200微升Blocking buffer(BPS,79743)于室温封闭90分钟。分别将PARP14(BPS,80514)与5微升受试化合物、生物素标记的底生物(BPS,78371)混合液添加384反应板中，混合液在PARP缓冲溶液(BPS,80602)中进行稀释，室温孵育1小时。PBST进行清洗，添加50微升辣根过氧化物酶标记链霉亲和素(BPS,80611)，室温孵育30分钟。PBST清洗板子，添加100微升ELISA底物A和底物B混合溶液(BPS,79670)，10分钟后用PHERAstar FSX BMG读取化学发光信号值。通过GraphPad Prism8.0软件中的抑制-剂量(四参数)方程进行IC50计算。The ELISA method was used to test the inhibitory effect of 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. IC50 was calculated using the inhibition-dose (four-parameter) equation in GraphPad Prism 8.0 software.

表1 PARP14激酶活性测试结果
Table 1 PARP14 kinase activity test results

注：表1中A：<30nM。Note: A in Table 1: <30nM.

结论：本发明化合物，例如实施例化合物对PARP14有抑制作用，具体的如化合物2、3、4、5、6、7、8、9、11、12、13、14、15和16对PARP14具有良好的抑制活性。Conclusion: The compounds of the present invention, such as the example compounds, have an inhibitory effect on PARP14. Specifically, compounds 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15 and 16 have good inhibitory activity on PARP14.

大鼠药代动力学测试Pharmacokinetic test in rats

试验动物：雄性SD大鼠，220g左右，6～8周龄，6只/化合物。购于成都达硕实验动物有限公司。Experimental animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

试验设计：试验当天，6只SD大鼠/化合物，按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。Experimental design: On the day of the experiment, 6 SD rats/compound were randomly divided into groups according to body weight. The rats were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.

给药信息
Dosing Information

注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.2％Tween 80+99.8％的0.5％MC。Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.2% Tween 80 + 99.8% 0.5% MC.

(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；0.5％MC：0.5％的甲基纤维素的水溶液。(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.

于给药前及给药后异氟烷麻醉经眼眶取血0.10mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为：0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after drug administration, 0.10 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

受试化合物大鼠要药代动力学结果
Pharmacokinetic results of test compounds in rats

结论：本发明化合物，例如实施例化合物在大鼠体内具有良好的药代动力学性能，具体的如化合物3在大鼠体内具有较好的口服吸收性能或/和清除率更低。Conclusion: The compounds of the present invention, such as the example compounds, have good pharmacokinetic properties in rats. Specifically, compound 3 has better oral absorption performance and/or lower clearance rate in rats.

小鼠药代动力学测试Mouse pharmacokinetic test

试验动物：雄性BALB/c小鼠，20～25g，6只/化合物。购于成都达硕实验动物有限公司。Experimental animals: Male BALB/c mice, 20-25 g, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

试验设计：试验当天，6只BALB/c小鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。
Experimental design: On the day of the experiment, six BALB/c mice were randomly divided into groups according to their body weight. They were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.

注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.2％Tween 80+99.8％的0.5％MC。Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.2% Tween 80 + 99.8% 0.5% MC.

(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；0.5％MC：0.5％的甲基纤维素的水溶液。)(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.)

于给药前及给药后异氟烷麻醉经眼眶取血0.06mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after drug administration, 0.06 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

结论：本发明化合物，例如实施例化合物在小鼠体内具有良好的药代动力学性能。 Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in mice.

比格犬药代动力学测试Beagle dog pharmacokinetic testing

试验动物：雄性比格犬，8～11kg左右，5-6只/化合物，购于北京玛斯生物技术有限公司。Experimental animals: Male beagle dogs, about 8-11 kg, 5-6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

试验方法：试验当天，比格犬5-6只/化合物按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。
Test method: On the test day, 5-6 beagle dogs/compound were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours one day before administration, and food was given 4 hours after administration.

注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.2％Tween 80+99.8％的0.5％MC。Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.2% Tween 80 + 99.8% 0.5% MC.

(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；0.5％MC：0.5％的甲基纤维素的水溶液。)(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.)

于给药前及给药后通过颈静脉或四肢静脉取血1ml，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。G1和G2组静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,10,12,24,48h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。Before and after administration, 1 ml of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group in the G1 and G2 groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

结论：本发明化合物，例如实施例化合物在比格犬体内具有较好的口服吸收性能。Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in beagle dogs.

猴药代动力学测试Monkey pharmacokinetic testing

试验动物：雄性食蟹猴，3～5kg，3～6年龄，4-6只/化合物。购于苏州西山生物技术有限公司。Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

试验方法：试验当天，猴4-6只/化合物按体重随机分组。给药前1天禁食不禁水14～18h，给药后4h给食。
Test method: On the test day, 4-6 monkeys/compound were randomly divided into groups according to body weight. The monkeys were fasted but not watered for 14-18 hours one day before administration and were fed 4 hours after administration.

注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.2％Tween 80+99.8％的0.5％MC。Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.2% Tween 80 + 99.8% 0.5% MC.

(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；0.5％MC：0.5％的甲基纤维素的水溶液。(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.

于给药前及给药后通过四肢静脉取血1.0mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5min,15min,30min,1,2,4,6,8,10,12,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。 Before and after administration, 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

结论：本发明化合物，例如实施例化合物在猴体内具有较好的口服吸收性能。Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in monkeys.

Caco2渗透性测试Caco2 permeability test

试验使用单层Caco-2细胞，在96孔Transwell板中采用三平行孵育。将含有本发明化合物(5μM)的转运缓冲溶液(HBSS，10mM HEPES，pH 7.4±0.05)加入顶端侧或基底侧的给药端孔中。对应接收端孔中加入含DMSO的转运缓冲溶液。在37±1℃条件下孵育2小时后，取出细胞板并从顶端和底端各取出适量样品至新的96孔板中。随后加入含内标的乙腈沉淀蛋白。使用LC MS/MS分析样品并测定本发明化合物和对照化合物的浓度。浓度数据用于计算从单层细胞顶端侧向基底侧、以及基底侧向顶端转运的表观渗透系数，从而计算外排率。用荧光黄的渗漏评价孵育2小时后单层细胞的完整性。The experiment used a monolayer of Caco-2 cells and three parallel incubations were performed in a 96-well Transwell plate. A transport buffer solution (HBSS, 10mM HEPES, pH 7.4±0.05) containing the compound of the present invention (5μM) was added to the dosing port hole on the apical side or the basolateral side. A transport buffer solution containing DMSO was added to the corresponding receiving port hole. After incubation at 37±1°C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate. Subsequently, acetonitrile containing an internal standard was added to precipitate the protein. The samples were analyzed using LC MS/MS and the concentrations of the compounds of the present invention and the control compounds were determined. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical side to the basolateral side of the monolayer cells and from the basolateral side to the apical side, thereby calculating the efflux rate. The integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.

本发明化合物的Caco2测试结果
Caco2 test results of the compounds of the present invention

结论：本发明化合物具有良好的Caco2渗透性，与对照化合物1相比较，例如化合物3具有更优异的渗透性和更低的外排率。Conclusion: The compounds of the present invention have good Caco2 permeability. Compared with the control compound 1, for example, compound 3 has better permeability and lower efflux rate.

肝微粒体稳定性测试Liver microsome stability test

本实验采用人、犬、大鼠和小鼠五种属肝微粒体作为体外模型来评价受试物的代谢稳定性。In this study, liver microsomes from five species, including humans, dogs, rats and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.

在37℃条件下，1μM的受试物与微粒体蛋白、辅酶NADPH共同孵育，反应至一定时间(5,10,20,30,60min)加入冰冷含内标的乙腈终止反应，采用LC-MS/MS方法检测样品中受试物浓度，以孵育体系中药物剩余率的ln值和孵育时间求得T1/2，并进一步计算肝微粒体固有清除率CLint(mic)和肝固有清除率CLint(Liver)。At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. After a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS/MS. T 1/2 was calculated by the ln value of the drug residual rate in the incubation system and the incubation time, and the liver microsomal intrinsic clearance CLint(mic) and liver intrinsic clearance CLint(Liver) were further calculated.

结论：本发明化合物，例如实施例化合物具有良好的肝微粒体代谢稳定性。 Conclusion: The compounds of the present invention, such as the compounds in the examples, have good metabolic stability in liver microsomes.

Claims (14)

一种通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
A compound represented by general formula (I) or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof,
Y1、Y2、Y3各自独立地选自N或CRy；Y 1 , Y 2 , and Y 3 are each independently selected from N or CR y ; R1选自C6-10芳基、5至10元杂芳基、非芳香的C3-12碳环基或者非芳香的4至12元杂环基，所述的芳基、杂芳基、碳环基或杂环基任选被1至4个R1a取代；R 1 is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, non-aromatic C 3-12 carbocyclyl or non-aromatic 4- to 12-membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R 1a ; L选自键、-O-、-S-、-NH-、-N(C1-4烷基)-、-O-C1-4亚烷基-、-NH-C1-4亚烷基-、-N(C1-4烷基)-C1-4亚烷基-、-C1-4亚烷基-，所说的亚烷基或烷基任选被1至4个Rk取代；L is selected from a bond, -O-, -S-, -NH-, -N(C 1-4 alkyl)-, -OC 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 being optionally substituted with 1 to 4 R k ; 环B选自C3-7环烷基、C8-12环烷基、4至10元杂环烷基、11至13元杂环烷基、11至13元杂环基、C6-10芳基、5至10元杂芳基；Ring B is selected from C 3-7 cycloalkyl, C 8-12 cycloalkyl, 4- to 10-membered heterocycloalkyl, 11- to 13-membered heterocycloalkyl, 11- to 13-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; R2选自H、-C(＝O)R2a、-NHC(＝O)R2a、-N(C1-6烷基)C(＝O)R2a、-S(＝O)2R2a、-NHS(＝O)2R2a、-C(＝S)R2a、-NHC(＝S)R2a、NHR2a、5至10元杂芳基、5至10元含内酰胺的杂环烷基、5至10元含脲基的杂环烷基，所述杂芳基、杂环烷基、烷基任选进一步被1至4个选自氘、卤素、OH、NH2、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6卤代烯基、C2-6炔基、C2-6卤代炔基的取代基取代；R 2 is selected from H, -C(＝O)R 2a , -NHC(＝O)R 2a , -N(C 1-6 alkyl)C(＝O)R 2a , -S(＝O) 2 R 2a , -NHS(＝O) 2 R 2a , -C(＝S)R 2a , -NHC(＝S)R 2a , NHR 2a , 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl containing lactam, 5- to 10-membered heterocycloalkyl containing urea, wherein the heteroaryl, heterocycloalkyl, alkyl is optionally further substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl; R2a选自C1-6烷基、C2-6烯基、C2-6炔基、-C0-4亚烷基-C3-12碳环基、-C0-4亚烷基-4至12元杂环基、-C1-6亚烷基-NHC(＝O)-C1-6亚烷基-NR2aaR2ab、-C1-6亚烷基-C(＝O)NR2aaR2ab、-C1-6亚烷基-NR2aaC(＝O)R2ab、-C1-6亚烷基-N(C1-6亚烷基)R2aa、-C1-6亚烷基-SR2ac、-C1-6亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C1-6亚烷基-R2ae、-C0-6亚烷基-C3-12碳环基-R2ae、-C0-6亚烷基-4至12元杂环基-R2ae，所述亚烷基或烷基任选被1至3个NH2取代，所述的烷基、烯基、炔基、亚烷基、碳环基、杂环基任选被1至4个Rk取代；R 2a is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-12 carbocyclyl, -C 0-4 alkylene-4 to 12-membered heterocyclyl, -C 1-6 alkylene-NHC(═O)-C 1-6 alkylene-NR 2aa R 2ab , -C 1-6 alkylene-C(═O)NR 2aa R 2ab , -C 1-6 alkylene-NR 2aa C(═O)R 2ab , -C 1-6 alkylene-N(C 1-6 alkylene)R 2aa , -C 1-6 alkylene-SR 2ac , -C 1-6 alkylene-NHC(═NR 2ad )NR 2aa R 2ab , -C 1-6 alkylene-R 2ae , -C 0-6 alkylene-C 3-12 carbocyclyl-R 2ae , -C 0-6 alkylene-4 to 12 membered heterocyclyl-R 2ae , the alkylene or alkyl group is optionally substituted by 1 to 3 NH 2 , and the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R k ; Q选自O、NRq、S、S(＝O)、S(＝O)2；Q is selected from O, NR q , S, S(═O), S(═O) 2 ; R3、R4各自独立地选自H、卤素、CN、OH、C1-6烷基、C2-6烯基、C2-6炔基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-4至7元杂环基，所述的烷基、烯基、炔基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；R 3 and R 4 are each 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 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ; 作为选择，R3与R4直接连接形成C3-6碳环基或4至7元杂环基，所述的碳环基或杂环基任选被1至4个Rk取代；Alternatively, R 3 and R 4 are directly linked to form a C 3-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ; R2aa、R2ab、R2ac、R2ad、Rq、R5各自独立地选自H、C1-6烷基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-4至7元杂环基，所述的烷基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-6 alkyl, -C 0-4 alkylene-C 3-6 carbocyclyl, and -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ; R2ae选自NHC1-6烷基、N(C1-6烷基)2、-NHC(＝O)-C1-6烷基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-4至7元杂环基，所述的烷基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；R 2ae is 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 carbocyclyl, -C 0-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ; Ry、R1a、Rb自独立地选自H、氘、卤素、OH、＝O、CN、NH2、NO2、COOH、CONH2、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、NHC1-6烷基、N(C1-6烷基)2、-O-C3-10碳环基、-O-4至10元杂环基、-NH-C3-10碳环基、-NH-4至10元杂环基、-S-C3-10碳环基、-S-4至10元杂 环基、-C0-4亚烷基-C3-10碳环基、-C0-4亚烷基-4至10元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；R y , R 1a , and R b are independently selected from H, deuterium, halogen, OH, ═O, CN, NH 2 , NO 2 , COOH, CONH 2 , 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 3-10 carbocyclyl, —O-4 to 10 membered heterocyclyl, —NH-C 3-10 carbocyclyl, —NH-4 to 10 membered heterocyclyl, —SC 3-10 carbocyclyl, —S-4 to 10 membered heterocyclyl Cycyl, -C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ; Rk各自独立的选自氘、卤素、OH、＝O、CN、NO2、COOH、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、-O-C3-6碳环基、-O-3至7元杂环基、-NH-C3-6碳环、-NH-3至7元杂环基、-S-C3-6碳环基、-S-3至7元杂环基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-3至7元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-6烷基、C1-6烷氧基的取代基所取代；R k is each independently selected from deuterium, halogen, OH, =O, CN, NO 2 , COOH, C 1-6 alkyl, OC 1-6 alkyl, SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -SC 3-6 carbocyclyl, -S-3 to 7 membered heterocyclyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-3 to 7 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy; n选自1、2或3；n is selected from 1, 2 or 3; m选自0、1、2、3或4；m is selected from 0, 1, 2, 3 or 4; 条件是当n选自1，Q选自S、S(＝O)、S(＝O)2，环B选自C3-7环烷基、4至10元杂环烷基、C6-10芳基、5至10元杂芳基，R1选自任选被1至4个R1a取代的非芳香的C3-12碳环基或者非芳香的4至12元杂环基时，满足如下条件之一：1)R2选自-C(＝O)R2a、-NHC(＝O)R2a、-N(C1-6烷基)C(＝O)R2a、-S(＝O)2R2a，R2a选自-C1-4亚烷基-NHC(＝O)-C1-4亚烷基-NR2aaR2ab、-C1-4亚烷基-C(＝O)NR2aaR2ab、-C1-6亚烷基-NR2aaC(＝O)R2ab、-C1-6亚烷基-N(C1-6亚烷基)R2aa、-C1-6亚烷基-R2ae、-C1-4亚烷基-SR2ac、-C1-4亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C0-4亚烷基-C3-12碳环基-R2ae、-C0-4亚烷基-4至12元杂环基-R2ae，所述亚烷基任选被NH2取代，所述的亚烷基、碳环基、杂环基任选被1至4个Rk取代；2)R2选自-C(＝S)R2a、-NHC(＝S)R2a；3)m选自1、2、3或4，至少有1个Rb为Rb1，Rb1选自C1-6烷基，所述烷基被1个选自氘、OH、＝O、CN、C1-6烷氧基的取代基所取代，所述烷基进一步任选被1至3个Rk取代。Provided that when n is selected from 1, Q is selected from S, S(=O), S(=O) 2 , Ring B is selected from C 3-7 cycloalkyl, 4 to 10 membered heterocycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, R 1 is selected from a non-aromatic C 3-12 carbocyclic group or a non-aromatic 4 to 12 membered heterocyclic group optionally substituted by 1 to 4 R 1a , one of the following conditions is satisfied: 1) R 2 is selected from -C(=O)R 2a , -NHC(=O)R 2a , -N(C 1-6 alkyl)C(=O)R 2a , -S(=O) 2 R 2a , R 2a is selected from -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 1-6 alkylene-NR 2aa C(＝O)R 2ab , -C 1-6 alkylene-N(C 1-6 alkylene)R 2aa , -C 1-6 alkylene-R 2ae , -C 1-4 alkylene-SR 2ac , -C 1-4 alkylene-NHC(＝NR 2ad )NR 2aa R 2ab , -C 0-4 alkylene-C 3-12 carbocyclyl-R 2ae , -C 0-4 alkylene-4 to 12 membered heterocyclyl-R 2ae , the alkylene is optionally substituted by NH 2 , and the alkylene, carbocyclyl and heterocyclyl are optionally substituted by 1 to 4 R k ; 2) R 2 is selected from -C(＝S)R 2a , -NHC(＝S)R 2a ; 3) m is selected from 1, 2, 3 or 4, at least one R b is R b1 , R b1 is selected from C 1-6 alkyl, the alkyl is substituted by one substituent selected from deuterium, OH, =O, CN, C 1-6 alkoxy, and the alkyl is further optionally substituted by 1 to 3 R k . 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 1 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R1选自任选被1至4个R1a取代的如下基团之一：苯基、萘基、5至6元杂芳基、8至10元并环杂芳基、C3-7单环烷基、C4-7单环烯基、C5-12并环烷基、C5-12螺环烷基、C5-12桥环烷基、4至7元单杂环烷基、6至12元并杂环烷基、6至12元螺杂环烷基、6至12元桥杂环烷基；R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : phenyl, naphthyl, 5 to 6 membered heteroaryl, 8 to 10 membered cycloheteroaryl, C 3-7 monocycloalkyl, C 4-7 monocycloalkenyl, 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; 环B选自C3-7环烷基、C8-12并环烷基、C8-12螺环烷基、C8-12桥环烷基、4至7元单杂环烷基、6至10元并杂环烷基、6至10元螺杂环烷基、6至10元桥杂环烷基、11至13元二环杂环烷基、11至13元三环杂环烷基、苯基、萘基、5至6元杂芳基、8至10元并环杂芳基、苯并C7-9环烷基、苯并7至9元杂环烷基、5至6元杂芳基并C7-9环烷基、5至6元杂芳基并7至9元杂环烷基；Ring B is selected from C3-7 cycloalkyl, C8-12 cycloalkyl, C8-12 spirocycloalkyl, C8-12 bridged cycloalkyl, 4 to 7 membered monoheterocycloalkyl, 6 to 10 membered cycloheterocycloalkyl, 6 to 10 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, benzoC7-9cycloalkyl , benzo7 to 9 membered heterocycloalkyl, 5 to 6 membered heteroaryl andC7-9cycloalkyl , 5 to 6 membered heteroaryl and7 to 9 membered heterocycloalkyl; R2选自H、-C(＝O)R2a、-NHC(＝O)R2a、-N(C1-4烷基)C(＝O)R2a、-S(＝O)2R2a、-NHS(＝O)2R2a、-C(＝S)R2a、-NHC(＝S)R2a、NHR2a、5至7元杂芳基、5至7元含内酰胺的杂环烷基、5至7元含脲基的杂环烷基，所述烷基、杂芳基、杂环烷基任选进一步被1至4个选自氘、卤素、OH、NH2、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C2-4卤代炔基的取代基取代； R2 is selected from H, -C(=O) R2a , -NHC(=O) R2a , -N( C1-4 alkyl)C(=O) R2a , -S(=O) 2R2a , -NHS(=O) 2R2a , -C(= S ) R2a , -NHC(=S) R2a , NHR2a , 5- to 7-membered heteroaryl, 5- to 7-membered heterocycloalkyl containing lactam, 5- to 7-membered heterocycloalkyl containing urea, wherein the alkyl, heteroaryl, heterocycloalkyl is optionally further substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2 , C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 haloalkenyl, C2-4 alkynyl, C2-4 haloalkynyl ; R2a选自C1-4烷基、C2-4烯基、C2-4炔基、-C0-4亚烷基-C3-6碳环基、-C0-4亚烷基-4至6元杂环基、-C1-4亚烷基-NHC(＝O)-C1-4亚烷基-NR2aaR2ab、-C1-4亚烷基-C(＝O)NR2aaR2ab、-C1-4亚烷基-NR2aaC(＝O)R2ab、-C1-4亚烷基-N(C1-4亚烷基)R2aa、-C1-4亚烷基-SR2ac、-C1-4亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C1-6亚烷基-R2ae、-C0-4亚烷基-C3-6碳环基-R2ae、-C0-4亚烷基-4至6元杂 环基-R2ae，所述烷基、亚烷基任选被1至3个NH2取代，所述的亚烷基、碳环基、杂环基任选被1至4个Rk取代；R 2a is selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -C 0-4 alkylene-C 3-6 carbocyclyl, -C 0-4 alkylene-4 to 6-membered heterocyclyl, -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-NR 2aa C(═O)R 2ab , -C 1-4 alkylene-N(C 1-4 alkylene)R 2aa , -C 1-4 alkylene-SR 2ac , -C 1-4 alkylene-NHC(═NR 2ad )NR 2aa R 2ab , -C 1-6 alkylene-R 2ae , -C 0-4 alkylene-C 3-6 carbocyclyl-R 2ae , -C 0-4 alkylene-4 to 6 membered hetero Cyclic group -R 2ae , the alkyl group or alkylene group may be substituted by 1 to 3 NH 2 groups, and the alkylene group, carbocyclic group or heterocyclic group may be substituted by 1 to 4 R k groups; R3、R4各自独立地选自H、卤素、CN、OH、C1-4烷基、C2-4烯基、C2-4炔基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至7元杂环基，所述的烷基、烯基、炔基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；R 3 and R 4 are each 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 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ; 作为选择，R3与R4直接连接形成C3-6碳环基或4至7元杂环基，所述的碳环基或杂环基任选被1至4个Rk取代；Alternatively, R 3 and R 4 are directly linked to form a C 3-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ; R2aa、R2ab、R2ac、R2ad、Rq、R5各自独立地选自H、C1-4烷基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至7元杂环基，所述的烷基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；R 2aa , R 2ab , R 2ac , R 2ad , R q , and R 5 are each independently selected from H, C 1-4 alkyl, -C 0-2 alkylene-C 3-6 carbocyclyl, and -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ; R2ae选自NHC1-4烷基、N(C1-4烷基)2、-NHC(＝O)-C1-4烷基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至7元杂环基，所述的烷基、亚烷基、碳环基或杂环基任选被1至4个Rk取代；R 2ae is 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 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ; Ry、R1a、Rb自独立地选自H、氘、卤素、OH、＝O、CN、NH2、NO2、COOH、CONH2、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-O-C3-6碳环基、-O-4至6元杂环基、-NH-C3-6碳环基、-NH-4至6元杂环基、-S-C3-6碳环基、-S-4至6元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-4至6元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个Rk取代；R y , R 1a , R b are independently selected from H, deuterium, halogen, OH, ＝O, CN, NH 2 , NO 2 , COOH, CONH 2 , C 1-4 alkyl, OC 1-4 alkyl, 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 carbocyclyl, -O-4 to 6 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-4 to 6 membered heterocyclyl, -SC 3-6 carbocyclyl, -S-4 to 6 membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ; Rk各自独立的选自氘、卤素、OH、＝O、CN、NO2、COOH、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、-O-C3-6碳环基、-O-3至7元杂环基、-NH-C3-6碳环、-NH-3至7元杂环基、-S-C3-6碳环基、-S-3至7元杂环基、-C0-2亚烷基-C3-6碳环基、-C0-2亚烷基-3至7元杂环基，所述的烷基、亚烷基、烯基、炔基、碳环基或杂环基任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代。R k is each independently selected from deuterium, halogen, OH, =O, CN, NO 2 , COOH, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -NH-C 3-6 carbocyclyl, -NH-3 to 7 membered heterocyclyl, -SC 3-6 carbocyclyl, -S-3 to 7 membered heterocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-3 to 7 membered heterocyclyl, and the alkyl, alkylene, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy. 根据权利要求2所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 2 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R1选自任选被1至4个R1a取代的如下基团之一：苯基、萘基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、异喹唑啉基、吡啶并吡唑基、吡啶并咪唑基、吡啶并呋喃基、吡啶并噻吩基、吡啶并噁唑基、吡啶并噻唑基、嘧啶并吡唑基、嘧啶并咪唑基、嘧啶并呋喃基、嘧啶并噻吩基、嘧啶并噁唑基、嘧啶并噻唑基、环丙基、环丁基、环戊基、环己基、环己烯基、苯基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丙基并氧杂环丁基、环丙基并四氢呋喃基、环丙基并四氢吡喃基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环丁基并氧杂环丁基、环丁基并四氢呋喃基、环丁基并四氢吡喃基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环戊基并氧杂环丁基、环戊基并四氢呋喃基、环戊基并四氢吡喃基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、环己基并氧杂环丁基、环己基并四氢呋喃基、 环己基并四氢吡喃基、环丙基螺氮杂环丁基、环丙基螺吡咯烷基、环丙基螺哌啶基、环丙基螺氧杂环丁基、环丙基螺四氢呋喃基、环丙基螺四氢吡喃基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环丁基螺氧杂环丁基、环丁基螺四氢呋喃基、环丁基螺四氢吡喃基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环戊基螺氧杂环丁基、环戊基螺四氢呋喃基、环戊基螺四氢吡喃基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、环己基螺氧杂环丁基、环己基螺四氢呋喃基、环己基螺四氢吡喃基、氮杂环己基螺氮杂环己基、氮杂环戊基螺氮杂环己基、氮杂环戊基螺氮杂环戊基、氮杂环己基并氮杂环己基、氮杂环戊基并氮杂环己基、氮杂环戊基并氮杂环戊基、双环[1.1.1]戊烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.1.1]庚烷基、金刚烷基、 R 1 is selected from one of the following groups optionally substituted with 1 to 4 R 1a : 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, cyclo propyltetrahydrofuranyl, cyclopropyltetrahydropyranyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclobutyloxetanyl, cyclobutyltetrahydrofuranyl, cyclobutyltetrahydropyranyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclopentyloxetanyl, cyclopentyltetrahydrofuranyl, cyclopentyltetrahydropyranyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, cyclohexyloxetanyl, cyclohexyltetrahydrofuranyl, Cyclohexyltetrahydropyranyl, 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 cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, cyclohexylspirooxetanyl, cyclohexylspirotetrahydrofuranyl, cyclohexylspirotetrahydropyranyl, azacyclohexylspiroazacyclohexyl, azacyclopentylspiroazacyclohexyl, azacyclopentylspiroazacyclopentyl, azacyclohexylazacyclohexyl, azacyclopentylazacyclohexyl, azacyclopentylazacyclohexyl, azacyclopentylazacyclohexyl, azacyclopentylazacyclopentyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.1]heptanyl, adamantyl, 环B选自苯基、萘基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、异喹唑啉基、吡啶并吡唑基、吡啶并咪唑基、吡啶并呋喃基、吡啶并噻吩基、吡啶并噁唑基、吡啶并噻唑基、嘧啶并吡唑基、嘧啶并咪唑基、嘧啶并呋喃基、嘧啶并噻吩基、嘧啶并噁唑基、嘧啶并噻唑基、 环丙基、环丁基、环戊基、环己基、环己烯基、苯基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、氧杂环丁基、四氢呋喃基、四氢吡喃基、环丙基并环丙基、环丙基并环丁基、环丙基并环戊基、环丙基并环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丙基并氮杂环丁基、环丙基并吡咯烷基、环丙基并哌啶基、环丙基并氧杂环丁基、环丙基并四氢呋喃基、环丙基并四氢吡喃基、环丁基并氮杂环丁基、环丁基并吡咯烷基、环丁基并哌啶基、环丁基并氧杂环丁基、环丁基并四氢呋喃基、环丁基并四氢吡喃基、环戊基并氮杂环丁基、环戊基并吡咯烷基、环戊基并哌啶基、环戊基并氧杂环丁基、环戊基并四氢呋喃基、环戊基并四氢吡喃基、环己基并氮杂环丁基、环己基并吡咯烷基、环己基并哌啶基、环己基并氧杂环丁基、环己基并四氢呋喃基、环己基并四氢吡喃基、环丙基螺氮杂环丁基、环丙基螺吡咯烷基、环丙基螺哌啶基、环丙基螺氧杂环丁基、环丙基螺四氢呋喃基、环丙基螺四氢吡喃基、环丁基螺氮杂环丁基、环丁基螺吡咯烷基、环丁基螺哌啶基、环丁基螺氧杂环丁基、环丁基螺四氢呋喃基、环丁基螺四氢吡喃基、环戊基螺氮杂环丁基、环戊基螺吡咯烷基、环戊基螺哌啶基、环戊基螺氧杂环丁基、环戊基螺四氢呋喃基、环戊基螺四氢吡喃基、环己基螺氮杂环丁基、环己基螺吡咯烷基、环己基螺哌啶基、环己基螺氧杂环丁基、环己基螺四氢呋喃基、环己基螺四氢吡喃基、氮杂环己基螺氮杂环己基、氮杂环戊基螺氮杂环己基、氮杂环戊基螺氮杂环戊基、氮杂环己基并氮杂环己基、氮杂环戊基并氮杂环己基、氮杂环戊基并氮杂环戊基、氮杂环己基螺四氢吡喃基、双环[1.1.1]戊烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.1.1]庚烷基、金刚烷基、 Ring B is selected from 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, cyclopropyltetra ... cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclopropyloxetanyl, cyclopropyltetrahydrofuranyl, cyclopropylcyclopropyl furanyl, cyclopropyltetrahydropyranyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclobutyloxetanyl, cyclobutyltetrahydrofuranyl, cyclobutyltetrahydropyranyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclopentyloxetanyl, cyclopentyltetrahydrofuranyl, cyclopentyltetrahydropyranyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, cyclohexyloxetanyl, cyclohexyltetrahydrofuranyl, cyclohexyltetrahydropyranyl, 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 spiroazetidinyl, cyclohexyl spiropyrrolidinyl, cyclohexylspiropiperidinyl, cyclohexylspiroxetanyl, cyclohexylspirotetrahydrofuranyl, cyclohexylspirotetrahydropyranyl, azacyclohexylspiroazacyclohexyl, 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, R2选自H、-C(＝O)R2a、-NHC(＝O)R2a、-N(CH3)C(＝O)R2a、-N(CH2CH3)C(＝O)R2a、-S(＝O)2R2a、-NHS(＝O)2R2a、-C(＝S)R2a、-NHC(＝S)R2a、NHR2a、5元杂芳基、6元杂芳基、5元含内酰胺的杂环烷基、6元含内酰胺的杂环烷基、7元含内酰胺的杂环烷基、咪唑烷酮基、四氢-2-嘧啶酮基，所述CH3、CH2、杂芳基、杂环烷基、咪唑烷酮基、四氢-2-嘧啶酮基任选进一步被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代； R2 is selected from H, -C(=O) R2a , -NHC(=O) R2a , -N ( CH3 )C(=O) R2a , -N( CH2CH3 )C(=O) R2a , -S(=O )2R2a , -NHS(=O) 2R2a , -C(=S ) R2a , -NHC(=S) R2a , NHR2a , 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl containing lactam, 6-membered heterocycloalkyl containing lactam, 7-membered heterocycloalkyl containing lactam, imidazolidinone, tetrahydro-2-pyrimidone, wherein CH3 , CH2 , heteroaryl, heterocycloalkyl, imidazolidinone, tetrahydro-2-pyrimidone, optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl; R2a选自任选被1至4个Rk取代的如下基团之一：甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-吡咯烷基、-CH2-哌啶基、-CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2CH2CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2CH2CH2CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2CH2CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2CH2CH2CH2-NHC(＝O)-CH2CH2-NR2aaR2ab、-CH2-C(＝O)NR2aaR2ab、-CH2CH2-C(＝O)NR2aaR2ab、-CH2CH2CH2-C(＝O)NR2aaR2ab、-CH2CH2CH2CH2-C(＝O)NR2aaR2ab、-CH2-SR2ac、-CH2CH2-SR2ac、-CH2CH2CH2-SR2ac、-CH2CH2CH2CH2-SR2ac、-CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2-R2ae、-CH2CH2-R2ae、-CH2CH2CH2-R2ae、-CH2CH2CH2CH2-R2ae、-CH2CH2CH2CH2CH2-R2ae、-CH2-NR2aaC(＝O)R2ab、-CH2CH2CH2CH2-NR2aaC(＝O)R2ab、-CH2-N(甲基)R2aa、-CH2CH2-NR2aaC(＝O)R2ab、-CH2CH2CH2-NR2aaC(＝O)R2ab、-CH2CH2CH2CH2-N(甲基)R2aa、-CH2CH2CH2-N(甲基)R2aa、-CH2CH2-N(甲基)R2aa、-CH2CH2CH2-N(乙基)R2aa、-CH2CH2CH2CH2-N(乙基)R2aa-、-CH2CH2-N(乙基)R2aa、-CH2-N(乙基)R2aa、-环丙基-R2ae、-环丁基-R2ae、-环戊基-R2ae、-环己基-R2ae、-氮杂环丁基-R2ae、-吡咯烷基-R2ae、-哌啶基-R2ae，所述的甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、CH2任选被1至3个NH2取代；R 2a is selected from one of the following groups optionally substituted with 1 to 4 R k : methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 -NHC (＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(＝O)-CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(=O)-CH 2 -NR 2aa R 2ab , -CH 2 -NHC(=O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 -NHC(=O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC(=O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 CH 2 CH 2 CH 2 -NHC(=O)-CH 2 CH 2 -NR 2aa R 2ab , -CH 2 -C(=O)NR 2aa R 2ab , -CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH 2 CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH 2 CH 2 CH 2 CH 2 -C(=O)NR 2aa R 2ab , -CH 2 -SR 2ac , -CH 2 CH 2 -SR 2ac , -CH 2 CH 2 CH 2 -SR 2ac , -CH 2 CH 2 CH 2 CH 2 -SR 2ac , -CH 2 -NHC(=NR 2ad )NR 2aa R 2ab , -CH 2 CH 2 -NHC(=NR 2ad )NR 2aa R 2ab , -CH 2 CH 2 CH 2 -NHC (＝NR 2ad )NR 2aa R 2ab , -CH 2 CH 2 CH 2 CH 2 -NHC (＝NR 2ad )NR 2aa R 2ab , -CH 2 -R 2ae , -CH 2 CH 2 -R 2ae , -CH 2 CH 2 CH 2 -R 2ae ,-CH -R 2ae , -CH 2 CH 2 CH 2 CH 2 CH 2 -R 2ae , -CH 2 -NR 2aa C ( ═O)R 2ab , -CH 2 CH 2 CH 2 CH 2 -NR 2aa C(═O)R 2ab , -CH 2 -N(methyl) R 2aa , -CH 2 CH 2 -NR 2aa C(═O)R 2ab , -CH 2 CH 2 -NR 2aa C(═O)R 2ab , -CH 2 CH 2 CH 2 -NR 2aa C(═O)R 2ab , -CH 2 CH 2 CH 2 -N(methyl)R 2aa , -CH 2 CH 2 CH 2 -N ( methyl )R 2aa , -CH 2 CH 2 CH 2 -N(methyl)R 2aa , -CH 2 CH 2 -N(methyl)R 2aa , -CH 2 CH 2 CH 2 -N(ethyl)R 2aa , -CH 2 CH 2 CH 2 CH 2 -N(ethyl)R 2aa -, -CH 2 CH 2 -N(ethyl)R 2aa , -CH 2 -N(ethyl)R 2aa , -cyclopropyl-R 2ae , -cyclobutyl-R 2ae , -cyclopentyl-R 2ae , -cyclohexyl-R 2ae , -azetidinyl-R 2ae , -pyrrolidinyl-R 2ae , -piperidinyl-R 2ae , the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, CH 2 are optionally substituted by 1 to 3 NH 2 ; R2aa、R2ab、R2ac、R2ad各自独立地选自H、甲基、乙基、CF3、-CH2-环丙基、环丙基；R 2aa , R 2ab , R 2ac , R 2ad are each independently selected from H, methyl, ethyl, CF 3 , -CH 2 -cyclopropyl, cyclopropyl; R2ae选自-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH2CH3)2、-NHC(＝O)-CH3、-NHC(＝O)-CH2CH3、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、哌嗪基、氧杂环丁基、四氢呋喃基、四氢吡喃基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、-CH2-环丙基、-CH2-环丁基、-CH2-环戊基、-CH2-环己基、-CH2-氮杂环丁基、-CH2-吡咯烷基、-CH2-哌啶基、-CH2-吗啉基、-CH2-哌嗪基、-CH2-氧杂环丁基、-CH2-四氢呋喃基、-CH2-四氢吡喃基，所述的-CH2-、甲基、乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、吗啉基、哌嗪基、氧杂环丁基、四氢呋喃基、四氢吡喃基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、 哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基任选被1至4个Rk取代； R2ae is selected from the group consisting of -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, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, -CH2 -cyclopropyl, -CH2 -cyclobutyl, -CH2 -cyclopentyl, -CH2 -cyclohexyl, -CH2 -azetidinyl, -CH2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -morpholinyl, -CH 2 -piperazinyl, -CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 -tetrahydropyranyl, the -CH 2 -, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, Pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl are optionally substituted with 1 to 4 R k ; Rq、R5各自独立地选自H或甲基；R q , R 5 are each independently selected from H or methyl; Ry、R1a、Rb各自独立地选自H、氘、F、Cl、Br、I、CN、OH、＝O、甲基、乙基、乙烯基、乙炔基、丙炔基、甲氧基、乙氧基、环丙基、-CH2-环丙基，所述的-CH2-、甲基、乙基、乙烯基、乙炔基、甲氧基、乙氧基、丙炔基、环丙基任选被1至4个Rk取代；R y , R 1a , and R b are each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, ═O, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, and —CH 2 -cyclopropyl, wherein the —CH 2 -, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, propynyl, and cyclopropyl are optionally substituted by 1 to 4 R k ; Rb1选自甲基、乙基、丙基、异丙基，所述的甲基、乙基、丙基、异丙基被1个选自氘、OH、＝O、CN、甲氧基、乙氧基的取代基所取代，所述的甲基、乙基、丙基、异丙基进一步任选被1至3个Rk取代；R b1 is selected from methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is substituted by one substituent selected from deuterium, OH, =O, CN, methoxy, ethoxy, and the methyl, ethyl, propyl, isopropyl is further optionally substituted by 1 to 3 R k ; R3、R4各自独立地选自H、F、Cl、Br、I、CN、OH、甲基、乙基、环丙基、-CH2-环丙基，所述的-CH2-、甲基、乙基、环丙基任选被1至4个Rk取代；R 3 and R 4 are each independently selected from H, F, Cl, Br, I, CN, OH, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl, wherein the -CH 2 -, methyl, ethyl, cyclopropyl is optionally substituted by 1 to 4 R k ; 作为选择，R3与R4直接连接形成环丙基、环丁基、环戊基或环己基，所述的环丙基、环丁基、环戊基或环己基任选被1至4个Rk取代；Alternatively, R 3 and R 4 are directly linked to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted by 1 to 4 R k ; Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、COOH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基，所述的甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基任选被1至4个选自氘、F、Cl、Br、I、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代。R k is each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy. 根据权利要求3所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 3 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L选自键、-O-、-S-、-NH-、-OCH2-、-OCH2CH2-、-OCH2CH2CH2-、-NHCH2-、-NHCH2CH2-、-NHCH2CH2CH2-，所述的-CH2-任选被1至4个Rk取代；L is selected from a bond, -O-, -S-, -NH-, -OCH2- , -OCH2CH2- , -OCH2CH2CH2- , -NHCH2-, -NHCH2CH2-, -NHCH2CH2- , -NHCH2CH2CH2- , said -CH2- being optionally substituted with 1 to 4 Rk ; Q选自O、NH或S；Q is selected from O, NH or S; R3、R4各自独立地选自H、F或甲基；R 3 and R 4 are each independently selected from H, F or methyl; R5选自H； R5 is selected from H; R1选自任选被1至4个R1a取代的如下基团之一： R 1 is selected from one of the following groups optionally substituted by 1 to 4 R 1a : R2选自H、-C(＝O)R2a、-NHC(＝O)R2a、-N(CH3)C(＝O)R2a、-N(CH2CH3)C(＝O)R2a、-S(＝O)2R2a、-NHS(＝O)2R2a、-C(＝S)R2a、-NHC(＝S)R2a、NHR2a、吡咯基、吡唑基、咪唑基、噁唑基、噁二唑基、三唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、所述CH2、CH3、吡咯基、吡唑基、咪唑基、 噁唑基、噁二唑基、三唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、任选进一步被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代； R2 is selected from H, -C(=O) R2a , -NHC(=O) R2a , -N ( CH3 )C(=O) R2a , -N ( CH2CH3 )C(=O) R2a , -S(=O) 2R2a , -NHS(=O) 2R2a , -C(=S) R2a , -NHC(=S) R2a , NHR2a, pyrrolyl, pyrazolyl , imidazolyl, oxazolyl , oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, The CH 2 , CH 3 , pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl; R2a选自甲基、乙基、氮杂环丁基、吡咯烷基、哌啶基、-CH2-NHC(＝O)-CH2-NR2aaR2ab、-CH(NH2)-CH2-SR2ac、-CH(NH2)-CH2CH2-SR2ac、-CH(NH2)-CH2-C(＝O)NR2aaR2ab、-CH(NH2)-CH2CH2-C(＝O)NR2aaR2ab、-CH(NH2)-CH2-NHC(＝NR2ad)NR2aaR2ab、-CH(NH2)-CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2CH2CH2-R2ae、-CH(NH2)-CH2CH2CH2-NHC(＝NR2ad)NR2aaR2ab、-CH2-R2ae、-CH2CH2-R2ae、-CH2CH2CH2CH2-R2ae、-CH2CH2CH2CH2CH2-R2ae、-CH(NH2)CH2CH2CH2CH2-R2ae、-环丙基-R2ae、-环丁基-R2ae、-环戊基-R2ae、-环己基-R2ae、-氮杂环丁基-R2ae、-吡咯烷基-R2ae、-哌啶基-R2ae，所述的甲基或乙基任选被1至2个NH2取代；R 2a is selected from methyl, ethyl, azetidinyl, pyrrolidinyl, piperidinyl, -CH 2 -NHC(═O)-CH 2 -NR 2aa R 2ab , -CH(NH 2 )-CH 2 -SR 2ac , -CH(NH 2 )-CH 2 CH 2 -SR 2ac , -CH(NH 2 )-CH 2 -C(═O)NR 2aa R 2ab , -CH(NH 2 )-CH 2 CH 2 -C(═O)NR 2aa R 2ab , -CH(NH 2 )-CH 2 -NHC(═NR 2ad )NR 2aa R 2ab , -CH(NH 2 )-CH 2 CH 2 -NHC(═NR 2ad )NR 2aa R 2ab , -CH(NH 2 )-CH 2 CH 2 -NHC(═NR 2ad )NR 2aa R 2ab , -CH 2 CH 2 CH 2 -R 2ae , -CH(NH 2 )-CH2CH2CH2- NHC (＝ NR2ad ) NR2aaR2ab , -CH2 - R2ae , -CH2CH2 - R2ae , -CH2CH2CH2CH2 -R2ae , -CH2CH2CH2CH2CH2 - R2ae , -CH ( NH2 ) CH2CH2CH2CH2CH2- R2ae , -cyclopropyl - R2ae , -cyclobutyl - R2ae , -cyclopentyl - R2ae , -cyclohexyl- R2ae , -azetidinyl- R2ae , -pyrrolidinyl- R2ae , -piperidinyl- R2ae , the methyl or ethyl group is optionally substituted by 1 to 2 NH2 ; R2aa、R2ab、R2ac、R2ad各自独立地选自H、甲基、乙基；R 2aa , R 2ab , R 2ac , and R 2ad are each independently selected from H, methyl, and ethyl; R2ae选自-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH2CH3)2、-NHC(＝O)-CH3、-NHC(＝O)-CH2CH3、环丙基、环丁基、吡唑基、咪唑基；R 2ae is selected from -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -NHC(=O)-CH 3 , -NHC(=O)-CH 2 CH 3 , cyclopropyl, cyclobutyl, pyrazolyl, imidazolyl; Rb1选自-CH2OH、-CH2-OCH3、-CH2CN；R b1 is selected from -CH 2 OH, -CH 2 -OCH 3 , -CH 2 CN; Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、炔丙基、环丙基。R k is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, and cyclopropyl. 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，通式(I)所示化合物选自通式(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)所示化合物，
The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia), (Ib), (Ic), (Id), (Ie) and (If),
R2A选自-C(＝S)R2a、-NHC(＝S)R2a、-C(＝O)R2af、-NHC(＝O)R2af；R 2A is selected from -C(=S)R 2a , -NHC(=S)R 2a , -C(=O)R 2af , -NHC(=O)R 2af ; R2af选自-C1-4亚烷基-NHC(＝O)-C1-4亚烷基-NR2aaR2ab、-C1-4亚烷基-C(＝O)NR2aaR2ab、-C1-4亚 烷基-SR2ac、-C1-4亚烷基-NHC(＝NR2ad)NR2aaR2ab、-C1-4亚烷基-R2ae、-C0-4亚烷基-C3-12碳环基-R2ae、-C0-4亚烷基-4至12元杂环基-R2ae，所述亚烷基任选被NH2取代，所述的烷基、亚烷基、碳环基、杂环基任选被1至4个Rk取代；R 2af is selected from -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- Alkyl-SR 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 heterocyclyl-R 2ae , the alkylene is optionally substituted by NH 2 , and the alkyl, alkylene, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R k ; R1A选自C6-10芳基、5至10元杂芳基，所述的芳基或杂芳基任选被1至4个R1a取代；R 1A is selected from C 6-10 aryl, 5 to 10 membered heteroaryl, said aryl or heteroaryl being optionally substituted by 1 to 4 R 1a ; Q1选自O或NH；Q 1 is selected from O or NH; 环B1选自C8-12环烷基、11至13元杂环基或11至13元杂环烷基；Ring B1 is selected from C8-12 cycloalkyl, 11 to 13 membered heterocyclyl or 11 to 13 membered heterocycloalkyl; m1选自0、1、2或3；m1 is selected from 0, 1, 2 or 3; p选自2或3；p is selected from 2 or 3; 其余基团定义与权利要求1相同。The remaining groups are defined the same as in claim 1. 根据权利要求5所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，The compound according to claim 5 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, R2A选自 R 2A is selected from 环B1选自 Ring B 1 is selected from R1A选自任选被1至4个R1a取代的如下基团之一：苯基、萘基、吡咯基、吡唑基、咪唑基、三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基、异喹唑啉基、吡啶并吡唑基、吡啶并咪唑基、吡啶并呋喃基、吡啶并噻吩基、吡啶并噁唑基、吡啶并噻唑基、嘧啶并吡唑基、嘧啶并咪唑基、嘧啶并呋喃基、嘧啶并噻吩基、嘧啶并噁唑基、嘧啶并噻唑基、 R 1A is selected from one of the following groups optionally substituted with 1 to 4 R 1a : 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, 其余基团定义与权利要求2-4任一项相同。The remaining groups are defined the same as in any one of claims 2 to 4. 根据权利要求6所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound according to claim 6 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L选自-OCH2-；L is selected from -OCH 2 -; R2选自 或R2A；R 2 is selected from or R 2A ; R1选自R1A或任选被1至4个R1a取代的 R 1 is selected from R 1A or R 1A optionally substituted by 1 to 4 R 1A 环B选自或环B1，且左侧与L直接连接。Ring B is selected from Or ring B 1 , and the left side is directly connected to L. 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，通式(I)所示化合物选自通式(I-h)、(I-I)所示化合物，

The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the compounds represented by general formula (Ih) and (II),

环B2选自C8-12桥环烷基或6至10元螺杂环烷基，优选地，环B2选自 左侧与亚甲基相连；Ring B2 is selected from C8-12 bridged cycloalkyl or 6 to 10 membered spiro heterocycloalkyl, preferably, Ring B2 is selected from The left side is connected to the methylene group; Rb选自H、氘、卤素、甲基、CF3、CHF2、CH2F、CD3、CHD2、CH2D；R b is selected from H, deuterium, halogen, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D; Ry选自F、Cl、Br、甲基、CF3、CHF2、CH2F、CD3、CHD2、CH2D；R y is selected from F, Cl, Br, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D; R2B选自-C(＝O)C1-3烷基、-NHC(＝O)-C1-3烷基、-NHC(＝O)-C3-6环烷基、-N(C1-2烷基)C(＝O)-C1-3烷基、-N(C1-2烷基)C(＝O)-C3-6环烷基、5至6元杂芳基、5至6元含内酰胺的杂环烷基，所述R2B任选进一步被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代；R 2B is selected from -C(＝O)C 1-3 alkyl, -NHC(＝O)-C 1-3 alkyl, -NHC(＝O)-C 3-6 cycloalkyl, -N(C 1-2 alkyl)C(＝O)-C 1-3 alkyl, -N(C 1-2 alkyl)C(＝O)-C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, 5- to 6-membered lactam-containing heterocycloalkyl, said R 2B is optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl; 优选地，R2B选自-C(＝O)-甲基、-C(＝O)-乙基、-NHC(＝O)-甲基、-NHC(＝O)-乙基、-NHC(＝O)-环丙基、-NHC(＝O)-环丁基、-NHC(＝O)-环戊基、-NHC(＝O)-环己基、-N(CH3)C(＝O)-甲基、-N(CH3)C(＝O)-环丙基、吡咯基、吡唑基、咪唑基、噁唑基、噁二唑基、三唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基，所述R2B任选进一步被1至4个选自氘、F、Cl、Br、I、甲基、乙基、CF3、CHF2、CH2F的取代基取代；Preferably, R 2B is selected from -C(=O)-methyl, -C(=O)-ethyl, -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl, -NHC(=O)-cyclohexyl, -N(CH 3 )C(=O)-methyl, -N(CH 3 )C(=O)-cyclopropyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, said R 2B is optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, methyl, ethyl, CF 3 , CHF 2 , CH 2 F; 更优选地，R2B选自 More preferably, R 2B is selected from R2C选自-C(＝S)C1-3烷基、-C(＝O)N(C1-3烷基)2、-C(＝O)-C1-4亚烷基-NHC(＝NH)NH2、-C(＝O)-C1-4亚烷基-C(＝O)NH2、-C(＝O)-C1-4亚烷基-NHC(＝O)C1-3烷基，所述亚烷基任选被NH2取代，所述烷基、亚烷基任选被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代； R2C is selected from -C(＝S) C1-3alkyl , -C(＝O)N( C1-3alkyl ) 2 , -C(＝O)-C1-4alkylene-NHC(＝ NH ) NH2 , -C(＝O)-C1-4alkylene- C (＝O) NH2 , -C(＝O)-C1-4alkylene- NHC (＝O) C1-3alkyl , the alkylene is optionally substituted with NH2 , the alkyl and alkylene are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF3 , CHF2 , CH2F , vinyl, ethynyl; 优选地，R2C选自-C(＝S)-甲基、-C(＝S)-乙基、-C(＝O)N(甲基)2、-C(＝O)N(乙基)2、-C(＝O)-CH2CH2CH2CH2-NHC(＝NH)NH2、-C(＝O)-CH2CH2CH2-NHC(＝NH)NH2、-C(＝O)-CH2CH2-NHC(＝NH)NH2、-C(＝O)-CH2CH2CH2CH2-C(＝O)NH2、-C(＝O)-CH2CH2CH2-C(＝O)NH2、-C(＝O)-CH2CH2-C(＝O)NH2、-C(＝O)-CH2CH2CH2CH2-NHC(＝O)-甲基、-C(＝O)-CH2CH2CH2CH2-NHC(＝O)-乙基、-C(＝O)-CH2CH2CH2-NHC(＝O)-甲基、-C(＝O)-CH2CH2CH2-NHC(＝O)-乙基、-C(＝O)-CH2CH2-NHC(＝O)-甲基、-C(＝O)-CH2CH2-NHC(＝O)-乙基，所述CH2任选被NH2取代，所述甲基、乙基、CH2任选被1至4个选自氘、F、Cl、Br、I、 OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代；Preferably, R2C is selected from -C(＝S)-methyl, -C(＝S)-ethyl, -C(＝O)N(methyl) 2 , -C(＝O)N( ethyl ) 2 , -C(＝O) -CH2CH2CH2CH2 - NHC ( ＝ NH) NH2 , -C(＝O)-CH2CH2CH2-NHC(＝NH ) NH2 , -C( ＝ O ) -CH2CH2CH2- NHC (＝ NH ) NH2 , -C(＝O)-CH2CH2CH2-NHC(＝ NH ) NH2 , -C(＝O)-CH2CH2CH2CH2- C (＝O) NH2 , -C(＝O)-CH2CH2CH2CH2 -C (＝O) NH2 , -C(＝O)-CH2CH2CH2- C (＝O) NH2 , -C ( ＝O)-CH2CH2CH2- C (＝O) NH2 , -C(＝ O ) -CH2CH2CH2CH2 -NHC(＝O)-methyl, -C(＝O)-CH 2 CH 2 CH 2 CH 2 -NHC(＝O)-ethyl, -C(＝O)-CH 2 CH 2 CH 2 -NHC(＝O)-methyl, -C(＝O)-CH 2 CH 2 CH 2 -NHC(＝O)-ethyl, -C(＝O)-CH 2 CH 2 -NHC(＝O)-methyl, -C(＝O)-CH 2 CH 2 -NHC(＝O)-ethyl, -C(＝O)-CH 2 CH 2 -NHC(＝O)-methyl, -C(＝O)-CH 2 CH 2 -NHC(＝O)-ethyl, the CH 2 is optionally substituted with NH 2 , the methyl, ethyl, CH 2 is optionally substituted with 1 to 4 atoms selected from deuterium, F, Cl, Br, I, Substitution with OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl; 更优选地，R2C选自 More preferably, R 2C is selected from 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，通式(I)所示化合物选自通式(I-J)所示化合物，
The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the compound represented by general formula (IJ),
Ry选自F、Cl、Br、甲基、CF3、CHF2、CH2F、CD3、CHD2、CH2D；R y is selected from F, Cl, Br, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D; R3B选自-NHC(＝O)-C1-3烷基、-NHC(＝O)-C3-6环烷基、-N(C1-2烷基)C(＝O)-C1-3烷基、5至6元杂芳基、5至6元含内酰胺的杂环烷基，所述R2B任选进一步被1至4个选自氘、F、Cl、Br、I、OH、NH2、甲基、乙基、异丙基、丁基、异丁基、CF3、CHF2、CH2F、乙烯基、乙炔基的取代基取代；R 3B is selected from -NHC(=O)-C 1-3 alkyl, -NHC(=O)-C 3-6 cycloalkyl, -N(C 1-2 alkyl)C(=O)-C 1-3 alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered lactam-containing heterocycloalkyl, said R 2B is optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 , methyl, ethyl, isopropyl, butyl, isobutyl, CF 3 , CHF 2 , CH 2 F, vinyl, ethynyl; 优选地，R3B选自-NHC(＝O)-甲基、-NHC(＝O)-乙基、-NHC(＝O)-环丙基、-NHC(＝O)-环丁基、-NHC(＝O)-环戊基、-NHC(＝O)-环己基、-N(CH3)C(＝O)-甲基、-N(CH3)C(＝O)-环丙基、 吡咯基、吡唑基、咪唑基、噁唑基、噁二唑基、三唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、噻唑基、喹啉基、异喹啉基、喹唑啉基，所述R2B任选进一步被1至4个选自氘、F、Cl、Br、I、甲基、乙基、CF3、CHF2、CH2F的取代基取代；Preferably, R 3B is selected from -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl, -NHC(=O)-cyclohexyl, -N(CH 3 )C(=O)-methyl, -N(CH 3 )C(=O)-cyclopropyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, quinolyl, isoquinolyl, quinazolinyl, said R 2B is optionally further substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, methyl, ethyl, CF 3 , CHF 2 , CH 2 F; 更优选地，R3B选自 More preferably, R 3B is selected from Rb选自H、氘、卤素、甲基、CF3、CHF2、CH2F、CD3、CHD2、CH2D。R b is selected from H, deuterium, halogen, methyl, CF 3 , CHF 2 , CH 2 F, CD 3 , CHD 2 , CH 2 D. 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，化合物选自表S中所示结构之一。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. 一种药物组合物，包括权利要求1-10任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载 体。A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier body. 一种药物组合物或药物制剂，所述的药物组合物或药物制剂包含选1-1500mg的权利要求1-10任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和药用赋型剂。A pharmaceutical composition or pharmaceutical preparation comprising 1-1500 mg of a compound according to any one of claims 1-10 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof and a pharmaceutical excipient. 根据权利要求1-10任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备PARP14相关疾病的药物中的应用，优选肿瘤、特应性皮炎和自身免疫性疾病。Use of the compound according to any one of claims 1 to 10 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal for preparing a medicament for PARP14-related diseases, preferably tumors, atopic dermatitis and autoimmune diseases. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-10任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选1-1500mg，所述的疾病优选PARP14相关的疾病如肿瘤、特应性皮炎和自身免疫性疾病。 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 10 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1 to 1500 mg, and the disease preferably being a PARP14-related disease such as a tumor, atopic dermatitis and an autoimmune disease.
PCT/CN2024/097795 2023-06-06 2024-06-06 Quinazolinone derivative and medical use thereof Pending WO2024251205A1 (en)

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