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WO2025113705A1 - N-substituted amide derivative inhibitor, and preparation method and use therefor - Google Patents

N-substituted amide derivative inhibitor, and preparation method and use therefor Download PDF

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Publication number
WO2025113705A1
WO2025113705A1 PCT/CN2024/136103 CN2024136103W WO2025113705A1 WO 2025113705 A1 WO2025113705 A1 WO 2025113705A1 CN 2024136103 W CN2024136103 W CN 2024136103W WO 2025113705 A1 WO2025113705 A1 WO 2025113705A1
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Prior art keywords
alkyl
cyano
cycloalkyl
alkoxy
aryl
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French (fr)
Chinese (zh)
Inventor
吴建睿
高鹏
董加强
丁露
郑露露
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to an N-substituted amide derivative inhibitor and a preparation method and application thereof.
  • Protein arginase methyltransferases are divided into three categories based on catalytic activity and product type: type I, type II, and type III.
  • Type I mainly includes PRMT1/2/3/4/6/8, which catalyze the substrate to form asymmetric dimethylarginine (ADMA);
  • type II includes PRMT5/9, which catalyzes the substrate to form symmetric dimethylarginine (SDMA);
  • type III only includes PRMT7, which is responsible for catalyzing the substrate to form monomethylarginine (MMA).
  • PRMT5 uses S-adenosyl-L-methionine (SAM) as a methyl donor to transfer methyl groups to substrates such as DNA, RNA, and histones.
  • SAM S-adenosyl-L-methionine
  • the arginine residues of the substrate undergo symmetrical dimethylation to generate SDMA, thereby regulating multiple key cellular processes, including transcription, translation, and DNA repair, maintaining cell homeostasis, and also participating in regulating the growth and survival pathways of tumor cells and promoting tumor occurrence and development.
  • Increased expression of PRMT5 has also been shown to be associated with poor prognosis in a variety of cancers, making it a highly potential epigenetic target.
  • Methylthioadenosine phosphorylase catalyzes methylthioadenosine (MTA) to generate methionine, which is essential for maintaining normal cell function.
  • MTA methylthioadenosine
  • the deletion mutation of the MTAP gene causes MTA to accumulate in cells. MTA competes with the substrate SAM of PRMT5, which reduces the activity of PRMT5 and produces a large number of PRMT5-MTA complexes.
  • the deletion of the MTAP gene increases the dependence of tumors on PRMT5.
  • Inhibiting PRMT5 can have a "synthetic lethal" effect in tumors with MTAP deletion.
  • PARP inhibitors based on the "synthetic lethal" theory have achieved great success in the field of precision treatment of tumors.
  • the MTAP gene is adjacent to the most common tumor suppressor gene CDKN2A in human cancers, and is often co-deleted with CDKN2A. This co-deletion accounts for 10%-15% of all cancers, mainly occurring in non-small cell lung cancer (12%-20%), glioma (53%), pancreatic cancer (30%), and DLBCL (20%), with huge market prospects.
  • PRMT5 inhibitors there are no PRMT5 inhibitors on the market. Early PRMT5 inhibitors are non-selective substrate SAM competitive inhibitors, which have serious blood toxicity and side effects in clinical practice and a small safety window.
  • the first-generation PRMT5 inhibitors GSK-3326595, JNJ-64619178 and PF-06939999 have not made good clinical progress.
  • the new generation of PRMT5 inhibitors targeting the PRMT5-MTA complex are only effective against MTAP-deficient and MTA-enriched tumors, have high selectivity for wild-type MTAP, reduce blood toxicity from a mechanistic perspective, and have been verified in preclinical studies, which is expected to significantly increase the safety window.
  • This patent involves a new PRMT5-MTA selective inhibitor, which is only active against MTAP-deficient cells and has weak inhibition on MTAP wild-type cells, thus avoiding the side effects such as blood toxicity caused by the clinical inhibition of MTAP wild-type by non-selective PRMT5 inhibitors.
  • highly selective PRMT5-MTA inhibitors can be used to treat various tumors, cancers and other diseases.
  • the object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the general formula (I) is as follows:
  • M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; preferably -CR b -; M3 is selected from N or C; preferably N;
  • Ring A is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; preferably C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • Ring B is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; preferably C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; preferably C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 fused cycloalkyl, 6-10 membered fused heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • L1 is selected from a bond, -(CRaaRbb)m2- , - ( CRaaRbb ) m2C (O)-, - ( CRaaRbb ) m2C (S)-, -( CRaaRbb ) m2C ( NRcc )-, -( CRaaRbb ) m2NRccC (O)-, - ( CRaaRbb ) m2S (O) m1- , -( CRaaRbb ) m2NRcc- , -( CRaaRbb ) m2P (O ) 2- , -( CRaaRbb ) m2P ( O ) ( ORcc )- , C3-12cycloalkylene , 3-12memberedheterocyclylene, C6-12arylene or 5-12memberedheteroarylene, wherein the
  • L2 is selected from a bond, -(CRaaRbb)m2- , - ( CRaaRbb ) m2C ( O )-, -( CRaaRbb ) m2NRccC (O), -( CRaaRbb ) m2S (O) m1- or -( CRaaRbb ) m2NRcc- ; preferably -CRaaRbb- , -C(O)-, -S( O ) m1- or NRcc ;
  • R3 are linked to their adjacent atoms to form C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl; preferably, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alky
  • 6-10 membered aryl and 5-10 membered heteroaryl optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
  • Ra , Rb , Rc , Re and Rf are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -( CH2 ) n2ORee , -( CH2 ) n2NReeRff , - ( CH2 ) n2C (O) Ree , -( CH2 ) n2C (O )ORee, -(CH2)n2C ( O ) NRee wherein the
  • Ra and Rb are linked to form a C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C6-12 aryl, and a 5-12 membered heteroaryl, which is optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, a 3-12 membered heterocyclyl, C6-12 aryl, and a 5-12 membered heteroaryl;
  • Y is selected from a bond, -O-, -S-, -C(O), -NRj- , -C(O) NRj- , -NRjC (O)-, -S (O) 2NRj- , -NRjS (O ) 2- , C1-6alkylene , -OC1-6alkylene-, -C1-6alkylene- O- , -NRj - C1-6alkylene- , -C1-6alkylene -NRj-, C2-6alkenylene or C2-6alkynylene , wherein said C1-6alkylene , C2-6alkenylene and C2-6alkynylene are optionally deuterated, halogen, amino , hydroxyl, cyano, nitro, C1-6alkyl , C2-6alkenyl , C2-6alkynyl, oxo, thio, C1-6deuteratedalkyl , C1-6haloalkyl
  • Rg , Rh , R , and Rj are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C
  • R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C C 1-6
  • R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substitute
  • Rgg and Rhh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alky
  • n1 is selected from 0, 1, 2, 3 or 4;
  • n2 is selected from 0, 1, 2, 3 or 4.
  • the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that Selected from
  • the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (III-C):
  • R 1-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -(CH 2 ) n2 OR ee , -(CH 2 ) n2 NR ee R ff , -(CH 2 ) n2 C(O)R ee , -(CH 2 ) n2 C(O)OR ee , -(CH 2 ) n2 C(O)NR
  • R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substitute
  • Rgg and Rhh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alky
  • Ring A, Ring B, M 1 , M 2 , M 3 , L 2 , R 2 , R 3 , R c , x and y are as defined in any of the above embodiments.
  • the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that Ring A is selected from a 3-12-membered heterocyclic group or a 5-12-membered heteroaryl group; preferably a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered heteroaryl group or a 6-membered heteroaryl group; more preferably More preferred
  • the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that ring B is selected from 3-6 membered heterocyclic phenyl or 3-6 membered heterocyclic 5-6 membered heteroaryl; preferably
  • the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that ring B is selected from a 6-14-membered tricyclic heterocyclic group; preferably a 6-14-membered tricyclic spiro heterocyclic group or a 6-14-membered tricyclic fused heterocyclic group; more preferably
  • the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (IV-A):
  • M 4 is selected from N or CR 3a ; M 4 is selected from N or CR 3b ;
  • R 3a , R 3c and R 3d are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl
  • R 3b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 1-3 alkyl substituted with cyano, C 3-8
  • the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (IV-B):
  • M5 is selected from N or C
  • M6 is selected from N or C
  • Ring C is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R3e is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl,
  • R3f is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl,
  • n3 is selected from 0, 1 or 2; p is selected from 0, 1, 2, 3 or 4; q is selected from 0, 1 or 2.
  • the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl or -C(O) NReeRff , wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkyl substituted with cyano and C3-8 cycloalkyl are optionally substituted with deuterium, halogen , amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl
  • R ee and R ff are each independently selected from hydrogen, deuterium, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl;
  • the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that R b is selected from hydrogen, deuterium, halogen, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, --(CH 2 ) n2 OR ee , --(CH 2 ) n2 NR ee R ff , --(CH 2 ) n2 C( O )R ee , --(CH 2 ) n2 C(O)OR ee , --(CH 2 ) n2 C(O)NR ee R ff , --(CH 2 ) n2 C(
  • R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O) -C 1-3 al
  • 3-8 -membered cycloalkyl and 3-8-membered heterocyclyl optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
  • n2 is selected from 0, 1 or 2;
  • the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that R1-1 is selected from C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl or C1-3 alkyl substituted with cyano, wherein the C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl and C1-3 alkyl substituted with cyano are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6
  • R1-1 is selected from C1-3 alkyl, C1-3 deuterated alkyl, C
  • the present invention also provides an intermediate, characterized in that the intermediate is a compound represented by the general formula (IV-AI) or (IV-BI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1-1 is as described in claim 3;
  • M4 , M5 , M6 , R1-1 , R3a , R3b , R3c , R3d , R3e , R3f , p, q, n3 and n4 are as described in any of the above embodiments.
  • the present invention also provides a method for preparing a compound represented by general formula (III-C), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that:
  • the compound represented by the general formula (III-C-I) reacts with the compound represented by the general formula (III-C-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (III-C-III), and the protecting group is further removed to obtain the compound represented by the general formula (III-C);
  • the method is a method for preparing a compound represented by general formula (IV-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • the compound represented by the general formula (IV-A-I) reacts with the compound represented by the general formula (IV-A-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (IV-A-III), and the protecting group is further removed to obtain the compound represented by the general formula (IV-A);
  • the method is a method for preparing a compound represented by general formula (IV-B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • the compound represented by the general formula (IV-B-I) reacts with the compound represented by the general formula (IV-B-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (IV-B-III), and the protecting group is further removed to obtain the compound represented by the general formula (IV-B);
  • Pg 1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably benzyl, p-methoxybenzyl or tert-butyloxycarbonyl;
  • Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably hydrogen, benzyl, p-methoxybenzyl or tert-butyloxycarbonyl;
  • Ring A M1 , M2 , M3 , M4 , M5 , M6 , Ra, Rb , Rc, R2 , R1-1 , R3a , R3b , R3c , R3d , R3e , R3f , x, p, q, n3 and n4 are as described in any of the embodiments above.
  • the condensing agent is selected from thionyl chloride, phosphorus oxychloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyldiimidazole, ethyl chloroformate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate or tetramethylchlorouronium hexafluorophosphonate; preferably phosphorus oxychloride, 2-(7-azobenzotriazole)-N,N,N'
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of a compound shown in any one of the embodiments, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention further relates to the use of the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of PRMT5 inhibitor drugs.
  • the present invention further relates to the use of the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating cancer; preferably, the cancer is a cancer with MTAP gene deletion.
  • the present invention further relates to a method for preparing a method for treating cancer using the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition; preferably, the cancer is a cancer with MTAP gene deletion.
  • the cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colon cancer, colorectal cancer, biliary tract cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung carcinoma or adenocarcinom
  • the present invention also relates to a method for preventing and/or treating cancer, which comprises administering to a patient a therapeutically effective dose of a compound shown in any embodiment, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present invention also relates to a method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • the weight percentage of the compound, its stereoisomer or pharmaceutically acceptable salt thereof in the pharmaceutical composition, calculated as free base is 0.1% to 95%, preferably 90%, 85%, 80%, 75%, 70%, 60%, 50%.
  • the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, preferably, further comprising a filler, optionally a disintegrant, or further comprising one or more of a glidant or a lubricant.
  • the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.
  • the pharmaceutical composition calculated as a free base, has a unit dose of 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.
  • the compound, its stereoisomer or a pharmaceutically acceptable salt thereof may be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.
  • the compound, its stereoisomer or a pharmaceutically acceptable salt thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.
  • the method relates to the treatment of conditions such as lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colon cancer, colorectal cancer, biliary tract cancer, or bile duct cancer.
  • conditions such as lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer
  • the lung cancer is selected from non-small cell lung cancer, lung squamous cell carcinoma, or lung adenocarcinoma; and the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group, which may be optionally substituted with one or more substituents.
  • the alkyl group refers to a straight chain saturated hydrocarbon group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 ) carbon atoms, or a branched saturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms.
  • C 1-6 alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms.
  • the C 1-6 alkyl contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
  • alkylene refers to an alkyl group in which one hydrogen atom is further substituted, wherein “alkyl” is as defined above.
  • alkylene include: methylene ( -CH2- ), ethylene (-( CH2 ) 2- ), propylene (-( CH2 ) 3- ) or butylene (-( CH2)4- ) .
  • the alkylene is an optionally substituted alkyl group as described elsewhere herein.
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond and the carbon-carbon double bond may be located at any position within the alkenyl group, and the alkenyl group may be optionally substituted with one or more substituents.
  • alkenyl is a straight chain unsaturated hydrocarbon group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a branched unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms.
  • alkenyl as used herein includes both straight chain and branched alkenyl groups.
  • C2-6 alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms.
  • the C2-6 alkenyl contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms.
  • Non-limiting examples of alkenyl include:
  • alkenyl may also include groups having "cis” and “trans” configurations, or alternatively, groups having "E” and "Z” configurations.
  • the alkenyl is an optionally substituted alkenyl described elsewhere herein.
  • alkenylene refers to a further substitution of a hydrogen atom of an alkenyl group, wherein “alkenyl” is as defined above.
  • the alkenylene group is an optionally substituted alkyl group as described elsewhere herein.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and the carbon-carbon triple bond can be located at any position within the alkynyl group, and the alkynyl group can be optionally substituted with one or more substituents.
  • the alkynyl group is a straight chain unsaturated hydrocarbon group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a branched unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms.
  • alkynyl as used herein includes both straight-chain and branched alkynyl groups.
  • C2-6 alkynyl refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms.
  • the C2-6 alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms.
  • Non-limiting examples of alkynyl groups include:
  • the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.
  • alkynylene refers to an alkynyl group in which one of its hydrogen atoms is further substituted, wherein “alkynyl” is as defined above.
  • the alkynylene group is an optionally substituted alkyl group as described elsewhere herein.
  • cycloalkyl refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic, polycyclic (two or more) cyclic group, which may be optionally substituted by one or more substituents.
  • the cycloalkyl ring contains 3 to 20 (C 3-20 ), 3 to 14 (C 3-14 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring contains 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) carbon atoms; it may contain one or more double bonds, but does not have a completely conjugated ⁇ electron system.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl in one embodiment.
  • the cycloalkyl is an optionally substituted cycloalkyl or a cycloalkyl optionally fused to a heterocyclyl, aryl or heteroaryl group as described elsewhere herein, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.
  • spirocycloalkyl refers to an aliphatic hydrocarbon polycyclic group that shares a carbon atom (called a spiral atom) between monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the spirocycloalkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms.
  • the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, in one embodiment, a single spiral cycloalkyl and a double spiral cycloalkyl. In one embodiment, it is a 4 yuan/4 yuan, 3 yuan/5 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral cycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl described elsewhere herein. Non-limiting examples of spirocycloalkyl include:
  • fused cycloalkyl refers to a full carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the fused cycloalkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7- 10 ) (e.g., 7, 8, 9, 10) carbon atoms.
  • the number of constituent rings it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, in one embodiment, a bicyclic or tricyclic, and further in one embodiment, a 3 yuan/5 yuan, 4 yuan/5 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyl.
  • the fused cycloalkyl is an optionally substituted fused cycloalkyl described elsewhere herein or a fused cycloalkyl optionally fused to a heterocyclic radical, an aryl or a heteroaryl.
  • fused cycloalkyl include:
  • bridged cycloalkyl refers to a full carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the bridged cycloalkyl contains 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms.
  • the bridged cycloalkyl is an optionally substituted bridged cycloalkyl described elsewhere herein.
  • Non-limiting examples of bridged cycloalkyl include:
  • cycloalkylene refers to a divalent cycloalkyl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the cycloalkylene group is optionally substituted or unsubstituted, and the cycloalkyl group is as defined above.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, the ring carbon atoms may be optionally substituted by oxygen, but does not include the ring parts of -O-O-, -O-S-, and the remaining ring atoms are carbon, which may contain one or more double bonds but do not have a completely conjugated ⁇ electron system.
  • the heterocyclyl contains 3 to 20, 8 to 20, 10 to 20, 3 to 16, 8 to 16, 10 to 16, 3 to 14, 5 to 14, 8 to 14, 3 to 12, 5 to 12, 8 to 12, 3 to 8, or 3 to 6 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl contains 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclyl contains 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms.
  • monocyclic heterocyclic radical examples include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl etc.
  • Polycyclic heterocyclic radical includes spiro heterocyclic radical, condensed heterocyclic radical and bridge heterocyclic radical.
  • the heterocyclic radical is the optionally substituted described elsewhere herein, or the heterocyclic radical further and ring-connected with other cycloalkyl, heterocyclic radical, aryl and heteroaryl by any two or more atoms on the ring.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon, which may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the spiroheterocyclyl contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; according to the number of spiro atoms shared between the rings, the spiroheterocyclyl is divided into a monospiroheterocyclyl, a bispiroheterocyclyl or a polyspiroheterocyclyl; preferably a monospiroheterocyclyl and a bispiroheterocyclyl; in one embodiment, the spiroheterocyclyl is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl; in one embodiment, the spiroheterocyclyl is an optionally substituted s
  • fused heterocyclic group refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon.
  • the fused heterocyclic group is a heterocyclic group containing 5 to 20 or 6 to 14 ring atoms, and in one embodiment contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group; preferably a bicyclic or tricyclic group; in one embodiment, it is a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is a fused heterocyclic group described elsewhere herein that is optionally substituted or fused with a cycloalkyl, heterocyclic, aryl or heteroaryl group; non-limiting examples of fused heterocyclic groups include:
  • bridged heterocyclic group refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon.
  • the bridged heterocyclic group contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group; preferably a bicyclic, tricyclic or tetracyclic group; in one embodiment, it is a bicyclic or tricyclic group; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:
  • tricyclic heterocyclic group refers to a heterocyclic group having three rings in the system, wherein the three rings may be a paracyclic system, a spirocyclic system or a bridged ring system.
  • the tricyclic heterocyclic group is a system in which at least one of the three rings is a heterocyclic group, and the other two rings may be cycloalkyl, heterocyclic group, aryl or heteroaryl.
  • the definitions of cycloalkyl, heterocyclic group, aryl or heteroaryl are as described above, and non-limiting examples thereof are preferably the following tricyclic heterocyclic groups:
  • heterocyclylene refers to a divalent heterocyclic group in which one hydrogen atom of a heterocyclic group is further substituted, wherein the heterocyclic group is optionally substituted or unsubstituted, and the heterocyclic group is as defined above.
  • aryl refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group containing at least one conjugated ⁇ electron system, which may be optionally substituted by one or more substituents.
  • the aryl group contains 6 to 20, 6 to 14, 6 to 12, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from a benzo 5-10 membered heteroaryl, a benzo 3-10 membered cycloalkyl, or a benzo 3-10 membered heterocyclyl.
  • the aryl group is selected from a benzo 5-6 membered heteroaryl, a benzo 3-6 membered cycloalkyl, or a benzo 3-6 membered heterocyclyl, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms.
  • Non-limiting examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetralinyl),
  • arylene group refers to a divalent aromatic group formed by further replacing one hydrogen atom of an aryl group, wherein the arylene group is optionally substituted or unsubstituted, and the aryl group is as defined above.
  • heteroaryl refers to an optionally substituted monocyclic, polycyclic group or ring system containing at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N.
  • the heteroaryl group contains 5 to 20, 5 to 14, 5 to 12 or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group contains 5 or 6 ring atoms; in specific embodiments, the heteroaryl group may further refer to a bicyclic, tricyclic or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated carbocyclic rings or rings containing one or more heteroatoms independently selected from O, S and N.
  • the heteroaryl group is selected from heteroaryl and 6-10 membered aryl, heteroaryl and 3-10 membered cycloalkyl or heteroaryl and 3-10 membered heterocyclyl; further in one embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl and 6-10 membered aryl, 5- or 6-membered heteroaryl and 3-6 membered cycloalkyl, 5- or 6-membered heteroaryl and 3-6 membered heterocyclyl, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms or sulfur atoms.
  • Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothiophenyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl , indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, nap
  • heteroarylene refers to a divalent heteroaryl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the heteroarylene group is optionally substituted or unsubstituted, and the heteroaryl group is as defined above.
  • heteroalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (in one embodiment, one to three) heteroatoms selected from O, N, Si and S, and wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatoms O, N and S may be placed at any interior position of the heteroalkyl group.
  • the heteroatom Si may be placed at any position (e.g., interior or terminal position) of the heteroalkyl group, including the position where the alkyl group is attached to the remainder of the molecule.
  • heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.
  • the alkoxy is an optionally substituted alkoxy described elsewhere herein.
  • alkylacyl refers to a -C(O)-alkyl group, wherein alkyl is as previously defined.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein the definition of alkyl is the same as above.
  • Non-limiting examples of the haloalkyl group include: trifluoromethyl, -CH 2 CF 3 ,
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • haloalkylthio refers to an alkylthio group substituted with one or more halogens, wherein alkylthio is as defined above.
  • aminocarbonyl refers to NH2- C (O)-.
  • alkylaminocarbonyl refers to an aminocarbonyl ( NH2 -C(O)-) group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.
  • alkylamino refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydrogen includes protons ( 1H ), deuterium ( 2H ), tritium ( 3H ) and/or mixtures thereof.
  • one or more positions occupied by hydrogen in the compound may be enriched with deuterium and/or tritium.
  • isotopically enriched analogs may be prepared by appropriately isotopically labeled starting materials obtained from commercial sources or by known literature procedures.
  • the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, sulfhydryl, hydroxyl, nitro, cyano, azido, oxime, phosphate, oxo, thio, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkyloxy, cycloalkylthio, or heterocycloalkylthio.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.
  • linking substituents are described.
  • the Markush variable listed for that group should be understood as a linking group.
  • the Markush group definition for that variable lists “alkyl” or “aryl”, it should be understood that the "alkyl” or “aryl” represents an alkylene group or an arylene group, respectively, that is linked.
  • Substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable in one embodiment. In one embodiment.
  • optionally substituted means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent can be arbitrary on the basis that it can be realized chemically. It goes without saying that the substituent is only in their possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution without paying too much effort.
  • an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.
  • the substituent can be selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl.
  • Substituted or unsubstituted means that it may be substituted or unsubstituted.
  • R and R' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, --C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.
  • Steps encompass all enantiomerically/diastereomerically/stereomerically pure and enantiomerically/diastereomerically/stereomerically enriched forms of the compounds of the invention.
  • Stepomerically pure refers to a composition comprising one stereoisomer of a compound and being substantially free of another stereoisomer of the compound.
  • a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of another stereoisomer of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of another stereoisomer of the compound.
  • Stepoisomerically enriched refers to a composition comprising greater than about 55% by weight, greater than about 60% by weight, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.
  • Enantiomerically pure refers to a stereomerically pure composition of a compound having one chiral center.
  • enantiomerically enriched refers to a stereomerically enriched composition of a compound having one chiral center.
  • Optically active and “enantiomeric activity” refer to a combination of molecules having an enantiomeric or diastereomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.
  • the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer, based on the total weight of the racemate.
  • the prefixes R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound.
  • the prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise.
  • the prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise.
  • the signs (+) and (-) of the optical rotation have nothing to do with the absolute configuration, R and S, of the molecule.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shift ( ⁇ ) is given in units of 10 -6 (ppm). NMR measurements are performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was determined using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • HPLC analysis was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C 18 150 ⁇ 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150 ⁇ 4.6 mm column).
  • the average kinase inhibition rate and IC50 value were determined using NovoStar microplate reader (BMG, Germany).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.
  • the reactions can be carried out under argon atmosphere or nitrogen atmosphere.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L
  • hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, and the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • TLC thin layer chromatography
  • the eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include: A: n-hexane and ethyl acetate system, B: n-hexane and tetrahydrofuran system.
  • A n-hexane and ethyl acetate system
  • B n-hexane and tetrahydrofuran system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • Step 1 Dissolve 2-methyl-1H-imidazole 1a (5 g, 60.89 mmol) in DMSO (50 mL), slowly add DBU (13.91 g, 91.35 mmol, 14 mL) and methyl 3-fluoro-4-nitrobenzoate (13.34 g, 66.99 mmol), and stir the reaction at 25°C for 2 hours; add water (200 mL) to the reaction solution, extract with ethyl acetate (200 mL ⁇ 3); combine the organic phases, wash with saturated brine (200 mL ⁇ 3), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system C to obtain 1b (9 g), yield: 56.6%. MS m/z (ESI): 262[M+1] +
  • Step 3 1c (1 g, 4.32 mmol) was dissolved in DCM (15 mL), and DMAP (265 mg, 2.16 mmol) and 1-(isocyanate methyl)-4-methoxybenzene (1.06 g, 6.49 mmol, 926 ⁇ L) were added. The reaction was stirred at 80°C for 16 hours; the reaction solution was concentrated under reduced pressure, and dichloromethane (10 mL) and methyl tert-butyl ether (10 mL) were added to the concentrated residue, and stirred for 15 minutes, filtered, and the filter cake was collected and dried under reduced pressure to obtain 1g (750 mg). Yield: 45.8%. MS m/z (ESI): 380 [M+1] +
  • Step 4 1g (600mg, 1.52mmol) was dissolved in pyridine (2mL), phosphorus oxychloride (280mg, 1.83mmol, 171 ⁇ L) was added, and the reaction was stirred at 120°C for 16 hours; the reaction solution was concentrated under reduced pressure, water (50mL) was added to the concentrated residue, and extracted with ethyl acetate (50mL ⁇ 3); the organic phases were combined, washed with saturated brine (50mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain 1d (250mg), yield: 43.7%. MS m/z(ESI):377[M+1] +
  • Step 5 1d (250 mg, 664 ⁇ mol) was dissolved in water (2 mL)/methanol (2 mL)/tetrahydrofuran (6 mL), lithium hydroxide (32 mg, 1.33 mmol) was added, and the reaction was stirred at 80°C for 3 hours; the pH of the system was adjusted to 5 with 0.5 M hydrochloric acid, filtered, and the filter cake was stirred with ethanol (5 mL) for 0.5 hours, filtered, and dried under reduced pressure to obtain 1h (110 mg), yield: 45.7%.
  • Step 6 1h (50 mg, 138 ⁇ mol) and N-methyl-2-(trifluoromethyl)-6,8-dihydro-5H-pyran-[3,4-b]pyridin-5-amine (39 mg, 166 ⁇ mol, synthesized by the known method "Patent WO2021163344”) were dissolved in DMF (2 mL), and N-methylimidazole (46 mg, 552 ⁇ mol, 44 ⁇ L) and TCFH (58 mg, 207 ⁇ mol) were added.
  • reaction was stirred for 1.5 hours at 25 ° C.; the reaction solution was concentrated under reduced pressure, water (15 mL) was added to the concentrated residue, and extracted with ethyl acetate (20 mL ⁇ 3); the organic phases were combined, washed with saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue was separated by high performance liquid chromatography to obtain 1i (55 mg), with a yield of 68.9%.
  • Step 7 1i (45 mg, 78 ⁇ mol) was dissolved in trifluoroacetic acid (3 mL), and the reaction was stirred at 90°C for 16 hours; the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated by HPLC to obtain Example 1 (20 mg), with a yield of 56.2%. MS m/z (ESI): 458 [M+1] +
  • Step 1 Disperse 6-methoxy-2-methylnicotinate methyl ester 2a (15.00 g, 82.87 mmol), N-bromosuccinimide (29.00 g, 162.92 mmol) and azobisisobutyronitrile (2.60 g, 15.85 mmol) in 150 mL of carbon tetrachloride and stir at 80°C for 16 hours. The reaction solution was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure to obtain 2b (30.50 g, crude product). MS m/z (ESI): 338 [M+1] +
  • Step 2 Disperse 2b (30.50 g, crude product), diethyl phosphite (14.00 g, 101.45 mmol) and N,N-diisopropylethylamine (26.00 g, 201.55 mmol) in 400 mL of dichloromethane and stir at 25°C for 2 hours.
  • the reaction solution was concentrated and the residue was purified by silica gel column chromatography with eluent system B to obtain 2c (12.00 g) with a yield of 55.9%.
  • Step 3 Disperse methyl 2-hydroxyacetate (8.50 g, 94.44 mmol) in 200 mL N,N-dimethylformamide, add sodium hydride (5.70 g, 142.48 mmol, 60% dispersed in mineral oil) at 0°C, and stir to react for 1 hour. Add 2c (12.00 g, 46.33 mmol), stir to react at 25°C for 16 hours. Pour the reaction solution into 2000 mL of water and extract with ethyl acetate (300 mL ⁇ 3); combine the organic phases, wash with saturated brine (200 mL ⁇ 3), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 2d (22.00 g, crude product). MS m/z(ESI):238[M+1] +
  • Step 4 Disperse 2d (22.00 g, crude product) in 100 mL of ethanol and 100 mL of concentrated hydrochloric acid, and stir at 100°C for 2 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain 2e (4.00 g), yield: 52.3%.
  • Step 5 Disperse 2e (4.00 g, 24.24 mmol) in 30 mL of phosphorus oxychloride and stir at 90°C for 2 hours. Concentrate under reduced pressure, disperse the residue in 300 mL of dichloromethane, wash with saturated sodium bicarbonate solution (200 mL ⁇ 2) and sodium chloride solution (200 mL ⁇ 2) in sequence, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2f (4.30 g), yield: 96.9%. MS m/z (ESI): 184 [M+1] +
  • Step 6 Disperse 2f (300 mg, 1.64 mmol), 3,3-difluorotrimethyleneimine hydrochloride (260 mg, 2.02 mmol) and N,N-diisopropylethylamine (800 mg, 6.20 mmol) in 5 mL of acetonitrile and stir at 80°C for 16 hours.
  • the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system B to obtain 2g (240 mg), yield: 61.0%.
  • Step 7 Disperse 2g (240 mg, 1.00 mmol) and methylamine (310 mg, 3.00 mmol, 30% methanol solution) in 3 mL of trifluoroethanol and stir at 25°C for 16 hours. Add sodium cyanoborohydride (130 mg, 2.06 mmol) and stir at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain 2h (150 mg), yield: 58.8%. MS m/z (ESI): 256 [M+1] +
  • Example 2 (9 mg) was obtained by 2h (50 mg, 0.20 mmol), with a yield of 9.3%.
  • Step 1 Dissolve 4-amino-3-nitro-benzoic acid methyl ester 3a (5 g, 25.49 mmol) in dichloromethane (50 mL), and add DIEA (3.95 g, 30.59 mmol, 5.5 mL), DMAP (155.70 mg, 1.27 mmol), di-tert-butyl dicarbonate (6.68 g, 30.59 mmol) in sequence, and stir the reaction at 25 ° C for 2 hours; add water (100 mL) to the reaction solution, and extract with dichloromethane (100 mL ⁇ 3); combine the organic phases, wash with saturated brine (100 mL ⁇ 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The concentrated residue is purified with eluent system C to obtain 3b (6.5 g), yield: 86.0%.
  • Step 2 3b (5 g, 16.88 mmol) was dissolved in methanol (60 mL), Pd/C (2.05 g, 1.69 mmol, 10% purity) was added, and the reaction was stirred at 50°C for 16 hours; a layer of diatomaceous earth was spread on the suction funnel, the reaction solution was filtered, the filtrate was collected, and it was concentrated under reduced pressure to obtain 3c (4 g), yield: 89.0%. MS m/z (ESI): 267 [M+1] +
  • Step 3 3c (1 g, 3.76 mmol) was dissolved in N,N-dimethylformamide (12 mL), and ethyl 2-oxoacetate 3d (575.05 mg, 5.63 mmol, 559 ⁇ L) was added. The reaction was stirred at 100° C. in a microwave for 10 minutes. After the reaction was completed, 3e was obtained, which was used directly in the next step.
  • Step 4 Dissolve 3e (600 mg, 1.78 mmol) in N,N-dimethylformamide (7 mL), add tosylmethyl isocyanate 3f (417.95 mg, 2.14 mmol) and potassium carbonate (493.11 mg, 3.57 mmol), and stir the reaction in a microwave at 80°C for 10 minutes; add water (60 mL) to the reaction solution, and extract with ethyl acetate (60 mL ⁇ 3); combine the organic phases, wash with saturated brine (60 mL ⁇ 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 3g (700 mg), which is directly used in the next step.
  • Step 5 3g (600 mg, 1.54 mmol) was dissolved in 1,2-dichloroethane (6 mL)/trifluoroacetic acid (0.6 mL), and the reaction was stirred for 10 minutes at 80°C in a microwave oven; the reaction solution was concentrated under reduced pressure, and the concentrated residue was stirred with dichloromethane (10 mL) for 15 minutes, filtered, and the filter cake was dried under reduced pressure to obtain 3h (200 mg), with a yield of 53.4%.
  • Step 6 3h (200 mg, 822 ⁇ mol) was dissolved in phosphorus oxychloride (3 mL), and the reaction was stirred at 180°C for 8 hours; the reaction solution was concentrated under reduced pressure, water (15 mL) was added to the concentrated residue, and the organic phase was separated; the aqueous layer was extracted with ethyl acetate (15 mL ⁇ 3); the organic phases were combined, washed with saturated brine (15 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3i (100 mg), which was directly used in the next step.
  • Step 7 3i (100 mg, 383 ⁇ mol) was dissolved in N,N-dimethylformamide (2 mL), and 4-methoxybenzylamine (99.52 mg, 726 ⁇ mol) and potassium carbonate (150.40 mg, 1.09 mmol) were added in sequence.
  • the reaction was stirred at 120°C for 2 hours; water (20 mL) was added to the reaction solution, and the organic phase was separated; the aqueous layer was extracted with ethyl acetate (20 mL ⁇ 3); the organic phases were combined, washed with saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3j (200 mg), which was directly used in the next step.
  • Step 8 3j (100 mg, 276 ⁇ mol) was dissolved in water (1 mL)/methanol (1 mL)/tetrahydrofuran (3 mL), lithium hydroxide (25.45 mg, 1.06 mmol) was added, and the reaction was stirred at 80°C for 3 hours; the pH was adjusted to 5 with 0.5 M hydrochloric acid, filtered, the filter cake was rinsed with water (5 mL), and the filter cake was dried under reduced pressure to obtain 3k (60 mg), yield: 62.4%. MS m/z (ESI): 349 [M+1] +
  • Step 9 3k (50 mg, 144 ⁇ mol) and N-(cyclopropylmethyl)-2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-amine 3l (40 mg, 172 ⁇ mol) were dissolved in N,N-dimethylformamide, and N-methylpyrazole (45.31 mg, 552 ⁇ mol, 46 ⁇ L) and TCFH (58.07 mg, 207 ⁇ mol) were added. The reaction was stirred at 25 °C for 16 hours; the reaction solution was directly separated and purified by Pre-HPLC to obtain 3m (18 mg), with a yield of 22.3%. MS m/z (ESI): 563 [M+1] +
  • Step 10 3m (18 mg, 32 ⁇ mol) was dissolved in trifluoroacetic acid (2 mL), and the reaction was stirred at 90°C for 3 hours; the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated by Pre-HPLC (acid method) to obtain Example 3 (6 mg), with a yield of 42.4%.
  • Step 1 Dissolve 2-(trifluoromethyl)-8H-pyrano[3,4-b]pyridin-5-one 4a (500 mg, 2.30 mmol) and cyclopropylmethylamine (1.31 g, 18.42 mmol, 1.6 mL) in methanol (15 mL), add tetraisopropyl titanate (1.96 g, 6.91 mmol, 2 mL), stir the reaction at 25°C for 16 hours, add sodium acetate borohydride (732.02 mg, 3.45 mmol), stir at 25°C for 30 minutes; add saturated sodium bicarbonate aqueous solution (8 mL) to the reaction solution, filter, collect the filtrate, concentrate under reduced pressure, and separate the concentrated residue by Pre-TLC to obtain 4b (52 mg), yield: 8.3%. MS m/z (ESI): 273 [M+1] +
  • Step 2 4c (5 g, 25.49 mmol) was dissolved in dichloromethane (50 mL), and DIEA (3.95 g, 30.59 mmol, 5.5 mL), DMAP (155.70 mg, 1.27 mmol), and di-tert-butyl dicarbonate (6.68 g, 30.59 mmol) were added in sequence.
  • the reaction was stirred at 25°C for 2 hours.
  • Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL ⁇ 3). The organic phases were combined, washed with saturated brine (100 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified with eluent system C to obtain 4d (6.5 g). Yield: 86.0%.
  • Step 3 4d (5 g, 16.88 mmol) was dissolved in methanol (60 mL), Pd/C (2.05 g, 1.69 mmol, 10% purity) was added, and the reaction was stirred at 50°C for 16 hours; a layer of diatomaceous earth was spread on the suction funnel, the reaction solution was filtered, the filtrate was collected, and it was concentrated under reduced pressure to obtain 4e (4 g), with a yield of 89.0%.
  • Step 4 Dissolve 4e (1 g, 3.76 mmol) in N,N-dimethylformamide (12 mL), add ethyl 2-oxoacetate (575.05 mg, 5.63 mmol, 559 ⁇ L), and stir the reaction in a microwave at 100°C for 10 minutes. After the reaction is complete, the solution is used directly in the next step.
  • Step 5 4f (500 mg, 1.49 mmol) was dissolved in N,N-dimethylformamide (7 mL), and 1-methyl-1-toluenesulfonylmethyl isocyanate (373.30 mg, 1.78 mmol) and potassium carbonate (410.92 mg, 2.97 mmol) were added.
  • the reaction was stirred at 80°C in a microwave for 10 minutes.
  • Water 60 mL was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL ⁇ 3). The organic phases were combined, washed with saturated brine (60 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4 g, which was directly used in the next step.
  • Step 6 4g (600 mg, 1.49 mmol) was dissolved in 1,2-dichloroethane (6 mL)/trifluoroacetic acid (0.6 mL), and the reaction was stirred for 10 minutes at 80°C in a microwave oven; the reaction solution was concentrated under reduced pressure, and the concentrated residue was stirred with dichloromethane (10 mL) for 15 minutes, filtered, and the filter cake was dried under reduced pressure to obtain 4h (200 mg), with a yield of 52.3%.
  • Step 7 4h (200 mg, 778 ⁇ mol) was dissolved in phosphorus oxychloride (3 mL), and the reaction was stirred at 180°C for 8 hours; the reaction solution was concentrated under reduced pressure, water (15 mL) was added to the concentrated residue, and the organic phase was separated; the aqueous layer was extracted with ethyl acetate (15 mL ⁇ 3); the organic phases were combined, washed with saturated brine (15 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4i (100 mg), which was directly used in the next step.
  • Step 8 Dissolve 4i (100 mg, 363 ⁇ mol) in N,N-dimethylformamide (2 mL), add 4-methoxybenzylamine (99.52 mg, 726 ⁇ mol) and potassium carbonate (150.40 mg, 1.09 mmol) in sequence, and stir the reaction at 120°C for 2 hours; add water (20 mL) to the reaction solution, separate the organic phase; extract the aqueous layer with ethyl acetate (20 mL ⁇ 3); combine the organic phases, wash with saturated brine (20 mL ⁇ 3), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 4j (200 mg), which is directly used in the next step.
  • Step 9 4j (100 mg, 266 ⁇ mol) was dissolved in water (1 mL)/methanol (1 mL)/tetrahydrofuran (3 mL), and lithium hydroxide (25.45 mg, 1.06 mmol) was added. The reaction was stirred at 80°C for 3 hours; the pH was adjusted to 5 with 0.5 M hydrochloric acid, filtered, the filter cake was rinsed with water (5 mL), and the filter cake was dried under reduced pressure to obtain 4k (60 mg), yield: 62.3%. MS m/z (ESI): 363 [M+1] +
  • Step 10 4k (50 mg, 138 ⁇ mol) and 4b (45.08 mg, 166 ⁇ mol) were dissolved in N,N-dimethylformamide, and N-methylpyrazole (45.31 mg, 552 ⁇ mol, 46 ⁇ L) and TCFH (58.07 mg, 207 ⁇ mol) were added. The reaction was stirred at 25°C for 16 hours. The reaction solution was directly separated and purified by Pre-HPLC to obtain 4 (18 mg). The yield was 21.2%. MS m/z (ESI): 617 [M+1] +
  • Step 11 4 (18 mg, 29 ⁇ mol) was dissolved in trifluoroacetic acid (2 mL), and the reaction was stirred at 90°C for 3 hours; the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated by Pre-HPLC (acid method) to obtain Example 4 (6 mg), with a yield of 41.4%.
  • Example 5 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid 5a (90 mg) and N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine 5c (40 mg, synthesized by the known method "Patent WO2022169948") were used to obtain Example 5 (10.9 mg), with a yield of 26%.
  • Step 1 Dissolve 2-chloro-6-methoxy-pyridine-3-carboxylic acid methyl ester 6a (9 g, 44.64 mmol), potassium vinyl fluoroborate (11.96 g, 89.28 mmol) and potassium carbonate (12.34 g, 89.28 mmol) in water (20 mL) and 1'4-dioxane (100 mL), replace nitrogen three times, add 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) (3.27 g, 4.46 mmol), and stir the reaction system at 90 ° C for 15 hours.
  • II 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride
  • Step 3 Dissolve 6c (5.9 g, 30.22 mmol), azobisisobutyronitrile (496 mg, 3.02 mmol) and N-bromosuccinimide (8.61 g, 48.36 mmol) in carbon tetrachloride (60 mL), replace nitrogen three times, and heat the system to 90 ° C for reaction.
  • the reaction was cooled to room temperature, concentrated, added with water, washed with ethyl acetate (100 mL ⁇ 3), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the residue was purified by silica gel column chromatography with eluent system B to give 6d (7.50 g), yield: 90.5%.
  • Step 6 Dissolve 6f (0.5 g, 2.79 mmol) in dichloromethane (40 mL), replace nitrogen three times, cool to 0 ° C, add triethylamine (339 mg, 3.35 mmol, 0.47 mL) and trifluoromethanesulfonic anhydride (866 mg, 3.07 mmol) and react at 25 ° C for 2 hours.
  • Sodium iodide (2.09 g, 13.95 mmol) and concentrated hydrochloric acid (12 M, 0.28 mL) were added to the system, and the system was reacted at 20 ° C for 15 hours. Filter and concentrate. The residue was purified by silica gel column chromatography with eluent system B to obtain 6g (0.35 g), with a yield of 43.4%.
  • Step 7 Dissolve 6g (0.32g, 1.11mmol) and cuprous iodide (527mg, 2.77mmol) in N,N-dimethylformamide (5mL), add methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (532mg, 2.77mmol), replace nitrogen three times, and heat to 100°C for 2 hours.
  • the reaction was cooled to room temperature, concentrated, added with water, washed with ethyl acetate (5mL ⁇ 3), washed with brine (3mL), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the residue was purified by silica gel column chromatography with eluent system B to obtain 6h (0.14g), yield: 54.7%.
  • Step 8 6h (0.14 g, 0.61 mmol) and methylamine alcohol solution (314 mg, 3.03 mmol, 30% purity) were dissolved in trifluoroethanol (10 mL), nitrogen was replaced three times, and the reaction was carried out at 25 ° C for 2 hours. Sodium cyanoborohydride (76 mg, 1.21 mmol) was added to the system. After the addition, the system was reacted at 25 ° C for 1 hour.
  • Step 1 Dissolve 2-chloro-3-methyl-pyridine-4-carboxylic acid methyl ester 7a (5 g, 26.94 mmol), diphenylmethaneimine (5.37 g, 29.63 mmol), tris(dibenzylideneacetone)dipalladium (2.47 g, 2.69 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.12 g, 5.39 mmol) and cesium carbonate (13.17 g, 40.41 mmol) in dioxane (25 mL), react at 100°C for 16 hours, and the reaction solution turns yellow.
  • Step 2 Dissolve 7b (1.4 g, 8.42 mmol), 2-bromo-1,1-dimethoxy-ethane (1.42 g, 8.42 mmol) and p-toluenesulfonic acid (725 mg, 4.21 mmol) in N,N-dimethylformamide (15 mL) and react at 100°C for 16 hours. The reaction solution is yellow. After the reaction is completed, 10 mL of saturated ammonium chloride is added to quench, and the mixture is extracted with ethyl acetate (100 mL ⁇ 3). The organic phases are combined and washed with saturated sodium chloride solution (30 mL ⁇ 2).
  • Step 3 Dissolve 7c (60 mg, 0.315 mmol), N-bromosuccinimide (56 mg, 0.31 mmol) and azobisisobutyronitrile (15 mg, 0.094 mmol) in carbon tetrachloride (4 mL) and react at 80 ° C for 16 hours.
  • the reaction solution is yellow.
  • cool and concentrate add 10 mL of water to quench, extract with ethyl acetate (50 mL ⁇ 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography with eluent system A to obtain 7d (0.06 g), yield: 70%.
  • Step 4 Dissolve 7d (30 mg, 0.11 mmol), N-bromosuccinimide (20 mg, 0.11 mmol) and azobisisobutyronitrile (6 mg, 0.034 mmol) in carbon tetrachloride (3 mL), react at 80°C for 16 hours, the reaction solution turns yellow, and stir at 90°C for 16 hours. After the reaction is complete, cool, filter, and spin dry to obtain 7e (25 mg), yield: 64%. MS m/z (ESI): 349 [M+1] +
  • Step 5 Dissolve 7e (380 mg, 1.09 mmol), methyl glycolate (216 mg, 2.40 mmol) and sodium hydride (65 mg, 2.73 mmol) in N,N-dimethylformamide (8 mL) and react at 20°C for 16 hours. After the reaction is completed, add 10 mL of water to quench, extract with ethyl acetate (100 mL ⁇ 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography with eluent system A to obtain 7f (180 mg), yield: 46%. MS m/z (ESI): 357 [M+1] +
  • Step 6 Dissolve 7f (50 mg, 0.14 mmol) and lithium bis(trimethylsilyl)amide (46 mg, 0.28 mmol) in tetrahydrofuran (2 mL) and react at -55°C for 1 hour. The reaction solution is yellow. After the reaction is completed, the crude product is purified by C18 column chromatography with eluent system A to obtain 7g (35 mg). Yield: 76%. MS m/z (ESI): 325 [M+1] +
  • Step 7 Dissolve 7g (26 mg, 0.08 mmol) and hydrochloric acid (2 mL) in ethanol (2 mL), react at 80°C for 16 hours, and the reaction solution turns yellow. After the reaction is completed, cool, concentrate, and spin dry. The crude product is purified by C18 column chromatography with eluent system A to obtain 7h (8 mg), yield: 37%. MS m/z (ESI): 267 [M+1] +
  • Step 8 7h (30 mg, 0.11 mmol), methylamine (7 mg, 0.225 ⁇ mol) and trifluoroethanol (2 mL) were reacted at 60°C for 2 hours. The reaction solution was yellow. After the reaction was completed, the mixture was cooled, concentrated, and dried by spin drying. The crude product was purified by C18 column chromatography with eluent system A to obtain 7i (15 mg). The yield was 47%. MS m/z (ESI): 282 [M+1] +
  • Step 9 7i (24 mg, 0.086 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (36 mg, 0.13 mmol) and N-methylimidazole (21 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (4 mL) and reacted at 40°C for 1 hour. The reaction solution was yellow. After the reaction was completed, 10 mL of water was added to quench, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • Step 1 Disperse 2-amino-3-methylisomethyl ester 8a (5 g, 30.12 mmol) and bromoacetaldehyde dimethyl acetal (10.12 g, 60.24 mmol) in 50 mL of ethanol and 10 mL of hydrochloric acid (2 M/L), and stir at 80°C for 16 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain 8b (3.2 g), with a yield of 55.9%.
  • Step 2 Disperse 8b (3.2 g, 16.84 mmol) in 50 mL of acetonitrile and add N-iodosuccinimide (4.5 g, 20 mmol). Stir and react for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain 8c (2.80 g) with a yield of 52.6%. MS m/z (ESI): 317 [M+1] +
  • Step 3 Disperse 8c (2.80 g, 8.86 mmol), cuprous iodide (8.42 g, 44.30 mmol), and potassium fluoride (1.54 g, 26.58 mmol) in 30 mL of N,N-dimethylformamide, and add (trifluoromethyl)trimethylsilane (3.77 g, 26.58 mmol). Stir and react at 90°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain 8d (830 mg), with a yield of 36.3%. MS m/z (ESI): 259 [M+1] +
  • Example 8 (19 mg) was obtained by 8d (400 mg, 1.55 mmol), with a yield of 2.5%.
  • Step 1 Dissolve 3-bromo-N-methyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridine-7-amine (220 mg, 0.78 mmol), di-tert-butyl dicarbonate (218 mg, 1.17 mmol) and diisopropylethylamine (302 mg, 2.34 mmol) in dichloromethane and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain 112a (240 mg) with a yield of 80.5%. MS m/z (ESI): 382 [M+1] +
  • Step 2 Dissolve 112a (100 mg, 0.26 mmol), imino-dimethyl-carbonyl-sulfane (37 mg, 0.39 mmol), cesium carbonate (127 mg, 0.39 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg, 0.5 mmol) and tris(dibenzylideneacetone)palladium (24 mg, 0.03 mmol) in 5 mL of dioxane and stir at 80 °C for 2 hours under nitrogen protection.
  • Step 3 Dissolve 112b (57 mg, 0.13 mmol) in 5 mL of 2M hydrochloric acid dioxane and stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 112c (33 mg), with a yield of 85.7%. MS m/z (ESI): 295 [M+1] +
  • Example 112 (4.2 mg) was obtained by using 112c (33 mg, 0.11 mmol). Yield: 7.4%. MS m/z (ESI): 519 [M+1] +
  • Examples 9, 10, and 66 may be performed by the following preparation method:
  • Step 1 Dissolve 2-(trifluoromethyl)-6H-pyrano[3,4-b]pyridin-5(8H)-one 1f (500 mg, 2.30 mmol, synthesized by the known method "Patent WO2022169948 A1") in methanol, add sodium borohydride (435 mg, 11.51 mmol) in batches under ice bath, and stir at 0°C for 1 hour.
  • Step 2 9b (470 mg, 2.14 mmol) and triethylamine (651 mg, 6.43 mmol) were dissolved in 10 mL of dichloromethane, and methylsulfonic anhydride (560 mg, 3.22 mmol) was added and stirred at room temperature for 1 hour. Saturated ammonium chloride solution (30 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL ⁇ 2). The organic phase was taken after extraction, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 9c (430 mg), with a yield of 66.8%. MS m/z (ESI): 298 [M+1] +
  • Step 3 Dissolve 9c (220 mg, 0.74 mmol) in 10 mL of acetonitrile, add potassium carbonate (511 mg, 3.7 mmol), and stir at 80°C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain 9d (139 mg), with a yield of 75.7%. MS m/z (ESI): 249 [M+1] +
  • Step 4 9d (139 mg, 0.56 mmol) and 4-((3,4-dimethylbenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid 9e (241 mg, 0.62 mmol) were dissolved in 5 mL of dichloromethane, phosphorus oxychloride (257 mg, 1.68 mmol) and pyridine (265 mg, 3.36 mmol) were added in sequence, and the mixture was stirred at room temperature for 2 hours. 2M hydrochloric acid (30 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (30 mL ⁇ 2).
  • Example 9 (20.2 mg) was obtained by using 9f (67 mg, 0.11 mmol). Yield: 38.9%. MS m/z (ESI): 473 [M+1] +
  • Example 66 (12 mg, 0.023 mmol) was separated by chiral preparative HPLC to give (S)-4-amino-7-fluoro-N-methoxy-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 66-P1 (5.1 mg) with a yield of 42.5% and 4-amino-7-fluoro-N-methoxy-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 66-P2 (5.5 mg) with a yield of 45.8%.
  • Embodiment 154 is a diagrammatic representation of Embodiment 154.
  • Step 1 4-((2,4-dimethoxyphenyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid 154a (160 mg, 0.40 mmol), O-(2-butynyl)hydroxylamine (344 mg, 4.04 mmol), DIEA (156 mg, 1.21 mmol), HOBT (109 mg, 0.80 mmol), HATU (305 mg, 0.81 mmol) were dissolved in 5 mL of N,N-dimethylformamide and stirred at 20°C for 1 hour.
  • Step 2 154b (160 mg, 0.40 mmol), methanesulfonic acid [5-trifluoromethyl-12-oxa-3,6-diazatricyclo[7.4.0.02,6]tridecane-1(9),2,4,7-tetraen-10-yl] ester (148 mg, 0.44 ⁇ mol), and Cs 2 CO 3 (215 mg, 0.66 mmol) were dissolved in 15 mL N,N-dimethylformamide and stirred at 60°C for 12 hours. The system was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to give 154c (43 mg) in a yield of 17.8%. MS m/z (ESI): 704 [M+1] +
  • Step 3 Disperse 154c (30 mg, 0.04 mmol) and DDQ (19 mg, 0.09 mmol) in 2 mL of water and 10 mL of dichloromethane, and stir at room temperature for 12 hours. The system was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give Example 154 (18 mg), yield: 76.2%. MS m/z (ESI): 554 [M+1] +
  • Test Example 1 Determination of the ability of the compounds of the present invention to enhance the thermal stability (melting temperature) of the PRMT5/MEP50-MTA protein complex.
  • Quantitative PCR instrument (Quantstudio6 Flex) was purchased from Life Company; pipettes were purchased from Eppendorf or Rainin Company.
  • PRMT5/MEP50 protein was prepared by Via Biotechnology; HEPES was purchased from Thermo Fisher with the catalog number 15630080; DTT was purchased from Sigma with the catalog number 43816-10ml; sodium chloride was purchased from Invitrogen with the catalog number AM9760G; Protein Thermal ShiftTM Dye Kit was purchased from Thermo Fisher with the catalog number 4461146; methylthioadenosine (MTA) was purchased from Sigma with the catalog number D5011.
  • This experiment uses the thermal shift method to test the degree of change in the melting temperature (Tm) of the PRMT5/MEP50-MTA protein complex before and after the compound binds to characterize the ability of the compound to enhance the thermal stability of the PRMT5/MEP50-MTA protein complex.
  • Tm melting temperature
  • the above reaction mixture is divided into 8 strips of PCR tubes, 19.5 ⁇ L per tube, and 0.5 ⁇ L of the test compound or DMSO is added respectively, so the total reaction system is 20 ⁇ L, the final concentration of the compound is 8 ⁇ M, and 2.5% DMSO is set as the solvent control.
  • Test Example 2 Determination of the inhibitory effect of the compounds of the present invention on the proliferation activity of HCT116 and MTAP Knockout HCT116 cells
  • HCT116 and MTAP Knockout HCT116 cells were purchased from Nanjing Kebai; Cell Titer-Glo was purchased from Promega with the catalog number G7573; McCoy ⁇ 5A was purchased from Gibco with the catalog number 12330031; FBS was purchased from Gibco with the catalog number 10091148; PBS was purchased from Gibco with the catalog number 10010023; trypsin was purchased from Gibco with the catalog number 25200056; cell culture plates were purchased from Corning with the catalog number 3610.
  • HCT116 and MTAP Knockout HCT116 cells were cultured to an appropriate cell density using McCoy'5A medium containing 10% FBS, the cells were collected and adjusted to an appropriate cell concentration using complete medium.
  • the cell suspension was plated on a 96-well plate at 90 ⁇ L per well and placed in a 37°C, 5% CO2 incubator to adhere overnight.
  • Compound solutions of different concentrations were prepared using DMSO and culture medium, and a solvent control was set up.
  • the compound solution was added to a 96-well plate at 10 ⁇ L per well and placed in a 37°C, 5% CO2 incubator for continued culture for 72 to 240 hours.
  • the CellTiter-Glo solution was added, the plates were shaken to mix evenly, incubated in the dark for 10 to 30 minutes, and read using a Synergy H1 or Envision microplate reader.
  • Test Example 3 Pharmacokinetics of the compounds of the present invention in mice (plasma) after oral administration
  • mice were used as test animals to study the pharmacokinetic behavior of the compound in mice (plasma) after oral administration.
  • Test drugs Compounds of the present invention, homemade.
  • mice Balb/c mice, male, purchased from Shanghai JXJ Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006, No. 311620400001794).
  • Drug preparation for oral administration 0.5% CMC-Na (1% Tween 80).
  • HEC hydroxyethyl cellulose
  • Test Example 4 Pharmacokinetics of the compounds of the present invention in rats (plasma) after oral administration
  • Study purpose SD rats were used as test animals to study the pharmacokinetic behavior of the following compound examples in rat plasma after oral administration at a dose of 5 mg/kg.
  • Liquid A is 0.1% formic acid aqueous solution
  • Liquid B is methanol
  • Flow rate 1.0mL/min
  • Test Example 5 hERG potassium channel inhibition activity test
  • CHO cells stably expressing hERG potassium channels used in the experiment were obtained from Sophion Biosciences (Ballerup, Denmark) and cryopreserved at Shanghai WuXi AppTec.
  • CHO-hERG was cultured and passaged in Ham's F-12 medium containing 1 ⁇ GlutaMAX, 10% fetal bovine serum, 100 ⁇ g/mL G418, and 100 ⁇ g/mL hygromycin B, 5% CO 2 , and 37°C.
  • Extracellular fluid was prepared once a month and stored in 1L storage bottles. Intracellular fluid was prepared once every three months and stored in aliquots at -20°C. The intracellular fluid was melted in a 37°C water bath before the experiment and placed in an ice bath for later use.
  • Preliminary preparation of cells The CHO-hERG cells used in the experiment were cultured for at least two days. When the cell density reached more than 75%, the cells were digested with TrypLE, then resuspended with extracellular solution and centrifuged. After removing the supernatant, 2 mL of extracellular solution was added for resuspending.
  • IC50 The half-maximal inhibitory concentration of the test compound on hERG. If the inhibition rate at the lowest concentration exceeds half inhibition or the inhibition rate at the highest concentration does not reach half inhibition, the corresponding IC50 of the compound is lower than the lowest concentration or the IC50 value is greater than the highest concentration.
  • the inhibitory activity (IC 50 ) of the advantageous compounds of the present invention on cardiac hERG potassium channels is greater than 5 ⁇ M, even greater than 15 ⁇ M.
  • the inhibitory activity (IC 50 ) of some embodiments is greater than 30 ⁇ M, which can avoid cardiac toxicity at high doses.
  • Test Example 6 In vivo pharmacodynamic study of the compound of the present invention in a subcutaneous transplanted tumor model of nude mice with human lung cancer cell line LU99
  • RPMI-1640 culture medium (22400-089, Gibco); fetal bovine serum (FBS) (A5669701, Gibco); phosphate buffered saline (PBS) (10010-023, Gibco); Matrigel matrix glue (356234, Corning); sodium carboxymethyl cellulose (30036365, Sinopharm Reagent); Tween-80 (30189828, Sinopharm Reagent).
  • FBS fetal bovine serum
  • PBS phosphate buffered saline
  • Matrigel matrix glue 356234, Corning
  • sodium carboxymethyl cellulose 30036365, Sinopharm Reagent
  • Tween-80 (30189828, Sinopharm Reagent).
  • a) Take out a strain of LU99 cells from the cell bank, resuscitate the cells with RPMI-1640 medium (RPMI-1640+10% FBS), and place the resuscitated cells in a cell culture flask in a CO 2 incubator (the incubator temperature is 37° C. and the CO 2 concentration is 5%).
  • nude mice were marked with disposable ear tags for both adults and mice;
  • mice were inoculated sequentially (0.1 mL of cell suspension was inoculated per mouse).
  • tumor volume (mm 3 ) length (mm) ⁇ width (mm) ⁇ width (mm)/2;
  • mice were randomly divided into groups according to their weight and tumor size;
  • test drug administration method: oral administration; administration volume: 10 mL/kg; administration frequency: 1 time/day or 2 times/day; administration cycle: 28 days; solvent: 0.5% CMC-Na (1% Tween 80)).
  • Tumors were measured and weighed twice a week after the start of administration of the test drug.
  • TGI (%) [1-(average tumor volume at the end of a certain treatment group administration - average tumor volume at the beginning of administration of the treatment group)/(average tumor volume at the end of treatment of the solvent control group - average tumor volume at the beginning of treatment of the solvent control group)] ⁇ 100%.
  • TGI (%) [1-(average tumor volume at the end of administration of a certain treatment group - average tumor volume at the beginning of administration of the treatment group)/average tumor volume at the beginning of administration of the treatment group] ⁇ 100%.
  • the advantageous compounds of the present invention have a tumor inhibition rate (TGI) greater than 80% or even greater than 90% at low doses, and have a significant tumor growth inhibition effect.
  • TGI tumor inhibition rate
  • the tumor inhibition rate (TGI) of the compounds at high doses is greater than 100% or even greater than 150%, and has a significant tumor regression effect.

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Abstract

An N-substituted amide derivative inhibitor, and a preparation method and use therefor. In particular, the present invention relates to an N-substituted amide derivative compound, a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof in treating cancer.

Description

N-取代酰胺类衍生物抑制剂、其制备方法和应用N-substituted amide derivative inhibitors, preparation method and application thereof 技术领域Technical Field

本发明属于药物合成领域，具体涉及一种N-取代酰胺类衍生物抑制剂及其制备方法和应用。The invention belongs to the field of drug synthesis, and specifically relates to an N-substituted amide derivative inhibitor and a preparation method and application thereof.

背景技术Background Art

蛋白质精氨酸酶甲基转移酶(PRMT)根据催化活性和产物类型，分为三大类：Ⅰ、Ⅱ、Ⅲ型。I型主要包括PRMT1/2/3/4/6/8，催化底物形成非对称二甲基精氨酸(ADMA)；Ⅱ型包括PRMT5/9，催化底物形成对称二甲基精氨酸(SDMA)；Ⅲ型仅包括PRMT7，负责催化底物形成单甲基精氨酸(MMA)。PRMT5以S-腺苷-L-甲硫氨酸(SAM)作为甲基供体，将甲基转移到DNA、RNA、组蛋白等底物上，底物的精氨酸残基发生对称二甲基化生成SDMA，以此调控多个关键细胞过程，包括转录、翻译和DNA修复，维持细胞稳态，同时还能参与调控肿瘤细胞的生长及生存途径并促进肿瘤发生与发展。PRMT5的表达升高也被证明与多种癌症的不良预后相关，是一个极具潜力的表观遗传学靶点。Protein arginase methyltransferases (PRMTs) are divided into three categories based on catalytic activity and product type: type I, type II, and type III. Type I mainly includes PRMT1/2/3/4/6/8, which catalyze the substrate to form asymmetric dimethylarginine (ADMA); type II includes PRMT5/9, which catalyzes the substrate to form symmetric dimethylarginine (SDMA); type III only includes PRMT7, which is responsible for catalyzing the substrate to form monomethylarginine (MMA). PRMT5 uses S-adenosyl-L-methionine (SAM) as a methyl donor to transfer methyl groups to substrates such as DNA, RNA, and histones. The arginine residues of the substrate undergo symmetrical dimethylation to generate SDMA, thereby regulating multiple key cellular processes, including transcription, translation, and DNA repair, maintaining cell homeostasis, and also participating in regulating the growth and survival pathways of tumor cells and promoting tumor occurrence and development. Increased expression of PRMT5 has also been shown to be associated with poor prognosis in a variety of cancers, making it a highly potential epigenetic target.

甲基硫代腺苷磷酸化酶(MTAP)催化甲硫腺苷(MTA)生成甲硫氨酸，对维持正常细胞功能至关重要。MTAP基因的缺失突变使细胞内积累MTA，MTA和PRMT5的底物SAM竞争，使PRMT5活性下降，并产生大量PRMT5-MTA复合物。MTAP基因的缺失会使肿瘤对PRMT5的依赖性增加，抑制PRMT5在MTAP缺失的肿瘤中可以起到“合成致死”的效应，基于“合成致死”理论的PARP抑制剂已在肿瘤领域精准治疗领域取得了巨大成功。MTAP基因与人类癌症中最常见的肿瘤抑制基因CDKN2A相邻，且常与CDKN2A共缺失，这种共缺失在所有癌症中占10％-15％，主要发生在非小细胞肺癌(12％～20％)、胶质瘤(53％)、胰腺癌(30％)、DLBCL(20％)，市场前景巨大。Methylthioadenosine phosphorylase (MTAP) catalyzes methylthioadenosine (MTA) to generate methionine, which is essential for maintaining normal cell function. The deletion mutation of the MTAP gene causes MTA to accumulate in cells. MTA competes with the substrate SAM of PRMT5, which reduces the activity of PRMT5 and produces a large number of PRMT5-MTA complexes. The deletion of the MTAP gene increases the dependence of tumors on PRMT5. Inhibiting PRMT5 can have a "synthetic lethal" effect in tumors with MTAP deletion. PARP inhibitors based on the "synthetic lethal" theory have achieved great success in the field of precision treatment of tumors. The MTAP gene is adjacent to the most common tumor suppressor gene CDKN2A in human cancers, and is often co-deleted with CDKN2A. This co-deletion accounts for 10%-15% of all cancers, mainly occurring in non-small cell lung cancer (12%-20%), glioma (53%), pancreatic cancer (30%), and DLBCL (20%), with huge market prospects.

目前尚无PRMT5抑制剂上市，早期PRMT5抑制剂均为非选择性的底物SAM竞争性抑制剂，临床上血液毒副作用严重，安全窗小。一代PRMT5抑制剂GSK-3326595、JNJ-64619178和PF-06939999的临床进展不佳。靶向PRMT5-MTA复合物的新一代PRMT5抑制剂仅对MTAP缺失、MTA富集的肿瘤有效，对MTAP野生型有较高选择性，从机制上降低血液毒性，且在临床前研究中得到验证，有望大幅提高安全窗。Currently, there are no PRMT5 inhibitors on the market. Early PRMT5 inhibitors are non-selective substrate SAM competitive inhibitors, which have serious blood toxicity and side effects in clinical practice and a small safety window. The first-generation PRMT5 inhibitors GSK-3326595, JNJ-64619178 and PF-06939999 have not made good clinical progress. The new generation of PRMT5 inhibitors targeting the PRMT5-MTA complex are only effective against MTAP-deficient and MTA-enriched tumors, have high selectivity for wild-type MTAP, reduce blood toxicity from a mechanistic perspective, and have been verified in preclinical studies, which is expected to significantly increase the safety window.

本专利涉及到一种新的PRMT5-MTA选择性抑制剂，仅对MTAP缺失细胞有活性，对MTAP野生型细胞抑制较弱，可避免临床上非选择性PRMT5抑制剂对MTAP野生型抑制带来的血液毒性等副作用。高选择性PRMT5-MTA抑制剂作为新型PRMT5-MTA抑制剂可用于各种肿瘤、癌症等疾病的治疗。This patent involves a new PRMT5-MTA selective inhibitor, which is only active against MTAP-deficient cells and has weak inhibition on MTAP wild-type cells, thus avoiding the side effects such as blood toxicity caused by the clinical inhibition of MTAP wild-type by non-selective PRMT5 inhibitors. As a new type of PRMT5-MTA inhibitor, highly selective PRMT5-MTA inhibitors can be used to treat various tumors, cancers and other diseases.

发明内容Summary of the invention

本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其中通式(I)如下：
The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the general formula (I) is as follows:

M1选自-N-或-CRa-；M2选自-N-或-CRb-；优选-CRb-；M3选自N或C；优选N； M1 is selected from -N- or -CR a -; M2 is selected from -N- or -CR b -; preferably -CR b -; M3 is selected from N or C; preferably N;

环A选自C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基；优选C3-6环烷基、3-6元杂环基、苯基或5-6元杂芳基；Ring A is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; preferably C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

环B选自C3-14环烷基、3-14元杂环基、C6-14芳基或5-14元杂芳基；优选C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；优选C3-6环烷基、3-6元杂环基、C6-10稠环烷基、6-10元稠杂环基、C6-10芳基或5-10元杂芳基；Ring B is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; preferably C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; preferably C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 fused cycloalkyl, 6-10 membered fused heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

L1选自键、-(CRaaRbb)m2-、-(CRaaRbb)m2C(O)-、-(CRaaRbb)m2C(S)-、-(CRaaRbb)m2C(NRcc)-、-(CRaaRbb)m2NRccC(O)-、-(CRaaRbb)m2S(O)m1-、-(CRaaRbb)m2NRcc-、-(CRaaRbb)m2P(O)2-、-(CRaaRbb)m2P(O)(ORcc)-、C3-12亚环烷基、3-12元亚杂环基、C6-12亚芳基或5-12元亚杂芳基，所述的C3-12亚环烷基、3-12元亚杂环基、C6-12亚芳基和5-12元亚杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选-CRaaRbb-、-C(O)-、-S(O)m1-或NRcc； L1 is selected from a bond, -(CRaaRbb)m2- , - ( CRaaRbb ) m2C (O)-, - ( CRaaRbb ) m2C (S)-, -( CRaaRbb ) m2C ( NRcc )-, -( CRaaRbb ) m2NRccC (O)-, - ( CRaaRbb ) m2S (O) m1- , -( CRaaRbb ) m2NRcc- , -( CRaaRbb ) m2P (O ) 2- , -( CRaaRbb ) m2P ( O ) ( ORcc )- , C3-12cycloalkylene , 3-12memberedheterocyclylene, C6-12arylene or 5-12memberedheteroarylene, wherein the C3-12cycloalkylene , 3-12memberedheterocyclylene, C6-12arylene or 5-12memberedheteroarylene 6-12 membered arylene and 5-12 membered heteroarylene, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably -CR aa R bb -, -C(O)-, -S(O) m1 - or NR cc ;

L2选自键、-(CRaaRbb)m2-、-(CRaaRbb)m2C(O)-、-(CRaaRbb)m2NRccC(O)、-(CRaaRbb)m2S(O)m1-或-(CRaaRbb)m2NRcc-；优选-CRaaRbb-、-C(O)-、-S(O)m1-或NRcc； L2 is selected from a bond, -(CRaaRbb)m2- , - ( CRaaRbb ) m2C ( O )-, -( CRaaRbb ) m2NRccC (O), -( CRaaRbb ) m2S (O) m1- or -( CRaaRbb ) m2NRcc- ; preferably -CRaaRbb- , -C(O)-, -S( O ) m1- or NRcc ;

R1选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1- 6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、-(CRccRdd)n1-C3-12环烷基、-(CRccRdd)n1-3-12元杂环基、-(CRccRdd)n1-C6-12芳基、-(CRccRdd)n1-5-12元杂芳基、-SF5、-ORe、-NReRf、-C(O)Re、-C(O)ORe、-C(O)NReRf、-N＝S(O)ReRf、-S(O)Re(＝NRf)或-P(O)ReRf，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1- 6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基和＝CRggRhh中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、-(CRccRdd)n1-C3-8环烷基、-(CRccRdd)n1-3-8元杂环基、-(CRccRdd)n1-C6-10芳基、-(CRccRdd)n1-5-10元杂芳基、-ORe、-NReRf、-C(O)Re、-C(O)NReRf或-P(O)ReRf，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, -( CRccRdd ) n1 - C3-12 cycloalkyl, - ( CRccRdd ) n1-3-12 membered heterocyclyl, - ( CRccRdd ) n1 - C6-12 aryl, - (CRccRdd ) n1-5-12 membered heteroaryl, -SF5 , -ORe , -NReRf, -C(O ) Re , -C(O) ORe , -C ( O) NReRf , -N = S (O) ReRf wherein the amino, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C The group is preferably substituted by one or more substituents selected from the group consisting of: C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl and =CR gg R hh ; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, -(CR cc R dd ) n1 -C 3-8 cycloalkyl, -(CR cc R dd ) n1 -3-8 membered heterocyclyl, -(CR cc R dd ) n1 -C 6-10 aryl, -(CR cc R dd ) n1 -5-10 membered heteroaryl, -ORe , -NReRf , -C (O)Re, -C(O ) NReRf or -P(O) ReRf , the amino, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 The alkyl group is substituted with one or more substituents selected from C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

R2选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-(CH2)n2ORee、-(CH2)n2NReeRff、-(CH2)n2C(O)Ree、-(CH2)n2C(O)NReeRff、-(CH2)n2P(O)ReeRff或＝CReeRff，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6- 10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1- 3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6- 10芳基和5-10元杂芳基中的一个或多个取代基所取代； R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, cyano-substituted C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -( CH2 ) n2ORee , - ( CH2 ) n2NReeRff , -( CH2 ) n2C (O) Ree , -( CH2 ) n2C (O ) NReeRff , -( CH2 ) n2P ( O )ReeRff or = CReeRff , the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl The alkylene group is substituted with one or more substituents selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl , 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl;

R3选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-Y1-C3-12环烷基、-Y1-3-12元杂环基、-Y1-C6-12芳基、-Y1-5-12元杂芳基、-SF5、-ORg、-NRgRh、-C(O)Rg、-C(O)ORg、-C(O)NRgRh、-N＝S(O)RgRh、-S(O)Rg(＝NRh)、-P(O)RgRh、-C(＝NRi)NRgRh或＝RgRh，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、取代或未取代的C3-12环烷基、取代或未取代的3-12元杂环基、取代或未取代的C6-12芳基、取代或未取代的5-12元杂芳基和＝CReRf中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基和＝CReRf中的一个或多个取代基所取代； R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, cyano-substituted C1-6 alkyl, -Y1 -C3-12 cycloalkyl, -Y1-3-12 membered heterocyclyl, -Y1 - C6-12 aryl, -Y1-5-12 membered heteroaryl, -SF5 , -ORg , -NRgRh , -C(O) Rg , -C ( O) ORg , -C(O) NRgRh , -N= S (O) RgRh , -S(O) Rg ( = NRh ) , -P(O)R wherein the amino, C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl , 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano The alkyl radicals are substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, and =CR e R f ; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl and =CR e R f ;

或者任意两个R3与其相邻的原子链接形成C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选形成C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选进一步被氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；or any two R3 are linked to their adjacent atoms to form C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl; preferably, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, cyano substituted C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl. 6-10 membered aryl and 5-10 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

Ra、Rb、Rc、Re和Rf各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-(CH2)n2ORee、-(CH2)n2NReeRff、-(CH2)n2C(O)Ree、-(CH2)n2C(O)ORee、-(CH2)n2C(O)NReeRff、-(CH2)n2N＝S(O)ReeRff、-(CH2)n2S(O)Ree(＝NRff)或-(CH2)n2P(O)ReeRff，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基和＝CRggRhh中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； Ra , Rb , Rc , Re and Rf are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -( CH2 ) n2ORee , -( CH2 ) n2NReeRff , - ( CH2 ) n2C (O) Ree , -( CH2 ) n2C (O )ORee, -(CH2)n2C ( O ) NRee wherein the amino, C 1-6 alkyl , C 2-6 alkenyl , C 2-6 alkynyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with deuterium , halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, oxo , thio, C 1-6 The alkyl radicals are preferably substituted with one or more substituents selected from the group consisting of: C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl and =CR gg R hh ; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C The amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C substituted by one or more substituents selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

或者Ra与Rb链接形成C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；or Ra and Rb are linked to form a C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C6-12 aryl, and a 5-12 membered heteroaryl, which is optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, a 3-12 membered heterocyclyl, C6-12 aryl, and a 5-12 membered heteroaryl;

Y1选自键、-O-、-S-、-C(O)、-NRj-、-C(O)NRj-、-NRjC(O)-、-S(O)2NRj-、-NRjS(O)2-、C1-6亚烷基、-O-C1-6亚烷基-、-C1-6亚烷基-O-、-NRj-C1-6亚烷基-、-C1-6亚烷基-NRj-、C2-6亚烯基或C2-6亚炔基，所述的C1-6亚烷基、C2-6亚烯基和C2-6亚炔基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3- 12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；Y is selected from a bond, -O-, -S-, -C(O), -NRj- , -C(O) NRj- , -NRjC (O)-, -S (O) 2NRj- , -NRjS (O ) 2- , C1-6alkylene , -OC1-6alkylene-, -C1-6alkylene- O- , -NRj - C1-6alkylene- , -C1-6alkylene -NRj-, C2-6alkenylene or C2-6alkynylene , wherein said C1-6alkylene , C2-6alkenylene and C2-6alkynylene are optionally deuterated, halogen, amino , hydroxyl, cyano, nitro, C1-6alkyl , C2-6alkenyl , C2-6alkynyl, oxo, thio, C1-6deuteratedalkyl , C1-6haloalkyl , C1-6alkoxy , C1-6 The alkyl group is substituted with one or more substituents selected from C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl;

Rg、Rh、Ri和Rj各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1- 6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； Rg , Rh , R , and Rj are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, or 5-12 membered heteroaryl The invention also comprises a C 1-6 alkyl, C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl, which are optionally substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , oxo , thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, C 6-12 aryl and a 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C The alkyl radical is substituted with one or more substituents selected from C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

Raa、Rbb、Rcc和Rdd各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1- 6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6- 12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1- 3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1- 3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 membered aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

Ree和Rff各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl The invention also comprises a C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl, which are optionally substituted by one or more substituents of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C The alkyl radical is substituted with one or more of C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

Rgg和Rhh各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； Rgg and Rhh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl The invention also comprises a C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl, which are optionally substituted by one or more substituents of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C The alkyl radical is substituted with one or more of C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

x选自0、1、2、3、4、5或6；y选自0、1、2、3、4、5或6；x is selected from 0, 1, 2, 3, 4, 5 or 6; y is selected from 0, 1, 2, 3, 4, 5 or 6;

m1选自0、1或2；n1选自0、1、2、3或4；且m1 is selected from 0, 1 or 2; n1 is selected from 0, 1, 2, 3 or 4; and

n2选自0、1、2、3或4。n2 is selected from 0, 1, 2, 3 or 4.

在本发明地一个优选地实施方案中，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述选自 In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that Selected from

在本发明的一个优选的实施方案中，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步如通式(III-C)所示：
In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (III-C):

R1-1选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-(CH2)n2ORee、-(CH2)n2NReeRff、-(CH2)n2C(O)Ree、-(CH2)n2C(O)ORee、-(CH2)n2C(O)NReeRff、-(CH2)n2N＝S(O)ReeRff、-(CH2)n2S(O)Ree(＝NRff)或-(CH2)n2P(O)ReeRff，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基和＝CRggRhh中的一个或多个取代基所取代；R 1-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -(CH 2 ) n2 OR ee , -(CH 2 ) n2 NR ee R ff , -(CH 2 ) n2 C(O)R ee , -(CH 2 ) n2 C(O)OR ee , -(CH 2 ) n2 C(O)NR ee R ff , -(CH 2 ) n2 N＝S(O)R ee R ff , -(CH 2 ) n2 S(O)R ee (＝NR ff ) or -(CH 2 ) n2 P(O)R ee R ff , the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl The group is substituted by one or more of C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl and =CR gg R hh ;

Ree和Rff各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl;

Rgg和Rhh各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；n2选自0、1、2、3或4； Rgg and Rhh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; n2 is selected from 0, 1, 2, 3 or 4;

环A、环B、M1、M2、M3、L2、R2、R3、Rc、x和y的定义如上述任一实施方案中所定义。Ring A, Ring B, M 1 , M 2 , M 3 , L 2 , R 2 , R 3 , R c , x and y are as defined in any of the above embodiments.

在本发明的一个优选的实施方案中，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环A选自3-12元杂环基或5-12元杂芳基；优选5元杂环基、6元杂环基、5元杂芳基或6元杂芳基；更优选 更优选 In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that Ring A is selected from a 3-12-membered heterocyclic group or a 5-12-membered heteroaryl group; preferably a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered heteroaryl group or a 6-membered heteroaryl group; more preferably More preferred

在本发明的一个优选的实施方案中，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环B选自3-6元杂环基并苯基或3-6元杂环基并5-6元杂芳基；优选 In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, is characterized in that ring B is selected from 3-6 membered heterocyclic phenyl or 3-6 membered heterocyclic 5-6 membered heteroaryl; preferably

在本发明的一个优选的实施方案中，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环B选自6-14元三环杂环基；优选6-14元三环螺杂环基或6-14元三环稠杂环基；更优选 In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that ring B is selected from a 6-14-membered tricyclic heterocyclic group; preferably a 6-14-membered tricyclic spiro heterocyclic group or a 6-14-membered tricyclic fused heterocyclic group; more preferably

在本发明的一个优选的实施方案中，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步如通式(IV-A)所示：
In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (IV-A):

M4选自N或CR3a；M4选自N或CR3b；M 4 is selected from N or CR 3a ; M 4 is selected from N or CR 3b ;

R3a、R3c和R3d各自独立地选自氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6- 10芳基、5-10元杂芳基和＝CReRf中的一个或多个取代基所取代；R 3a , R 3c and R 3d are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl C1-3 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl and =CR e R f ;

R3b选自氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1- 3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基和＝CReRf中的一个或多个取代基所取代；n3选自0、1或2。R 3b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl R is a C 3-8 cycloalkyl group, a 3-8 membered heterocyclyl group, a C 6-10 aryl group, and a 5-10 membered heteroaryl group, which are optionally substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , oxo , thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, a 3-8 membered heterocyclyl group, a C 6-10 aryl group, a 5-10 membered heteroaryl group, and =CR e R f ; n3 is selected from 0, 1 or 2.

在本发明的一个优选的实施方案中，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步如通式(IV-B)所示：
In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that it is further represented by the general formula (IV-B):

M5选自N或C；M6选自N或C； M5 is selected from N or C; M6 is selected from N or C;

环C选自C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基；Ring C is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

R3e选自氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1- 3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基和＝CReRf中的一个或多个取代基所取代； R3e is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl and =CR e R f ;

R3f选自氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1- 3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基和＝CReRf中的一个或多个取代基所取代； R3f is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl and =CR e R f ;

n3选自0、1或2；p选自0、1、2、3或4；q选自0、1或2。n3 is selected from 0, 1 or 2; p is selected from 0, 1, 2, 3 or 4; q is selected from 0, 1 or 2.

在本发明的一个优选的实施方案中，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R2选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、氰基取代的C1-3烷基、C3-8环烷基或-C(O)NReeRff，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、氰基取代的C1-3烷基和C3-8环烷基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、氰基取代的C1-3烷基和C3-8环烷基中的一个或多个取代基所取代；In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl or -C(O) NReeRff , wherein the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkyl substituted with cyano and C3-8 cycloalkyl are optionally substituted with deuterium, halogen , amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkyl substituted with cyano and C3-8 cycloalkyl. substituted by one or more substituents selected from C 1-3 haloalkyl, C 1-3 alkyl substituted by cyano, and C 3-8 cycloalkyl;

Ree和Rff各自独立地选自氢、氘、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基或氰基取代的C1-3烷基；R ee and R ff are each independently selected from hydrogen, deuterium, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 alkyl;

优选氢、氘、氟、氯、甲基、氘代甲基、二氟甲基、三氟甲基、 Preferred are hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, trifluoromethyl,

在本发明的一个优选的实施方案中，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，Ra选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基或氰基取代的C1-3烷基；优选氢、氘、氟、氯、甲基、氘代甲基、二氟甲基或三氟甲基。In a preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that Ra is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl or C1-3 alkyl substituted with cyano; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl or trifluoromethyl.

在本发明的一个优选的实施方案中，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，Rb选自氢、氘、卤素、氰基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、卤代C1-3烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、--(CH2)n2ORee、-(CH2)n2NReeRff、-(CH2)n2C(O)Ree、-(CH2)n2C(O)ORee、-(CH2)n2C(O)NReeRff、-(CH2)n2N＝S(O)ReeRff、-(CH2)n2S(O)Ree(＝NRff)或-(CH2)n2P(O)ReeRff，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、卤代C1-3烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基和3-8元杂环基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1- 3烷基、C3-8环烷基、3-8元杂环基和＝CRggRhh中的一个或多个取代基所取代；优选氢、氘、卤素、氰基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、卤代C1-3烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、-(CH2)n2ORee、-(CH2)n2NReeRff、-(CH2)n2C(O)Ree、-(CH2)n2C(O)NReeRff或-(CH2)n2P(O)ReeRff，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、卤代C1-3烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基和3-8元杂环基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3- 8环烷基或3-8元杂环基中的一个或多个取代基所取代；In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that R b is selected from hydrogen, deuterium, halogen, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, --(CH 2 ) n2 OR ee , --(CH 2 ) n2 NR ee R ff , --(CH 2 ) n2 C( O )R ee , --(CH 2 ) n2 C(O)OR ee , --(CH 2 ) n2 C(O)NR ee R ff , --(CH 2 ) n2 N＝S(O)R ee R ff wherein the amino , C 1-3 alkyl , C 2-4 alkenyl , C 2-4 alkynyl , C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl and 3-8 membered heterocyclic group are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl , C 1-3 alkoxy, C 1-3 haloalkoxy , C The present invention is substituted by one or more substituents selected from the group consisting of : C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl and =CR gg R hh ; preferably hydrogen, deuterium, halogen, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halo-C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH 2 ) n2 OR ee , -(CH 2 ) n2 NR ee R ff , -(CH 2 ) n2 C(O)R ee , -(CH 2 ) n2 C(O)NR ee R ff or -(CH 2 ) n2 P(O)R ee R ff , the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl and 3-8 membered heterocyclic group, are optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl or 3-8 membered heterocyclic group ;

Ree和Rff各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基或3-8元杂环基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1- 3羟烷基、氰基取代的C1-3烷基、C3-8环烷基和3-8元杂环基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1- 3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O) -C 1-3 alkyl , C 3-8 cycloalkyl or 3-8 membered heterocyclyl. 3-8 -membered cycloalkyl and 3-8-membered heterocyclyl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

n2选自0、1或2；n2 is selected from 0, 1 or 2;

优选氢、氘、氟、氯、氰基、甲基、乙基、乙炔基、丙炔基、氘代甲基、氘代乙基、二氟甲基、三氟甲基、三氟乙基、甲氧基、乙氧基、氘代甲氧基、二氟甲氧基、三氟甲氧基、 Preferred are hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy,

在本发明的一个优选的实施方案中，所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R1-1选自C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基或氰基取代的C1-3烷基，所述的C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基和氰基取代的C1-3烷基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3- 12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基和＝CRggRhh中的一个或多个取代基所取代。In a preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that R1-1 is selected from C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl or C1-3 alkyl substituted with cyano, wherein the C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl and C1-3 alkyl substituted with cyano are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 The group may be substituted with one or more of: C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl and =CR gg R hh .

本发明还提供一种中间体，其特征在于，所述中间体为如通式(IV-A-I)或(IV-B-I)所示的化合物、其立体异构体或其药学上可接受盐：
The present invention also provides an intermediate, characterized in that the intermediate is a compound represented by the general formula (IV-AI) or (IV-BI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

R1-1如权利要求3所述；R 1-1 is as described in claim 3;

M4、M5、M6、R1-1、R3a、R3b、R3c、R3d、R3e、R3f、p、q、n3和n4如上述任一实施方案中所述。 M4 , M5 , M6 , R1-1 , R3a , R3b , R3c , R3d , R3e , R3f , p, q, n3 and n4 are as described in any of the above embodiments.

本发明还提供一种制备通式(III-C)所示的化合物、其立体异构体或其药学上可接受的盐的方法，其特征在于：
The present invention also provides a method for preparing a compound represented by general formula (III-C), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that:

通式(III-C-I)所示的化合物与通式(III-C-II)所示的化合物在缩合剂和碱存在条件下反应得到通式(III-C-III)所示的化合物，进一步脱除保护基得到通式(III-C)所示的化合物；The compound represented by the general formula (III-C-I) reacts with the compound represented by the general formula (III-C-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (III-C-III), and the protecting group is further removed to obtain the compound represented by the general formula (III-C);

优选地，所述方法为制备通式(IV-A)所示的化合物、其立体异构体或其药学上可接受的盐的方法：
Preferably, the method is a method for preparing a compound represented by general formula (IV-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

通式(IV-A-I)所示的化合物与通式(IV-A-II)所示的化合物在缩合剂和碱存在条件下反应得到通式(IV-A-III)所示的化合物，进一步脱除保护基得到通式(IV-A)所示的化合物；The compound represented by the general formula (IV-A-I) reacts with the compound represented by the general formula (IV-A-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (IV-A-III), and the protecting group is further removed to obtain the compound represented by the general formula (IV-A);

或，所述方法为制备通式(IV-B)所示的化合物、其立体异构体或其药学上可接受的盐的方法：
Or, the method is a method for preparing a compound represented by general formula (IV-B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

通式(IV-B-I)所示的化合物与通式(IV-B-II)所示的化合物在缩合剂和碱存在条件下反应得到通式(IV-B-III)所示的化合物，进一步脱除保护基得到通式(IV-B)所示的化合物；The compound represented by the general formula (IV-B-I) reacts with the compound represented by the general formula (IV-B-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (IV-B-III), and the protecting group is further removed to obtain the compound represented by the general formula (IV-B);

Pg1选自氢、烯丙氧羰基、三氟乙酰基、叔丁基亚磺酰基、2,4-二甲氧基苄基、3,5-二甲氧基苄基、硝基苯磺酰基、三苯甲基、笏甲氧羰基、9-芴甲氧羰基、苄基、对甲苯磺酰基、对甲氧基苄基、甲酸酯、乙酰基、苄氧羰基、邻苯二甲酰基、叔丁氧羰基、苄基或对甲氧苯基；优选苄基、对甲氧基苄基或叔丁氧羰基；Pg 1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably benzyl, p-methoxybenzyl or tert-butyloxycarbonyl;

Pg2选自氢、烯丙氧羰基、三氟乙酰基、叔丁基亚磺酰基、2,4-二甲氧基苄基、3,5-二甲氧基苄基、硝基苯磺酰基、三苯甲基、笏甲氧羰基、9-芴甲氧羰基、苄基、对甲苯磺酰基、对甲氧基苄基、甲酸酯、乙酰基、苄氧羰基、邻苯二甲酰基、叔丁氧羰基、苄基或对甲氧苯基；优选氢、苄基、对甲氧基苄基或叔丁氧羰基； Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably hydrogen, benzyl, p-methoxybenzyl or tert-butyloxycarbonyl;

环A、M1、M2、M3、M4、M5、M6、Ra、Rb、Rc、R2、R1-1、R3a、R3b、R3c、R3d、R3e、R3f、x、p、q、n3和n4如上述任一实施方案中所述。Ring A, M1 , M2 , M3 , M4 , M5 , M6 , Ra, Rb , Rc, R2 , R1-1 , R3a , R3b , R3c , R3d , R3e , R3f , x, p, q, n3 and n4 are as described in any of the embodiments above.

在本发明的一个优选的实施方案中，所述的制备方法中缩合剂选自二氯亚砜、三氯氧磷、对甲苯磺酰氯、甲烷磺酰氯、二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲胺基丙基)-3-乙基碳二亚胺、羰基二咪唑、氯甲酸乙酯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、O-苯并三氮唑-四甲基脲六氟磷酸酯或四甲基氯代脲六氟膦酸酯；优选三氯氧磷、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、O-苯并三氮唑-四甲基脲六氟磷酸酯或四甲基氯代脲六氟膦酸酯；碱选自碳酸钾、甲胺、三乙胺、二异丙胺、吡啶、咪唑、N-甲基咪唑或N-甲基吗啉。In a preferred embodiment of the present invention, in the preparation method, the condensing agent is selected from thionyl chloride, phosphorus oxychloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, carbonyldiimidazole, ethyl chloroformate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate or tetramethylchlorouronium hexafluorophosphonate; preferably phosphorus oxychloride, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate or tetramethylchlorouronium hexafluorophosphonate; the base is selected from potassium carbonate, methylamine, triethylamine, diisopropylamine, pyridine, imidazole, N-methylimidazole or N-methylmorpholine.

本发明进一步涉及一种药物组合物，其包括治疗有效剂量的任一实施方案中所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound shown in any one of the embodiments, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

本发明进一步涉及任一实施方案中所示的化合物、其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备PRMT5抑制剂药物中的应用。The present invention further relates to the use of the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of PRMT5 inhibitor drugs.

本发明进一步涉及任一实施方案中所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗癌症的药物中的应用；优选地，所述癌症是MTAP基因缺失的癌症。The present invention further relates to the use of the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating cancer; preferably, the cancer is a cancer with MTAP gene deletion.

本发明进一步涉及任一实施方案中所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗癌症的方法；优选地，所述癌症是MTAP基因缺失的癌症。The present invention further relates to a method for preparing a method for treating cancer using the compound shown in any embodiment, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition; preferably, the cancer is a cancer with MTAP gene deletion.

在一些实施方案中，所述癌症选自肺癌、肝细胞癌、乳腺癌、皮肤癌、膀胱癌、肝癌、胰腺癌、头颈癌、胶质瘤、胶质母细胞瘤、食管癌、胰腺癌、间皮瘤、黑色素瘤、星形细胞瘤、未分化的多形性肉瘤、弥漫性大B细胞淋巴瘤、白血病、胃腺癌、粘液纤维肉瘤、胆管肉瘤、脑癌、胃癌、肾癌、子宫内膜癌、卵巢瘤、前列腺癌、淋巴癌、非霍奇金淋巴瘤、尿路癌、软组织癌、胸膜癌、大肠癌、结直肠癌、胆道癌或胆管癌；所述肺癌选自非小细胞肺癌、肺鳞癌或肺腺癌；所述食管癌选自食管鳞状细胞癌或食管腺癌。In some embodiments, the cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colon cancer, colorectal cancer, biliary tract cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung carcinoma or adenocarcinoma of the lung; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

本发明还涉及一种治疗预防和/或治疗癌症的方法，其包括向患者施用治疗有效剂量的任一实施方案中所示的化合物其立体异构体或其药学上可接受的盐，或其药物组合物。The present invention also relates to a method for preventing and/or treating cancer, which comprises administering to a patient a therapeutically effective dose of a compound shown in any embodiment, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

本发明还涉及治疗哺乳动物中的癌症的方法，其包括向所述哺乳动物施用治疗有效量的本发明的化合物或其药学上可接受的盐、酯、前药、溶剂化物、水合物或衍生物。The present invention also relates to a method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

在本发明的某些实施方案中，所述的药物组合物，以游离碱计，所述化合物、其立体异构体或其药学上可接受盐的重量百分比为0.1％～95％，优选90％、85％、80％、75％、70％、60％、50％。In certain embodiments of the present invention, the weight percentage of the compound, its stereoisomer or pharmaceutically acceptable salt thereof in the pharmaceutical composition, calculated as free base, is 0.1% to 95%, preferably 90%, 85%, 80%, 75%, 70%, 60%, 50%.

在本发明的某些实施方案中，所述药物组合物选自片剂、胶囊剂、液体制剂或注射剂，优选的，还包含填充剂，任选的还包含崩解剂，或者进一步包含助流剂或润滑剂中的一种或多种。In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, preferably, further comprising a filler, optionally a disintegrant, or further comprising one or more of a glidant or a lubricant.

在本发明的某些实施方案中，所述药物组合物为速释制剂或缓释制剂。In certain embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

在本发明的某些实施方案中，所述的药物组合物，以游离碱计，所述化合物、其立体异构体或其药学上可接受盐的单位剂量为1-1000mg，优选1-500mg，或者优选1mg、2mg、3mg、5mg、10mg、20mg、40mg、50mg、60mg、80mg、100mg、200mg、300mg、400mg或500mg。In certain embodiments of the present invention, the pharmaceutical composition, calculated as a free base, has a unit dose of 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

在本发明的某些实施方案中，所述化合物、其立体异构体或其药学上可接受盐，可以通过任何便利的方法给予，例如，通过口服，肠胃外，口腔，舌下，鼻腔，直肠，鞘内或经皮给予，以及相应地调整的药物组合物。In certain embodiments of the invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, may be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.

在本发明的某些实施方案中，所述化合物、其立体异构体或其药学上可接受盐，可以配制成液体或固体制剂，例如糖浆剂，混悬剂，乳剂，片剂，胶囊剂，粉剂，颗粒剂，或锭剂。In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

在一些实施方案中，本方法涉及诸如肺癌、肝细胞癌、乳腺癌、皮肤癌、膀胱癌、肝癌、胰腺癌、头颈癌、胶质瘤、胶质母细胞瘤、食管癌、胰腺癌、间皮瘤、黑色素瘤、星形细胞瘤、未分化的多形性肉瘤、弥漫性大B细胞淋巴瘤、白血病、胃腺癌、粘液纤维肉瘤、胆管肉瘤、脑癌、胃癌、肾癌、子宫内膜癌、卵巢瘤、前列腺癌、淋巴癌、非霍奇金淋巴瘤、尿路癌、软组织癌、胸膜癌、大肠癌、结直肠癌、胆道癌或胆管癌等病症的治疗。In some embodiments, the method relates to the treatment of conditions such as lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, lymphoma, non-Hodgkin lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colon cancer, colorectal cancer, biliary tract cancer, or bile duct cancer.

在一些实施方案中，所述肺癌选自非小细胞肺癌、肺鳞癌或肺腺癌；所述食管癌选自食管鳞状细胞癌或食管腺癌。In some embodiments, the lung cancer is selected from non-small cell lung cancer, lung squamous cell carcinoma, or lung adenocarcinoma; and the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.

发明的详细说明Detailed description of the invention

除非有相反陈述，此处所用的所有技术和科学术语通常与本领域普通技术人员的一般理解具有相同的含义，具体而言，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, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Specifically, the terms used in the specification and claims have the following meanings.

术语“烷基”指直链或支链的饱和脂肪族烃基团，所述烷基可任选地被一个或多个取代基取代。在特定的实施方式中，烷基是指具有1至20(C1-20)、1至15(C1-15)、1至12(C1-12)、1至10(C1-10)、1至8(C1-8)、1至6(C1-6)或1至3(C1-3)个碳原子的直链饱和烃基，或者具有3至20(C3-20)、3至15(C3-15)、3至12(C3-12)、3至10(C3-10)、3至8(C3-8)或3至6(C3-6)个碳原子的带支链饱和烃基。此处所用的直链C1-6烷基和带支链C3-6烷基基团也称为“低级烷基”。例如，C1-6烷基指具有1至6个碳原子的线性饱和单价烃基或者具有3至6个碳原子的带支链饱和单价烃基。在一个实施方式中，所述C1-6烷基含有1至6个(例如1个、2个、3个、4个、5个、6个)碳原子。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基及其各种支链异构体等。在一个实施方式中，该烷基是本文别处描述的任选地取代的烷基。The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, which may be optionally substituted with one or more substituents. In a specific embodiment, the alkyl group refers to a straight chain saturated hydrocarbon group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 ) carbon atoms, or a branched saturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, straight-chain C 1-6 alkyl and branched C 3-6 alkyl groups are also referred to as "lower alkyl". For example, C 1-6 alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 1-6 alkyl contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-ethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched chain isomers thereof, and the like. In one embodiment, the alkyl group is an optionally substituted alkyl group described elsewhere herein.

术语“亚烷基”是指烷基的一个氢原子进一步被取代，其中“烷基”的定义同前所述。“亚烷基”的非限制性实例包括：亚甲基(-CH2-)、亚乙基(-(CH2)2-)、亚丙基(-(CH2)3-)或亚丁基(-(CH2)4-)。在一个实施方式中，该亚烷基是本文别处描述的任选地取代的烷基。The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, wherein "alkyl" is as defined above. Non-limiting examples of "alkylene" include: methylene ( -CH2- ), ethylene (-( CH2 ) 2- ), propylene (-( CH2 ) 3- ) or butylene (-( CH2)4- ) . In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

术语“烯基”指直链或支链的不饱和脂肪族烃基团，其含有至少一个碳碳双键且碳碳双键可以位于烯基内的任何位置，所述烯基可任选地被一个或多个取代基所取代。在特定的实施方式中，烯基是具有2至20(C2-20)、2至15(C2-15)、2至12(C2-12)、2至10(C2-10)、2至8(C2-8)、2至6(C2-6)或2至4(C2-4)个碳原子的直链不饱和烃基，或者具有3至20(C3-20)、3至15(C3-15)、3至12(C3-12)、3至10(C3-10)、3至8(C3-8)或3至6(C3-6)个碳原子的带支链不饱和烃基。除非另行指明，此处所用的术语“烯基”同时包括了直链和带支链的烯基。例如，C2-6烯基指具有2至6个碳原子的直链不饱和烃基或者具有3至6个碳原子的带支链不饱和烃基。在一个实施方式中，所述C2-6烯基含有2至6个(例如2个、3个、4个、5个、6个)碳原子。烯基的非限制性实例包括： 本领域普通技术人员可以理解，术语“烯基”还可包括具有“顺式”和“反式”构型的基团，或者替代性地，“E”和“Z”构型的基团。在一个实施方式中，该烯基是本文别处描述的任选地取代的烯基。The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond and the carbon-carbon double bond may be located at any position within the alkenyl group, and the alkenyl group may be optionally substituted with one or more substituents. In certain embodiments, alkenyl is a straight chain unsaturated hydrocarbon group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a branched unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight chain and branched alkenyl groups. For example, C2-6 alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C2-6 alkenyl contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl include: One of ordinary skill in the art will appreciate that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl described elsewhere herein.

术语“亚烯基”是指烯基的一个氢原子进一步被取代，其中“烯基”的定义同前所述。在一个实施方式中，该亚烯基是本文别处描述的任选地取代的烷基。The term "alkenylene" refers to a further substitution of a hydrogen atom of an alkenyl group, wherein "alkenyl" is as defined above. In one embodiment, the alkenylene group is an optionally substituted alkyl group as described elsewhere herein.

术语“炔基”指直链或支链不饱和脂肪族烃基团，其含有至少一个碳碳三键且碳碳三键可以位于炔基内的任何位置，所述炔基可任选地被一个或多个取代基所取代。在特定的实施方式中，炔基是具有2至20(C2-20)、2至15(C2-15)、2至12(C2-12)、2至10(C2-10)、2至8(C2-8)、2至6(C2-6)或2至4(C2-4)个碳原子的直链不饱和烃基，或者具有3至20(C3-20)、3至15(C3-15)、3至12(C3-12)、3至10(C3-10)、3至8(C3-8)或3至6(C3-6)个碳原子的带支链不饱和烃基。除非另行指明，此处所用的术语“炔基”同时包括了直链和带支链的炔基。例如，C2-6炔基指具有2至6个碳原子的直链不饱和烃基或者具有3至6个碳原子的带支链不饱和烃基。在一个实施方式中，所述C2-6炔基含有2至6个(例如2个、3个、4个、5个、6个)碳原子。炔基的非限制性实例包括：在一个实施方式中，该炔基是本文别处描述的任选地取代的炔基。The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and the carbon-carbon triple bond can be located at any position within the alkynyl group, and the alkynyl group can be optionally substituted with one or more substituents. In a specific embodiment, the alkynyl group is a straight chain unsaturated hydrocarbon group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a branched unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms. Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C2-6 alkynyl refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C2-6 alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.

术语“亚炔基”是指炔基的一个氢原子进一步被取代，其中“炔基”的定义同前所述。在一个实施方式中，该亚炔基是本文别处描述的任选地取代的烷基。The term "alkynylene" refers to an alkynyl group in which one of its hydrogen atoms is further substituted, wherein "alkynyl" is as defined above. In one embodiment, the alkynylene group is an optionally substituted alkyl group as described elsewhere herein.

术语“环烷基”指饱和或部分不饱和的脂肪烃单环、多环(两个及以上)环状基团，其可任选地被一个或多个取代基取代。在特定的实施方式中，环烷基环包含3至20(C3-20)、3至14(C3-14)、3至12(C3-12)、3至8(C3-8)或3至6(C3-6)个碳原子；在一个实施方式中，环烷基环包含6至14(C6-14)或7至10(C7-10)个碳原子；其可以含有一个或多个双键，但不具有完全共轭的π电子系统。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基或环辛基等；多环环烷基包括螺环烷基、稠环烷基和桥环烷基在一个实施方式中。在一个实施方式中，该环烷基是本文别处描述的任选地取代的环烷基或任选与杂环基、芳基或杂芳基稠合的环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。The term "cycloalkyl" refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic, polycyclic (two or more) cyclic group, which may be optionally substituted by one or more substituents. In a specific embodiment, the cycloalkyl ring contains 3 to 20 (C 3-20 ), 3 to 14 (C 3-14 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring contains 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) carbon atoms; it may contain one or more double bonds, but does not have a completely conjugated π electron system. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl in one embodiment. In one embodiment, the cycloalkyl is an optionally substituted cycloalkyl or a cycloalkyl optionally fused to a heterocyclyl, aryl or heteroaryl group as described elsewhere herein, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

术语“螺环烷基”指单环之间共用一个碳原子(称螺原子)的脂肪烃多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。在特定的实施方式中，螺环烷基包含5至20(C5-20)、6至14(C6-14)或7至10(C7-10)(例如7个、8个、9个、10个)个碳原子。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，在一个实施方式中为单螺环烷基和双螺环烷基。在一个实施方式中为4元/4元、3元/5元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。在一个实施方式中，该螺环烷基是本文别处描述的任选地取代的螺环烷基。螺环烷基的非限制性实例包括：
The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group that shares a carbon atom (called a spiral atom) between monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the spirocycloalkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, in one embodiment, a single spiral cycloalkyl and a double spiral cycloalkyl. In one embodiment, it is a 4 yuan/4 yuan, 3 yuan/5 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral cycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl described elsewhere herein. Non-limiting examples of spirocycloalkyl include:

术语“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。在特定的实施方式中，稠环烷基包含5至20(C5-20)、6至14(C6-14)或7至10(C7- 10)(例如7个、8个、9个、10个)个碳原子。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，在一个实施方式中为双环或三环，进一步在一个实施方式中为3元/5元、4元/5元、5元/5元或5元/6元双环烷基。在一个实施方式中，该稠环烷基是本文别处描述的任选地取代的稠环烷基或任选与杂环基、芳基或杂芳基稠合的稠环烷基。稠环烷基的非限制性实例包括：
The term "fused cycloalkyl" refers to a full carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the fused cycloalkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7- 10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, in one embodiment, a bicyclic or tricyclic, and further in one embodiment, a 3 yuan/5 yuan, 4 yuan/5 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyl. In one embodiment, the fused cycloalkyl is an optionally substituted fused cycloalkyl described elsewhere herein or a fused cycloalkyl optionally fused to a heterocyclic radical, an aryl or a heteroaryl. Non-limiting examples of fused cycloalkyl include:

术语“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。在特定的实施方式中，桥环烷基包含5至20(C5-20)、6至14(C6-14)或7至10(C7-10)(例如7个、8个、9个、10个)个碳原子。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选双环或三环。在一个实施方式中，该桥环烷基是本文别处描述的任选地取代的桥环烷基。桥环烷基的非限制性实例包括：
The term "bridged cycloalkyl" refers to a full carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the bridged cycloalkyl contains 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic or tricyclic. In one embodiment, the bridged cycloalkyl is an optionally substituted bridged cycloalkyl described elsewhere herein. Non-limiting examples of bridged cycloalkyl include:

术语“亚环烷基”是指环烷基的一个氢原子进一步被取代形成的二价环烷基，其中，亚环烷基是任选取代的或非取代的，环烷基定义如上所述。The term "cycloalkylene" refers to a divalent cycloalkyl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the cycloalkylene group is optionally substituted or unsubstituted, and the cycloalkyl group is as defined above.

术语“杂环基”指饱和或部分不饱和单环或多环环状烃基团，其中一个或多个环原子为选自氮、氧、硼、磷或硫的杂原子，其中该氮、磷或硫原子可被任选地氧化，氮原子可被任选地季铵化，环碳原子可任选地被氧取代，但不包括-O-O-、-O-S-的环部分，其余环原子为碳，其可以含有一个或多个双键，但不具有完全共轭的π电子系统。在特定实施方式中，杂环基包含3至20、8至20、10至20、3至16、8至16、10至16、3至14、5至14、8至14、3至12、5至12、8至12、3至8或3至6个环原子，其中1～4个是杂原子；在一个实施方式中，杂环基包含3至6、4至6、3至8、3至10、6至10或7至11个环原子；在一个实施方式中，杂环基包含3至8个(例如3个、4个、5个、6个、7个、8个)环原子。单环杂环基的非限制性实例包括四氢吡咯基、氮杂环丁烷基、氧杂环丁烷基、氧杂环己烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基和吡喃基等。多环杂环基包括螺杂环基、稠杂环基和桥杂环基。在一个实施方式中，所述的杂环基是本文别处描述的任选地取代的，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接的杂环基。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, the ring carbon atoms may be optionally substituted by oxygen, but does not include the ring parts of -O-O-, -O-S-, and the remaining ring atoms are carbon, which may contain one or more double bonds but do not have a completely conjugated π electron system. In certain embodiments, the heterocyclyl contains 3 to 20, 8 to 20, 10 to 20, 3 to 16, 8 to 16, 10 to 16, 3 to 14, 5 to 14, 8 to 14, 3 to 12, 5 to 12, 8 to 12, 3 to 8, or 3 to 6 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl contains 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclyl contains 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. The limiting examples of monocyclic heterocyclic radical include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl etc..Polycyclic heterocyclic radical includes spiro heterocyclic radical, condensed heterocyclic radical and bridge heterocyclic radical.In one embodiment, the heterocyclic radical is the optionally substituted described elsewhere herein, or the heterocyclic radical further and ring-connected with other cycloalkyl, heterocyclic radical, aryl and heteroaryl by any two or more atoms on the ring.

术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧、硼、磷或硫的杂原子，其余环原子为碳，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。在特定实施方式中，螺杂环基包含5至20或6至14个环原子；在一个实施方式中包含7至11个(例如7个、8个、9个、10个、11个)个环原子；根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基；优选单螺杂环基和双螺杂环基；在一个实施方式中，螺杂环基为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基；在一个实施方式中，该螺杂环基是本文别处描述的任选地取代的螺杂环基；螺杂环基的非限制性实例包括：
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. In a specific embodiment, the spiroheterocyclyl contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; according to the number of spiro atoms shared between the rings, the spiroheterocyclyl is divided into a monospiroheterocyclyl, a bispiroheterocyclyl or a polyspiroheterocyclyl; preferably a monospiroheterocyclyl and a bispiroheterocyclyl; in one embodiment, the spiroheterocyclyl is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl; in one embodiment, the spiroheterocyclyl is an optionally substituted spiroheterocyclyl described elsewhere herein; non-limiting examples of spiroheterocyclyls include:

术语“稠杂环基”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杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧、硼、磷或硫的杂原子，其余环原子为碳。在特定实施方式中，稠杂环基为包含5至20或6至14个环原子，在一个实施方式中包含7至10个(例如7个、8个、9个、10个)环原子；根据组成环的数目可以分为双环、三环、四环或多环稠杂环基；优选双环或三环；在一个实施方式中为5元/5元或5元/6元双环稠杂环基；在一个实施方式中，该稠杂环基是本文别处描述的任选地取代的，或可与环烷基、杂环基、芳基或杂芳基稠合的稠杂环基；稠杂环基的非限制性实例包括：
The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a specific embodiment, the fused heterocyclic group is a heterocyclic group containing 5 to 20 or 6 to 14 ring atoms, and in one embodiment contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group; preferably a bicyclic or tricyclic group; in one embodiment, it is a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is a fused heterocyclic group described elsewhere herein that is optionally substituted or fused with a cycloalkyl, heterocyclic, aryl or heteroaryl group; non-limiting examples of fused heterocyclic groups include:

术语“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧、硼、磷或硫的杂原子，其余环原子为碳。在特定的实施方式中，桥杂环基包含5至20或6至14个环原子；在一个实施方式中包含7至10个(例如7个、8个、9个、10个)环原子；根据组成环的数目可以分为双环、三环、四环或多环桥杂环基；优选双环、三环或四环；在一个实施方式中为双环或三环；在一个实施方式中，该桥杂环基是本文别处描述的任选地取代的桥杂环基；桥杂环基的非限制性实例包括：
The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon. In a specific embodiment, the bridged heterocyclic group contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group; preferably a bicyclic, tricyclic or tetracyclic group; in one embodiment, it is a bicyclic or tricyclic group; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

术语“三环杂环基”指系统中组成环的数目为三环的杂环基，其中三环可以是并环体系、螺环体系或桥环体系，在一个实施方式中，三环杂环基是系统中的三个环至少有一个环为杂环基，其他两个环可以是环烷基、杂环基、芳基或杂芳基，环烷基、杂环基、芳基或杂芳基的定义如上所述，其非限制性实例优选如下三环杂环基：
The term "tricyclic heterocyclic group" refers to a heterocyclic group having three rings in the system, wherein the three rings may be a paracyclic system, a spirocyclic system or a bridged ring system. In one embodiment, the tricyclic heterocyclic group is a system in which at least one of the three rings is a heterocyclic group, and the other two rings may be cycloalkyl, heterocyclic group, aryl or heteroaryl. The definitions of cycloalkyl, heterocyclic group, aryl or heteroaryl are as described above, and non-limiting examples thereof are preferably the following tricyclic heterocyclic groups:

术语“亚杂环基”是指杂环基的一个氢原子进一步被取代形成的二价杂环基，其中，亚杂环基是任选取代的或非取代的，杂环基定义如上所述。The term "heterocyclylene" refers to a divalent heterocyclic group in which one hydrogen atom of a heterocyclic group is further substituted, wherein the heterocyclic group is optionally substituted or unsubstituted, and the heterocyclic group is as defined above.

术语“芳基”指至少含有一个具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，其可任选地被一个或多个取代基取代。在特定的实施方式中，芳基包含6至20个、6至14个、6至12个或6至10个环原子；在一个实施方式中，芳基可以进一步指双环、三环或四环的环系统，其中至少一个环是芳香族环，其他的环可以是饱和的、部分不饱和的碳环或包含一个或多个独立选自O、S和N的杂原子的环；在一个实施方式中，所述芳基选自苯并5-10元杂芳基、苯并3-10元环烷基或苯并3-10元杂环基。在一个实施方式中，所述芳基选自苯并5-6元杂芳基、苯并3-6元环烷基或苯并3-6元杂环基，其中杂环基为含1-3个氮原子、氧原子或硫原子的杂环基。其非限制性实例包括苯基、萘基、芴基、甘菊环基、蒽基、菲基、芘基、联苯基、三联苯基、二氢萘基、茚基、四氢萘基(萘满基)、 The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group containing at least one conjugated π electron system, which may be optionally substituted by one or more substituents. In a particular embodiment, the aryl group contains 6 to 20, 6 to 14, 6 to 12, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from a benzo 5-10 membered heteroaryl, a benzo 3-10 membered cycloalkyl, or a benzo 3-10 membered heterocyclyl. In one embodiment, the aryl group is selected from a benzo 5-6 membered heteroaryl, a benzo 3-6 membered cycloalkyl, or a benzo 3-6 membered heterocyclyl, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetralinyl),

术语“亚芳基”是指芳基的一个氢原子进一步被取代形成的二价芳基，其中，亚芳基是任选取代的或非取代的，芳基定义如上所述。The term "arylene group" refers to a divalent aromatic group formed by further replacing one hydrogen atom of an aryl group, wherein the arylene group is optionally substituted or unsubstituted, and the aryl group is as defined above.

术语“杂芳基”指包含至少一个芳香族环的任选地取代的单环、多环基团或环系统，其中该芳香族环具有一个或多个独立选自O、S和N的杂原子。在特定的实施方式中，杂芳基包含5至20个、5至14个、5至12个或者5至10个环原子，其中1至4个为杂原子；在一个实施方式中，杂芳基包含5个或6个环原子；在特定的实施方式中，杂芳基可以进一步指双环、三环或四环状环，其中至少含有一个环是具有一个或多个独立选自O、S和N的杂原子的芳香族环，其他的环可以是饱和的、部分不饱和的碳环或包含一个或多个独立选自O、S和N的杂原子的环。在一个实施方式中，所述杂芳基选自杂芳基并6-10元芳基、杂芳基并3-10元环烷基或杂芳基并3-10元杂环基；进一步在一个实施方式中，所述杂芳基选自5元或6元杂芳基并6-10元芳基、5元或6元杂芳基并3-6元环烷基、5元或6元杂芳基并3-6元杂环基，其中杂环基为含1-3个氮原子、氧原子或硫原子的杂环基。其非限制性实例包括：呋喃基、咪唑基、异噻唑基、异噁唑基、噁二唑基、噁唑基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、噻二唑基、噻唑基、噻吩基、四唑基、三嗪基、三唑基、苯并呋喃基、苯并咪唑基、苯并异噁唑基、苯并吡喃基、苯并噻二唑基、苯并噻吩基、苯并苯硫基、苯并噻吩基、苯并三唑基、咪唑并吡啶基、咪唑并噻唑基、吲嗪基、吲哚基、吲唑基、异苯并呋喃基、异苯并噻吩基、异吲哚基、异喹啉基、萘啶基、噁唑并吡啶基、酞嗪基、蝶啶基、嘌呤基、吡啶并吡啶基、吡咯并吡啶基、喹啉基、喹喔啉基、喹唑啉基、噻二唑并嘧啶基、噻吩并吡啶基、吖啶基、苯并吲哚基、咔唑基、联苯并呋喃基、菲咯啉基、菲啶基、吩吡嗪基、吩嗪基、吩噻嗪基、吩噁嗪基、呫吨基、 The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system containing at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N. In specific embodiments, the heteroaryl group contains 5 to 20, 5 to 14, 5 to 12 or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group contains 5 or 6 ring atoms; in specific embodiments, the heteroaryl group may further refer to a bicyclic, tricyclic or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated carbocyclic rings or rings containing one or more heteroatoms independently selected from O, S and N. In one embodiment, the heteroaryl group is selected from heteroaryl and 6-10 membered aryl, heteroaryl and 3-10 membered cycloalkyl or heteroaryl and 3-10 membered heterocyclyl; further in one embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl and 6-10 membered aryl, 5- or 6-membered heteroaryl and 3-6 membered cycloalkyl, 5- or 6-membered heteroaryl and 3-6 membered heterocyclyl, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms or sulfur atoms. Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothiophenyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl , indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzindolyl, carbazolyl, bibenzofuranyl, phenanthrolinyl, phenanthridinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,

术语“亚杂芳基”是指环烷基的一个氢原子进一步被取代形成的二价杂芳基，其中，亚杂芳基是任选取代的或非取代的，杂芳基定义如上所述。The term "heteroarylene" refers to a divalent heteroaryl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the heteroarylene group is optionally substituted or unsubstituted, and the heteroaryl group is as defined above.

术语“杂烷基”指稳定的直链或支链，或者环状的烃基，或其组合，其由所示数量的碳原子和选自O、N、Si和S的一个或多个(在一个实施方式中为一至三个)杂原子组成，且其中氮和硫原子任选地被氧化，该氮杂原子可任选地被季铵化。在一个实施方式中，杂原子O、N和S可被放在杂烷基基团的任意内部位置。在一个实施方式中，杂原子Si可被放在杂烷基基团的任意位置(例如，内部或末端位置)，包括烷基基团与分子的剩余部分连接的位置。其非限制性实例包括：-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-Si(CH3)3、-CH2-CH＝N-OCH3和-CH＝CH-N(CH3)-CH3。最多两个杂原子可以是连续的，例如，-CH2-NH-O-CH3和-CH2-O-Si(CH3)3。在特定的实施方式中，该杂烷基是本文别处描述的任选地取代的杂烷基。The term "heteroalkyl" refers to a stable straight or branched chain, or cyclic hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (in one embodiment, one to three) heteroatoms selected from O, N, Si and S, and wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. In one embodiment, the heteroatoms O, N and S may be placed at any interior position of the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position (e.g., interior or terminal position) of the heteroalkyl group, including the position where the alkyl group is attached to the remainder of the molecule. Non-limiting examples thereof include: -CH2- CH2 -O - CH3 , -CH2 -CH2 - NH - CH3 , -CH2 -CH2 - N ( CH3 ) -CH3 , -CH2 - S- CH2 - CH3 , -CH2 -CH2 -S (O) -CH3 , -CH2 -CH2 - S(O) 2- CH3 , -CH=CH-O- CH3 , -Si( CH3 ) 3 , -CH2 -CH=N- OCH3 , and -CH=CH-N( CH3 ) -CH3 . Up to two heteroatoms may be consecutive, for example, -CH2- NH-O- CH3 and -CH2 -O-Si( CH3 ) 3 . In a particular embodiment, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基或环烷基的定义同前所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基或环己氧基。在一个实施方式中，该烷氧基是本文别处描述的任选地取代的烷氧基。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy. In one embodiment, the alkoxy is an optionally substituted alkoxy described elsewhere herein.

术语“烷基酰基”指-C(O)-烷基，其中烷基的定义同前所述。The term "alkylacyl" refers to a -C(O)-alkyl group, wherein alkyl is as previously defined.

术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基的定义同前所述。所述卤代烷基非限制性实例包括：三氟甲基、-CH2CF3、 The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein the definition of alkyl is the same as above. Non-limiting examples of the haloalkyl group include: trifluoromethyl, -CH 2 CF 3 ,

术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基的定义同前所述。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.

术语“羟烷基”指被羟基取代的烷基，其中烷基的定义同前所述。The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

术语“烷硫基”指-S-(烷基)和-S-(非取代的环烷基)，其中烷基或环烷基的定义同前所述。烷硫基的非限制性实例包括：甲硫基、乙硫基、丙硫基、丁硫基、环丙硫基、环丁硫基、环戊硫基或环己硫基。在一个实施方式中，该烷硫基是本文别处描述的任选地取代的烷硫基。The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio or cyclohexylthio. In one embodiment, the alkylthio is an optionally substituted alkylthio described elsewhere herein.

术语“卤代烷硫基”指被一个或多个卤素取代的烷硫基，其中烷硫基的定义同前所述。The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogens, wherein alkylthio is as defined above.

术语“烯基羰基”指-C(O)-(烯基)，其中烯基的定义同前所述。烯基羰基的非限制性实例包括：乙烯基羰基、丙烯基羰基或丁烯基羰基。在一个实施方式中，该烯基羰基是本文别处描述的任选地取代的烯基羰基。The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, or butenylcarbonyl. In one embodiment, the alkenylcarbonyl is an optionally substituted alkenylcarbonyl described elsewhere herein.

术语“氨基羰基”指NH2-C(O)-。The term "aminocarbonyl" refers to NH2- C (O)-.

术语“烷基氨基羰基”指氨基羰基(NH2-C(O)-)上的两个氢中的一个或全部被烷基取代，其中烷基的定义同前所述。The term "alkylaminocarbonyl" refers to an aminocarbonyl ( NH2 -C(O)-) group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.

术语“烷基氨基”指氨基上的两个氢中的一个或全部被烷基取代，其中烷基的定义同前所述。The term "alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.

术语“羰基””指-C(O)-、-(CO)-或-C(＝O)-基团。所有的标记在说明书中可交换使用。The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.

术语“卤素”指氟、氯、溴或碘。术语“氧代”或“侧氧”指＝O。The term "halogen" refers to fluorine, chlorine, bromine or iodine. The term "oxo" or "oxo" refers to =0.

术语“C(X)”或“C(＝X)”指基团。当X为O时代表该基团为羰基；当X为S时代表该基团为巯基；当X为NR时代表该基团为当X为CRR时代表该基团为 The term "C(X)" or "C(＝X)" refers to When X is O, it means that the group is a carbonyl group; when X is S, it means that the group is a thiol group; when X is NR, it means that the group is When X is CRR, it represents the group

术语“氢”包括质子(1H)、氘(2H)、氚(3H)和/或其混合物。在特定的实施方式中，化合物中一个或多个被氢占据的位置可被氘和/或氚富集。该种同位素富集类似物可通过由商业来源获得的合适的同位素标记起始原料制备得到或者由已知的文献步骤制备得到。The term "hydrogen" includes protons ( 1H ), deuterium ( 2H ), tritium ( 3H ) and/or mixtures thereof. In certain embodiments, one or more positions occupied by hydrogen in the compound may be enriched with deuterium and/or tritium. Such isotopically enriched analogs may be prepared by appropriately isotopically labeled starting materials obtained from commercial sources or by known literature procedures.

所述烷基、亚烷基、烯基、炔基、环烷基、杂环基、芳基、亚芳基、杂芳基、亚杂芳基、杂烷基、烷氧基、烷硫基、羟烷基、烯基羰基、氨基羰基、烷基氨基羰基、烷基氨基、烷基酰基可以是取代的或非取代的，在一个实施方式中，取代基选自一个或多个以下基团：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、烷基酰基、卤素、巯基、羟基、硝基、氰基、叠氮基、肟基、磷酸酯基、氧代基、硫代基、羧基、羧酸酯基、环烷基、杂环基、芳基、杂芳基、杂环烷氧基、环烷硫基或杂环烷硫基。The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, sulfhydryl, hydroxyl, nitro, cyano, azido, oxime, phosphate, oxo, thio, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkyloxy, cycloalkylthio, or heterocycloalkylthio.

“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is linked.

“取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的在一个实施方式中在一个实施方式中。当取代基为氧代(即＝O)时，意味着两个氢原子被取代。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。取代基可以选自氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、氧代基、硫代基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基或杂芳基。"Substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable in one embodiment. In one embodiment. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent can be arbitrary on the basis that it can be realized chemically. It goes without saying that the substituent is only in their possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution without paying too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond. The substituent can be selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano substituted alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl.

“取代或未取代的”是指可以被取代，也可以不被取代。当可以被取代时，取代基选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-SF5、-C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、C(O)R、C(O)OR、C(O)NRR’、N＝S(O)RR’、S(O)R(＝NR’)、P(O)RR’或＝RR’；"Substituted or unsubstituted" means that it may be substituted or unsubstituted. When it may be substituted, the substituent is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -SF 5 , -C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, C(O)R, C(O)OR, C(O)NRR', N=S(O)RR', S(O)R(=NR'), P(O)RR' or =RR';

R和R’各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、--C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基。R and R' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, --C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl.

除非有相反的陈述，在本说明书和权利要求书中的不定冠词“一个”和“一种”以及定冠词“该”包括复数和单数形式。In this specification and the claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular, unless stated to the contrary.

“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

“立体异构体”包含了所有的对映异构/非对应异构/立体异构纯和对映异构/非对应异构/立体异构富集的本发明化合物。"Stereoisomers" encompass all enantiomerically/diastereomerically/stereomerically pure and enantiomerically/diastereomerically/stereomerically enriched forms of the compounds of the invention.

“立体异构纯”指一种包含某化合物的一种立体异构体而基本没有该化合物的另一立体异构体的组合物。例如，一种具有一个手性中心的化合物的立体异构纯组合物将基本没有该化合物的相对的对映异构体。一种具有两个手性中心的化合物的立体异构纯组合物将基本不含该化合物的其它非对映异构体。典型的立体异构纯化合物包含质量含量大于约80％的该化合物的一种立体异构体和质量含量少于约20％的该化合物另一立体异构体、质量含量大于约90％的该化合物的一种立体异构体和质量含量少于约10％的该化合物另一立体异构体、质量含量大于约95％的该化合物的一种立体异构体和质量含量少于约5％的该化合物另一立体异构体、质量含量大于约97％的该化合物的一种立体异构体和质量含量少于约3％的该化合物另一立体异构体或者质量含量大于约99％的该化合物的一种立体异构体和质量含量少于约1％的该化合物另一立体异构体。"Stereomerically pure" refers to a composition comprising one stereoisomer of a compound and being substantially free of another stereoisomer of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of another stereoisomer of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of another stereoisomer of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of another stereoisomer of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of another stereoisomer of the compound.

“立体异构富集”指包含了质量含量大于约55％、质量含量大于约60％、质量含量大于约70％或质量含量大于约80％的某化合物的一种立体异构体的组合物。"Stereoisomerically enriched" refers to a composition comprising greater than about 55% by weight, greater than about 60% by weight, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.

“对映异构纯”指一种具有一个手性中心的化合物的立体异构纯组合物。类似地，术语“对映异构富集”指一种具有一个手性中心的化合物的立体异构富集组合物。"Enantiomerically pure" refers to a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereomerically enriched composition of a compound having one chiral center.

“光学活性”和“对映异构活性”指一个分子组合，其具有不少于约50％、不少于约70％、不少于约80％、不少于约90％、不少于约91％、不少于约92％、不少于约93％、不少于约94％、不少于约95％、不少于约96％、不少于约97％、不少于约98％、不少于约99％、不少于约99.5％或不少于约99.8％的对映体过量或非对映体过量。在特定的实施方式中，该化合物包含了占外消旋物总重约95％或更多的所需对映体或非对映体和约5％或更少的次优选对映体或非对映体。"Optically active" and "enantiomeric activity" refer to a combination of molecules having an enantiomeric or diastereomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer, based on the total weight of the racemate.

在描述光学活性化合物时，前缀R和S被用于表示该分子相对于其手性中心的绝对构型。(+)和(-)被用于表示该化合物的光学旋转，即，经该光学活性化合物旋转的偏振光的平面的方向。前缀(-)表示该化合物是左旋的，即，该化合物将偏振光的平面向左或逆时针旋转。前缀(+)表示该化合物是右旋的，即，该化合物将偏振光的平面向右或顺时针旋转。然而，光学旋转的符号(+)和(-)与分子的绝对构型R和S无关。When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) of the optical rotation have nothing to do with the absolute configuration, R and S, of the molecule.

具体实施方式DETAILED DESCRIPTION

以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

实施例Example

本发明的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-400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 of the present invention are determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shift (δ) is given in units of 10 -6 (ppm). NMR measurements are performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号：Finnigan LCQ advantage MAX)。MS was determined using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。HPLC analysis was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C 18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150×4.6 mm column).

激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。The average kinase inhibition rate and IC50 value were determined using NovoStar microplate reader (BMG, Germany).

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～0.2mm，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 HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, 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.

本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.

实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行，氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球，氢气氛是指反应瓶连接一个约1L容积的氢气气球。Unless otherwise specified in the embodiments, the reactions can be carried out under argon atmosphere or nitrogen atmosphere. Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L, and hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 L.

加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。氢化反应通常抽真空，充入氢气，反复操作3次。The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator. The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

微波反应使用CEM Discover-S 908860型微波反应器。Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.

实施例中无特殊说明，溶液是指水溶液。Unless otherwise specified in the examples, the solution refers to an aqueous solution.

实施例中无特殊说明，反应的温度为室温，为20℃～30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, and the volume ratio of the solvent is adjusted according to the polarity of the compound.

纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：正己烷和乙酸乙酯体系，B：正己烷和四氢呋喃体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include: A: n-hexane and ethyl acetate system, B: n-hexane and tetrahydrofuran system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

实施例1Example 1

(4-氨基-1-甲基咪唑[1,5-a]喹喔啉-8-基)(3-(4-(三氟甲基)苯基)吗啉基)甲酮
(4-amino-1-methylimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone

第一步：将2-甲基-1H-咪唑1a(5g，60.89mmol)溶于DMSO(50mL)中，缓慢加入DBU(13.91g，91.35mmol，14mL)和3-氟-4-硝基苯甲酸甲酯(13.34g，66.99mmol)，该反应在25℃下搅拌2小时；向反应液入水(200mL)，用乙酸乙酯(200mL×3)萃取；合并有机相，用饱和食盐水(200mL×3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系C纯化所得残余物得到1b(9g)，产率：56.6％。MS m/z(ESI):262[M+1]+ Step 1: Dissolve 2-methyl-1H-imidazole 1a (5 g, 60.89 mmol) in DMSO (50 mL), slowly add DBU (13.91 g, 91.35 mmol, 14 mL) and methyl 3-fluoro-4-nitrobenzoate (13.34 g, 66.99 mmol), and stir the reaction at 25°C for 2 hours; add water (200 mL) to the reaction solution, extract with ethyl acetate (200 mL×3); combine the organic phases, wash with saturated brine (200 mL×3), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system C to obtain 1b (9 g), yield: 56.6%. MS m/z (ESI): 262[M+1] +

第二步：将1b(2g，7.66mmol)溶于甲醇(20mL)中，加入Pd/C(816mg，766μmol，10％purity)，氢气置换3次，在氢气保护下，该反应在50℃下搅拌12小时；将反应液进行过滤，滤液减压浓缩，用甲醇：EA＝1：10(10mL)混合溶剂搅拌滤饼15分钟，过滤，滤饼减压干燥，得到1c(1.45g)，产率：81.9％。MS m/z(ESI):232[M+1]+ Step 2: 1b (2 g, 7.66 mmol) was dissolved in methanol (20 mL), Pd/C (816 mg, 766 μmol, 10% purity) was added, and hydrogen was replaced 3 times. Under the protection of hydrogen, the reaction was stirred at 50°C for 12 hours; the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the filter cake was stirred with a mixed solvent of methanol: EA = 1:10 (10 mL) for 15 minutes, filtered, and the filter cake was dried under reduced pressure to obtain 1c (1.45 g), with a yield of 81.9%. MS m/z (ESI): 232 [M+1] +

第三步：将1c(1g，4.32mmol)溶于DCM(15mL)中，加入DMAP(265mg，2.16mmol)、1-(异氰酸酯甲基)-4-甲氧基苯(1.06g，6.49mmol，926μL)，该反应在80℃下搅拌16小时；将反应液减压浓缩，向浓缩残余物中加入二氯甲烷(10mL)，甲基叔丁基醚(10mL)，并搅拌15分钟，过滤，收集滤饼，减压干燥，得到1g(750mg)，产率：45.8％。MS m/z(ESI):380[M+1]+ Step 3: 1c (1 g, 4.32 mmol) was dissolved in DCM (15 mL), and DMAP (265 mg, 2.16 mmol) and 1-(isocyanate methyl)-4-methoxybenzene (1.06 g, 6.49 mmol, 926 μL) were added. The reaction was stirred at 80°C for 16 hours; the reaction solution was concentrated under reduced pressure, and dichloromethane (10 mL) and methyl tert-butyl ether (10 mL) were added to the concentrated residue, and stirred for 15 minutes, filtered, and the filter cake was collected and dried under reduced pressure to obtain 1g (750 mg). Yield: 45.8%. MS m/z (ESI): 380 [M+1] +

第四步：将1g(600mg，1.52mmol)溶于吡啶(2mL)中，加入三氯氧磷(280mg，1.83mmol，171μL)，该反应在120℃下搅拌16小时；将反应液减压浓缩，向浓缩残余物中加入水(50mL)，用乙酸乙酯(50mL×3)萃取；合并有机相，用饱和食盐水(50mL×3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系C纯化所得残余物得到1d(250mg)，产率：43.7％。MS m/z(ESI):377[M+1]+ Step 4: 1g (600mg, 1.52mmol) was dissolved in pyridine (2mL), phosphorus oxychloride (280mg, 1.83mmol, 171μL) was added, and the reaction was stirred at 120°C for 16 hours; the reaction solution was concentrated under reduced pressure, water (50mL) was added to the concentrated residue, and extracted with ethyl acetate (50mL×3); the organic phases were combined, washed with saturated brine (50mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system C to obtain 1d (250mg), yield: 43.7%. MS m/z(ESI):377[M+1] +

第五步：将1d(250mg，664μmol)溶于水(2mL)/甲醇(2mL)/四氢呋喃(6mL)，加入氢氧化锂(32mg，1.33mmol)，该反应在80℃下搅拌3小时；用0.5M盐酸调体系pH至5，过滤，用乙醇(5mL)搅拌滤饼0.5小时，过滤，减压干燥滤饼，得到1h(110mg)，产率：45.7％。MS m/z(ESI):363[M+1]+ Step 5: 1d (250 mg, 664 μmol) was dissolved in water (2 mL)/methanol (2 mL)/tetrahydrofuran (6 mL), lithium hydroxide (32 mg, 1.33 mmol) was added, and the reaction was stirred at 80°C for 3 hours; the pH of the system was adjusted to 5 with 0.5 M hydrochloric acid, filtered, and the filter cake was stirred with ethanol (5 mL) for 0.5 hours, filtered, and dried under reduced pressure to obtain 1h (110 mg), yield: 45.7%. MS m/z (ESI): 363 [M+1] +

第六步：将1h(50mg，138μmol)和N-甲基-2-(三氟甲基)-6,8-二氢-5H-吡喃-[3,4-b]吡啶基-5-胺(39mg，166μmol，采用公知的方法“专利WO2021163344”合成得到)溶于DMF(2mL)中，加入N-甲基咪唑(46mg，552μmol，44μL)和TCFH(58mg，207μmol)，该反应在25℃下继续搅拌1.5小时；将反应液进行减压浓缩，向浓缩残余物中加入水(15mL)，用乙酸乙酯(20mL×3)萃取；合并有机相，用饱和食盐水(20mL×3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，用高效液相色谱制备分离浓缩残余物，得到1i(55mg)，产率：68.9％。Step 6: 1h (50 mg, 138 μmol) and N-methyl-2-(trifluoromethyl)-6,8-dihydro-5H-pyran-[3,4-b]pyridin-5-amine (39 mg, 166 μmol, synthesized by the known method "Patent WO2021163344") were dissolved in DMF (2 mL), and N-methylimidazole (46 mg, 552 μmol, 44 μL) and TCFH (58 mg, 207 μmol) were added. The reaction was stirred for 1.5 hours at 25 ° C.; the reaction solution was concentrated under reduced pressure, water (15 mL) was added to the concentrated residue, and extracted with ethyl acetate (20 mL×3); the organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrated residue was separated by high performance liquid chromatography to obtain 1i (55 mg), with a yield of 68.9%.

第七步：将1i(45mg，78μmol)溶于三氟乙酸(3mL)中，该反应在90℃下继续搅拌16小时；反应液进行减压浓缩，高效液相色谱制备分离浓缩残余物，得到实施例1(20mg)，产率：56.2％。MS m/z(ESI):458[M+1]+ Step 7: 1i (45 mg, 78 μmol) was dissolved in trifluoroacetic acid (3 mL), and the reaction was stirred at 90°C for 16 hours; the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated by HPLC to obtain Example 1 (20 mg), with a yield of 56.2%. MS m/z (ESI): 458 [M+1] +

1H NMR(400MHz,DMSO)δ8.23-8.11(m,2H),7.86(d,2H),7.60-7.38(m,4H),5.80(s,1H),4.81(dd,2H),4.20(d,2H),2.97(s,3H),2.87-2.71(m,3H). 1 H NMR (400MHz, DMSO) δ8.23-8.11(m,2H),7.86(d,2H),7.60-7.38(m,4H),5.80(s,1H),4.81(dd,2H),4.20(d,2H),2.97(s,3H),2.87-2.71(m,3H).

实施例1手性异构体制备Example 1 Preparation of Chiral Isomers

P1：(R)-(4-氨基-1-甲基咪唑[1,5-a]喹喔啉-8-基)(3-(4-(三氟甲基)苯基)吗啉基)甲酮&P1: (R)-(4-amino-1-methylimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone&

P2：(S)-(4-氨基-1-甲基咪唑[1,5-a]喹喔啉-8-基)(3-(4-(三氟甲基)苯基)吗啉基)甲酮
P2: (S)-(4-amino-1-methylimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholinyl)methanone

将实施例1(20mg，0.044mmol)用Chiral-HPLC拆分，分别得到实施例1-P1(9.5mg)，产率：47.5％。MS m/z(ESI):487[M+1]+；实施例1-P2(9.8mg)，产率：49.0％。MS m/z(ESI):487[M+1]+ Example 1 (20 mg, 0.044 mmol) was separated by Chiral-HPLC to obtain Example 1-P1 (9.5 mg), yield: 47.5%. MS m/z (ESI): 487 [M+1] + ; Example 1-P2 (9.8 mg), yield: 49.0%. MS m/z (ESI): 487 [M+1] +

实施例2Example 2

4-氨基-N-(2-(3,3-二氟氮杂环丁烷-1-基)-5,8-二氢-6H-吡喃[3,4-b]吡啶-5-基)-N,1-二甲基-1H-吡唑并[4,3-c]喹啉-8-甲酰胺
4-amino-N-(2-(3,3-difluoroazetidin-1-yl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

第一步：将6-甲氧基-2-甲基烟酸甲酯2a(15.00g，82.87mmol)，N-溴代丁二酰亚胺(29.00g，162.92mmol)和偶氮二异丁腈(2.60g，15.85mmol)分散于150mL四氯化碳中，80℃搅拌反应16小时。反应液过滤除去不溶物，滤液减压浓缩得到2b(30.50g，粗品)。MS m/z(ESI):338[M+1]+ Step 1: Disperse 6-methoxy-2-methylnicotinate methyl ester 2a (15.00 g, 82.87 mmol), N-bromosuccinimide (29.00 g, 162.92 mmol) and azobisisobutyronitrile (2.60 g, 15.85 mmol) in 150 mL of carbon tetrachloride and stir at 80°C for 16 hours. The reaction solution was filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure to obtain 2b (30.50 g, crude product). MS m/z (ESI): 338 [M+1] +

第二步：将2b(30.50g，粗品)，亚磷酸二乙酯(14.00g，101.45mmol)和N,N-二异丙基乙胺(26.00g，201.55mmol)分散于400mL二氯甲烷中，25℃搅拌反应2小时。反应液浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到2c(12.00g)，产率：55.9％。MS m/z(ESI):260[M+1]+ Step 2: Disperse 2b (30.50 g, crude product), diethyl phosphite (14.00 g, 101.45 mmol) and N,N-diisopropylethylamine (26.00 g, 201.55 mmol) in 400 mL of dichloromethane and stir at 25°C for 2 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography with eluent system B to obtain 2c (12.00 g) with a yield of 55.9%. MS m/z (ESI): 260 [M+1] +

第三步：将2-羟基乙酸甲酯(8.50g，94.44mmol)分散于200mL N,N-二甲基甲酰胺中，0℃下加入氢化钠(5.70g，142.48mmol，60％分散在矿物油中)，搅拌反应1小时。加入2c(12.00g，46.33mmol)，25℃搅拌反应16小时。反应液倾入2000mL水中，用乙酸乙酯(300mL×3)萃取；合并有机相，用饱和食盐水(200mL×3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到2d(22.00g，粗品)。MS m/z(ESI):238[M+1]+ Step 3: Disperse methyl 2-hydroxyacetate (8.50 g, 94.44 mmol) in 200 mL N,N-dimethylformamide, add sodium hydride (5.70 g, 142.48 mmol, 60% dispersed in mineral oil) at 0°C, and stir to react for 1 hour. Add 2c (12.00 g, 46.33 mmol), stir to react at 25°C for 16 hours. Pour the reaction solution into 2000 mL of water and extract with ethyl acetate (300 mL×3); combine the organic phases, wash with saturated brine (200 mL×3), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 2d (22.00 g, crude product). MS m/z(ESI):238[M+1] +

第四步：将2d(22.00g，粗品)分散于100mL乙醇和100mL浓盐酸中，100℃搅拌反应2小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到2e(4.00g)，产率：52.3％。MS m/z(ESI):166[M+1]+ Step 4: Disperse 2d (22.00 g, crude product) in 100 mL of ethanol and 100 mL of concentrated hydrochloric acid, and stir at 100°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain 2e (4.00 g), yield: 52.3%. MS m/z (ESI): 166 [M+1] +

第五步：将2e(4.00g，24.24mmol)分散于30mL三氯氧磷中，90℃搅拌反应2小时。减压浓缩，残余物分散于300mL二氯甲烷中，依次用饱和碳酸氢钠溶液(200mL×2)和氯化钠溶液(200mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到2f(4.30g)，产率：96.9％。MS m/z(ESI):184[M+1]+ Step 5: Disperse 2e (4.00 g, 24.24 mmol) in 30 mL of phosphorus oxychloride and stir at 90°C for 2 hours. Concentrate under reduced pressure, disperse the residue in 300 mL of dichloromethane, wash with saturated sodium bicarbonate solution (200 mL×2) and sodium chloride solution (200 mL×2) in sequence, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2f (4.30 g), yield: 96.9%. MS m/z (ESI): 184 [M+1] +

第六步：将2f(300mg，1.64mmol)，3,3-二氟三甲叉亚胺盐酸盐(260mg，2.02mmol)和N,N-二异丙基乙胺(800mg，6.20mmol)分散于5mL乙腈中，80℃搅拌反应16小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到2g(240mg)，产率：61.0％。MS m/z(ESI):241[M+1]+ Step 6: Disperse 2f (300 mg, 1.64 mmol), 3,3-difluorotrimethyleneimine hydrochloride (260 mg, 2.02 mmol) and N,N-diisopropylethylamine (800 mg, 6.20 mmol) in 5 mL of acetonitrile and stir at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system B to obtain 2g (240 mg), yield: 61.0%. MS m/z (ESI): 241 [M+1] +

第七步：将2g(240mg，1.00mmol)和甲胺(310mg，3.00mmol，30％甲醇溶液)分散于3mL三氟乙醇中，25℃搅拌反应16小时。加入氰基硼氢化钠(130mg，2.06mmol)，25℃搅拌反应1小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到2h(150mg)，产率：58.8％。MS m/z(ESI):256[M+1]+ Step 7: Disperse 2g (240 mg, 1.00 mmol) and methylamine (310 mg, 3.00 mmol, 30% methanol solution) in 3 mL of trifluoroethanol and stir at 25°C for 16 hours. Add sodium cyanoborohydride (130 mg, 2.06 mmol) and stir at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain 2h (150 mg), yield: 58.8%. MS m/z (ESI): 256 [M+1] +

参考实施例1第六步的合成方法，通过2h(50mg，0.20mmol)得到实施例2(9mg)，产率：9.3％。MS m/z(ESI):480[M+1]+ Referring to the synthesis method of step 6 of Example 1, Example 2 (9 mg) was obtained by 2h (50 mg, 0.20 mmol), with a yield of 9.3%. MS m/z (ESI): 480 [M+1] +

实施例3Example 3

4-氨基-N-甲基-N-[2-(三氟甲基)-6,8-二氢-5H-吡喃并[3,4-b]吡啶-5-基]咪唑并[1,5-a]喹喔啉-8-羧酰胺
4-amino-N-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide

第一步：将4-氨基-3-硝基-苯甲酸甲酯3a(5g，25.49mmol)溶于二氯甲烷(50mL)中，依次加入DIEA(3.95g，30.59mmol，5.5mL)、DMAP(155.70mg，1.27mmol)、二碳酸二叔丁酯(6.68g，30.59mmol)，该反应在25℃下搅拌2小时；向反应液中加入水(100mL)，用二氯甲烷(100mL×3)萃取；合并有机相，用饱和食盐水(100mL×3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，浓缩残余物用洗脱剂体系C纯化，得到3b(6.5g)，产率：86.0％。Step 1: Dissolve 4-amino-3-nitro-benzoic acid methyl ester 3a (5 g, 25.49 mmol) in dichloromethane (50 mL), and add DIEA (3.95 g, 30.59 mmol, 5.5 mL), DMAP (155.70 mg, 1.27 mmol), di-tert-butyl dicarbonate (6.68 g, 30.59 mmol) in sequence, and stir the reaction at 25 ° C for 2 hours; add water (100 mL) to the reaction solution, and extract with dichloromethane (100 mL×3); combine the organic phases, wash with saturated brine (100 mL×3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The concentrated residue is purified with eluent system C to obtain 3b (6.5 g), yield: 86.0%.

第二步：将3b(5g，16.88mmol)溶于甲醇(60mL)中，加入Pd/C(2.05g，1.69mmol，10％purity)，该反应在50℃下搅拌16小时；在抽滤漏斗中平铺一层硅藻土，反应液进行过滤，收集滤液，减压浓缩，得到3c(4g)，产率：89.0％。MS m/z(ESI):267[M+1]+ Step 2: 3b (5 g, 16.88 mmol) was dissolved in methanol (60 mL), Pd/C (2.05 g, 1.69 mmol, 10% purity) was added, and the reaction was stirred at 50°C for 16 hours; a layer of diatomaceous earth was spread on the suction funnel, the reaction solution was filtered, the filtrate was collected, and it was concentrated under reduced pressure to obtain 3c (4 g), yield: 89.0%. MS m/z (ESI): 267 [M+1] +

第三步：将3c(1g，3.76mmol)溶于N,N-二甲基甲酰胺(12mL)中，加入2-氧代乙酸乙酯3d(575.05mg，5.63mmol，559μL)，该反应在微波100℃下，搅拌10分钟，反应结束得到3e，直接用于下一步。Step 3: 3c (1 g, 3.76 mmol) was dissolved in N,N-dimethylformamide (12 mL), and ethyl 2-oxoacetate 3d (575.05 mg, 5.63 mmol, 559 μL) was added. The reaction was stirred at 100° C. in a microwave for 10 minutes. After the reaction was completed, 3e was obtained, which was used directly in the next step.

第四步：将3e(600mg，1.78mmol)溶于N,N-二甲基甲酰胺(7mL)中，加入甲苯磺酰基甲基异氰3f(417.95mg，2.14mmol)、碳酸钾(493.11mg，3.57mmol)，该反应在微波，80℃下，搅拌10分钟；向反应液中加入水(60mL)，用乙酸乙酯(60mL×3)萃取；合并有机相，用饱和食盐水(60mL×3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得到3g(700mg)，直接用于下一步。Step 4: Dissolve 3e (600 mg, 1.78 mmol) in N,N-dimethylformamide (7 mL), add tosylmethyl isocyanate 3f (417.95 mg, 2.14 mmol) and potassium carbonate (493.11 mg, 3.57 mmol), and stir the reaction in a microwave at 80°C for 10 minutes; add water (60 mL) to the reaction solution, and extract with ethyl acetate (60 mL×3); combine the organic phases, wash with saturated brine (60 mL×3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 3g (700 mg), which is directly used in the next step.

第五步：将3g(600mg，1.54mmol)溶于1,2-二氯乙烷(6mL)/三氟乙酸(0.6mL)中，该反应在微波，80℃下，搅拌10分钟；反应液减压浓缩，浓缩残余物用二氯甲烷(10mL)搅拌15分钟，过滤，滤饼减压干燥，得到3h(200mg)，产率：53.4％。MS m/z(ESI):244[M+1]+ Step 5: 3g (600 mg, 1.54 mmol) was dissolved in 1,2-dichloroethane (6 mL)/trifluoroacetic acid (0.6 mL), and the reaction was stirred for 10 minutes at 80°C in a microwave oven; the reaction solution was concentrated under reduced pressure, and the concentrated residue was stirred with dichloromethane (10 mL) for 15 minutes, filtered, and the filter cake was dried under reduced pressure to obtain 3h (200 mg), with a yield of 53.4%. MS m/z (ESI): 244 [M+1] +

第六步：将3h(200mg，822μmol)溶于三氯氧磷(3mL)中，该反应在180℃下搅拌8小时；反应液减压浓缩，向浓缩残余物加入水(15mL)，分出有机相；水层用乙酸乙酯(15mL×3)萃取；合并有机相，用饱和食盐水(15mL×3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得到3i(100mg)，直接用于下一步。MS m/z(ESI):262[M+1]+ Step 6: 3h (200 mg, 822 μmol) was dissolved in phosphorus oxychloride (3 mL), and the reaction was stirred at 180°C for 8 hours; the reaction solution was concentrated under reduced pressure, water (15 mL) was added to the concentrated residue, and the organic phase was separated; the aqueous layer was extracted with ethyl acetate (15 mL×3); the organic phases were combined, washed with saturated brine (15 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3i (100 mg), which was directly used in the next step. MS m/z (ESI): 262 [M+1] +

第七步：将3i(100mg，383μmol)溶于N,N-二甲基甲酰胺(2mL)中，依次加入4-甲氧基苄胺(99.52mg，726μmol)、碳酸钾(150.40mg，1.09mmol)，该反应在120℃下搅拌2小时；向反应液中加入水(20mL)，分出有机相；水层用乙酸乙酯(20mL×3)萃取；合并有机相，用饱和食盐水(20mL×3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得到3j(200mg)，直接用于下一步。MS m/z(ESI):363[M+1]+ Step 7: 3i (100 mg, 383 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 4-methoxybenzylamine (99.52 mg, 726 μmol) and potassium carbonate (150.40 mg, 1.09 mmol) were added in sequence. The reaction was stirred at 120°C for 2 hours; water (20 mL) was added to the reaction solution, and the organic phase was separated; the aqueous layer was extracted with ethyl acetate (20 mL × 3); the organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3j (200 mg), which was directly used in the next step. MS m/z (ESI): 363 [M + 1] +

第八步：将3j(100mg,276μmol)溶于水(1mL)/甲醇(1mL)/四氢呋喃(3mL)，加入氢氧化锂(25.45mg,1.06mmol)，该反应在80℃下搅拌3小时；用0.5M盐酸调pH至5，过滤，水(5mL)淋洗滤饼，减压干燥滤饼，得到3k(60mg)，产率：62.4％。MS m/z(ESI):349[M+1]+ Step 8: 3j (100 mg, 276 μmol) was dissolved in water (1 mL)/methanol (1 mL)/tetrahydrofuran (3 mL), lithium hydroxide (25.45 mg, 1.06 mmol) was added, and the reaction was stirred at 80°C for 3 hours; the pH was adjusted to 5 with 0.5 M hydrochloric acid, filtered, the filter cake was rinsed with water (5 mL), and the filter cake was dried under reduced pressure to obtain 3k (60 mg), yield: 62.4%. MS m/z (ESI): 349 [M+1] +

第九步：将3k(50mg,144μmol)和N-(环丙基甲基)-2-(三氟甲基)-6,8-二氢-5H-吡喃[3,4-b]吡啶-5-胺3l(40mg,172μmol)溶于N,N-二甲基甲酰胺中，加入N-甲基吡唑(45.31mg,552μmol,46μL)和TCFH(58.07mg，207μmol)，该反应在25℃下继续搅拌16小时；反应液直接用Pre-HPLC制备分离纯化，得到3m(18mg)，产率：22.3％。MS m/z(ESI):563[M+1]+Step 9: 3k (50 mg, 144 μmol) and N-(cyclopropylmethyl)-2-(trifluoromethyl)-6,8-dihydro-5H-pyrano[3,4-b]pyridin-5-amine 3l (40 mg, 172 μmol) were dissolved in N,N-dimethylformamide, and N-methylpyrazole (45.31 mg, 552 μmol, 46 μL) and TCFH (58.07 mg, 207 μmol) were added. The reaction was stirred at 25 °C for 16 hours; the reaction solution was directly separated and purified by Pre-HPLC to obtain 3m (18 mg), with a yield of 22.3%. MS m/z (ESI): 563 [M+1] +

第十步：将3m(18mg,32μmol)溶于三氟乙酸(2mL)中，该反应在90℃下继续搅拌3小时；反应液减压浓缩，用Pre-HPLC(酸法)制备分离浓缩残余物，得到实施例3(6mg)，产率：42.4％。MS m/z(ESI):443[M+1]+ Step 10: 3m (18 mg, 32 μmol) was dissolved in trifluoroacetic acid (2 mL), and the reaction was stirred at 90°C for 3 hours; the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated by Pre-HPLC (acid method) to obtain Example 3 (6 mg), with a yield of 42.4%. MS m/z (ESI): 443 [M+1] +

1H NMR(400MHz,DMSO)δ9.21(s,2H),8.38(s,1H),8.12(d,1H),7.94(s,1H),7.87(d,1H),7.62–7.44(m,3H),5.83(s,1H),4.93–4.61(m,2H),4.21(s,2H),2.81(s,3H). 1 H NMR(400MHz,DMSO)δ9.21(s,2H),8.38(s,1H),8.12(d,1H),7.94(s,1H),7.87(d, 1H),7.62–7.44(m,3H),5.83(s,1H),4.93–4.61(m,2H),4.21(s,2H),2.81(s,3H).

实施例4Example 4

4-氨基-N-(环丙基甲基)-3-甲基-N-[2-(三氟甲基)-6,8-二氢-5-吡喃并[3,4-b]]吡啶-5基]咪唑-[1,5-a]喹喔啉-8-甲酰胺
4-amino-N-(cyclopropylmethyl)-3-methyl-N-[2-(trifluoromethyl)-6,8-dihydro-5-pyrano[3,4-b]]pyridin-5-yl]imidazo[1,5-a]quinoxaline-8-carboxamide

第一步：将2-(三氟甲基)-8H-吡喃并[3,4-b]吡啶-5-酮4a(500mg，2.30mmol)和环丙基甲胺(1.31g，18.42mmol，1.6mL)溶于甲醇(15mL)中，加入钛酸四异丙酯(1.96g，6.91mmol，2mL)，该反应在25℃下搅拌16小时，加入醋酸硼氢化钠(732.02mg，3.45mmol)，在25℃下搅拌30分钟；向反应液加入饱和碳酸氢钠水溶液(8mL)，过滤，收集滤液，减压浓缩，浓缩残余物用Pre-TLC制备分离得到4b(52mg)，产率：8.3％。MS m/z(ESI):273[M+1]+ Step 1: Dissolve 2-(trifluoromethyl)-8H-pyrano[3,4-b]pyridin-5-one 4a (500 mg, 2.30 mmol) and cyclopropylmethylamine (1.31 g, 18.42 mmol, 1.6 mL) in methanol (15 mL), add tetraisopropyl titanate (1.96 g, 6.91 mmol, 2 mL), stir the reaction at 25°C for 16 hours, add sodium acetate borohydride (732.02 mg, 3.45 mmol), stir at 25°C for 30 minutes; add saturated sodium bicarbonate aqueous solution (8 mL) to the reaction solution, filter, collect the filtrate, concentrate under reduced pressure, and separate the concentrated residue by Pre-TLC to obtain 4b (52 mg), yield: 8.3%. MS m/z (ESI): 273 [M+1] +

第二步：将4c(5g，25.49mmol)溶于二氯甲烷(50mL)中，依次加入DIEA(3.95g，30.59mmol，5.5mL)、DMAP(155.70mg，1.27mmol)、二碳酸二叔丁酯(6.68g，30.59mmol)，该反应在25℃下搅拌2小时；向反应液中加入水(100mL)，用二氯甲烷(100mL×3)萃取；合并有机相，用饱和食盐水(100mL×3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，浓缩残余物用洗脱剂体系C纯化，得到4d(6.5g)，产率：86.0％。Step 2: 4c (5 g, 25.49 mmol) was dissolved in dichloromethane (50 mL), and DIEA (3.95 g, 30.59 mmol, 5.5 mL), DMAP (155.70 mg, 1.27 mmol), and di-tert-butyl dicarbonate (6.68 g, 30.59 mmol) were added in sequence. The reaction was stirred at 25°C for 2 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified with eluent system C to obtain 4d (6.5 g). Yield: 86.0%.

第三步：将4d(5g，16.88mmol)溶于甲醇(60mL)中，加入Pd/C(2.05g，1.69mmol，10％purity)，该反应在50℃下搅拌16小时；在抽滤漏斗中平铺一层硅藻土，反应液进行过滤，收集滤液，减压浓缩，得到4e(4g)，产率：89.0％。MS m/z(ESI):267[M+1]+ Step 3: 4d (5 g, 16.88 mmol) was dissolved in methanol (60 mL), Pd/C (2.05 g, 1.69 mmol, 10% purity) was added, and the reaction was stirred at 50°C for 16 hours; a layer of diatomaceous earth was spread on the suction funnel, the reaction solution was filtered, the filtrate was collected, and it was concentrated under reduced pressure to obtain 4e (4 g), with a yield of 89.0%. MS m/z (ESI): 267 [M+1] +

第四步：将4e(1g，3.76mmol)溶于N,N-二甲基甲酰胺(12mL)中，加入2-氧代乙酸乙酯(575.05mg，5.63mmol，559μL)，该反应在微波100℃下，搅拌10分钟，反应结束，直接用于下一步。Step 4: Dissolve 4e (1 g, 3.76 mmol) in N,N-dimethylformamide (12 mL), add ethyl 2-oxoacetate (575.05 mg, 5.63 mmol, 559 μL), and stir the reaction in a microwave at 100°C for 10 minutes. After the reaction is complete, the solution is used directly in the next step.

第五步：将4f(500mg，1.49mmol)溶于N,N-二甲基甲酰胺(7mL)中，加入1-甲基-1-甲苯磺酰基甲基异氰(373.30mg，1.78mmol)、碳酸钾(410.92mg，2.97mmol)，该反应在微波，80℃下，搅拌10分钟；向反应液中加入水(60mL)，用乙酸乙酯(60mL×3)萃取；合并有机相，用饱和食盐水(60mL×3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得到4g，直接用于下一步。Step 5: 4f (500 mg, 1.49 mmol) was dissolved in N,N-dimethylformamide (7 mL), and 1-methyl-1-toluenesulfonylmethyl isocyanate (373.30 mg, 1.78 mmol) and potassium carbonate (410.92 mg, 2.97 mmol) were added. The reaction was stirred at 80°C in a microwave for 10 minutes. Water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL×3). The organic phases were combined, washed with saturated brine (60 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4 g, which was directly used in the next step.

第六步：将4g(600mg，1.49mmol)溶于1,2-二氯乙烷(6mL)/三氟乙酸(0.6mL)中，该反应在微波，80℃下，搅拌10分钟；反应液减压浓缩，浓缩残余物用二氯甲烷(10mL)搅拌15分钟，过滤，滤饼减压干燥，得到4h(200mg)，产率：52.3％。MS m/z(ESI):258[M+1]+ Step 6: 4g (600 mg, 1.49 mmol) was dissolved in 1,2-dichloroethane (6 mL)/trifluoroacetic acid (0.6 mL), and the reaction was stirred for 10 minutes at 80°C in a microwave oven; the reaction solution was concentrated under reduced pressure, and the concentrated residue was stirred with dichloromethane (10 mL) for 15 minutes, filtered, and the filter cake was dried under reduced pressure to obtain 4h (200 mg), with a yield of 52.3%. MS m/z (ESI): 258 [M+1] +

第七步：将4h(200mg，778μmol)溶于三氯氧磷(3mL)中，该反应在180℃下搅拌8小时；反应液减压浓缩，向浓缩残余物加入水(15mL)，分出有机相；水层用乙酸乙酯(15mL×3)萃取；合并有机相，用饱和食盐水(15mL×3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得到4i(100mg)，直接用于下一步。MS m/z(ESI):276[M+1]+ Step 7: 4h (200 mg, 778 μmol) was dissolved in phosphorus oxychloride (3 mL), and the reaction was stirred at 180°C for 8 hours; the reaction solution was concentrated under reduced pressure, water (15 mL) was added to the concentrated residue, and the organic phase was separated; the aqueous layer was extracted with ethyl acetate (15 mL×3); the organic phases were combined, washed with saturated brine (15 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4i (100 mg), which was directly used in the next step. MS m/z (ESI): 276 [M+1] +

第八步：将4i(100mg，363μmol)溶于N,N-二甲基甲酰胺(2mL)中，依次加入4-甲氧基苄胺(99.52mg，726μmol)、碳酸钾(150.40mg，1.09mmol)，该反应在120℃下搅拌2小时；向反应液中加入水(20mL)，分出有机相；水层用乙酸乙酯(20mL×3)萃取；合并有机相，用饱和食盐水(20mL×3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得到4j(200mg)，直接用于下一步。MS m/z(ESI):377[M+1]+ Step 8: Dissolve 4i (100 mg, 363 μmol) in N,N-dimethylformamide (2 mL), add 4-methoxybenzylamine (99.52 mg, 726 μmol) and potassium carbonate (150.40 mg, 1.09 mmol) in sequence, and stir the reaction at 120°C for 2 hours; add water (20 mL) to the reaction solution, separate the organic phase; extract the aqueous layer with ethyl acetate (20 mL×3); combine the organic phases, wash with saturated brine (20 mL×3), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 4j (200 mg), which is directly used in the next step. MS m/z (ESI): 377 [M+1] +

第九步：将4j(100mg，266μmol)溶于水(1mL)/甲醇(1mL)/四氢呋喃(3mL)，加入氢氧化锂(25.45mg，1.06mmol)，该反应在80℃下搅拌3小时；用0.5M盐酸调pH至5，过滤，水(5mL)淋洗滤饼，减压干燥滤饼，得到4k(60mg)，产率：62.3％。MS m/z(ESI):363[M+1]+ Step 9: 4j (100 mg, 266 μmol) was dissolved in water (1 mL)/methanol (1 mL)/tetrahydrofuran (3 mL), and lithium hydroxide (25.45 mg, 1.06 mmol) was added. The reaction was stirred at 80°C for 3 hours; the pH was adjusted to 5 with 0.5 M hydrochloric acid, filtered, the filter cake was rinsed with water (5 mL), and the filter cake was dried under reduced pressure to obtain 4k (60 mg), yield: 62.3%. MS m/z (ESI): 363 [M+1] +

第十步：将4k(50mg，138μmol)和4b(45.08mg，166μmol)溶于N,N-二甲基甲酰胺中，加入N-甲基吡唑(45.31mg，552μmol，46μL)和TCFH(58.07mg，207μmol)，该反应在25℃下继续搅拌16小时；反应液直接用Pre-HPLC制备分离纯化，得到4(18mg)，产率：21.2％。MS m/z(ESI):617[M+1]+ Step 10: 4k (50 mg, 138 μmol) and 4b (45.08 mg, 166 μmol) were dissolved in N,N-dimethylformamide, and N-methylpyrazole (45.31 mg, 552 μmol, 46 μL) and TCFH (58.07 mg, 207 μmol) were added. The reaction was stirred at 25°C for 16 hours. The reaction solution was directly separated and purified by Pre-HPLC to obtain 4 (18 mg). The yield was 21.2%. MS m/z (ESI): 617 [M+1] +

第十一步：将4(18mg，29μmol)溶于三氟乙酸(2mL)中，该反应在90℃下继续搅拌3小时；反应液减压浓缩，用Pre-HPLC(酸法)制备分离浓缩残余物，得到实施例4(6mg)，产率：41.4％。MS m/z(ESI):497[M+1]+ Step 11: 4 (18 mg, 29 μmol) was dissolved in trifluoroacetic acid (2 mL), and the reaction was stirred at 90°C for 3 hours; the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated by Pre-HPLC (acid method) to obtain Example 4 (6 mg), with a yield of 41.4%. MS m/z (ESI): 497 [M+1] +

1H NMR(400MHz,DMSO)δ9.07(s,1H),8.25(d,2H),7.81(d,1H),7.41(s,2H),6.88(s,2H),5.32(t,1H),4.94–4.63(m,2H),4.28(s,2H),2.63(s,3H),2.00(q,1H),1.26–1.21(m,2H),1.09–0.73(m,2H),0.32(d,2H). 1 H NMR(400MHz,DMSO)δ9.07(s,1H),8.25(d,2H),7.81(d,1H),7.41(s,2H),6.88(s,2H),5.32(t,1H),4.94 –4.63(m,2H),4.28(s,2H),2.63(s,3H),2.00(q,1H),1.26–1.21(m,2H),1.09–0.73(m,2H),0.32(d,2H).

实施例5Example 5

4-氨基-N-甲基-N-(6-(三氟甲基)-2,3-二氢苯并呋喃-3-基)咪唑并[1,5-a]喹喔啉-8-甲酰胺
4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

参考实施例3第九步到第十步，通过4-((2,4-二甲氧苄基)氨基)咪唑并[1,5-a]喹喔啉-8-羧酸5a(90mg)和N-甲基-6-(三氟甲基)-2,3-二氢苯并呋喃-3-胺5c(40mg，采用公知的方法“专利WO2022169948”合成得到)，得到实施例5(10.9mg)，产率：26％。MS m/z(ESI):428[M+1]+ Referring to the ninth to tenth steps of Example 3, 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid 5a (90 mg) and N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine 5c (40 mg, synthesized by the known method "Patent WO2022169948") were used to obtain Example 5 (10.9 mg), with a yield of 26%. MS m/z (ESI): 428 [M+1] +

1HNMR(400MHz,DMSO)δ9.16(s,1H),8.32(s,1H),7.91(s,1H),7.64(d,1H),7.48(s,2H),7.41(s,2H),7.33(d,1H),7.24(s,1H),4.82–4.65(m,2H),2.68(s,3H),1.99(s,1H). 1 HNMR(400MHz,DMSO)δ9.16(s,1H),8.32(s,1H),7.91(s,1H),7.64(d,1H),7.48(s,2H) ,7.41(s,2H),7.33(d,1H),7.24(s,1H),4.82–4.65(m,2H),2.68(s,3H),1.99(s,1H).

实施例6Example 6

4-氨基-N,7-二甲基-N-(8-甲基-2-(三氟甲基)-5,8-二氢-6H-吡喃并[3,4-b]吡啶-5-基)咪唑并[1,5-a]喹喔啉-8-甲酰胺
4-amino-N,7-dimethyl-N-(8-methyl-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

第一步：将2-氯-6-甲氧基-吡啶-3-羧酸甲酯6a(9g，44.64mmol)，乙烯基氟硼酸钾(11.96g，89.28mmol)和碳酸钾(12.34g，89.28mmol)溶于水(20mL)和1'4-二氧六环(100mL)中，抽换氮气三次，加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)(3.27g，4.46mmol)，反应体系在90℃下搅拌15小时。反应冷却至室温，加水，用乙酸乙酯(500mL×3)萃取，合并有机相，用饱和食盐水(200mL)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化得到6b(6g)，产率：69.6％。MS m/z(ESI):194[M+1]+ Step 1: Dissolve 2-chloro-6-methoxy-pyridine-3-carboxylic acid methyl ester 6a (9 g, 44.64 mmol), potassium vinyl fluoroborate (11.96 g, 89.28 mmol) and potassium carbonate (12.34 g, 89.28 mmol) in water (20 mL) and 1'4-dioxane (100 mL), replace nitrogen three times, add 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) (3.27 g, 4.46 mmol), and stir the reaction system at 90 ° C for 15 hours. The reaction was cooled to room temperature, water was added, and extracted with ethyl acetate (500 mL×3), the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to obtain 6b (6 g), yield: 69.6%. MS m/z (ESI): 194 [M+1] +

第二步：将6b(6g，31.06mmol)溶于甲醇(100mL)中，抽换氮气三次，加入钯碳(377mg，0.31mmol，10％purity)，反应体系在氢气球下25℃下搅拌2小时。反应过滤，浓缩，得到6c(5.90g，粗品)。MS m/z(ESI):196[M+1]+ Step 2: Dissolve 6b (6 g, 31.06 mmol) in methanol (100 mL), replace nitrogen three times, add palladium carbon (377 mg, 0.31 mmol, 10% purity), and stir the reaction system at 25 ° C for 2 hours under a hydrogen balloon. Filter the reaction and concentrate to obtain 6c (5.90 g, crude product). MS m/z (ESI): 196 [M+1] +

第三步：将6c(5.9g，30.22mmol)，偶氮二异丁腈(496mg，3.02mmol)和N-溴代丁二酰亚胺(8.61g，48.36mmol)溶于四氯化碳(60mL)中，抽换氮气三次，体系加热至90℃反应。反应冷却至室温，浓缩，加水，用乙酸乙酯(100mL×3)，用食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残余物用硅胶柱色谱法以洗脱剂体系B纯化得到6d(7.50g)，产率：90.5％。MS m/z(ESI):275[M+1]+ Step 3: Dissolve 6c (5.9 g, 30.22 mmol), azobisisobutyronitrile (496 mg, 3.02 mmol) and N-bromosuccinimide (8.61 g, 48.36 mmol) in carbon tetrachloride (60 mL), replace nitrogen three times, and heat the system to 90 ° C for reaction. The reaction was cooled to room temperature, concentrated, added with water, washed with ethyl acetate (100 mL × 3), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system B to give 6d (7.50 g), yield: 90.5%. MS m/z (ESI): 275 [M + 1] +

参考实施例2第三步至第四步的合成方法，通过6d(7.80g，28.46mmol)得到2-羟基-8-甲基-6H-吡喃并[3,4-b]吡啶-5(8H)-酮6f(2.60g)，产率：51.0％MS m/z(ESI):180[M+1]+ Referring to the synthesis method of the third step to the fourth step of Example 2, 2-hydroxy-8-methyl-6H-pyrano[3,4-b]pyridin-5(8H)-one 6f (2.60 g) was obtained by 6d (7.80 g, 28.46 mmol). Yield: 51.0% MS m/z (ESI): 180 [M+1] +

第六步：将6f(0.5g,2.79mmol)溶于二氯甲烷(40mL)中，抽换氮气三次，冷却至0℃，加入三乙胺(339mg，3.35mmol，0.47mL)和三氟甲磺酸酐(866mg，3.07mmol)体系在25℃下反应2小时。再向体系中加入碘化钠(2.09g，13.95mmol)和浓盐酸(12M，0.28mL)，体系在20℃反应15小时。过滤，浓缩。残余物用硅胶柱色谱法以洗脱剂体系B纯化得到6g(0.35g)，产率：43.4％。MS m/z(ESI):290[M+1]+ Step 6: Dissolve 6f (0.5 g, 2.79 mmol) in dichloromethane (40 mL), replace nitrogen three times, cool to 0 ° C, add triethylamine (339 mg, 3.35 mmol, 0.47 mL) and trifluoromethanesulfonic anhydride (866 mg, 3.07 mmol) and react at 25 ° C for 2 hours. Sodium iodide (2.09 g, 13.95 mmol) and concentrated hydrochloric acid (12 M, 0.28 mL) were added to the system, and the system was reacted at 20 ° C for 15 hours. Filter and concentrate. The residue was purified by silica gel column chromatography with eluent system B to obtain 6g (0.35 g), with a yield of 43.4%. MS m/z (ESI): 290 [M + 1] +

第七步：将6g(0.32g，1.11mmol)和碘化亚铜(527mg，2.77mmol)溶于N,N-二甲基甲酰胺(5mL)，加入甲基2,2-二氟-2-(氟磺酰)乙酸酯(532mg，2.77mmol)，抽换氮气三次，加热至100℃下反应2小时。反应冷却至室温，浓缩，加水，用乙酸乙酯(5mL×3)，用食盐水(3mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残余物用硅胶柱色谱法以洗脱剂体系B纯化得到6h(0.14g)，产率：54.7％。MS m/z(ESI):232[M+1]+ Step 7: Dissolve 6g (0.32g, 1.11mmol) and cuprous iodide (527mg, 2.77mmol) in N,N-dimethylformamide (5mL), add methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (532mg, 2.77mmol), replace nitrogen three times, and heat to 100°C for 2 hours. The reaction was cooled to room temperature, concentrated, added with water, washed with ethyl acetate (5mL×3), washed with brine (3mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system B to obtain 6h (0.14g), yield: 54.7%. MS m/z (ESI): 232[M+1] +

第八步：将6h(0.14g，0.61mmol)和甲胺醇溶液(314mg，3.03mmol，30％purity)溶于三氟乙醇(10mL)中，抽换氮气三次，反应在25℃反应2小时，向体系中加入氰基硼氢化钠(76mg，1.21mmol)，加完后体系在25℃反应1小时。反应加入10mL饱和碳酸氢钠溶液，体系在室温下搅拌一小时，用二氯甲烷/甲醇＝10/1(50mL×3)萃取，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残余物用硅胶柱色谱法以洗脱剂体系A纯化得到6i(80mg)，产率：53.6％。MS m/z(ESI):247[M+1]+ Step 8: 6h (0.14 g, 0.61 mmol) and methylamine alcohol solution (314 mg, 3.03 mmol, 30% purity) were dissolved in trifluoroethanol (10 mL), nitrogen was replaced three times, and the reaction was carried out at 25 ° C for 2 hours. Sodium cyanoborohydride (76 mg, 1.21 mmol) was added to the system. After the addition, the system was reacted at 25 ° C for 1 hour. 10 mL of saturated sodium bicarbonate solution was added to the reaction, and the system was stirred at room temperature for one hour, extracted with dichloromethane/methanol = 10/1 (50 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system A to obtain 6i (80 mg), with a yield of 53.6%. MS m/z (ESI): 247 [M+1] +

参考实施例3第九步至第十步的合成方法，通过4-[(3,5-二甲氧苯基)甲基氨基]-7-甲基-咪唑并[1,5-a]喹喔啉-8-羧酸6j(160mg，0.41mol)和6i(100mg，0.41mmol)得到实施例6，进一步拆分得到实施例6-1(23mg)和实施例6-2(10mg)，产率：9.5％Referring to the synthesis method of steps 9 to 10 of Example 3, 4-[(3,5-dimethoxyphenyl)methylamino]-7-methyl-imidazo[1,5-a]quinoxaline-8-carboxylic acid 6j (160 mg, 0.41 mol) and 6i (100 mg, 0.41 mmol) were used to obtain Example 6, which was further separated to obtain Example 6-1 (23 mg) and Example 6-2 (10 mg). Yield: 9.5%

实施例6-1：MS m/z(ESI):471[M+1]+ Example 6-1: MS m/z (ESI): 471 [M+1] +

1H NMR(400MHz,DMSO)δ9.05(s,1H),8.12(s,2H),7.89(s,2H),7.36(s,1H),7.12(s,2H),5.96(s,1H),4.96(s,1H),4.31(s,1H),4.08(s,1H),2.73(d,3H),2.38(s,3H),1.50(d,3H). 1 H NMR(400MHz,DMSO)δ9.05(s,1H),8.12(s,2H),7.89(s,2H),7.36(s,1H),7.12(s,2H),5. 96(s,1H),4.96(s,1H),4.31(s,1H),4.08(s,1H),2.73(d,3H),2.38(s,3H),1.50(d,3H).

实施例6-2：MS m/z(ESI):471[M+1]+ Example 6-2: MS m/z (ESI): 471 [M+1] +

1H NMR(400MHz,DMSO)δ9.05(s,1H),8.11(d,2H),7.98–7.78(m,2H),7.36(s,1H),7.21(s,2H),5.93(s,1H),4.85(s,1H),4.26(d,2H),2.68(s,3H),2.36(s,3H),1.59(d,3H). 1 H NMR(400MHz,DMSO)δ9.05(s,1H),8.11(d,2H),7.98–7.78(m,2H),7.36(s,1H),7.21( s,2H),5.93(s,1H),4.85(s,1H),4.26(d,2H),2.68(s,3H),2.36(s,3H),1.59(d,3H).

实施例7Example 7

4-氨基-N-(2-溴-7,10-二氢-8H-咪唑并[1,2-a]吡喃并[3,4-c]吡啶-7-基)-N,1-二甲基-1H-吡唑并[4,3-c]喹啉-8-甲酰胺
4-Amino-N-(2-bromo-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

第一步：将2-氯-3-甲基-吡啶-4-羧酸甲酯7a(5g，26.94mmol)，二苯基甲亚胺(5.37g，29.63mmol)，三(二苯亚甲基丙酮)二钯(2.47g,2.69mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(3.12g,5.39mmol)和碳酸铯(13.17g,40.41mmol)溶于二氧六环(25mL)，100℃下反应16小时，反应液呈黄色。反应完毕后，先加入H2O淬灭，再向混合溶液中加入50mL水和300mL乙酸乙酯，有机相用饱和食盐水洗涤三次，每次30mL，再将有机相干燥，旋干。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物得到7b(1.9g)，产率：42％。MS m/z(ESI):167[M+1]+ Step 1: Dissolve 2-chloro-3-methyl-pyridine-4-carboxylic acid methyl ester 7a (5 g, 26.94 mmol), diphenylmethaneimine (5.37 g, 29.63 mmol), tris(dibenzylideneacetone)dipalladium (2.47 g, 2.69 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.12 g, 5.39 mmol) and cesium carbonate (13.17 g, 40.41 mmol) in dioxane (25 mL), react at 100°C for 16 hours, and the reaction solution turns yellow. After the reaction is completed, H 2 O is added to quench, and then 50 mL of water and 300 mL of ethyl acetate are added to the mixed solution. The organic phase is washed three times with saturated brine, 30 mL each time, and then the organic phase is dried and spin-dried. The residue is purified by silica gel column chromatography with eluent system A to obtain 7b (1.9 g), with a yield of 42%. MS m/z(ESI):167[M+1] +

第二步：将7b(1.4g，8.42mmol)、2-溴-1,1-二甲氧基-乙烷(1.42g，8.42mmol)和对甲苯磺酸(725mg，4.21mmol)溶于N,N-二甲基甲酰胺(15mL)，100℃下反应16小时，反应液呈黄色。反应完毕后，加入10mL饱和氯化铵淬灭，用乙酸乙酯萃取(100mL×3)，合并有机相，用饱和氯化钠溶液洗涤(30mL×2)，分层得到有机相后，用无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物得到7c(0.64g),产率：39％。MS m/z(ESI):191[M+1]+ Step 2: Dissolve 7b (1.4 g, 8.42 mmol), 2-bromo-1,1-dimethoxy-ethane (1.42 g, 8.42 mmol) and p-toluenesulfonic acid (725 mg, 4.21 mmol) in N,N-dimethylformamide (15 mL) and react at 100°C for 16 hours. The reaction solution is yellow. After the reaction is completed, 10 mL of saturated ammonium chloride is added to quench, and the mixture is extracted with ethyl acetate (100 mL×3). The organic phases are combined and washed with saturated sodium chloride solution (30 mL×2). After the organic phases are separated by stratification, they are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography with eluent system A to obtain 7c (0.64 g), with a yield of 39%. MS m/z(ESI):191[M+1] +

第三步：将7c(60mg，0.315mmol)，N-溴代丁二酰亚胺(56mg，0.31mmol)和偶氮二异丁腈(15mg，0.094mmol)溶于四氯化碳(4mL)，80℃下反应16小时，反应液呈黄色。反应完毕后，冷却，浓缩，加入10mL水淬灭，用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物得到7d(0.06g)，产率：70％。MS m/z(ESI):269[M+1]+ Step 3: Dissolve 7c (60 mg, 0.315 mmol), N-bromosuccinimide (56 mg, 0.31 mmol) and azobisisobutyronitrile (15 mg, 0.094 mmol) in carbon tetrachloride (4 mL) and react at 80 ° C for 16 hours. The reaction solution is yellow. After the reaction is completed, cool and concentrate, add 10 mL of water to quench, extract with ethyl acetate (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography with eluent system A to obtain 7d (0.06 g), yield: 70%. MS m/z (ESI): 269 [M + 1] +

第四步：将7d(30mg，0.11mmol)，N-溴代丁二酰亚胺(20mg，0.11mmol)和偶氮二异丁腈(6mg，0.034mmol)溶于四氯化碳(3mL)，80℃下反应16小时，反应液呈黄色，90℃搅拌反应16小时。反应完毕后，冷却，过滤，旋干得到7e(25mg)，产率：64％。MS m/z(ESI):349[M+1]+ Step 4: Dissolve 7d (30 mg, 0.11 mmol), N-bromosuccinimide (20 mg, 0.11 mmol) and azobisisobutyronitrile (6 mg, 0.034 mmol) in carbon tetrachloride (3 mL), react at 80°C for 16 hours, the reaction solution turns yellow, and stir at 90°C for 16 hours. After the reaction is complete, cool, filter, and spin dry to obtain 7e (25 mg), yield: 64%. MS m/z (ESI): 349 [M+1] +

第五步：将7e(380mg，1.09mmol)，羟基乙酸甲酯(216mg，2.40mmol)和氢化钠(65mg,2.73mmol)溶于N,N-二甲基甲酰胺(8mL)，20℃下反应16小时。反应完毕后，加入10mL水淬灭，用乙酸乙酯(100mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物得到7f(180mg)，产率：46％。MS m/z(ESI):357[M+1]+ Step 5: Dissolve 7e (380 mg, 1.09 mmol), methyl glycolate (216 mg, 2.40 mmol) and sodium hydride (65 mg, 2.73 mmol) in N,N-dimethylformamide (8 mL) and react at 20°C for 16 hours. After the reaction is completed, add 10 mL of water to quench, extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography with eluent system A to obtain 7f (180 mg), yield: 46%. MS m/z (ESI): 357 [M+1] +

第六步：将7f(50mg，0.14mmol)和双三甲基硅基胺基锂(46mg,0.28mmol)溶于四氢呋喃(2mL)，-55℃下反应1小时，反应液呈黄色。反应完毕后，粗品用C18柱色谱法以洗脱剂体系A纯化所得残余物得到7g(35mg)，产率：76％。MS m/z(ESI):325[M+1]+ Step 6: Dissolve 7f (50 mg, 0.14 mmol) and lithium bis(trimethylsilyl)amide (46 mg, 0.28 mmol) in tetrahydrofuran (2 mL) and react at -55°C for 1 hour. The reaction solution is yellow. After the reaction is completed, the crude product is purified by C18 column chromatography with eluent system A to obtain 7g (35 mg). Yield: 76%. MS m/z (ESI): 325 [M+1] +

第七步：将7g(26mg，0.08mmol)和盐酸(2mL)溶于乙醇(2mL)，80℃下反应16小时，反应液呈黄色。反应完毕后，冷却，浓缩，旋干，粗品用C18柱色谱法以洗脱剂体系A纯化所得残余物得到7h(8mg)，产率：37％。MS m/z(ESI):267[M+1]+ Step 7: Dissolve 7g (26 mg, 0.08 mmol) and hydrochloric acid (2 mL) in ethanol (2 mL), react at 80°C for 16 hours, and the reaction solution turns yellow. After the reaction is completed, cool, concentrate, and spin dry. The crude product is purified by C18 column chromatography with eluent system A to obtain 7h (8 mg), yield: 37%. MS m/z (ESI): 267 [M+1] +

第八步：将7h(30mg，0.11mmol)，甲胺(7mg，0.225μmol)和三氟乙醇(2mL)，60℃下反应2小时，反应液呈黄色。反应完毕后，冷却，浓缩，旋干，粗品用C18柱色谱法以洗脱剂体系A纯化所得残余物得到7i(15mg)，产率：47％。MS m/z(ESI):282[M+1]+ Step 8: 7h (30 mg, 0.11 mmol), methylamine (7 mg, 0.225 μmol) and trifluoroethanol (2 mL) were reacted at 60°C for 2 hours. The reaction solution was yellow. After the reaction was completed, the mixture was cooled, concentrated, and dried by spin drying. The crude product was purified by C18 column chromatography with eluent system A to obtain 7i (15 mg). The yield was 47%. MS m/z (ESI): 282 [M+1] +

第九步：将7i(24mg，0.086mmol)，N,N,N',N'-四甲基氯甲脒六氟磷酸盐(36mg，0.13mmol)和N-甲基咪唑(21mg,0.26mmol)溶于N,N-二甲基甲酰胺(4mL)，40℃下反应1小时，反应液呈黄色。反应完毕后，加入10mL水淬灭，用乙酸乙酯萃取(20mL×3)，合并有机相，用水(10mL)和饱和氯化钠溶液洗涤(10mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物得到实施例7(16.8mg)，产率：38％。MS m/z(ESI):506[M+1]+ Step 9: 7i (24 mg, 0.086 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (36 mg, 0.13 mmol) and N-methylimidazole (21 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (4 mL) and reacted at 40°C for 1 hour. The reaction solution was yellow. After the reaction was completed, 10 mL of water was added to quench, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with water (10 mL) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain Example 7 (16.8 mg) with a yield of 38%. MS m/z (ESI): 506 [M+1] +

1HNMR(400MHz,DMSO)δ8.35(d,1H),8.27(d,2H),7.72-7.61(m,3H),7.15(s,3H),4.94(d,3H),4.42(s,3H),4.30(dd,1H),4.16(s,1H),2.84(s,3H). 1 HNMR (400MHz, DMSO) δ8.35(d,1H),8.27(d,2H),7.72-7.61(m,3H),7.15(s,3H),4.94(d,3H),4.42(s,3H),4.30(dd,1H),4.16(s,1H),2.84(s,3H).

实施例8Example 8

4-氨基-N,7-二甲基-N-(3-(三氟甲基)-7,10-二氢-8H-咪唑并[1,2-a]吡喃并[3,4-c]吡啶-7-基)咪唑并[1,5-a]喹喔啉-8-甲酰胺
4-amino-N,7-dimethyl-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

第一步：将2-氨基-3-甲基异盐酸甲酯8a(5g，30.12mmol)，溴代乙醛缩二甲醇(10.12g，60.24mmol)分散于50mL乙醇和10mL盐酸(2M/L)中，80℃搅拌反应16小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到8b(3.2g)，产率：55.9％。MS m/z(ESI):191[M+1]+ Step 1: Disperse 2-amino-3-methylisomethyl ester 8a (5 g, 30.12 mmol) and bromoacetaldehyde dimethyl acetal (10.12 g, 60.24 mmol) in 50 mL of ethanol and 10 mL of hydrochloric acid (2 M/L), and stir at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain 8b (3.2 g), with a yield of 55.9%. MS m/z (ESI): 191 [M+1] +

第二步：将8b(3.2g，16.84mmol)分散于50mL乙腈中，加入N-碘代丁二酰亚胺(4.5g，20mmol)。搅拌反应1小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到8c(2.80g)，产率：52.6％。MS m/z(ESI):317[M+1]+ Step 2: Disperse 8b (3.2 g, 16.84 mmol) in 50 mL of acetonitrile and add N-iodosuccinimide (4.5 g, 20 mmol). Stir and react for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain 8c (2.80 g) with a yield of 52.6%. MS m/z (ESI): 317 [M+1] +

第三步：将8c(2.80g，8.86mmol)，碘化亚铜(8.42g，44.30mmol)，氟化钾(1.54g，26.58mmol)分散于30mL N,N-二甲基甲酰胺中，加入(三氟甲基)三甲基硅烷(3.77g，26.58mmol)。90℃搅拌反应16小时。反应液过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到8d(830mg)，产率：36.3％。MS m/z(ESI):259[M+1]+ Step 3: Disperse 8c (2.80 g, 8.86 mmol), cuprous iodide (8.42 g, 44.30 mmol), and potassium fluoride (1.54 g, 26.58 mmol) in 30 mL of N,N-dimethylformamide, and add (trifluoromethyl)trimethylsilane (3.77 g, 26.58 mmol). Stir and react at 90°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain 8d (830 mg), with a yield of 36.3%. MS m/z (ESI): 259 [M+1] +

参考实施例6的第三步至第八步和实施例3第九步至第十步的合成方法，通过8d(400mg，1.55mmol)得到实施例8(19mg)，产率：2.5％。MS m/z(ESI):496[M+1]+ Referring to the synthesis method of steps 3 to 8 of Example 6 and steps 9 to 10 of Example 3, Example 8 (19 mg) was obtained by 8d (400 mg, 1.55 mmol), with a yield of 2.5%. MS m/z (ESI): 496 [M+1] +

1H NMR(400MHz,DMSO)δ9.29(s,1H),8.87(s,2H),8.31(dd,4H),7.50(s,1H),7.16(s,1H),5.93–4.56(m,3H),4.27(s,2H),2.79(d,3H),2.42(s,3H). 1 H NMR (400MHz, DMSO) δ9.29(s,1H),8.87(s,2H),8.31(dd,4H),7.50(s,1H),7.16(s,1H),5.93–4.56(m,3H),4.27(s,2H),2.79(d,3H),2.42(s,3H).

如下实施例参考4：




The following example is reference 4:




如下实施例参考实施例8合成：



The following examples are synthesized with reference to Example 8:



实施例112Embodiment 112

4-氨基-N-(3-((二甲基(羰基)-l6-硫烷亚基)氨基)-7,10-二氢-8H-咪唑并[1,2-a]吡喃并[3,4-c]吡啶-7-基)-N,7-二甲基咪唑并[1,5-a]喹喔啉-8-甲酰胺
4-amino-N-(3-((dimethyl(carbonyl)-16-sulfaneylidene)amino)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)-N,7-dimethylimidazo[1,5-a]quinoxaline-8-carboxamide

第一步：将3-溴-N-甲基-7,10-二氢-8H-咪唑并[1,2-a]吡喃并[3,4-c]吡啶-7-氨(220mg，0.78mmol)，二碳酸二叔丁酯(218mg，1.17mmol)与二异丙基乙胺(302mg，2.34mmol)溶于二氯甲烷中，室温下搅拌反应1小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到112a(240mg)，产率：80.5％。MS m/z(ESI):382[M+1]+ Step 1: Dissolve 3-bromo-N-methyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridine-7-amine (220 mg, 0.78 mmol), di-tert-butyl dicarbonate (218 mg, 1.17 mmol) and diisopropylethylamine (302 mg, 2.34 mmol) in dichloromethane and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain 112a (240 mg) with a yield of 80.5%. MS m/z (ESI): 382 [M+1] +

第二步：将112a(100mg，0.26mmol),亚氨基-二甲基-羰基-硫烷(37mg，0.39mmol)，碳酸铯(127mg，0.39mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(28mg，0.5mmol)与三(二亚苄基丙酮)钯(24mg，0.03mmol)溶解于5mL二氧六环中，氮气保护下80℃搅拌反应2小时。向反应液加入乙酸乙酯(50mL)萃取，用饱和食盐水(50mL×2)洗涤,萃取后取有机相，经无水硫酸钠干燥，过滤，滤液减压浓缩，得到112b(57mg)，产率：55.1％。MS m/z(ESI):395[M+1]+ Step 2: Dissolve 112a (100 mg, 0.26 mmol), imino-dimethyl-carbonyl-sulfane (37 mg, 0.39 mmol), cesium carbonate (127 mg, 0.39 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg, 0.5 mmol) and tris(dibenzylideneacetone)palladium (24 mg, 0.03 mmol) in 5 mL of dioxane and stir at 80 °C for 2 hours under nitrogen protection. Add ethyl acetate (50 mL) to the reaction solution for extraction, wash with saturated brine (50 mL × 2), take the organic phase after extraction, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 112b (57 mg), yield: 55.1%. MS m/z (ESI): 395 [M+1] +

第三步：将112b(57mg，0.13mmol)溶解于5mL 2M盐酸二氧六环中，室温搅拌反应2小时。反应液减压浓缩，得到112c(33mg)，产率：85.7％。MS m/z(ESI):295[M+1]+ Step 3: Dissolve 112b (57 mg, 0.13 mmol) in 5 mL of 2M hydrochloric acid dioxane and stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 112c (33 mg), with a yield of 85.7%. MS m/z (ESI): 295 [M+1] +

参考实施例306第九步，通过112c(33mg，0.11mmol)得到实施例112(4.2mg)，产率：7.4％。MS m/z(ESI):519[M+1]+ Referring to the ninth step of Example 306, Example 112 (4.2 mg) was obtained by using 112c (33 mg, 0.11 mmol). Yield: 7.4%. MS m/z (ESI): 519 [M+1] +

1H NMR(400MHz,DMSO)δ9.08(s,1H),8.13–8.06(m,2H),7.88(s,1H),7.34(d,2H),7.32(s,1H),7.00(d,1H),6.78(d,1H),5.74(s,1H),5.07(d,1H),4.78(d,1H),4.23(d,1H),4.15(dd,1H),3.30(d,6H),2.63(s,3H),2.33(s,3H). 1 H NMR(400MHz,DMSO)δ9.08(s,1H),8.13–8.06(m,2H),7.88(s,1H),7.34(d,2H),7.32(s,1H),7.00(d,1H),6.78(d ,1H),5.74(s,1H),5.07(d,1H),4.78(d,1H),4.23(d,1H),4.15(dd,1H),3.30(d,6H),2.63(s,3H),2.33(s,3H).

或，实施例9、10、66的合成参照如下制备方法：Alternatively, the synthesis of Examples 9, 10, and 66 may be performed by the following preparation method:

实施例9Example 9

4-氨基-N-甲氧基-7-甲基-N-(2-(三氟甲基)-5,8-二氢-6H-吡喃并[3,4-b]吡啶-5-基)咪唑并[1,5-a]喹喔啉-8-甲酰胺
4-amino-N-methoxy-7-methyl-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

第一步：将2-(三氟甲基)-6H-吡喃并[3,4-b]吡啶-5(8H)-酮1f(500mg，2.30mmol，采用公知的方法“专利WO2022169948 A1”合成得到)溶于甲醇中，冰浴下分批加入硼氢化钠(435mg，11.51mmol)，0℃搅拌反应1小时。向反应液加入饱和氯化铵溶液(30mL)淬灭反应，用乙酸乙酯(30mL×2)萃取，萃取后取有机相，经无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到9b(470mg)，产率：93.1％。MS m/z(ESI):220[M+1]+ Step 1: Dissolve 2-(trifluoromethyl)-6H-pyrano[3,4-b]pyridin-5(8H)-one 1f (500 mg, 2.30 mmol, synthesized by the known method "Patent WO2022169948 A1") in methanol, add sodium borohydride (435 mg, 11.51 mmol) in batches under ice bath, and stir at 0°C for 1 hour. Add saturated ammonium chloride solution (30 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (30 mL × 2), take the organic phase after extraction, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain 9b (470 mg), yield: 93.1%. MS m/z (ESI): 220 [M + 1] +

第二步：将9b(470mg，2.14mmol)与三乙胺(651mg，6.43mmol)溶解于10mL二氯甲烷中，加入甲基磺酸酐(560mg，3.22mmol)室温搅拌反应1小时。向反应液加入饱和氯化铵溶液(30mL)淬灭反应，用乙酸乙酯(30mL×2)萃取，萃取后取有机相，经无水硫酸钠干燥，过滤，滤液减压浓缩，得到9c(430mg)，产率：66.8％。MS m/z(ESI):298[M+1]+ Step 2: 9b (470 mg, 2.14 mmol) and triethylamine (651 mg, 6.43 mmol) were dissolved in 10 mL of dichloromethane, and methylsulfonic anhydride (560 mg, 3.22 mmol) was added and stirred at room temperature for 1 hour. Saturated ammonium chloride solution (30 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phase was taken after extraction, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 9c (430 mg), with a yield of 66.8%. MS m/z (ESI): 298 [M+1] +

第三步：将9c(220mg，0.74mmol)溶解于10mL乙腈中，加入碳酸钾(511mg，3.7mmol)，80℃封管搅拌反应16小时。反应液冷却至室温，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到9d(139mg)，产率：75.7％。MS m/z(ESI):249[M+1]+ Step 3: Dissolve 9c (220 mg, 0.74 mmol) in 10 mL of acetonitrile, add potassium carbonate (511 mg, 3.7 mmol), and stir at 80°C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain 9d (139 mg), with a yield of 75.7%. MS m/z (ESI): 249 [M+1] +

第四步：将9d(139mg，0.56mmol)与4-((3,4-二甲基苯甲基)氨基)-7-甲基咪唑并[1,5-a]喹喔啉-8-羧酸9e(241mg，0.62mmol)溶解于5mL二氯甲烷中，依次加入三氯氧磷(257mg，1.68mmol)与吡啶(265mg，3.36mmol)，室温搅拌反应2小时。向反应液加入2M盐酸(30mL)淬灭反应，用二氯甲烷(30mL×2)萃取，萃取后取有机相，经无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到9f(67mg)，产率：19.2％。MS m/z(ESI):623[M+1]+ Step 4: 9d (139 mg, 0.56 mmol) and 4-((3,4-dimethylbenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid 9e (241 mg, 0.62 mmol) were dissolved in 5 mL of dichloromethane, phosphorus oxychloride (257 mg, 1.68 mmol) and pyridine (265 mg, 3.36 mmol) were added in sequence, and the mixture was stirred at room temperature for 2 hours. 2M hydrochloric acid (30 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (30 mL×2). The organic phase was taken after extraction, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain 9f (67 mg) with a yield of 19.2%. MS m/z (ESI): 623[M+1] +

参考实施例1的第七步，通过9f(67mg，0.11mmol)，得到实施例9(20.2mg)，产率：38.9％。MS m/z(ESI):473[M+1]+ Referring to the seventh step of Example 1, Example 9 (20.2 mg) was obtained by using 9f (67 mg, 0.11 mmol). Yield: 38.9%. MS m/z (ESI): 473 [M+1] +

1H NMR(400MHz,DMSO)δ9.24(s,1H),8.32(s,1H),8.20(s,1H),8.13(d,1H),7.90(d,1H),7.38(s,1H),5.70(s,1H),4.90(d,1H),4.78(d,1H),4.37–4.15(m,2H),3.43(s,3H),2.38(s,3H). 1 H NMR (400MHz, DMSO) δ9.24(s,1H),8.32(s,1H),8.20(s,1H),8.13(d,1H),7.90(d,1H),7.38( s,1H),5.70(s,1H),4.90(d,1H),4.78(d,1H),4.37–4.15(m,2H),3.43(s,3H),2.38(s,3H).

实施例10Example 10

4-氨基-7-氟-N-甲氧基-N-(2-(三氟甲基)-5,8-二氢-6H-吡喃并[3,4-b]吡啶-5-基)咪唑并[1,5-a]喹喔啉-8-甲酰胺
4-amino-7-fluoro-N-methoxy-N-(2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

参考实施例9的第四步与实施例1的第七步，通过4-((3,4-二甲氧基苯甲基)氨基)-7-氟咪唑并[1,5-a]喹喔啉-8-羧10a(88mg，0.24mmol)，得到实施例10(20mg)，产率：17.4％。MS m/z(ESI):477[M+1]+ Referring to the fourth step of Example 9 and the seventh step of Example 1, 4-((3,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid 10a (88 mg, 0.24 mmol) was used to obtain Example 10 (20 mg), with a yield of 17.4%. MS m/z (ESI): 477 [M+1] +

1H NMR(400MHz,DMSO)δ9.14(s,1H),8.44(d,1H),8.07(d,1H),7.95–7.89(m,2H),7.65(s,2H),7.23(d,1H),5.68(s,1H),4.89(d,1H),4.78(d,1H),4.25(qd,2H),3.47(s,3H). 1 H NMR(400MHz,DMSO)δ9.14(s,1H),8.44(d,1H),8.07(d,1H),7.95–7.89(m,2H),7.65(s ,2H),7.23(d,1H),5.68(s,1H),4.89(d,1H),4.78(d,1H),4.25(qd,2H),3.47(s,3H).

实施例66Embodiment 66

4-氨基-7-氟-N-甲氧基-N-(3-(三氟甲基)-7,10-二氢-8H-咪唑并[1,2-a]吡喃并[3,4-c]吡啶-7-基)咪唑并[1,5-a]喹喔啉-8-甲酰胺
4-amino-7-fluoro-N-methoxy-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

参考实施例9的第一步至第四步与实施例1的第七步，通过3-(三氟甲基)-8H-咪唑并[1,2-a]吡喃并[3,4-c]吡啶-7(10H)-酮66a(300mg，0.24mmol)，得到实施例66(12mg)，产率：2.0％。MS m/z(ESI):516[M+1]+ Referring to the first to fourth steps of Example 9 and the seventh step of Example 1, 3-(trifluoromethyl)-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7(10H)-one 66a (300 mg, 0.24 mmol) was used to obtain Example 66 (12 mg) with a yield of 2.0%. MS m/z (ESI): 516 [M+1] +

1H NMR(400MHz,DMSO)δ9.15(s,1H),8.53(d,1H),8.45(d,1H),8.20(s,1H),7.93(s,1H),7.64(s,2H),7.24(d,1H),7.14(d,1H),5.64(s,1H),5.13(d,1H),4.92(d,1H),4.32(dd,1H),4.21(d,1H),3.45(s,3H). 1 H NMR(400MHz,DMSO)δ9.15(s,1H),8.53(d,1H),8.45(d,1H),8.20(s,1H),7.93(s,1H),7.64(s,2H),7.2 4(d,1H),7.14(d,1H),5.64(s,1H),5.13(d,1H),4.92(d,1H),4.32(dd,1H),4.21(d,1H),3.45(s,3H).

实施例66-P1&66-P2
Example 66-P1 & 66-P2

实施例66(12mg，0.023mmol)经过手性制备HPLC分离，得到(S)-4-氨基-7-氟-N-甲氧基-N-(3-(三氟甲基)-7,10-二氢-8H-咪唑并[1,2-a]吡喃并[3,4-c]吡啶-7-基)咪唑并[1,5-a]喹喔啉-8-甲酰胺66-P1(5.1mg)，产率42.5％和4-氨基-7-氟-N-甲氧基-N-(3-(三氟甲基)-7,10-二氢-8H-咪唑并[1,2-a]吡喃并[3,4-c]吡啶-7-基)咪唑并[1,5-a]喹喔啉-8-甲酰胺66-P2(5.5mg)，产率45.8％。Example 66 (12 mg, 0.023 mmol) was separated by chiral preparative HPLC to give (S)-4-amino-7-fluoro-N-methoxy-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 66-P1 (5.1 mg) with a yield of 42.5% and 4-amino-7-fluoro-N-methoxy-N-(3-(trifluoromethyl)-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 66-P2 (5.5 mg) with a yield of 45.8%.

手性制备条件：

Chiral preparation conditions:

手性分析条件：
Chiral analysis conditions:

66-P1(tR:4.343min):1H NMR(400MHz,DMSO)δ9.15(s,1H),8.53(d,1H),8.45(d,1H),8.20(s,1H),7.93(s,1H),7.64(s,2H),7.24(d,1H),7.14(d,1H),5.64(s,1H),5.13(d,1H),4.92(d,1H),4.32(dd,1H),4.21(d,1H),3.45(s,3H).66-P1( tR :4.343min): 1H NMR(400MHz,DMSO)δ9.15(s,1H),8.53(d,1H),8.45(d,1H),8.20(s,1H),7.93(s,1H),7.64(s,2H),7.2 4(d,1H),7.14(d,1H),5.64(s,1H),5.13(d,1H),4.92(d,1H),4.32(dd,1H),4.21(d,1H),3.45(s,3H).

66-P2(tR:5.530min):1H NMR(400MHz,DMSO)δ9.15(s,1H),8.53(d,1H),8.45(d,1H),8.20(s,1H),7.93(s,1H),7.64(s,2H),7.24(d,1H),7.14(d,1H),5.64(s,1H),5.13(d,1H),4.92(d,1H),4.32(dd,1H),4.21(d,1H),3.45(s,3H).66-P2( tR :5.530min): 1H NMR(400MHz,DMSO)δ9.15(s,1H),8.53(d,1H),8.45(d,1H),8.20(s,1H),7.93(s,1H),7.64(s,2H),7.2 4(d,1H),7.14(d,1H),5.64(s,1H),5.13(d,1H),4.92(d,1H),4.32(dd,1H),4.21(d,1H),3.45(s,3H).

如下实施例可参考实施例5合成：

The following examples can be synthesized with reference to Example 5:

如下实施例可参考实施例2合成：

The following examples can be synthesized with reference to Example 2:

如下实施例可参考实施例112合成：

The following examples can be synthesized with reference to Example 112:

如下实施例可参考实施例10合成：
The following examples can be synthesized with reference to Example 10:

实施例154Embodiment 154

4-氨基-7-氟-N-(3-三氟甲基-7,10-二氢-8H-咪唑并[1,2-a]吡喃并[3,4-c]吡啶-7-基)咪唑并[1,5-a]喹喔啉-8-甲酰胺
4-amino-7-fluoro-N-(3-trifluoromethyl-7,10-dihydro-8H-imidazo[1,2-a]pyrano[3,4-c]pyridin-7-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

第一步：将4-((2,4-二甲氧基苯基)氨基)-7-氟咪唑并[1,5-a]喹喔啉-8-羧酸154a(160mg，0.40mmol)、O-(2-丁炔基)羟胺(344mg，4.04mmol)、DIEA(156mg，1.21mmol)、HOBT(109mg，0.80mmol)、HATU(305mg，0.81mmol)溶解于5mL N,N-二甲基甲酰胺中，20℃搅拌反应1小时。体系减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到154b(150mg)，产率：80.2％。MS m/z(ESI):464[M+1]+ Step 1: 4-((2,4-dimethoxyphenyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid 154a (160 mg, 0.40 mmol), O-(2-butynyl)hydroxylamine (344 mg, 4.04 mmol), DIEA (156 mg, 1.21 mmol), HOBT (109 mg, 0.80 mmol), HATU (305 mg, 0.81 mmol) were dissolved in 5 mL of N,N-dimethylformamide and stirred at 20°C for 1 hour. The system was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to give 154b (150 mg) in a yield of 80.2%. MS m/z (ESI): 464 [M+1] +

第二步：将154b(160mg，0.40mmol)、甲磺酸[5-三氟甲基-12-氧杂-3,6-二氮杂三环[7.4.0.02,6]十三烷-1(9),2,4,7-四烯-10-基]酯(148mg，0.44μmol)、Cs2CO3(215mg，0.66mmol)溶解于15mL N,N-二甲基甲酰胺中，60℃搅拌反应12小时。体系减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到154c(43mg)，产率：17.8％。MS m/z(ESI):704[M+1]+ Step 2: 154b (160 mg, 0.40 mmol), methanesulfonic acid [5-trifluoromethyl-12-oxa-3,6-diazatricyclo[7.4.0.02,6]tridecane-1(9),2,4,7-tetraen-10-yl] ester (148 mg, 0.44 μmol), and Cs 2 CO 3 (215 mg, 0.66 mmol) were dissolved in 15 mL N,N-dimethylformamide and stirred at 60°C for 12 hours. The system was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to give 154c (43 mg) in a yield of 17.8%. MS m/z (ESI): 704 [M+1] +

第三步：将154c(30mg，0.04mmol)和DDQ(19mg，0.09mmol)分散于2mL水和10mL二氯甲烷中，室温搅拌反应12小时。体系减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到实施例154(18mg)，产率：76.2％。MS m/z(ESI):554[M+1]+ Step 3: Disperse 154c (30 mg, 0.04 mmol) and DDQ (19 mg, 0.09 mmol) in 2 mL of water and 10 mL of dichloromethane, and stir at room temperature for 12 hours. The system was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give Example 154 (18 mg), yield: 76.2%. MS m/z (ESI): 554 [M+1] +

1H NMR(400MHz,DMSO)δ9.11(s,1H),8.52(dd,2H),8.21(d,1H),7.95(s,1H),7.72(s,2H),7.30(d,1H),7.16(d,1H),5.23(s,1H),5.16(d,1H),4.81(d,1H),4.62(q,2H),4.19(dd,1H),3.90(dd,1H),1.83(t,3H). 1 H NMR(400MHz,DMSO)δ9.11(s,1H),8.52(dd,2H),8.21(d,1H),7.95(s,1H),7.72(s,2H),7.30(d,1H),7.1 6(d,1H),5.23(s,1H),5.16(d,1H),4.81(d,1H),4.62(q,2H),4.19(dd,1H),3.90(dd,1H),1.83(t,3H).

生物学测试评价Biological test evaluation

以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

测试例1、本发明化合物对提升PRMT5/MEP50-MTA蛋白复合物热稳定性(熔解温度)的能力测定。Test Example 1: Determination of the ability of the compounds of the present invention to enhance the thermal stability (melting temperature) of the PRMT5/MEP50-MTA protein complex.

1实验目的：测量化合物对提升PRMT5/MEP50-MTA蛋白复合物热稳定性，使蛋白熔解温度上升的能力。1 Experimental purpose: To measure the ability of compounds to enhance the thermal stability of the PRMT5/MEP50-MTA protein complex and increase the protein melting temperature.

2实验仪器：定量PCR仪(Quantstudio6 Flex)购自Life公司；移液器购自Eppendorf或Rainin公司。2 Experimental instruments: Quantitative PCR instrument (Quantstudio6 Flex) was purchased from Life Company; pipettes were purchased from Eppendorf or Rainin Company.

3实验试剂耗材：PRMT5/MEP50蛋白由维亚生物制备；HEPES购自Thermo fisher公司，货号为15630080；DTT购自Sigma，货号为43816-10ml；氯化钠购自Invitrogen，货号为AM9760G；Protein Thermal ShiftTMDye Kit购自Thermo fisher公司，货号为4461146；甲硫腺苷(MTA)购自Sigma，货号为D5011。3 Experimental reagents and consumables: PRMT5/MEP50 protein was prepared by Via Biotechnology; HEPES was purchased from Thermo Fisher with the catalog number 15630080; DTT was purchased from Sigma with the catalog number 43816-10ml; sodium chloride was purchased from Invitrogen with the catalog number AM9760G; Protein Thermal ShiftTM Dye Kit was purchased from Thermo Fisher with the catalog number 4461146; methylthioadenosine (MTA) was purchased from Sigma with the catalog number D5011.

4实验方法：本实验通过thermal shift方法测试化合物结合前后PRMT5/MEP50-MTA蛋白复合物熔解温度(Tm)的变化程度来表征化合物提升PRMT5/MEP50-MTA蛋白复合物热稳定性的能力。配制含50mM HEPES、10mM DTT、2μM MTA、SYPRO Orange和250mM NaCl的溶液作为实验缓冲液，并加入终浓度为2μM的人PRMT5/MEP50蛋白，室温孵育30分钟。将以上反应混合物分装到8联排PCR管中，每管19.5μL，分别加入0.5μL的测试化合物或者DMSO，则总反应体系为20μL，化合物终浓度为8μM，并设置2.5％DMSO为溶媒对照。室温孵育10分钟后将PCR管放入PCR仪中，选取melt curve功能检测不同处理组中PRMT5/MEP50-MTA蛋白复合物的熔解温度(从25℃加热至95℃，0.03℃/s)。4 Experimental methods: This experiment uses the thermal shift method to test the degree of change in the melting temperature (Tm) of the PRMT5/MEP50-MTA protein complex before and after the compound binds to characterize the ability of the compound to enhance the thermal stability of the PRMT5/MEP50-MTA protein complex. Prepare a solution containing 50mM HEPES, 10mM DTT, 2μM MTA, SYPRO Orange and 250mM NaCl as the experimental buffer, and add human PRMT5/MEP50 protein at a final concentration of 2μM, and incubate at room temperature for 30 minutes. The above reaction mixture is divided into 8 strips of PCR tubes, 19.5μL per tube, and 0.5μL of the test compound or DMSO is added respectively, so the total reaction system is 20μL, the final concentration of the compound is 8μM, and 2.5% DMSO is set as the solvent control. After incubation at room temperature for 10 minutes, place the PCR tube in the PCR instrument and select the melt curve function to detect the melting temperature of the PRMT5/MEP50-MTA protein complex in different treatment groups (heating from 25°C to 95°C, 0.03°C/s).

5实验数据处理与结果：将PCR仪实验数据文件导入至thermal shift软件，得出每个处理组的熔解温度(Tm)，并减去DMSO溶媒对照组的Tm，得到如下表所示的熔解温度变化值(ΔTm)：
5 Experimental data processing and results: The PCR instrument experimental data file was imported into the thermal shift software to obtain the melting temperature (Tm) of each treatment group, and the Tm of the DMSO solvent control group was subtracted to obtain the melting temperature change value (ΔTm) shown in the following table:

6实验结论：本发明化合物与PRMT5/MEP50-MTA蛋白有良好的结合能力。6 Experimental conclusion: The compounds of the present invention have good binding ability with PRMT5/MEP50-MTA protein.

测试例2、本发明化合物对HCT116和MTAP Knockout HCT116细胞增殖活性抑制作用的测定Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on the proliferation activity of HCT116 and MTAP Knockout HCT116 cells

1实验目的：测量化合物对HCT116野生型和HCT116 MTAP敲除细胞增殖活性的抑制作用。1 Experimental purpose: To measure the inhibitory effect of compounds on the proliferation activity of HCT116 wild-type and HCT116 MTAP knockout cells.

2实验仪器：离心机(Eppendorf 5810R)；酶标仪(BioTek Synergy H1或PerkinElmer Envision)；移液器(Eppendorf或Rainin)。2 Experimental instruments: centrifuge (Eppendorf 5810R); microplate reader (BioTek Synergy H1 or PerkinElmer Envision); pipette (Eppendorf or Rainin).

3实验试剂：HCT116和MTAP Knockout HCT116细胞购自南京科佰；Cell Titer-Glo购自Promega公司，货号为G7573；McCoy`5A购自Gibco，货号为12330031；FBS购自Gibco，货号为10091148；PBS购自Gibco，货号为10010023；胰酶购自Gibco，货号为25200056；细胞培养板购自Corning公司，货号为3610。3 Experimental reagents: HCT116 and MTAP Knockout HCT116 cells were purchased from Nanjing Kebai; Cell Titer-Glo was purchased from Promega with the catalog number G7573; McCoy`5A was purchased from Gibco with the catalog number 12330031; FBS was purchased from Gibco with the catalog number 10091148; PBS was purchased from Gibco with the catalog number 10010023; trypsin was purchased from Gibco with the catalog number 25200056; cell culture plates were purchased from Corning with the catalog number 3610.

4实验方法：使用含10％FBS的McCoy`5A培养基培养HCT116和MTAP Knockout HCT116细胞至合适的细胞密度时，收集细胞，使用完全培养基将细胞调整为合适的细胞浓度，将细胞悬液铺于96孔板，每孔90μL，放入37℃，5％ CO2培养箱贴壁过夜，使用DMSO以及培养基配制不同浓度的化合物溶液，设置溶媒对照，将化合物溶液加入到96孔板中，每孔10μL，放入37℃，5％ CO2培养箱中继续培养72～240小时后，加入CellTiter-Glo溶液，振荡混合均匀后，避光孵育10到30分钟，用Synergy H1或Envision酶标仪进行读数。4 Experimental method: When HCT116 and MTAP Knockout HCT116 cells were cultured to an appropriate cell density using McCoy'5A medium containing 10% FBS, the cells were collected and adjusted to an appropriate cell concentration using complete medium. The cell suspension was plated on a 96-well plate at 90 μL per well and placed in a 37°C, 5% CO2 incubator to adhere overnight. Compound solutions of different concentrations were prepared using DMSO and culture medium, and a solvent control was set up. The compound solution was added to a 96-well plate at 10 μL per well and placed in a 37°C, 5% CO2 incubator for continued culture for 72 to 240 hours. Then, the CellTiter-Glo solution was added, the plates were shaken to mix evenly, incubated in the dark for 10 to 30 minutes, and read using a Synergy H1 or Envision microplate reader.

5实验数据处理与结果：使用发光信号值计算抑制率，将浓度以及抑制率使用Graphpad Prism软件进行非线性回归曲线拟合，得到如下表所示的IC50值：

5 Experimental data processing and results: The inhibition rate was calculated using the luminescent signal value, and the concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC 50 values shown in the following table:

6实验结论：本发明所示的化合物对HCT116 MTAP敲除细胞有良好的增殖抑制活性，且对野生型HCT116细胞有良好的选择性。6 Experimental conclusion: The compounds shown in the present invention have good proliferation inhibitory activity against HCT116 MTAP knockout cells and good selectivity for wild-type HCT116 cells.

测试例3、本发明化合物口服给药在小鼠体内(血浆)的药代动力学测定Test Example 3: Pharmacokinetics of the compounds of the present invention in mice (plasma) after oral administration

1研究目的：以Balb/c小鼠为受试动物，研究化合物口服给药在小鼠体内(血浆)的药代动力学行为。1. Purpose of the study: Balb/c mice were used as test animals to study the pharmacokinetic behavior of the compound in mice (plasma) after oral administration.

2试验方案2 Experimental plan

2.1试验药品：本发明实施例化合物，自制。2.1 Test drugs: Compounds of the present invention, homemade.

2.2试验动物：Balb/c小鼠，雄性，购自上海杰思捷实验动物有限公司，动物生产许可证号(SCXK(沪)2013-0006，No.311620400001794)。2.2 Experimental animals: Balb/c mice, male, purchased from Shanghai JXJ Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006, No. 311620400001794).

2.3药物配制：口服给药药物配制：0.5％ CMC-Na(1％ Tween 80)。2.3 Drug preparation: Drug preparation for oral administration: 0.5% CMC-Na (1% Tween 80).

称取5g羟乙基纤维素(HEC，CMC-Na，粘度：800-1200Cps)，溶于1000mL纯净水，加入10g Tween80，混合均匀成澄清溶液。Weigh 5g hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200Cps), dissolve it in 1000mL pure water, add 10g Tween80, and mix well to form a clear solution.

称取实施例化合物4mg，溶于该溶液中，摇匀，细胞破碎机打碎1min，超声10分钟，得到混悬溶液，浓度为3mg/mL。4 mg of the example compound was weighed and dissolved in the solution, shaken, broken with a cell crusher for 1 min, and ultrasonicated for 10 minutes to obtain a suspension solution with a concentration of 3 mg/mL.

称取实施例化合物，按给药总体积比例先加入5％ DMSO，涡旋、超声2min，使其完全溶解；再加入10％ Solutol HS15，涡旋、超声2min，使其完全溶解；最后加入85％ PBS，涡旋、超声5min，过0.22um滤膜，得到无色透明澄清溶液，浓度为0.2mg/mL。Weigh the example compound, first add 5% DMSO according to the total volume ratio of the dosage, vortex and sonicate for 2 minutes to completely dissolve it; then add 10% Solutol HS15, vortex and sonicate for 2 minutes to completely dissolve it; finally add 85% PBS, vortex and sonicate for 5 minutes, and filter through a 0.22um filter membrane to obtain a colorless, transparent, clear solution with a concentration of 0.2 mg/mL.

2.4给药：Balb/c小鼠3只，雄性；禁食过夜后分别PO给药，剂量为30mg/kg，给药体积10mL/kg。2.4 Administration: 3 male Balb/c mice were fasted overnight and PO-administered at a dose of 30 mg/kg in a dosing volume of 10 mL/kg.

2.5样品采集：于给给药后0.083h、0.25h、0.5h、1h、2h、4h、6h、8h、24h眼眶采血0.04mL，血液置于EDTA-2K试管中，4℃6000rpm离心6min分离血浆，于-20℃保存，给药后4h进食。2.5 Sample collection: 0.04 mL of blood was collected from the eye socket at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood was placed in an EDTA-2K tube and centrifuged at 6000 rpm at 4 °C for 6 min to separate plasma, which was stored at -20 °C. Food was consumed 4 h after administration.

3测定结果：应用LCMS/MS方法得到最后测定结果，结果显示实施例化合物具有较高的口服暴露量。3. Measurement results: The final measurement results were obtained using the LCMS/MS method, and the results showed that the example compounds had a higher oral exposure.

测试例4、本发明化合物口服给药在大鼠体内(血浆)的药代动力学测定Test Example 4: Pharmacokinetics of the compounds of the present invention in rats (plasma) after oral administration

1研究目的：以SD大鼠为受试动物，研究以下化合物实施例，在5mg/kg剂量下口服给药在大鼠体内血浆的药代动力学行为。1. Study purpose: SD rats were used as test animals to study the pharmacokinetic behavior of the following compound examples in rat plasma after oral administration at a dose of 5 mg/kg.

2试验方案2 Experimental plan

2.1试验药品：溶媒配方：0.5％ CMC-Na(1％ Tween 80)；本发明实施例，自制。2.1 Experimental drug: Solvent formula: 0.5% CMC-Na (1% Tween 80); Example of the present invention, homemade.

2.2试验动物：SD大鼠每组3只，雄性。上海必凯科翼生物科技有限公司，动物许可证号(SCXK(沪)2018-0006，No.20180006037467)。2.2 Experimental animals: 3 male SD rats per group. Shanghai Bikeway Biotechnology Co., Ltd., animal license number (SCXK (Shanghai) 2018-0006, No. 20180006037467).

2.3给药：SD大鼠每组3只，雄性，禁食一夜后分别PO，剂量为5mg/kg，给药体积10mL/kg。2.3 Administration: 3 male SD rats were administered PO to each group after overnight fasting at a dose of 5 mg/kg in a dosing volume of 10 mL/kg.

2.4样品采集：大鼠给药前和给药后，在0、0.25、0.5、1、2、4、6、8和24小时，采用颈静脉采血0.2mL，置于EDTA-K2试管中，4℃6000rpm离心6min分离血浆，于-80℃保存，给药后4h进食。2.4 Sample collection: Before and after administration, 0.2 mL of blood was collected from the jugular vein of rats at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours. The blood was placed in an EDTA- K2 tube and centrifuged at 6000 rpm for 6 min at 4°C to separate plasma, which was stored at -80°C and fed 4 hours after administration.

2.5样品处理2.5 Sample processing

1)血浆样品40uL加入160uL乙腈沉淀，混合后3500×g离心5～20分钟。1) 40uL of plasma sample was added to 160uL of acetonitrile for precipitation, and after mixing, centrifuged at 3500×g for 5 to 20 minutes.

2)取处理后上清溶液100uL进行LC/MS/MS分析待测化合物的浓度。2) Take 100uL of the supernatant solution after treatment and perform LC/MS/MS analysis to determine the concentration of the test compound.

2.6液相分析2.6 Liquid phase analysis

●液相条件：Shimadzu LC-20AD泵Liquid phase conditions: Shimadzu LC-20AD pump

●质谱条件:AB Sciex API 4000质谱仪●Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

●色谱柱：phenomenex Gemiu 5um C18 50×4.6mm●Chromatographic column: phenomenex Gemiu 5um C 18 50×4.6mm

●移动相：A液为0.1％甲酸水溶液，B液为甲醇流速：1.0mL/min●Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is methanol Flow rate: 1.0mL/min

●洗脱时间：0-4.0分钟，洗脱液如下：
● Elution time: 0-4.0 minutes, eluent is as follows:

3试验结果与分析：药代动力学主要参数用WinNonlin 8.2计算得到大鼠药代实验结果，结果如下表所示：
3 Experimental results and analysis: The main pharmacokinetic parameters were calculated using WinNonlin 8.2 to obtain the results of the rat pharmacokinetic experiment. The results are shown in the following table:

4实验结论：口服给药5mg/kg剂量下，本发明实施例化合物表现出良好的代谢性质，暴露量AUC和最大血药浓度Cmax都表现良好。4 Experimental conclusion: At a dose of 5 mg/kg administered orally, the compounds of the present invention showed good metabolic properties, with both exposure AUC and maximum blood concentration Cmax showing good performance.

测试例5、hERG钾离子通道抑制活性测试Test Example 5: hERG potassium channel inhibition activity test

1研究目的：化合物对hERG钾离子通道活性的抑制能力。1. Research purpose: To investigate the inhibitory ability of compounds on the activity of hERG potassium ion channels.

2实验仪器和试剂：2 Experimental instruments and reagents:

2.1试剂
2.1 Reagents

2.2仪器和耗材
2.2 Instruments and consumables

3实验方法3 Experimental methods

3.1细胞培养：实验所用的稳定表达hERG钾离子通道的CHO细胞(CHO-hERG)来自于Sophion生物科学公司(巴勒鲁普，丹麦)在上海药明康德传代冻存。CHO-hERG于含1×GlutaMAX、10％胎牛血清、100μg/mL G418、100μg/mL潮霉素B的Ham’s F-12培养基，5％ CO2，37℃培养传代。3.1 Cell culture: CHO cells stably expressing hERG potassium channels (CHO-hERG) used in the experiment were obtained from Sophion Biosciences (Ballerup, Denmark) and cryopreserved at Shanghai WuXi AppTec. CHO-hERG was cultured and passaged in Ham's F-12 medium containing 1×GlutaMAX, 10% fetal bovine serum, 100 μg/mL G418, and 100 μg/mL hygromycin B, 5% CO 2 , and 37°C.

3.2细胞内外液的配制：细胞外液每个月配制一次，分装储存于1L的储液瓶中。细胞内液每三个月配制一次，分装冻存于-20℃。细胞内液于实验开始前37℃水浴中融化，置于冰浴中待用。3.2 Preparation of extracellular and extracellular fluids: Extracellular fluid was prepared once a month and stored in 1L storage bottles. Intracellular fluid was prepared once every three months and stored in aliquots at -20°C. The intracellular fluid was melted in a 37°C water bath before the experiment and placed in an ice bath for later use.

3.3化合物的配制：化合物于100％ DMSO(Sigma-Aldrich，D2650)配置成10mM或30mM的储备溶液。实验前分别用DMSO将上述待测化合物的储备溶液稀释为各个试验浓度1000倍或者333倍的溶液，然后再用细胞外液稀释1000倍或者333倍到所需浓度。3.3 Compound preparation: Compounds were prepared into 10mM or 30mM stock solutions in 100% DMSO (Sigma-Aldrich, D2650). Before the experiment, the stock solutions of the above test compounds were diluted with DMSO to 1000 times or 333 times the test concentration, and then diluted 1000 times or 333 times with extracellular fluid to the required concentration.

3.4细胞的前期准备：用于实验的CHO-hERG细胞至少培养两天以上，细胞密度达到75％以上时，用TrypLE消化细胞，然后用细胞外液重悬离心，去上清后另加2mL细胞外液重悬待用。3.4 Preliminary preparation of cells: The CHO-hERG cells used in the experiment were cultured for at least two days. When the cell density reached more than 75%, the cells were digested with TrypLE, then resuspended with extracellular solution and centrifuged. After removing the supernatant, 2 mL of extracellular solution was added for resuspending.

3.4实验数据处理：在数据处理中，判断对hERG的阻断效应时，将尾电流的峰值和其基线进行校正。用尾电流的抑制率表示不同浓度下各化合物的作用。IC50数值由Hill方程进行拟合所得：I/Icontrol＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))3.4 Experimental data processing: In data processing, when judging the blocking effect on hERG, the peak value of the tail current and its baseline are corrected. The inhibition rate of the tail current is used to represent the effect of each compound at different concentrations. The IC 50 value is obtained by fitting the Hill equation: I/Icontrol＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))

Top:最大效应；Bottom：最小效应；Hillslope:斜率；X：供试品浓度。Top: maximum effect; Bottom: minimum effect; Hillslope: slope; X: test sample concentration.

IC50：待测化合物对hERG的半数最大抑制浓度。若最低浓度下抑制率超过半数抑制或最高浓度下抑制率未达到半数抑制，则该化合物相应的IC50低于最低浓度或IC50值大于最高浓度。 IC50 : The half-maximal inhibitory concentration of the test compound on hERG. If the inhibition rate at the lowest concentration exceeds half inhibition or the inhibition rate at the highest concentration does not reach half inhibition, the corresponding IC50 of the compound is lower than the lowest concentration or the IC50 value is greater than the highest concentration.

4实验结论：本发明的优势化合物对于心脏hERG钾离子通道抑制活性(IC50)大于5μM，甚至大于15μM，部分实施例的抑制活性(IC50)大于30μM，可以避免高剂量时的心脏毒副作用。4 Experimental conclusion: The inhibitory activity (IC 50 ) of the advantageous compounds of the present invention on cardiac hERG potassium channels is greater than 5 μM, even greater than 15 μM. The inhibitory activity (IC 50 ) of some embodiments is greater than 30 μM, which can avoid cardiac toxicity at high doses.

测试例6、本发明化合物在人源肺癌细胞株LU99裸小鼠皮下移植瘤模型的体内药效学研究Test Example 6: In vivo pharmacodynamic study of the compound of the present invention in a subcutaneous transplanted tumor model of nude mice with human lung cancer cell line LU99

1研究目的：评价化合物在人源肺癌细胞株LU99裸小鼠皮下移植瘤模型的体内药效。1. Purpose of the study: To evaluate the in vivo efficacy of the compound in the subcutaneous transplanted tumor model of nude mice with human lung cancer cell line LU99.

2实验仪器与试剂2 Experimental instruments and reagents

2.1仪器：冰箱(BCD-268TN，Haier)；生物安全柜(BSC-1300II A2，上海博讯实业有限公司医疗设备厂)；超净工作台(CJ-2F，苏州市冯氏实验动物设备有限公司)；电动移液助吸器(Easypet 3，Eppendorf)；恒温水浴锅(HWS-12，上海一恒科学)；CO2培养箱(Thermo-311，Thermo)；离心机(Centrifuge 5720R，Eppendorf)；全自动细胞计数仪(Countess II，Life Technologies)；游标卡尺(CD-6”AX，日本三丰)；细胞培养瓶(T25/T75/T225，Corning)；电子天平(CPA2202S，赛多利斯)；电子天平(BSA2202S-CW，赛多利斯)；超声波清洗器(115F0032，上海科导)；纯水仪(Pacific TII，Thermo)；磁力搅拌器(08-2G，驰久)。2.1 Instruments: refrigerator (BCD-268TN, Haier); biological safety cabinet (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory); clean bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.); electric pipette assistant (Easypet 3, Eppendorf); constant temperature water bath (HWS-12, Shanghai Yiheng Science); CO2 incubator (Thermo-311, Thermo); centrifuge (Centrifuge 5720R, Eppendorf); automatic cell counter (Countess II, Life Science) Technologies); Vernier caliper (CD-6”AX, Mitutoyo, Japan); Cell culture flask (T25/T75/T225, Corning); Electronic balance (CPA2202S, Sartorius); Electronic balance (BSA2202S-CW, Sartorius); Ultrasonic cleaner (115F0032, Shanghai Kedao); Water purifier (Pacific TII, Thermo); Magnetic stirrer (08-2G, Chijiu).

2.2试剂：RPMI-1640培养基(22400-089，Gibco)；胎牛血清(FBS)(A5669701，Gibco)；磷酸盐缓冲液(PBS)(10010-023，Gibco)；Matrigel基质胶(356234，Corning)；羧甲基纤维素钠(30036365，国药试剂)；Tween-80(30189828，国药试剂)。2.2 Reagents: RPMI-1640 culture medium (22400-089, Gibco); fetal bovine serum (FBS) (A5669701, Gibco); phosphate buffered saline (PBS) (10010-023, Gibco); Matrigel matrix glue (356234, Corning); sodium carboxymethyl cellulose (30036365, Sinopharm Reagent); Tween-80 (30189828, Sinopharm Reagent).

3实验操作及数据处理3 Experimental operation and data processing

3.1动物：BALB/c裸小鼠，6-8周，雌性，购自北京维通利华实验动物技术有限公司。3.1 Animals: BALB/c nude mice, 6-8 weeks old, female, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

3.2细胞培养及细胞悬液制备3.2 Cell culture and cell suspension preparation

a)从细胞库中取出一株LU99细胞，用RPMI-1640培养基(RPMI-1640+10％ FBS)复苏细胞，复苏后的细胞置细胞培养瓶中置于CO2培养箱中培养(培养箱温度为37℃，CO2浓度为5％)。a) Take out a strain of LU99 cells from the cell bank, resuscitate the cells with RPMI-1640 medium (RPMI-1640+10% FBS), and place the resuscitated cells in a cell culture flask in a CO 2 incubator (the incubator temperature is 37° C. and the CO 2 concentration is 5%).

b)每三天传代一次，传代后细胞继续置于CO2培养箱中培养。重复该过程直到细胞数满足体内药效需求。b) Subculture once every three days, and continue to culture the cells in a CO2 incubator after subculture. Repeat this process until the cell number meets the in vivo drug efficacy requirements.

c)收集指数生长期的细胞，用全自动细胞计数仪计数，根据计数结果用PBS重悬，重悬后的细胞与基质胶1：1混合至浓度为5×107细胞/mL，置于冰盒中待用。c) Collect cells in the exponential growth phase, count them using an automatic cell counter, resuspend them in PBS according to the counting results, mix the resuspended cells with matrix gel at a ratio of 1:1 to a concentration of 5×10 7 cells/mL, and place them in an ice box for later use.

3.3细胞接种3.3 Cell seeding

a)接种前用一次性大小鼠通用耳标标记裸鼠；a) Before inoculation, nude mice were marked with disposable ear tags for both adults and mice;

b)接种时混匀细胞悬液，用1mL注射器抽取0.1-1mL细胞悬液、排除气泡，然后将注射器置于冰袋上待用；b) Mix the cell suspension during inoculation, draw 0.1-1 mL of the cell suspension with a 1 mL syringe, remove the bubbles, and then place the syringe on an ice pack for later use;

c)左手保定好裸鼠，用75％酒精棉球消毒裸鼠右侧背部靠右肩位置(接种部位)，30秒后开始接种；c) Secure the nude mouse with your left hand, and disinfect the right side of the nude mouse's back near the right shoulder (inoculation site) with a 75% alcohol cotton ball, and start inoculation after 30 seconds;

d)依次给试验裸鼠接种(每只小鼠接种0.1mL细胞悬液)。d) The nude mice were inoculated sequentially (0.1 mL of cell suspension was inoculated per mouse).

3.4荷瘤鼠量瘤、分组、给药3.4 Tumor measurement, grouping, and drug administration in tumor-bearing mice

a)根据肿瘤生长情况，在接种后第9-12天量瘤、并计算肿瘤大小；肿瘤体积计算：肿瘤体积(mm3)＝长(mm)×宽(mm)×宽(mm)/2；a) According to the tumor growth, the tumor was measured and the tumor size was calculated on the 9th to 12th day after inoculation; tumor volume calculation: tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm)/2;

b)根据荷瘤鼠体重和肿瘤大小，采用随机分组的方法进行分组；b) The mice were randomly divided into groups according to their weight and tumor size;

c)根据分组结果，开始给予测试药物(给药方式：口服给药；给药体积：10mL/kg；给药频率：1次/天或2次/天；给药周期：28天；溶媒：0.5％ CMC-Na(1％ Tween 80))。c) According to the grouping results, start administering the test drug (administration method: oral administration; administration volume: 10 mL/kg; administration frequency: 1 time/day or 2 times/day; administration cycle: 28 days; solvent: 0.5% CMC-Na (1% Tween 80)).

d)开始给予测试药物后每周两次量瘤、称重。d) Tumors were measured and weighed twice a week after the start of administration of the test drug.

e)实验结束后安乐死动物。e) Animals were euthanized after the experiment.

f)用Excel等软件处理数据。化合物抑瘤率TGI(％)的计算：当肿瘤无消退时，TGI(％)＝[1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。当肿瘤有消退时，TGI(％)＝[1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/该处理组开始给药时平均瘤体积]×100％。f) Process the data using software such as Excel. Calculation of the compound tumor inhibition rate TGI (%): When the tumor does not regress, TGI (%) = [1-(average tumor volume at the end of a certain treatment group administration - average tumor volume at the beginning of administration of the treatment group)/(average tumor volume at the end of treatment of the solvent control group - average tumor volume at the beginning of treatment of the solvent control group)] × 100%. When the tumor regresses, TGI (%) = [1-(average tumor volume at the end of administration of a certain treatment group - average tumor volume at the beginning of administration of the treatment group)/average tumor volume at the beginning of administration of the treatment group] × 100%.

4实验结论：4 Experimental conclusions:

本发明的优势化合物在低剂量下化合物抑瘤率(TGI)大于80％，甚至大于90％，有明显的抑制肿瘤生长作用。在高剂量下化合物抑瘤率(TGI)大于100％，甚至大于150％，有明显的肿瘤消退作用。The advantageous compounds of the present invention have a tumor inhibition rate (TGI) greater than 80% or even greater than 90% at low doses, and have a significant tumor growth inhibition effect. The tumor inhibition rate (TGI) of the compounds at high doses is greater than 100% or even greater than 150%, and has a significant tumor regression effect.

Claims (16)

一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐：
A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:
M1选自-N-或-CRa-； M1 is selected from -N- or -CR a -; M2选自-N-或-CRb-；优选-CRb-；M 2 is selected from -N- or -CR b -; preferably -CR b -; M3选自N或C；优选N；M 3 is selected from N or C; preferably N; 环A选自C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基；优选C3-6环烷基、3-6元杂环基、苯基或5-6元杂芳基；Ring A is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; preferably C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; 环B选自C3-14环烷基、3-14元杂环基、C6-14芳基或5-14元杂芳基；优选C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；优选C3-6环烷基、3-6元杂环基、C6-10稠环烷基、6-10元稠杂环基、C6-10芳基或5-10元杂芳基；Ring B is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; preferably C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; preferably C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 fused cycloalkyl, 6-10 membered fused heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; L1选自键、-(CRaaRbb)m2-、-(CRaaRbb)m2C(O)-、-(CRaaRbb)m2C(S)-、-(CRaaRbb)m2C(NRcc)-、-(CRaaRbb)m2NRccC(O)、-(CRaaRbb)m2S(O)m1-、-(CRaaRbb)m2NRcc-、-(CRaaRbb)m2P(O)2-、-(CRaaRbb)m2P(O)(ORcc)-、C3-12亚环烷基、3-12元亚杂环基、C6-12亚芳基或5-12元亚杂芳基，所述的C3-12亚环烷基、3-12元亚杂环基、C6-12亚芳基和5-12元亚杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选-CRaaRbb-、-C(O)-、-S(O)m1-或-NRcc-； L1 is selected from a bond, -(CRaaRbb)m2- , - ( CRaaRbb ) m2C (O)-, - (CRaaRbb ) m2C ( S)-, -( CRaaRbb ) m2C ( NRcc )-, -( CRaaRbb ) m2NRccC (O), -( CRaaRbb ) m2S (O) m1- , -( CRaaRbb ) m2NRcc- , -( CRaaRbb ) m2P (O ) 2- , -( CRaaRbb ) m2P (O ) ( ORcc ) - , C3-12cycloalkylene , 3-12memberedheterocyclylene, C6-12arylene or 5-12memberedheteroarylene , wherein the C3-12cycloalkylene , 3-12memberedheterocyclylene, C6-12arylene or 5-12memberedheteroarylene C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably -CR aa R bb -, -C(O)-, -S(O) m1 - or -NR cc -; L2选自键、-(CRaaRbb)m2-、-(CRaaRbb)m2C(O)-、-(CRaaRbb)m2NRccC(O)、-(CRaaRbb)m2S(O)m1-或-(CRaaRbb)m2NRcc-；优选-CRaaRbb-、-C(O)-、-S(O)m1-或NRcc； L2 is selected from a bond, -(CRaaRbb)m2- , - ( CRaaRbb ) m2C ( O )-, -( CRaaRbb ) m2NRccC (O), -( CRaaRbb ) m2S (O) m1- or -( CRaaRbb ) m2NRcc- ; preferably -CRaaRbb- , -C(O)-, -S( O ) m1- or NRcc ; R1选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1- 6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、-(CRccRdd)n1-C3-12环烷基、-(CRccRdd)n1-3-12元杂环基、-(CRccRdd)n1-C6-12芳基、-(CRccRdd)n1-5-12元杂芳基、-SF5、-ORe、-NReRf、-C(O)Re、-C(O)ORe、-C(O)NReRf、-N＝S(O)ReRf、-S(O)Re(＝NRf)或-P(O)ReRf，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1- 6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基和＝CRggRhh中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、-(CRccRdd)n1-C3-8环烷基、-(CRccRdd)n1-3-8元杂环基、-(CRccRdd)n1-C6-10芳基、-(CRccRdd)n1-5-10元杂芳基、-ORe、-NReRf、-C(O)Re、-C(O)NReRf或-P(O)ReRf，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, -( CRccRdd ) n1 - C3-12 cycloalkyl, - ( CRccRdd ) n1-3-12 membered heterocyclyl, - ( CRccRdd ) n1 - C6-12 aryl, - (CRccRdd ) n1-5-12 membered heteroaryl, -SF5 , -ORe , -NReRf, -C(O ) Re , -C(O) ORe , -C ( O) NReRf , -N = S (O) ReRf wherein the amino, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C The group is preferably substituted by one or more substituents selected from the group consisting of: C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl and =CR gg R hh ; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, -(CR cc R dd ) n1 -C 3-8 cycloalkyl, -(CR cc R dd ) n1 -3-8 membered heterocyclyl, -(CR cc R dd ) n1 -C 6-10 aryl, -(CR cc R dd ) n1 -5-10 membered heteroaryl, -ORe , -NReRf , -C (O)Re, -C(O ) NReRf or -P(O) ReRf , the amino, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 The alkyl group is substituted with one or more substituents selected from C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; R2选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-(CH2)n2ORee、-(CH2)n2NReeRff、-(CH2)n2C(O)Ree、-(CH2)n2C(O)NReeRff、-(CH2)n2P(O)ReeRff或＝CReeRff，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6- 10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1- 3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6- 10芳基和5-10元杂芳基中的一个或多个取代基所取代； R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, cyano-substituted C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -( CH2 ) n2ORee , - ( CH2 ) n2NReeRff , -( CH2 ) n2C (O) Ree , -( CH2 ) n2C (O ) NReeRff , -( CH2 ) n2P ( O )ReeRff or = CReeRff , the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl The alkylene group is substituted with one or more substituents selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl , 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl; R3选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-Y1-C3-12环烷基、-Y1-3-12元杂环基、-Y1-C6-12芳基、-Y1-5-12元杂芳基、-SF5、-ORg、-NRgRh、-C(O)Rg、-C(O)ORg、-C(O)NRgRh、-N＝S(O)RgRh、-S(O)Rg(＝NRh)、-P(O)RgRh、-C(＝NRi)NRgRh或＝RgRh，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、取代或未取代的C3-12环烷基、取代或未取代的3-12元杂环基、取代或未取代的C6-12芳基、取代或未取代的5-12元杂芳基和＝CReRf中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基和＝CReRf中的一个或多个取代基所取代； R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, cyano-substituted C1-6 alkyl, -Y1 -C3-12 cycloalkyl, -Y1-3-12 membered heterocyclyl, -Y1 - C6-12 aryl, -Y1-5-12 membered heteroaryl, -SF5 , -ORg , -NRgRh , -C(O) Rg , -C ( O) ORg , -C(O) NRgRh , -N= S (O) RgRh , -S(O) Rg ( = NRh ) , -P(O)R wherein the amino, C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl , 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano The alkyl radicals are substituted with one or more substituents selected from the group consisting of: C 1-6 alkyl, substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, and =CR e R f ; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl and =CR e R f ; 或者任意两个R3与其相邻的原子链接形成C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选形成C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选进一步被氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；or any two R3 are linked to their adjacent atoms to form C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl; preferably, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, cyano substituted C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl. 6-10 membered aryl and 5-10 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; Ra、Rb、Rc、Re和Rf各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-(CH2)n2ORee、-(CH2)n2NReeRff、-(CH2)n2C(O)Ree、-(CH2)n2C(O)ORee、-(CH2)n2C(O)NReeRff、-(CH2)n2N＝S(O)ReeRff、-(CH2)n2S(O)Ree(＝NRff)或-(CH2)n2P(O)ReeRff，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基和＝CRggRhh中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； Ra , Rb , Rc , Re and Rf are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, 5-12 membered heteroaryl, -( CH2 ) n2ORee , -( CH2 ) n2NReeRff , - ( CH2 ) n2C (O) Ree , -( CH2 ) n2C (O )ORee, -(CH2)n2C ( O ) NRee wherein the amino , C 1-6 alkyl , C 2-6 alkenyl , C 2-6 alkynyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl are optionally substituted with deuterium , halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, oxo , thio, C 1-6 The alkyl radicals are preferably substituted by one or more substituents selected from the group consisting of: C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted by cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl and =CR gg R hh ; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted by cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C The amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C substituted by one or more substituents selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; 或者Ra与Rb链接形成C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；or Ra and Rb are linked to form a C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C6-12 aryl, and a 5-12 membered heteroaryl, which is optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, a 3-12 membered heterocyclyl, C6-12 aryl, and a 5-12 membered heteroaryl; Y1选自键、-O-、-S-、-C(O)、-NRj-、-C(O)NRj-、-NRjC(O)-、-S(O)2NRj-、-NRjS(O)2-、C1-6亚烷基、-O-C1-6亚烷基-、-C1-6亚烷基-O-、-NRj-C1-6亚烷基-、-C1-6亚烷基-NRj-、C2-6亚烯基或C2-6亚炔基，所述的C1-6亚烷基、C2-6亚烯基和C2-6亚炔基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3- 12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；Y is selected from a bond, -O-, -S-, -C(O), -NRj- , -C(O) NRj- , -NRjC (O)-, -S (O) 2NRj- , -NRjS (O ) 2- , C1-6alkylene , -OC1-6alkylene-, -C1-6alkylene- O- , -NRj - C1-6alkylene- , -C1-6alkylene -NRj-, C2-6alkenylene or C2-6alkynylene , wherein said C1-6alkylene , C2-6alkenylene and C2-6alkynylene are optionally deuterated, halogen, amino , hydroxyl, cyano, nitro, C1-6alkyl , C2-6alkenyl , C2-6alkynyl, oxo, thio, C1-6deuteratedalkyl , C1-6haloalkyl , C1-6alkoxy , C1-6 The alkyl group is substituted with one or more substituents selected from C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; Rg、Rh、Ri和Rj各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1- 6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； Rg , Rh , R , and Rj are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, The invention also comprises a C 1-6 alkyl, a C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl, which are optionally substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , oxo , thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, C 6-12 aryl and a 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C The alkyl radical is substituted with one or more substituents selected from C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; 或者，Rg与Rh链接形成C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选进一步被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；Alternatively, Rg and Rh are linked to form C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl, which are optionally further substituted by one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl and 5-12 membered heteroaryl; Raa、Rbb、Rcc和Rdd各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1- 6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6- 12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1- 3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1- 3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 membered aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; Ree和Rff各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl The invention also comprises a C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl, which are optionally substituted by one or more substituents of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C The alkyl radical is substituted with one or more of C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; Rgg和Rhh各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；优选氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代； Rgg and Rhh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl The invention also comprises a C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl, which are optionally substituted by one or more substituents of deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C 6-12 aryl and a 5-12 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C The alkyl radical is substituted with one or more of C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; x选自0、1、2、3、4、5或6；x is selected from 0, 1, 2, 3, 4, 5 or 6; y选自0、1、2、3、4、5或6；y is selected from 0, 1, 2, 3, 4, 5 or 6; m1选自0、1或2；m1 is selected from 0, 1 or 2; n1选自0、1、2、3或4；且n1 is selected from 0, 1, 2, 3 or 4; and n2选自0、1、2、3或4。n2 is selected from 0, 1, 2, 3 or 4. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述选自 The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the Selected from 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步如通式(III-C)所示：
The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is further represented by general formula (III-C):
R1-1选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-(CH2)n2ORee、-(CH2)n2NReeRff、-(CH2)n2C(O)Ree、-(CH2)n2C(O)ORee、-(CH2)n2C(O)NReeRff、-(CH2)n2N＝S(O)ReeRff、-(CH2)n2S(O)Ree(＝NRff)或-(CH2)n2P(O)ReeRff，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基和＝CRggRhh中的一个或多个取代基所取代；优选C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基或氰基取代的C1-3烷基，所述的C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基和氰基取代的C1-3烷基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基和＝CRggRhh中的一个或多个取代基所取代；R 1-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -(CH 2 ) n2 OR ee , -(CH 2 ) n2 NR ee R ff , -(CH 2 ) n2 C(O)R ee , -(CH 2 ) n2 C(O)OR ee , -(CH 2 ) n2 C(O)NR ee R ff , -(CH 2 ) n2 N＝S(O)R ee R ff , -(CH 2 ) n2 S(O)R ee (＝NR ff ) or -(CH 2 ) n2 P(O)R ee R ff , the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl and =CR gg R hh ; preferably C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl or cyano substituted C 1-3 alkyl , said C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl and cyano substituted C 1-3 alkyl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C The group is preferably substituted with one or more of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl and =CR gg R hh ; Ree和Rff各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代；R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, -C(O)-C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; Rgg和Rhh各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、-C(O)-C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述的氨基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、氧代基、硫代基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基取代的C1-6烷基、C3-12环烷基、3-12元杂环基、C6-12芳基和5-12元杂芳基中的一个或多个取代基所取代； Rgg and Rhh are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 alkyl substituted with cyano, -C(O) -C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-12 aryl or 5-12 membered heteroaryl C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl; n2选自0、1、2、3或4；n2 is selected from 0, 1, 2, 3 or 4; 环A、环B、M1、M2、M3、L2、R2、R3、Rc、x和y的定义如权利要求1所定义。Ring A, Ring B, M 1 , M 2 , M 3 , L 2 , R 2 , R 3 , R c , x and y are as defined in claim 1 . 根据权利要求1-3任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环A选自3-12元杂环基或5-12元杂芳基；优选5元杂环基、6元杂环基、5元杂芳基或6元杂芳基；更优选 The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that Ring A is selected from a 3-12-membered heterocyclic group or a 5-12-membered heteroaryl group; preferably a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered heteroaryl group or a 6-membered heteroaryl group; more preferably 根据权利要求1-4任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环B选自3-6元杂环基并苯基或3-6元杂环基并5-6元杂芳基；优选 The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that ring B is selected from a 3-6-membered heterocyclic phenyl group or a 3-6-membered heterocyclic phenyl group and a 5-6-membered heteroaryl group; preferably 或，环B选自6-14元三环杂环基；优选6-14元三环螺杂环基或6-14元三环稠杂环基；更优选 Or, Ring B is selected from a 6-14 membered tricyclic heterocyclic group; preferably a 6-14 membered tricyclic spiro heterocyclic group or a 6-14 membered tricyclic fused heterocyclic group; more preferably 根据权利要求1-5任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步如通式(IV-A)所示：
The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is further represented by general formula (IV-A):
M4选自N或CR3a；M 4 is selected from N or CR 3a ; M4选自N或CR3b；M 4 is selected from N or CR 3b ; R3a、R3c和R3d各自独立地选自氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6- 10芳基、5-10元杂芳基和＝CReRf中的一个或多个取代基所取代；R 3a , R 3c and R 3d are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl C1-3 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl and =CR e R f ; R3b选自氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1- 3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基和＝CReRf中的一个或多个取代基所取代；R 3b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl and =CR e R f ; n3选自0、1或2。n3 is selected from 0, 1 or 2. 根据权利要求1-5任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，进一步如通式(IV-B)所示：
The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is further represented by general formula (IV-B):
M5选自N或C；M6选自N或C； M5 is selected from N or C; M6 is selected from N or C; 环C选自C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基；Ring C is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; R3e选自氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1- 3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基和＝CReRf中的一个或多个取代基所取代； R3e is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl and =CR e R f ; R3f选自氢、氘、氟、氯、溴、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1- 3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1- 3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基和＝CReRf中的一个或多个取代基所取代； R3f is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, oxo, thio, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C1-3 alkyl substituted with cyano, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl and =CR e R f ; n3选自0、1或2n3 is selected from 0, 1 or 2 p选自0、1、2、3或4；p is selected from 0, 1, 2, 3 or 4; q选自0、1或2。q is selected from 0, 1 or 2. 根据权利要求1-7任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R2选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、氰基取代的C1-3烷基、C3-8环烷基或-C(O)NReeRff，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、氰基取代的C1-3烷基和C3-8环烷基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、氰基取代的C1-3烷基和C3-8环烷基中的一个或多个取代基所取代；The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl or -C(O)NR ee R ff , wherein the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkyl substituted with cyano and C 3-8 cycloalkyl are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkyl substituted with cyano and C 3-8 cycloalkyl. substituted by one or more substituents selected from C 1-3 haloalkyl, C 1-3 alkyl substituted by cyano, and C 3-8 cycloalkyl; 优选氢、氘、氟、氯、甲基、氘代甲基、二氟甲基、三氟甲基、 Preferred are hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, trifluoromethyl, Rc选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1- 3氘代烷基、C1-3卤代烷基或氰基取代的C1-3烷基；优选氢、氘、氟、氯、甲基、氘代甲基、二氟甲基或三氟甲基；R c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl or C 1-3 alkyl substituted with cyano; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl or trifluoromethyl; Ra选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1- 3氘代烷基、C1-3卤代烷基或氰基取代的C1-3烷基；优选氢、氘、氟、氯、甲基、氘代甲基、二氟甲基或三氟甲基； Ra is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl or C1-3 alkyl substituted with cyano; preferably hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl or trifluoromethyl ; Rb选自氢、氘、卤素、氰基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、卤代C1-3烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、--(CH2)n2ORee、-(CH2)n2NReeRff、-(CH2)n2C(O)Ree、-(CH2)n2C(O)ORee、-(CH2)n2C(O)NReeRff、-(CH2)n2N＝S(O)ReeRff、-(CH2)n2S(O)Ree(＝NRff)或-(CH2)n2P(O)ReeRff，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、卤代C1-3烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基和3-8元杂环基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1- 3烷基、C3-8环烷基、3-8元杂环基和＝CRggRhh中的一个或多个取代基所取代；优选氢、氘、卤素、氰基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、卤代C1-3烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、-(CH2)n2ORee、-(CH2)n2NReeRff、-(CH2)n2C(O)Ree、-(CH2)n2C(O)NReeRff或-(CH2)n2P(O)ReeRff，所述的氨基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、卤代C1-3烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基和3-8元杂环基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3- 8环烷基或3-8元杂环基中的一个或多个取代基所取代；R b is selected from hydrogen, deuterium, halogen, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH 2 ) n2 OR ee , -(CH 2 ) n2 NR ee R ff , -(CH 2 ) n2 C(O)R ee , -(CH 2 ) n2 C(O)OR ee , -(CH 2 ) n2 C(O)NR ee R ff , -(CH 2 ) n2 N＝S(O)R ee R ff , -(CH 2 ) n2 S(O)R ee (＝NR ff ) wherein the amino, C 1-3 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl and 3-8 membered heterocyclic group are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl and 3-8 membered heterocyclic group. The amino group is substituted with one or more substituents selected from: C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH 2 ) n2 OR ee , -(CH 2 ) n2 NR ee R ff , -(CH 2 ) n2 C( O) R ee , -(CH 2 ) n2 C(O)NR ee R ff or -(CH 2 ) n2 P(O)R ee R ff ; the amino group, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH 2 ) n2 OR ee , -(CH 2 ) n2 NR ee R ff , - ( CH 2 ) n2 C(O)R ee , -(CH 2 ) n2 C(O)NR ee R ff or -(CH 2 ) n2 P(O)R ee R ff C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl or 3-8 membered heterocyclyl ; Ree和Rff各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、-C(O)-C1-3烷基、C3-8环烷基或3-8元杂环基，所述的氨基、C1-3烷基、C2-6烯基、C2-6炔基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1- 3羟烷基、氰基取代的C1-3烷基、C3-8环烷基和3-8元杂环基，任选的被氘、卤素、氨基、羟基、氰基、硝基、C1-3烷基、C2-4烯基、C2-4炔基、氧代基、硫代基、C1-3氘代烷基、C1- 3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、氰基取代的C1-3烷基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；R ee and R ff are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O)-C 1-3 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the amino, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, -C(O) -C 1-3 alkyl , C 3-8 cycloalkyl or 3-8 membered heterocyclyl. 3-8 -membered cycloalkyl and 3-8-membered heterocyclyl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 alkyl substituted with cyano, C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; n2选自0、1或2；n2 is selected from 0, 1 or 2; 优选氢、氘、氟、氯、氰基、甲基、乙基、乙炔基、丙炔基、氘代甲基、氘代乙基、二氟甲基、三氟甲基、三氟乙基、甲氧基、乙氧基、氘代甲氧基、二氟甲氧基、三氟甲氧基、 Preferred are hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy, 根据权利要求1-8任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物结构如下：





The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound has the following structure:





一种通式(IV-A-I)或(IV-B-I)所示的化合物、其立体异构体或其药学上可接受盐：
A compound represented by the general formula (IV-AI) or (IV-BI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
R1-1如权利要求3所述；R 1-1 is as described in claim 3; M4、R3a、R3b、R3c、R3d和n3如权利要求6所述；M 4 , R 3a , R 3b , R 3c , R 3d and n3 are as described in claim 6; M5、M6、R3e、R3f、p、q和n4如权利要求7所述。M 5 , M 6 , R 3e , R 3f , p, q and n4 are as described in claim 7. 根据权利要求10所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物结构如下：
The compound according to claim 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound has the following structure:
一种制备通式(III-C)所示的化合物、其立体异构体或其药学上可接受的盐的方法，其特征在于：
A method for preparing a compound represented by general formula (III-C), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that:
通式(III-C-I)所示的化合物与通式(III-C-II)所示的化合物在缩合剂和碱存在条件下反应得到通式(III-C-III)所示的化合物，进一步脱除保护基得到通式(III-C)所示的化合物；The compound represented by the general formula (III-C-I) reacts with the compound represented by the general formula (III-C-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (III-C-III), and the protecting group is further removed to obtain the compound represented by the general formula (III-C); 优选地，所述方法为制备通式(IV-A)所示的化合物、其立体异构体或其药学上可接受的盐的方法：
Preferably, the method is a method for preparing a compound represented by general formula (IV-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
通式(IV-A-I)所示的化合物与通式(IV-A-II)所示的化合物在缩合剂和碱存在条件下反应得到通式(IV-A-III)所示的化合物，进一步脱除保护基得到通式(IV-A)所示的化合物；The compound represented by the general formula (IV-A-I) reacts with the compound represented by the general formula (IV-A-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (IV-A-III), and the protecting group is further removed to obtain the compound represented by the general formula (IV-A); 或，所述方法为制备通式(IV-B)所示的化合物、其立体异构体或其药学上可接受的盐的方法：
Or, the method is a method for preparing a compound represented by general formula (IV-B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
通式(IV-B-I)所示的化合物与通式(IV-B-II)所示的化合物在缩合剂和碱存在条件下反应得到通式(IV-B-III)所示的化合物，进一步脱除保护基得到通式(IV-B)所示的化合物；The compound represented by the general formula (IV-B-I) reacts with the compound represented by the general formula (IV-B-II) in the presence of a condensing agent and a base to obtain the compound represented by the general formula (IV-B-III), and the protecting group is further removed to obtain the compound represented by the general formula (IV-B); Pg1选自氢、烯丙氧羰基、三氟乙酰基、叔丁基亚磺酰基、2,4-二甲氧基苄基、3,5-二甲氧基苄基、硝基苯磺酰基、三苯甲基、笏甲氧羰基、9-芴甲氧羰基、苄基、对甲苯磺酰基、对甲氧基苄基、甲酸酯、乙酰基、苄氧羰基、邻苯二甲酰基、叔丁氧羰基、苄基或对甲氧苯基；Pg 1 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 4-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; Pg2选自氢、烯丙氧羰基、三氟乙酰基、叔丁基亚磺酰基、2,4-二甲氧基苄基、3,5-二甲氧基苄基、硝基苯磺酰基、三苯甲基、笏甲氧羰基、9-芴甲氧羰基、苄基、对甲苯磺酰基、对甲氧基苄基、甲酸酯、乙酰基、苄氧羰基、邻苯二甲酰基、叔丁氧羰基、苄基或对甲氧苯基； Pg2 is selected from hydrogen, allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl, 2,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, 4-methoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; 环A、M1、M2、M3、Ra、Rb、Rc、R2和x如权利要求1所述；Ring A, M 1 , M 2 , M 3 , Ra , R b , R c , R 2 and x are as described in claim 1; R1-1如权利要求3所述；R 1-1 is as described in claim 3; M4、R3a、R3b、R3c、R3d和n3如权利要求6所述；M 4 , R 3a , R 3b , R 3c , R 3d and n3 are as described in claim 6; M5、M6、R3e、R3f、p、q和n4如权利要求7所述。M 5 , M 6 , R 3e , R 3f , p, q and n4 are as described in claim 7. 一种药物组合物，其包括治疗有效剂量的权利要求1-9任一项所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective dose of a compound as claimed in any one of claims 1 to 9, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients. 根据权利要求1-9任一项所示的化合物、其立体异构体或其药学上可接受的盐，或权利要求13所述的药物组合物在制备PRMT5抑制剂药物中的应用。Use of the compound according to any one of claims 1 to 9, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in the preparation of a PRMT5 inhibitor drug. 根据权利要求1-9任一项所示的化合物、其立体异构体或其药学上可接受的盐，或权利要求13所述的药物组合物在制备治疗癌症中的应用。Use of the compound according to any one of claims 1 to 9, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in the preparation of a drug for treating cancer. 根据权利要求15所述的应用，其特征在于，所述癌症选自肺癌、肝细胞癌、乳腺癌、皮肤癌、膀胱癌、肝癌、胰腺癌、头颈癌、胶质瘤、胶质母细胞瘤、食管癌、胰腺癌、间皮瘤、黑色素瘤、星形细胞瘤、未分化的多形性肉瘤、白血病、胃腺癌、粘液纤维肉瘤、胆管肉瘤、脑癌、胃癌、肾癌、子宫内膜癌、卵巢瘤、前列腺癌、弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、尿路癌、软组织癌、胸膜癌、大肠癌、结直肠癌、胆道癌或胆管癌；所述肺癌选自非小细胞肺癌、肺鳞癌或肺腺癌；所述食管癌选自食管鳞状细胞癌或食管腺癌。The use according to claim 15 is characterized in that the cancer is selected from lung cancer, hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, esophageal cancer, pancreatic cancer, mesothelioma, melanoma, astrocytoma, undifferentiated pleomorphic sarcoma, leukemia, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, brain cancer, gastric cancer, kidney cancer, endometrial cancer, ovarian tumor, prostate cancer, diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, urinary tract cancer, soft tissue cancer, pleural cancer, colorectal cancer, biliary tract cancer or bile duct cancer; the lung cancer is selected from non-small cell lung cancer, squamous cell lung carcinoma or lung adenocarcinoma; the esophageal cancer is selected from esophageal squamous cell carcinoma or esophageal adenocarcinoma.
PCT/CN2024/136103 2023-12-01 2024-12-02 N-substituted amide derivative inhibitor, and preparation method and use therefor Pending WO2025113705A1 (en)

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