Heterocyclic compounds, processes for their preparation and use in the preparation of GLP-1 receptor agonist prodrugs with oral PK properties and long-acting PK properties

Abstract

This invention provides a heterocyclic compound, its preparation method, and its use in preparing GLP-1 receptor agonist prodrugs with oral and long-acting pharmacokinetic properties, belonging to the field of medicinal chemistry. The compound provided by this invention can be used as a GLP-1 receptor agonist prodrug, which can release a parent drug with GLP-1 receptor agonist activity through hydrolysis in vivo. The compound provided by this invention can be used as a GLP-1 receptor agonist prodrug compound for the preparation of drugs for the prevention and / or treatment of GLP-1 receptor-related diseases. The compound of this invention exhibits good oral and long-acting pharmacokinetics, resulting in better medication adherence and broad application prospects.

Description

A heterocyclic compound, a preparation method thereof and use of the heterocyclic compound in preparing GLP-1 receptor agonist prodrugs with oral PK characteristics and long-acting PK characteristics TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a heterocyclic compound, a preparation method thereof and use of the heterocyclic compound in preparing GLP-1 receptor agonist prodrugs with oral PK characteristics and long-acting PK characteristics. BACKGROUND

[0002] The GLP-1 (glucagon-like peptide-1) receptor belongs to the B-type G protein-coupled receptor (GPCR) family and is an important drug target, especially in the treatment of type 2 diabetes and obesity. This type of receptor is characterized by having an N-terminal extracellular domain (ECD) and a C-terminal transmembrane domain (TMD), which plays a key role in the binding and activation of peptide hormones. The GLP-1 receptor mainly regulates insulin secretion in pancreatic beta cells and has effects such as appetite suppression, neuroprotection and anti-inflammation in the brain. Therefore, it is of great significance for disease diagnosis, treatment and drug research. GLP-1 is mainly secreted by Langerhans cells (L cells) in the terminal jejunum, ileum and colon and is a processing product after the translation of the proglucagon gene. The main target organ of GLP-1 is the pancreas, which regulates both beta cells and alpha cells. When blood glucose rises, GLP-1 binds to the receptor (GLP-1 receptor) on the beta cells of the islets to induce the exocytosis of insulin secretion vesicles, and also binds to the receptor of alpha cells or indirectly inhibits the secretion of glucagon by alpha cells. In addition, GLP-1 receptors are not only present in pancreatic cells, but also expressed in the gastrointestinal tract, heart, skin, nervous system and other organs. GLP-1 can achieve multi-pathway weight control by inhibiting gastric emptying and gastric acid secretion, acting on the central nervous system to reduce appetite and produce satiety; in other target organs of insulin action (such as liver, skeletal muscle, adipose tissue, etc.), it promotes the synthesis of glycogen and lipogenesis in the corresponding tissues through receptor binding to achieve the effects of lowering blood pressure, reducing lipids and protecting the cardiovascular system; it can also act on the central nervous system to enhance learning and memory function to protect the nerves. In summary, GLP-1 can act on a wide range of extrapancreatic tissues and organs such as the gastrointestinal tract, liver, skeletal muscle, brain, heart and kidney to produce diverse biological effects and participate in blood glucose regulation.

[0003] Orgforglipron from Oryzon is an orally effective small molecule GLP-1R agonist that can improve type 2 diabetes and is currently in phase III clinical trials; ECC5004, a small molecule GLP-1R receptor agonist independently developed by Chengyi Biotechnology, is mainly used for potential treatment of obesity, type 2 diabetes and other comorbidities and is also currently in clinical trials.

[0004] However, these GLP-1R agonists as small molecule drugs have problems of low bioavailability, poor pharmacokinetic properties, and possible gastrointestinal side effects (such as nausea and diarrhea), which will limit their clinical application. SUMMARY

[0005] In order to solve the above problems existing in the prior art, the purpose of the present application is to provide a heterocyclic compound and a preparation method thereof and a use of the heterocyclic compound for preparing GLP-1 receptor agonist prodrugs with oral PK characteristics and long-acting PK characteristics.

[0006] The present application provides a compound shown in formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

[0007] Among them, G is a GLP-1 receptor agonist; including but not limited to: Orforglipron, ECC5004, GSBR1290, SYH2086, HS10535, IBI3032, ASC30;

[0008] Y is nothing, -OY1-, -OCR Y1 R Y2 -, -NR Y3 CR Y1 R Y2 -; Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl; R Y1 , R Y2 , R Y3 are each independently selected from H, C1-C6 alkyl; Y and G can be connected with a heteroatom with exchangeable hydrogen;

[0009] R is selected from -COLR L ; L is selected from nothing, C1-C6 alkylene, O, S, NH; R L is selected from the following groups which are unsubstituted or substituted with halogen: C1-C 40 straight chain or branched chain saturated alkyl, C1-C 40 straight chain or branched chain saturated alkyl, C1-C A1 R A2 ;

[0010] R A1 , R A2 are each independently selected from hydrogen, C1-C 10 alkyl, or, R A1 , R A2 are connected to form a group which is unsubstituted or substituted with one or more C1-C 10alkyl substituted 3-8 membered nitrogen containing heterocycloalkyl.

[0011] Further, the structure of the compound is shown as Formula II:

[0012] wherein,

[0013] Ring A is selected from aromatic ring, unsaturated nitrogen containing heterocyclic ring, aromatic ring containing hydroxyl or amino or carboxyl, unsaturated nitrogen containing heterocyclic ring containing hydroxyl or amino or carboxyl, or tautomers thereof;

[0014] R A is selected from LR L ; L is selected from nothing, C1-C6 alkylene, O, S, NH; R L is selected from the following groups which are unsubstituted or substituted with halogen: C1-C 40 straight chain or branched saturated alkyl, C1-C 40 one or both of the alkylene groups in the straight chain or branched saturated alkyl is each independently replaced with an unsaturated double bond, an unsaturated triple bond, a 3-8 membered cycloalkyl, an aromatic group, a phenyl group, a 3-8 membered cycloalkyl group, NR A1 R A2 ;

[0015] R A1 , R A2 are each independently selected from hydrogen, C1-C 10 alkyl, or, R A1 , R A2 are linked to form a 3-8 membered nitrogen containing heterocycloalkyl which is unsubstituted or substituted with one or more C1-C 10 alkyl groups; Y is nothing, or -OY1-, Y1 is methylene or methylene substituted with one or two C1-C6 alkyl groups;

[0016] X is selected from O, S, SO2, NR X1 , CR X1 R X2 ;

[0017] R X1 , R X2 are each independently selected from hydrogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl; or, R X1 and R X2 are linked to form a 3-5 membered cycloalkyl which is substituted with one or more R X’ groups or unsubstituted, R X’ is each independently selected from C1-C6 alkyl, halogen substituted C1-C6 alkyl;

[0018] Ring B is a 5- or 6-membered heterocyclic ring containing 1-3 nitrogens;

[0019] RB Selected from hydrogen, halogens, CH2NR B1 R B2 Among them, R B1 R B2 Groups independently selected from hydrogen, C1-C6 alkyl, 3-6 membered cycloalkyl, halogen-substituted C1-C6 alkyl, and C1-C6 alkyl groups obtained by replacing one or more alkylene atoms with heteroatoms; or R B1 R B2 Connected into 4- to 6-membered heterocyclic groups;

[0020] The ring C is selected from phenyl, heteroaryl, 5-7 membered cycloalkyl, and 5-7 membered heterocyclic group containing 1-2 heteroatoms;

[0021] R C1 R C2 R C3 Each of the following is independently selected from hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, and C1-C6 alkoxy; or, R C1 R C2 R C3 They are interconnected to form 3- to 5-membered cycloalkyl groups;

[0022] R 1 R 2 Each of the following is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, halogen; or R 1 and R 2 Connected to form aromatic or non-aromatic rings;

[0023] Ring D is selected from phenyl, heteroaryl, and benzo[a]heterocyclic groups;

[0024] R D1 R D2 R D3 Each group is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amide, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy, C1-C6 alkyl groups obtained by replacing one or more alkylene groups with heteroatoms, or groups with one or more R groups. D’ Substituted C1-C6 alkyl groups, R D’ Selected from amino, sulfone, phosphine, and halogen groups; or, R D1 R D2 R D3 They connect to form aromatic or non-aromatic rings;

[0025] Ring E is selected from:

[0026] R E1 R E2each independently selected from hydrogen, halogen;

[0027] U, Y 0 , Z are independently selected from C, N, and are not simultaneously N;

[0028] Ring F is selected from phenyl, heteroaryl;

[0029] R F1 , R F2 , R F3 each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with one or more R F’ , R F’ selected from amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl, one or more alkylene of which is replaced with a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

[0030] Further, the structure of the compound is shown as Formula III:

[0031] wherein,

[0032] Ring A is selected from aromatic ring, unsaturated nitrogen-containing heterocyclic ring, aromatic ring containing hydroxyl or amino or carboxyl, unsaturated nitrogen-containing heterocyclic ring containing hydroxyl or amino or carboxyl, or a tautomer thereof, including but not limited to:

[0033] R A is selected from L L R; L is selected from null, C1-C3 alkylene, O, S, NH; R L is selected from the following groups which are unsubstituted or substituted with halogen: C1-C 30 linear or branched saturated alkyl, C1-C 30 linear or branched saturated alkyl, phenyl, 3-6 membered cycloalkyl, NR A1 R A2 ;

[0034] R A1 , R A2 each independently selected from hydrogen, C1-C 10 alkyl, or, R A1 , R A2R1and R2are independently selected from hydrogen, C1-C3alkyl, halogen-substituted C1-C3alkyl; or, R1and R2are linked to form a 3-4 membered cycloalkyl group, unsubstituted or substituted with one or two or more R3; 10 alkyl-substituted 3-8 membered nitrogen-containing heterocycloalkyl;

[0035] Y is absent or -OY1-, Y1is methylene or 1-2 C1-C6alkyl-substituted methylene;

[0036] X is selected from O, S, SO2, NR X1 , CR X1 R X2 ;

[0037] R X1 , R X2 are each independently selected from hydrogen, C1-C3alkyl, halogen-substituted C1-C3alkyl; or, R X1 and R X2 are linked to form a 3-4 membered cycloalkyl group, unsubstituted or substituted with one or two or more R X’ , each independently selected from C1-C3alkyl, halogen-substituted C1-C3alkyl; X’

[0038] Ring B is a 5- or 6-membered heterocyclic ring containing 1-3 nitrogens, selected from:

[0039] R B is selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3alkyl, 3-4 membered cycloalkyl, halogen-substituted C1-C3alkyl, a group obtained by replacing one or two alkylene groups in C1-C3alkyl with a heteroatom; or R B1 and R B2 are linked to form a 5-6 membered heterocyclyl group;

[0040] Ring C is selected from phenyl, heteroaryl, 5-6 membered cycloalkyl, 5-6 membered non-aromatic heterocyclyl containing 1-2 heteroatoms;

[0041] R C1 , R C2 , R C3 are each independently selected from hydrogen, halogen, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy; or, R C1 , R C2 , R C3 are linked to form a 3-5 membered cycloalkyl group;

[0042] R 1 , R 2 ​Each element is independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, 3-6 membered cycloalkyl, or halogen; or R 1 and R 2 Connected to form aromatic or non-aromatic rings;

[0043] Ring D is selected from phenyl, heteroaryl, and benzo[a]heterocyclic groups;

[0044] R D1 R D2 R D3 Groups independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amide, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, C1-C6 alkyl, or one or more alkylene groups obtained by replacing one or more heteroatoms with heteroatoms, or groups with one or more R D’ Substituted C1-C3 alkyl groups, R D’ Selected from amino, sulfone, phosphine, and halogen groups; or, R D1 R D2 R D3 They connect to form aromatic or non-aromatic rings;

[0045] Ring E is selected from:

[0046] R E1 R E2 Each is independently selected from hydrogen and halogen;

[0047] Ring F is selected from phenyl or heteroaryl groups;

[0048] R F1 R F2 R F3 Each group is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amide, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, C1-C3 alkyl containing heteroatoms, and is surrounded by one or more R groups. F’ Substituted C1-C3 alkyl groups, R F’ A group selected from amino, thioether, sulfoxide, sulfone, phosphine, halogen, or C1-C6 alkyl groups, obtained by replacing one or more alkylene groups with heteroatoms; or, R F1 R F2 R F3 They connect to form aromatic or non-aromatic rings.

[0049] Furthermore, the structure of the compound is shown in Formula IV:

[0050] in,

[0051] Ring A is selected from the group consisting of aromatic ring, unsaturated nitrogen-containing heterocyclic ring, aromatic ring containing hydroxyl or amino or carboxyl, unsaturated nitrogen-containing heterocyclic ring containing hydroxyl or amino or carboxyl, or tautomers thereof, including but not limited to:

[0052] R A selected from the group consisting of LR L ; L is selected from the group consisting of null, C1-C3 alkylene, O, S, NH; R L selected from the group consisting of C1-C 30 linear or branched saturated alkyl, C1-C 30 linear or branched saturated alkyl, C1-C A1 R A2 ;

[0053] R A1 , R A2 are each independently selected from the group consisting of hydrogen, C1-C 10 alkyl, or, R A1 , R A2 are linked to form a 3-8 membered nitrogen-containing heterocycloalkyl group which is unsubstituted or substituted with one or two C1-C 10 alkyl groups;

[0054] Y is null, or -OY1-, Y1 is methylene or methylene substituted with one or two C1-C6 alkyl groups;

[0055] R 3 selected from the group consisting of hydrogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl;

[0056] Ring B is a 5- or 6-membered heterocyclic ring containing 1-3 nitrogens, selected from the group consisting of:

[0057] R B selected from the group consisting of hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from the group consisting of hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen-substituted C1-C3 alkyl, a group obtained by replacing one or two alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5- or 6-membered heterocyclyl group;

[0058] Ring C is selected from the group consisting of phenyl, heteroaryl, 5- or 6-membered cycloalkyl, 5- or 6-membered non-aromatic heterocyclyl containing 1-2 heteroatoms;

[0059] R C1 R C2 R C3 Each of the following is independently selected from hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, and C1-C3 alkoxy; or, R C1 R C2 R C3 They are interconnected to form 3- to 5-membered cycloalkyl groups;

[0060] R 1 R 2 Each element is independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, 3-6 membered cycloalkyl, or halogen; or R 1 and R 2 Connected to form aromatic or non-aromatic rings;

[0061] Ring D is selected from phenyl, heteroaryl, and benzo[a]heterocyclic groups;

[0062] R D1 R D2 R D3 Groups independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amide, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, C1-C6 alkyl, or one or more alkylene groups obtained by replacing one or more heteroatoms with heteroatoms, or groups with one or more R D’ Substituted C1-C3 alkyl groups, R D’ Selected from amino, sulfone, phosphine, and halogen groups; or, R D1 R D2 R D3 They connect to form aromatic or non-aromatic rings;

[0063] Ring E is selected from:

[0064] R E1 R E2 Each is independently selected from hydrogen and halogen;

[0065] Ring F is selected from phenyl or heteroaryl groups;

[0066] R F1 R F2 R F3 Each group is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amide, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, C1-C3 alkyl containing heteroatoms, and is surrounded by one or more R groups. F’ Substituted C1-C3 alkyl groups, R F’A group selected from amino, thioether, sulfoxide, sulfone, phosphine, halogen, or C1-C6 alkyl groups, obtained by replacing one or more alkylene groups with heteroatoms; or, R F1 R F2 R F3 They connect to form aromatic or non-aromatic rings.

[0067] Furthermore, the structure of the compound is shown in Formula V:

[0068] in,

[0069] Ring A is selected from aromatic rings, unsaturated nitrogen-containing heterocycles, aromatic rings containing hydroxyl, amino, or carboxyl groups, unsaturated nitrogen-containing heterocycles containing hydroxyl, amino, or carboxyl groups, or their tautomers, including but not limited to:

[0070] R A Selected from LR L L is selected from none, C1-C3 alkylene, O, S, NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 30 Straight-chain or branched saturated alkyl groups, C1-C2 30 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 6-membered cycloalkyl group, or aromatic group; phenyl group; 3- to 6-membered cycloalkyl group; NR group A1 R A2 ;

[0071] R A1 R A2 Each is independently selected from hydrogen, C1 to C2. 10 Alkyl, or R A1 R A2 The connection is formed without being replaced or by one or more C1~C1. 10 Alkyl-substituted 3- to 8-membered nitrogen-containing heterocyclic alkyl groups;

[0072] Y is absent, or -OY1-, where Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl groups;

[0073] R 3 Selected from hydrogen, C1-C3 alkyl, and halogen-substituted C1-C3 alkyl;

[0074] Ring B is a 5-membered or 6-membered heterocycle containing 1 to 3 nitrogen atoms, selected from:

[0075] R B Selected from hydrogen, halogens, CH2NR B1 RB2 Among them, R B1 R B2 Groups independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen-substituted C1-C3 alkyl, and C1-C3 alkyl groups obtained by replacing one or more alkylene atoms with heteroatoms; or R B1 R B2 Connected into 5-6 member heterocyclic groups;

[0076] The ring C is selected from phenyl, heteroaryl, 5-6 membered cycloalkyl, and 5-6 membered non-aromatic heterocyclic groups containing 1-2 heteroatoms;

[0077] R C1 R C2 R C3 Each of the following is independently selected from hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, and C1-C3 alkoxy; or, R C1 R C2 R C3 They are interconnected to form 3- to 5-membered cycloalkyl groups;

[0078] Ring D is selected from phenyl, heteroaryl, and benzo[a]heterocyclic groups;

[0079] R D1 R D2 R D3 Groups independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amide, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, C1-C6 alkyl, or one or more alkylene groups obtained by replacing one or more heteroatoms with heteroatoms, or groups with one or more R D’ Substituted C1-C3 alkyl groups, R D’ Selected from amino, sulfone, phosphine, and halogen groups; or, R D1 R D2 R D3 They connect to form aromatic or non-aromatic rings;

[0080] Ring E is selected from:

[0081] R E1 R E2 Each is independently selected from hydrogen and halogen;

[0082] Ring F is selected from phenyl or heteroaryl groups;

[0083] R F1 R F2 R F3each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, substituted C1-C3 alkyl, R F’ substituted C1-C3 alkyl, R F’ is selected from the group consisting of amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl, one or more alkylene groups of which are replaced by a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

[0084] Further, the structure of the compound is shown in formula VI:

[0085] wherein,

[0086] Ring A is selected from the group consisting of an aromatic ring, an unsaturated nitrogen-containing heterocyclic ring, an aromatic ring containing a hydroxyl or amino or carboxyl group, an unsaturated nitrogen-containing heterocyclic ring containing a hydroxyl or amino or carboxyl group, or a tautomer thereof, including but not limited to:

[0087] R A is selected from the group consisting of L L ; L is selected from the group consisting of nothing, C1-C3 alkylene, O, S, NH; R L is selected from the group consisting of the following groups which are unsubstituted or substituted with halogen: C1-C 30 linear or branched saturated alkyl, C1-C 30 one or more alkylene groups of which are each independently replaced by an unsaturated double bond, an unsaturated triple bond, a 3-6 membered cycloalkyl, an aromatic group, a phenyl group, a 3-6 membered cycloalkyl group, NR A1 R A2 ;

[0088] R A1 , R A2 are each independently selected from the group consisting of hydrogen, C1-C 10 alkyl, or, R A1 , R A2 are connected to form a 3-8 membered nitrogen-containing heterocycloalkyl group which is unsubstituted or substituted with one or more C1-C 10 alkyl groups;

[0089] Y is nothing, or -OY1-, Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl groups;

[0090] R 3 is selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl;

[0091] Ring B is a 5- or 6-membered heterocyclic ring containing 1-3 nitrogens, selected from:

[0092] R B selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen-substituted C1-C3 alkyl, a group obtained by replacing one or more alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5- or 6-membered heterocyclyl group;

[0093] C 1 is selected from CH or N;

[0094] R C1 , R C2 , R C3 are each independently selected from hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy; or, R C1 , R C2 , R C3 are linked to each other to form a 3-5 membered cycloalkyl group;

[0095] Ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl;

[0096] R D1 , R D2 , R D3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, a group obtained by replacing one or more alkylene groups in C1-C6 alkyl with a heteroatom, C1-C3 alkyl substituted with one or more R D’ is selected from amine, sulfone, phosphine, halogen; or, R D’ , R D1 , R D2 , R D3 are linked to each other to form an aromatic or non-aromatic ring;

[0097] Ring E is selected from:

[0098] R E1 , R E2 are each independently selected from hydrogen, halogen;

[0099] R F1 , RF2 , R F3 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’ , R F’ is selected from the group consisting of amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl, one or more alkylene groups of which are replaced by a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

[0100] Further, the structure of the compound is shown as formula VII:

[0101] wherein,

[0102] R A is selected from the group consisting of L L ; L is selected from the group consisting of nothing, C1-C3 alkylene, O, S, NH; R L is selected from the group consisting of C1-C 30 linear or branched saturated alkyl, C1-C 30 linear or branched saturated alkyl, phenyl, 3-6 membered cycloalkyl, NR A1 R A2 ;

[0103] R A1 , R A2 are each independently selected from the group consisting of hydrogen, C1-C 10 alkyl, or, R A1 , R A2 are connected to form a 3-8 membered nitrogen-containing heterocycloalkyl which is unsubstituted or substituted with one or more C1-C 10 alkyl;

[0104] Y is nothing, or -OY1-, Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl;

[0105] R 3 is selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl;

[0106] Ring B is a 5- or 6-membered heterocycle containing 1-3 nitrogens, selected from the group consisting of:

[0107] RB Selected from hydrogen, halogens, CH2NR B1 R B2 Among them, R B1 R B2 Groups independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen-substituted C1-C3 alkyl, and C1-C3 alkyl groups obtained by replacing one or more alkylene atoms with heteroatoms; or R B1 R B2 Connected into 5-6 member heterocyclic groups;

[0108] C 1 Selected from CH or N;

[0109] R C1 R C2 R C3 Each of the following is independently selected from hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, and C1-C3 alkoxy; or, R C1 R C2 R C3 They are interconnected to form 3- to 5-membered cycloalkyl groups;

[0110] Ring D is selected from phenyl, heteroaryl, and benzo[a]heterocyclic groups;

[0111] R D1 R D2 R D3 Groups independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amide, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, C1-C6 alkyl, or one or more alkylene groups obtained by replacing one or more heteroatoms with heteroatoms, or groups with one or more R D’ Substituted C1-C3 alkyl groups, R D’ Selected from amino, sulfone, phosphine, and halogen groups; or, R D1 R D2 R D3 They connect to form aromatic or non-aromatic rings;

[0112] Ring E is selected from:

[0113] R E1 R E2 Each is independently selected from hydrogen and halogen;

[0114] R F1 R F2 R F3each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, substituted C1-C3 alkyl, R F’ substituted C1-C3 alkyl, R F’ substituted C1-C3 alkyl, R F1 substituted C1-C3 alkyl, R F2 substituted C1-C3 alkyl, R F3 substituted C1-C3 alkyl, R

[0115] Further, the structure of the compound is shown as Formula VIII:

[0116] wherein,

[0117] substituted C1-C3 alkyl, R A substituted C1-C3 alkyl, R L substituted C1-C3 alkyl, R L substituted C1-C3 alkyl, R 30 substituted C1-C3 alkyl, R 30 substituted C1-C3 alkyl, R A1 substituted C1-C3 alkyl, R A2 ;

[0118] substituted C1-C3 alkyl, R A1 substituted C1-C3 alkyl, R A2 substituted C1-C3 alkyl, R 10 substituted C1-C3 alkyl, R A1 substituted C1-C3 alkyl, R A2 substituted C1-C3 alkyl, R 10 substituted C1-C3 alkyl, R

[0119] Y is null, or -OY1-, Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl;

[0120] substituted C1-C3 alkyl, R 3 substituted C1-C3 alkyl, R

[0121] Ring B is a 5- or 6-membered heterocycle containing 1-3 nitrogens, selected from the group consisting of:

[0122] substituted C1-C3 alkyl, R B substituted C1-C3 alkyl, RB1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen-substituted C1-C3 alkyl, a group resulting from replacing one or more alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5-6 membered heterocyclyl group;

[0123] C 1 is selected from CH or N;

[0124] R C1 , R C2 , R C3 are each independently selected from hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy; or R C1 , R C2 , R C3 are linked to each other to form a 3-5 membered cycloalkyl group;

[0125] Ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl;

[0126] R D1 , R D2 , R D3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, a group resulting from replacing one or more alkylene groups in C1-C6 alkyl with a heteroatom, C1-C3 alkyl substituted with one or more R D’ , R D’ is selected from amine, sulfone, phosphine, halogen; or R D1 , R D2 , R D3 are linked to each other to form an aromatic or non-aromatic ring;

[0127] Ring E is selected from:

[0128] R E1 , R E2 are each independently selected from hydrogen, halogen;

[0129] R F1 , R F2 , R F3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’substituted C1-C3 alkyl, R F’ one or two or more alkylene groups in a straight chain or branched chain saturated alkyl are each independently replaced by an unsaturated double bond, an unsaturated triple bond, a 3-6 membered cycloalkyl, an aromatic group, a phenyl group, a 3-6 membered cycloalkyl group, a NR F1 , R F2 , R F3 are connected to form an aromatic or non-aromatic ring.

[0130] Further, the structure of the compound is shown in formula IX:

[0131] wherein,

[0132] R A is selected from the group consisting of L L ; L is selected from the group consisting of nothing, C1-C3 alkylene, O, S, NH; R L is selected from the group consisting of the following groups which are unsubstituted or substituted by halogen: C1-C 30 a straight chain or branched chain saturated alkyl, C1-C 30 one or two or more alkylene groups in a straight chain or branched chain saturated alkyl are each independently replaced by an unsaturated double bond, an unsaturated triple bond, a 3-6 membered cycloalkyl, an aromatic group, a phenyl group, a 3-6 membered cycloalkyl group, a NR A1 R A2 ;

[0133] R A1 , R A2 are each independently selected from the group consisting of hydrogen, C1-C 10 alkyl, or R A1 , R A2 are connected to form a 3-8 membered nitrogen-containing heterocycloalkyl group which is unsubstituted or substituted by one or two or more C1-C 10 alkyl groups;

[0134] Y is nothing or -OY1-, Y1 is methylene or methylene substituted by 1-2 C1-C6 alkyl groups;

[0135] R 3 is selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl;

[0136] ring B is a 5-membered or 6-membered heterocyclic ring containing 1-3 nitrogens, selected from the group consisting of:

[0137] R B is selected from the group consisting of hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3alkyl, 3-6 membered cycloalkyl, C1-C3alkoxy, C1-C3alkyl substituted with one or more R B1 , R B2 connected to form a 5-6 membered heterocyclyl;

[0138] C 1 selected from CH or N;

[0139] R C1 , R C2 , R C3 each independently selected from hydrogen, halogen, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy; or, R C1 , R C2 , R C3 interconnected to form a 3-5 membered cycloalkyl;

[0140] Ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl;

[0141] R D1 , R D2 , R D3 each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3alkyl, 3-6 membered cycloalkyl, C1-C3alkoxy, C1-C6alkyl substituted with one or more R D’ , R D’ selected from amine, sulfone, phosphine, halogen; or, R D1 , R D2 , R D3 interconnected to form an aromatic or non-aromatic ring;

[0142] Ring E is selected from:

[0143] R E1 , R E2 each independently selected from hydrogen, halogen;

[0144] R F1 , R F2 , R F3 each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3alkyl, 3-6 membered cycloalkyl, C1-C3alkoxy, C1-C3alkyl substituted with one or more R F’ , R F’one or more alkylene groups in a straight chain or branched chain saturated alkyl group are each independently replaced with an unsaturated double bond, an unsaturated triple bond, a 3-6 membered cycloalkyl group, an aromatic group, a phenyl group, a 3-6 membered cycloalkyl group, a NR F1 , R F2 , R F3 are connected to form a 3-8 membered nitrogen-containing heterocycloalkyl group which is unsubstituted or substituted with one or more C1-C3 alkyl groups;

[0145] Further, the structure of the compound is shown in formula X:

[0146] wherein,

[0147] R A is selected from the group consisting of L L R L is selected from the group consisting of the following groups which are unsubstituted or substituted with halogen: C1-C 30 a straight chain or branched chain saturated alkyl group, C1-C 30 one or more alkylene groups in a straight chain or branched chain saturated alkyl group are each independently replaced with an unsaturated double bond, an unsaturated triple bond, a 3-6 membered cycloalkyl group, an aromatic group, a phenyl group, a 3-6 membered cycloalkyl group, a NR A1 R A2 ;

[0148] R A1 , R A2 are each independently selected from the group consisting of hydrogen, C1-C 10 alkyl, or R A1 , R A2 are connected to form a 3-8 membered nitrogen-containing heterocycloalkyl group which is unsubstituted or substituted with one or more C1-C 10 alkyl groups;

[0149] R 3 is selected from the group consisting of hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl;

[0150] ring B is a 5- or 6-membered heterocyclic ring containing 1-3 nitrogens, selected from the group consisting of:

[0151] R B is selected from the group consisting of hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from the group consisting of hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen-substituted C1-C3 alkyl, one or more alkylene groups in a C1-C3 alkyl group are each independently replaced with a heteroatom; or R B1 , R B2 are connected to form a 5-6 membered heterocyclyl group;

[0152] C1 CH or N;

[0153] R C1 , R C2 , R C3 are each independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy; or, R C1 , R C2 , R C3 are mutually connected to form a 3-5 membered cycloalkyl;

[0154] Ring D is selected from the group consisting of phenyl, heteroaryl, benzo-heterocyclyl;

[0155] R D1 , R D2 , R D3 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, a group obtained by replacing one or more alkylene groups in C1-C6 alkyl with a heteroatom, C1-C3 alkyl substituted with one or more R D’ ; R D’ is selected from the group consisting of amine, sulfide, sulfoxide, sulfone, phosphine, halogen, a group obtained by replacing one or more alkylene groups in C1-C6 alkyl with a heteroatom; or, R D1 , R D2 , R D3 are mutually connected to form an aromatic or non-aromatic ring;

[0156] Ring E is selected from the group consisting of:

[0157] R E1 , R E2 are each independently selected from the group consisting of hydrogen, halogen;

[0158] R F1 , R F2 , R F3 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’ ; R F’ is selected from the group consisting of amine, sulfide, sulfoxide, sulfone, phosphine, halogen, a group obtained by replacing one or more alkylene groups in C1-C6 alkyl with a heteroatom; or, R F1 , R F2 , R F3 are mutually connected to form an aromatic or non-aromatic ring.

[0159] Further, the structure of the compound is shown in Formula XI:

[0160] wherein,

[0161] n is an integer selected from 0-29;

[0162] R 3 is selected from hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl;

[0163] Ring B is a 5- or 6-membered heterocyclic ring containing 1-3 nitrogens, selected from:

[0164] R B is selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3- to 4-membered cycloalkyl, halogen-substituted C1-C3 alkyl, a group obtained by replacing one or more alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5- to 6-membered heterocyclyl group;

[0165] C 1 is selected from CH or N;

[0166] R C1 , R C2 , R C3 are each independently selected from hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy; or, R C1 , R C2 , R C3 are linked to each other to form a 3- to 5-membered cycloalkyl group;

[0167] Ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl;

[0168] R D1 , R D2 , R D3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, a group obtained by replacing one or more alkylene groups in C1-C6 alkyl with a heteroatom, C1-C3 alkyl substituted with one or more R D’ , R D’ is selected from amine, sulfone, phosphine, halogen; or, R D1 , R D2 , R D3 are linked to each other to form an aromatic or non-aromatic ring;

[0169] Ring E is selected from:

[0170] R E1 , R E2 are each independently selected from hydrogen, halogen;

[0171] R F1 , R F2 , R F3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’ , R F’ is selected from amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl in which one or more alkylene groups are replaced with a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

[0172] Further, the structure of the compound is shown in Formula XII:

[0173] wherein,

[0174] n is selected from an integer from 0 to 29;

[0175] R 3 is selected from hydrogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl;

[0176] Ring B is a 5- or 6-membered heterocyclic ring containing 1-3 nitrogens, selected from:

[0177] R B is selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein, R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen-substituted C1-C3 alkyl, C1-C3 alkyl in which one or more alkylene groups are replaced with a heteroatom; or R B1 , R B2 are connected to form a 5- or 6-membered heterocyclic group;

[0178] C 1 is selected from CH or N;

[0179] R C1 , R C2 , R C3Each of the following is independently selected from hydrogen, halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, and C1-C3 alkoxy; or, R C1 R C2 R C3 They are interconnected to form 3- to 5-membered cycloalkyl groups;

[0180] Ring D is selected from phenyl, heteroaryl, and benzo[a]heterocyclic groups;

[0181] R D1 R D2 R D3 Groups independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amide, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, C1-C6 alkyl, or one or more alkylene groups obtained by replacing one or more heteroatoms with heteroatoms, or groups with one or more R D’ Substituted C1-C3 alkyl groups, R D’ Selected from amino, sulfone, phosphine, and halogen groups; or, R D1 R D2 R D3 They connect to form aromatic or non-aromatic rings;

[0182] Ring E is selected from:

[0183] R E1 R E2 Each is independently selected from hydrogen and halogen;

[0184] R F1 R F2 R F3 Each group is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amide, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, C1-C3 alkyl containing heteroatoms, and is surrounded by one or more R groups. F’ Substituted C1-C3 alkyl groups, R F’ A group selected from amino, thioether, sulfoxide, sulfone, phosphine, halogen, or C1-C6 alkyl groups, obtained by replacing one or more alkylene groups with heteroatoms; or, R F1 R F2 R F3 They connect to form aromatic or non-aromatic rings.

[0185] Furthermore, the structure of the compound is shown in formula XIII or XIV:

[0186] Among them, R A For LR L L is selected from none, C1-C3 alkylene, O, S; RL Selected from C1 to C 40 Straight-chain or branched alkyl groups, C2-C 30 Straight-chain or branched alkenyl groups, C2-C 30 Straight-chain or branched diene groups, C2-C 30 Straight-chain or branched triene groups, C2-C 30 Straight-chain or branched alkynyl groups, C2-C 30 Straight-chain or branched diynyl groups, C2-C 30 Straight-chain or branched triyneyl, 3- to 6-membered cycloalkyl or phenyl, NR A1 R A2 ;

[0187] R A1 R A2 Each is independently selected from hydrogen, C1 to C2. 10 Alkyl, or R A1 R A2 Together they form 5- to 8-membered cycloalkyl groups that are either unsubstituted or substituted by one or more C1- to C6 alkyl groups;

[0188] R 3 Selected from hydrogen and C1-C6 alkyl groups;

[0189] R F1 R F2 R F3 They are independently selected from hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, and 3-6 membered cycloalkyl.

[0190] Furthermore, the structure of the compound is shown in Formula XV:

[0191] in,

[0192] R A Selected from LR L L is selected from none, C1-C3 alkylene, O, S, NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 30 Straight-chain or branched saturated alkyl groups, C1-C2 30 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 6-membered cycloalkyl group, or aromatic group; phenyl group; 3- to 6-membered cycloalkyl group; NR group A1 R A2 ;

[0193] R A1 R A2 Each is independently selected from hydrogen, C1 to C2. 10 Alkyl, or R A1 RA2 Together they form 5- to 8-membered cycloalkyl groups that are either unsubstituted or substituted by one or more C1- to C6 alkyl groups;

[0194] Y is absent, or -OY1-, where Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl groups;

[0195] Furthermore, the structure of the compound is shown in Formula XVI:

[0196] Among them, R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 20 Straight-chain or branched saturated alkyl groups, C1-C2 20 One or more alkylene groups of a straight-chain or branched saturated alkyl group are independently replaced by heteroatoms, unsaturated double bonds, unsaturated triple bonds or 3- to 6-membered cycloalkyl groups.

[0197] Furthermore, the structure of the compound is shown in Formula XVII:

[0198] Among them, R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 20 Straight-chain or branched saturated alkyl groups, C1-C2 20 One or more alkylene groups of a straight-chain or branched saturated alkyl group are independently replaced by heteroatoms, unsaturated double bonds, unsaturated triple bonds or 3- to 6-membered cycloalkyl groups.

[0199] Furthermore, the structure of the compound is shown in Formula XVIII:

[0200] Among them, R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 20 Straight-chain or branched saturated alkyl groups, C1-C2 20 One or more alkylene groups of a straight-chain or branched saturated alkyl group are independently replaced by heteroatoms, unsaturated double bonds, unsaturated triple bonds or 3- to 6-membered cycloalkyl groups.

[0201] Furthermore, the structure of the compound is shown below:

[0202] The present application also provides a pharmaceutical composition which is a preparation prepared by adding a pharmaceutically acceptable adjuvant to the above-mentioned compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof as an active ingredient.

[0203] Further, the preparation is an oral preparation.

[0204] The present application also provides the use of the above-mentioned compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof in the preparation of a GLP-1 receptor agonist prodrug.

[0205] Further, the GLP-1 receptor agonist prodrug is a drug for preventing and / or treating a G protein-coupled receptor-related disease.

[0206] Further, the GLP-1 receptor-related disease is diabetes, hyperglycemia, diabetic complications, obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, metabolic fatty liver (MAFLD), metabolic steatohepatitis (MASH), polycystic ovary syndrome, Parkinson's disease, Alzheimer's disease, sleep apnea syndrome, arthritis.

[0207] Definitions of terms used in connection with the present application: Unless otherwise indicated, the initial definition of a group or term provided herein is intended to apply throughout the description of the specification, unless a different meaning dictates from the context of the use of such term. Where a term is not specifically defined herein, it should be given the meaning that would be given by a person of ordinary skill in the art in light of the disclosure and context.

[0208] "Heteroatom" means an O, N, or S atom.

[0209] "Substitution" means the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0210] The minimum and maximum number of carbon atoms in a hydrocarbon group is indicated by a prefix, e.g., the prefix C a～ C b A straight-chain or branched saturated alkyl group means any straight-chain or branched saturated alkyl group containing "a" to "b" carbon atoms. For example, C1-C40 means a straight-chain or branched saturated alkyl group containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 carbon atoms; and so on. 40 A straight-chain or branched saturated alkyl group means any straight-chain or branched saturated alkyl group containing "a" to "b" carbon atoms. For example, C1-C40 means a straight-chain or branched saturated alkyl group containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 carbon atoms; and so on.

[0211] "Alkyl" refers to a saturated hydrocarbon chain having the indicated number of members. Alkyl groups can be straight or branched, and the alkyl groups can be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl).

[0212] "Alkoxy" represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, unless otherwise specified. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy.

[0213] "Aryl" refers to a fully carbon monocyclic ring group having a conjugated pi-electron system, such as phenyl. The aryl group contains no heteroatoms, such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent molecule must be on a carbon atom on the ring having the conjugated pi-electron system.

[0214] "Heteroaryl" or "heteroaromatic" refers to a heteroaromatic group comprising one to several heteroatoms. Heteroatoms as referred to herein include, but are not limited to, oxygen, sulfur, nitrogen.

[0215] "Annulated" refers to a polycyclic ring having two rings sharing two adjacent ring atoms.

[0216] Halogen is fluorine, chlorine, bromine, iodine.

[0217] "Alkenyl" refers to an unsaturated hydrocarbon group containing 1 unsaturated double bond, "dienyl" refers to an unsaturated hydrocarbon group containing 2 unsaturated double bonds, and "trienyl" refers to an unsaturated hydrocarbon group containing 3 unsaturated double bonds.

[0218] "Alkynyl" refers to an unsaturated hydrocarbon group containing 1 unsaturated triple bond, "dialkynyl" refers to an unsaturated hydrocarbon group containing 2 unsaturated triple bonds, and "trialkynyl" refers to an unsaturated hydrocarbon group containing 3 unsaturated triple bonds.

[0219] C1-C 40 Groups resulting from replacing one or more than one alkylene of a straight chain or branched chain saturated alkyl group, each independently, with an unsaturated double bond include straight chain or branched chain alkenyl groups, straight chain or branched chain dienyl groups, straight chain or branched chain trienyl groups.

[0220] C1-C 40 Groups resulting from replacing one or more than one alkylene of a straight chain or branched chain saturated alkyl group, each independently, with an unsaturated triple bond include straight chain or branched chain alkynyl groups, straight chain or branched chain dialkynyl groups, straight chain or branched chain trialkynyl groups.

[0221] "Cycloalkyl" refers to a saturated cycloalkyl group.

[0222] The beneficial technical effects brought by the technical scheme are as follows:

[0223] The prodrugs are usually not bioactive or have low activity, and are converted into pharmacologically active drugs after metabolism in vivo. The present application provides a new type of GLP-1 receptor agonist prodrug compound, which can be hydrolyzed in vivo to release a parent drug having GLP-1 receptor agonist effect, such as Orforglipron and ECC5004. The compound provided by the present application can be used as a GLP-1 receptor agonist prodrug compound for preparing a drug for preventing and / or treating diabetes, obesity, fatty liver, polycystic ovary syndrome and the like. The GLP-1 receptor agonist prodrug compound of the present application has good long-acting pharmacokinetics, can maintain effective drug concentration and good drug efficacy for a long time after single administration, has good drug properties, better medication compliance, and has a wide application prospect.

[0224] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and common means in the art, other various forms of modifications, replacements or changes can be made without departing from the above basic technical idea of the present application.

[0225] The above content of the present application will be further described in detail through the following embodiment. However, it should not be understood that the above subject matter of the present application is limited to the following embodiment. Any technology realized based on the above content of the present application belongs to the scope of the present application. DETAILED DESCRIPTION

[0226] The raw materials and equipment used in the present application are known products, which are obtained by purchasing commercially available products.

[0227] The time of "overnight" referred to in the present application is 12±5 hours.

[0228] The general synthetic route of the target compound of the present application is as follows:

[0229] The parent drug compound and an appropriate amount of organic base or inorganic base are mixed in an organic solvent, and The reaction is carried out at 0-100℃. After the reaction is completed, the prodrug target compound is prepared by separation and purification.

[0230] Example 1: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl acetate

[0231] Dissolve 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (50 mg, 0.057 mmol) in 5 mL of anhydrous acetonitrile, add N,N-diisopropylethylamine (74 mg, 0.57 mmol), add chloromethyl acetate (32 mg, 0.28 mmol), protect with argon, 80 °C overnight. Concentrate dry under reduced pressure, separate and purify with column chromatography to obtain the product ((3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl acetate 22 mg, yield: 41%. LC / MS (ESI+) C 51 H 52 F2N 10 O7([M+H] + m / e 955.4, actual value: 955.4. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.26 (dd, J = 8.6, 2.5 Hz, 1H), 7.18 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.96 (s, 2H), 6.16 (d, J = 11.2 Hz, 1H), 5.56 (d, J = 7.5 Hz, 1H), 5.24 (d, J = 11.0 Hz, 1H), 4.27 (d, J = 8.5 Hz, 1H), 4.11 (s, 3H), 3.71 (d, J = 8.6 Hz, 2H), 3.56 (dd, J = 26.2, 13.9 Hz, 1H), 3.23 - 3.10 (m, 1H), 3.06 - 2.98 (m, 1H), 2.85 (d, J = 17.0 Hz, 1H), 2.26 (s, 6H), 1.86 (s, 3H), 1.68-1.63 (m, 3H), 1.52 (t, J = 11.9 Hz, 4H), 1.40 (d, J = 6.5 Hz, 3H), 1.27 (s, 3H), 1.25-1.21 (m, 3H), 1.18 (s, 3H).

[0232] Example 2: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl benzoate

[0233] The title compound was prepared in a similar manner as Example 1 in a yield of 50%. LC / MS (ESI+) C 56 H 54 F2N 10 O7([M+H] + m / e 1017.4, found: 1017.4. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 0.9 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.60 - 7.44 (m, 4H), 7.28 - 7.25 (m, 1H), 7.21 (d, J = 7.6 Hz, 2H), 7.18 (d, J = 6.3 Hz, 2H), 7.09 (d, J = 3.1 Hz, 1H), 7.05 (d, J = 7.6 Hz, 2H), 6.98 (s, 1H), 6.86 (s, 1H), 6.51 (d, J = 11.2 Hz, 1H), 5.59 (t, J = 10.9 Hz, 2H), 4.23 (d, J = 12.3 Hz, 1H), 4.12 (s, 3H), 3.67 (d, J = 8.1 Hz, 2H), 3.58 (t, J = 7.2 Hz, 1H), 3.24 - 3.10 (m, 1H), 2.82 (d, J = 13.9 Hz, 2H), 2.26 (s, 6H), 2.03 - 1.91 (m, 2H), 1.60-1.48 (m, 5H), 1.40 (d, J = 6.9 Hz, 3H), 1.26 (s, 3H), 1.23 (d, J = 6.7 Hz, 3H), 1.16 (s, 3H).

[0234] Example 3: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl 3,3-dimethylbutanoate

[0235] The target compound was prepared by a similar method to Example 1 to give white solid 10 mg in 22% yield. LC / MS (ESI+) C 55 H 60 F2N 10 O7([M+H] + m / e 1011.1, actual value: 1011.1. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.53 (s, 1H), 7.48 (dd, J = 8.8, 7.0 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.2 Hz, 1H), 6.96 (d, J = 11.2 Hz, 2H), 6.20 (d, J = 11.0 Hz, 1H), 5.56 (d, J = 6.9 Hz, 1H), 5.39 (d, J = 11.1 Hz, 1H), 4.24 (d, J = 13.5 Hz, 1H), 4.11 (s, 3H), 3.74 - 3.69 (m, 2H), 3.61 - 3.53 (m, 1H), 3.18-3.10 (m, 1H), 3.05 (d, J = 12.5 Hz, 1H), 2.84 (d, J = 16.0 Hz, 1H), 2.26 (s, 6H), 2.00 - 1.92 (m, 2H), 1.72 - 1.64 (m, 3H), 1.60-1.46 (m, 4H), 1.40 (d, J = 6.7 Hz, 3H), 1.27-1.19 (m, 9H), 0.64 (s, 9H).

[0236] Example 4: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl propanoate

[0237] The target compound was prepared by a method similar to Example 1 with a yield of 40%. LC / MS (ESI+) Theoretical value: C 52 H 54 F2N 10 O7([M+H] + m / e 969.3, Actual value: 969.3. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 6.1 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.97 (s, 2H), 6.21 (d, J = 11.3 Hz, 1H), 5.62 - 5.51 (m, 1H), 5.26 (d, J = 11.0 Hz, 1H), 4.28 (d, J = 8.9 Hz, 1H), 4.11 (s, 3H), 3.71 (d, J = 7.0 Hz, 2H), 3.58 (t, J = 12.8 Hz, 1H), 3.26 - 3.16 (m, 1H), 3.02 (d, J = 12.1 Hz, 1H), 2.85 (d, J = 15.5 Hz, 1H), 2.26 (s, 6H), 1.98 - 1.91 (m, 2H), 1.68 - 1.60 (m, 3H), 1.58 - 1.49 (m, 4H), 1.40 (d, J = 6.7 Hz, 3H), 1.27 (s, 3H), 1.24 - 1.20 (m, 3H), 1.18 (s, 3H), 0.55 (q, J = 7.6, 7.2 Hz, 3H).

[0238] Example 5: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl butanoate

[0239] The target compound was prepared by a method similar to Example 1 with a yield of 60%. LC / MS (ESI+) Theoretical value: C 53 H 56 F2N 10 O7([M+H] + m / e 983.4, actual value: 983.4. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 0.9 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.52 (s, 1H), 7.49 - 7.44 (m, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.96 (s, 2H), 6.23 (d, J = 11.2 Hz, 1H), 5.56 (d, J = 6.9 Hz, 1H), 5.31 (d, J = 10.9 Hz, 1H), 4.27 (d, J = 13.6 Hz, 1H), 4.11 (s, 3H), 3.71 (d, J = 7.4 Hz, 2H), 3.57 (t, J = 12.9 Hz, 1H), 3.18 (s, 1H), 3.06 - 2.98 (m, 1H), 2.84 (d, J = 15.8 Hz, 1H), 2.26 (s, 6H), 1.99 - 1.92 (m, 2H), 1.69 - 1.60 (m, 3H), 1.52 (t, J = 12.6 Hz, 4H), 1.40 (d, J = 6.6 Hz, 3H), 1.26 (s, 3H), 1.22 - 1.19 (m, 3H), 1.18 (s, 3H), 1.07 - 0.98 (m, 2H), 0.63 (q, J = 6.8 Hz, 3H).

[0240] Example 6: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl cyclopropane carboxylate

[0241] The title compound was prepared in a similar manner as Example 1. LC / MS (ESI+) calcd for C 53 H 55 F2N 10 O7([M+H] + m / e 981.4, found 981.4; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.52 (s, 1H), 7.50 - 7.45 (m, 1H), 7.41 - 7.34 (m, 1H), 7.30 - 7.24 (m, 1H), 7.18 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.2 Hz, 1H), 6.96 (s, 2H), 6.23 (d, J = 11.3 Hz, 1H), 5.55 (d, J = 6.9 Hz, 1H), 5.37 (d, J = 11.4 Hz, 1H), 4.26 (dd, J = 13.6, 5.2 Hz, 1H), 4.11 (s, 3H), 3.70 (d, J = 8.3 Hz, 2H), 3.55 (d, J = 14.2 Hz, 1H), 3.20 (d, J = 14.7 Hz, 1H), 3.01 (t, J = 12.5 Hz, 1H), 2.84 (d, J = 15.6 Hz, 1H), 2.26 (d, J = 2.0 Hz, 6H), 1.91 - 1.78 (m, 1H), 1.68 - 1.56 (m, 3H), 1.55 - 1.46 (m, 4H), 1.40 (d, J = 6.6 Hz, 3H), 0.61 - 0.48 (m, 2H), 0.36 - 0.22 (m, 2H).

[0242] Example 7: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl isobutyrate

[0243] The target compound was prepared in a similar manner to compound HC-12355-01. LC / MS (ESI+) calcd for C 53 H 56 F2N 10 O7([M+H] + m / e 983.4, found 983; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.2 Hz, 1H), 6.97 (s, 2H), 6.23 (d, J = 11.4 Hz, 1H), 5.56 (d, J = 6.9 Hz, 1H), 5.38 (d, J = 11.1 Hz, 1H), 4.26 (d, J = 13.7 Hz, 1H), 4.11 (s, 3H), 3.74 - 3.69 (m, 2H), 3.56 (d, J = 13.7 Hz, 1H), 3.24 - 3.13 (m, 1H), 3.07 - 2.97 (m, 1H), 2.84 (d, J = 15.3 Hz, 1H), 2.26 (d, J = 2.1 Hz, 6H), 1.98 (d, J = 11.7 Hz, 2H), 1.63 (q, J = 10.2, 6.1 Hz, 3H), 1.51 (t, J = 12.5 Hz, 3H), 1.40 (d, J = 6.7 Hz, 3H), 1.25 - 1.13 (m, 9H), 0.54 (dd, J = 13.5, 7.2 Hz, 6H).

[0244] Example 8: Methyl (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1- methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)cyclobutane carboxylate

[0245] The title compound was prepared by a similar procedure to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.54 (s, 1H), 7.51 - 7.42 (m, 2H), 7.29 (d, J = 10.3 Hz, 1H), 7.17 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.94 (t, J = 14.1 Hz, 2H), 6.24 (d, J = 10.7 Hz, 1H), 5.56 (s, 1H), 5.35 (d, J = 11.4 Hz, 1H), 4.25 (s, 1H), 3.73 (d, J = 9.6 Hz, 2H), 3.56 (s, 1H), 3.17 (s, 1H), 3.04 (d, J = 12.8 Hz, 1H), 2.84 (d, J = 16.5 Hz, 1H), 2.26 (d, J = 2.1 Hz, 6H), 2.21 (s, 1H), 1.63 (q, J = 15.7, 12.6 Hz, 7H), 1.53 (d, J = 12.3 Hz, 3H), 1.39 (d, J = 6.8 Hz, 2H), 1.30 - 1.22 (m, 10H), 1.18 (dd, J = 5.1, 2.0 Hz, 6H). LC / MS (ESI+) calcd for C 55 H 60 F2N 10 O7([M+H] + )m / z 995.43; found 995.5.

[0246] Example 9: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl pentanoic acid

[0247] The target compound was prepared by a method similar to Example 1 to obtain white solid 55 mg, yield: 44%. LC / MS (ESI+) calcd for C 54 H 58 F2N 10 O7([M+H] + )m / z 997.45; found 997.5. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 6.3 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 12.1 Hz, 1H), 7.29 (d, J = 9.3 Hz, 1H), 7.18 (d, J = 6.3 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.94 (d, J = 18.0 Hz, 2H), 6.23 (d, J = 11.3 Hz, 1H), 5.55 (d, J = 6.8 Hz, 1H), 5.31 (d, J = 10.9 Hz, 1H), 4.26 (d, J = 13.8 Hz, 1H), 3.74 - 3.68 (m, 2H), 3.57 (s, 1H), 3.21 (d, J = 18.8 Hz, 1H), 3.01 (d, J = 11.9 Hz, 1H), 2.84 (d, J = 15.4 Hz, 1H), 2.27 - 2.21 (m, 7H), 1.66 (t, J = 13.5 Hz, 3H), 1.52 (t, J = 12.6 Hz, 3H), 1.43 - 1.36 (m, 3H), 1.26 (d, J = 2.5 Hz, 7H), 1.17 (d, J = 1.4 Hz, 3H), 1.01 (s, 6H), 0.87 - 0.81 (m, 1H), 0.72 (s, 3H).

[0248] Example 10: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl hexanoate

[0249] The target compound was prepared by a method similar to Example 1 to obtain a white solid 56 mg, yield: 44%. LC / MS (ESI+) C 55 H 60 F2N 10 O7([M+H] + m / z 1011.46, found: 1011.5. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 3.0 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.35 (s, 1H), 7.29 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 6.3 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.92 (d, J = 38.4 Hz, 2H), 6.26 (d, J = 11.3 Hz, 1H), 5.55 (d, J = 7.3 Hz, 1H), 5.30 (d, J = 11.4 Hz, 1H), 4.25 (s, 1H), 3.71 (d, J = 8.3 Hz, 2H), 3.57 (s, 1H), 3.20 (s, 1H), 3.01 (d, J = 11.4 Hz, 1H), 2.92 - 2.74 (m, 1H), 2.27 - 2.19 (m, 7H), 1.65 (d, J = 13.9 Hz, 3H), 1.52 (t, J = 12.3 Hz, 4H), 1.40 (d, J = 6.9 Hz, 3H), 1.26 (d, J = 3.4 Hz, 5H), 1.23 (s, 2H), 1.19 - 1.13 (m, 7H), 0.99 (d, J = 19.2 Hz, 5H), 0.80 (q, J = 7.5 Hz, 3H).

[0250] Example 11: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl heptanoate

[0251] The target compound was prepared in a similar manner to Example 1 with a yield of 50%. LC / MS (ESI+) Theoretical value for C 56 H 62 F2N 10 O7([M+H] + m / e 1025.2, actual value: 1025.2. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.50 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 6.3 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.96 (s, 2H), 6.26 (d, J = 11.0 Hz, 1H), 5.55 (d, J = 6.8 Hz, 1H), 5.31 (d, J = 10.9 Hz, 1H), 4.25 (d, J = 14.5 Hz, 1H), 4.11 (s, 3H), 3.71 (d, J = 8.0 Hz, 2H), 3.55 (d, J = 14.1 Hz, 1H), 3.19 - 3.10 (m, 1H), 3.02 (t, J = 12.4 Hz, 1H), 2.84 (d, J = 15.7 Hz, 1H), 2.26 (s, 6H), 1.97 (d, J = 11.5 Hz, 2H), 1.69 - 1.63 (m, 3H), 1.54 - 1.47 (m, 4H), 1.40 (d, J = 6.6 Hz, 3H), 1.28 - 1.19 (m, 11H), 1.15 - 0.99 (m, 6H), 0.83 (d, J = 7.1 Hz, 3H).

[0252] Example 12: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl octanoate

[0253] The target compound was prepared by a method similar to Example 1 with a yield of 61%. LC / MS (ESI+) Theoretical value: C 57 H 64 F2N 10 O7([M+H] + m / e 1039.4, actual value: 1039.4. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 7.48-7.44 (m, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.18 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.96 (s, 2H), 6.27 (d, J = 11.1 Hz, 1H), 5.56 (q, J = 7.0, 6.5 Hz, 1H), 5.31 (d, J = 11.0 Hz, 1H), 4.25 (d, J = 13.5 Hz, 1H), 4.11 (s, 3H), 3.71 (d, J = 6.9 Hz, 2H), 3.63 - 3.51 (m, 1H), 3.21 (d, J = 17.9 Hz, 1H), 3.06 - 2.98 (m, 1H), 2.84 (d, J = 15.7 Hz, 1H), 2.26 (s, 6H), 1.95 - 1.89 (m, 2H), 1.70 - 1.61 (m, 3H), 1.57 - 1.48 (m, 4H), 1.40 (d, J = 6.6 Hz, 3H), 1.26 - 1.18 (m, 13H), 0.99 (m, 6H), 0.83 (t, J = 7.0 Hz, 3H).

[0254] Example 13: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl nonanoate

[0255] The target compound was prepared by a method similar to Example 1. LC / MS (ESI+) Theoretical value: C 59 H 68 F2N 10 O7([M+H] + m / z 1067.52, Actual value: 1067.6. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 0.9 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.38 (dd, J = 16.9, 8.4 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.2 Hz, 1H), 7.00 (d, J = 31.1 Hz, 2H), 6.34 - 6.17 (m, 1H), 5.55 (d, J = 6.7 Hz, 1H), 5.31 (d, J = 11.0 Hz, 1H), 4.26 (d, J = 13.1 Hz, 1H), 3.71 (d, J = 8.2 Hz, 2H), 3.55 (d, J = 13.2 Hz, 1H), 3.19 (s, 1H), 3.00 (d, J = 12.4 Hz, 1H), 2.92 - 2.70 (m, 2H), 2.30 - 2.17 (m, 7H), 1.66 (t, J = 13.5 Hz, 3H), 1.52 (t, J = 12.8 Hz, 4H), 1.40 (d, J = 6.7 Hz, 3H), 1.26 (d, J = 2.9 Hz, 6H), 1.23 (d, J = 2.2 Hz, 4H), 1.16 (d, J = 7.2 Hz, 10H), 1.09 (m, 2H), 0.99 (m, 7H).

[0256] Example 14: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl dodecanoate

[0257] The target compound was prepared by a method similar to Example 1 to give 20 mg of the target compound in a yield of 42%. LC / MS (ESI+) Theoretical value: C 61 H 72 F2N 10 O7([M+H] + m / e 1095.5, actual value: 1095.5. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 7.49 - 7.44 (m, 1H), 7.38 - 7.33 (m, 1H), 7.32 - 7.26 (m, 1H), 7.17 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.96 (s, 2H), 6.26 (d, J = 11.1 Hz, 1H), 5.55 (d, J = 7.1 Hz, 1H), 5.31 (d, J = 10.9 Hz, 1H), 4.26 (d, J = 14.0 Hz, 1H), 4.11 (s, 3H), 3.71 (d, J = 7.5 Hz, 2H), 3.64 - 3.52 (m, 1H), 3.24-3.16 (m, 1H), 3.02 (t, J = 12.3 Hz, 1H), 2.84 (d, J = 15.9 Hz, 1H), 2.26 (s, 6H), 1.99-1.93 (m, 2H), 1.68 - 1.60 (m, 3H), 1.52 (t, J = 15.5, 9.8 Hz, 4H), 1.40 (d, J = 6.8 Hz, 3H), 1.26 - 1.16 (m, 16H), 1.0 - 0.96 (m, 8H), 0.84 (t, J = 4.2 Hz, 3H).

[0258] Example 15: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl hexadecanoate

[0259] The title compound was prepared in a similar manner as Example 1. LC / MS (ESI+) Theoretical: C 65 H 80 F2N 10 O7([M+H] + m / e 1151.6, Actual: 1151.6. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.50 (s, 1H), 7.49 - 7.43 (m, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.17 (d, J = 6.3 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.95 (s, 2H), 6.27 (d, J = 11.1 Hz, 1H), 5.55 (dd, J = 13.1, 6.2 Hz, 1H), 5.31 (d, J = 11.0 Hz, 1H), 4.25 (d, J = 8.5 Hz, 1H), 4.11 (s, 3H), 3.71 (d, J = 7.1 Hz, 2H), 3.57 (t, J = 12.9 Hz, 1H), 3.20 (d, J = 13.3 Hz, 1H), 3.02 (t, J = 13.0 Hz, 1H), 2.84 (d, J = 14.3 Hz, 1H), 2.26 (s, 6H), 1.98 - 1.93 (m, 2H), 1.70 - 1.60 (m, 3H), 1.52 (dd, J = 15.4, 10.1 Hz, 4H), 1.40 (d, J = 6.6 Hz, 3H), 1.26 - 1.08 (m, 29H), 1.03 - 0.93 (m, 6H), 0.85 (t, J = 6.6 Hz, 3H).

[0260] Example 16: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl pyrrolidine-1-carboxylate

[0261] The title compound was prepared by a similar method to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.42 - 7.34 (m, 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.96 (s, 2H), 6.33 (s, 1H), 5.58 (s, 1H), 4.22 (d, J = 13.6 Hz, 1H), 3.83 (s, 1H), 3.72 (d, J = 8.5 Hz, 2H), 3.55 (s, 1H), 3.02 (s, 1H), 2.85 (s, 1H), 2.26 (d, J = 2.1 Hz, 6H), 1.81 (s, 5H), 1.66 (d, J = 13.0 Hz, 2H), 1.53 (d, J = 12.3 Hz, 2H), 1.39 (s, 3H), 1.25 (dd, J = 8.9, 5.2 Hz, 9H), 1.18 (d, J = 3.8 Hz, 3H), 0.95 - 0.79 (m, 6H). LC / MS (ESI+) calcd for C 54 H 57 F2N 11 O7([M+H] + )m / z 1010.44; found 1010.5.

[0262] Example 17: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl propylcarbamate

[0263] The title compound was prepared in a similar manner as Example 1. LC / MS (ESI+) calcd for C 53 H 57 F2N 11 O7([M+H] + )m / e 998.1, found 998; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.42 - 7.34 (m, 1H), 7.28 - 7.21 (m, 1H), 7.18 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.97 (s, 3H), 6.33 (s, 1H), 5.58 (s, 1H), 5.33 (s, 1H), 4.22 (d, J = 13.0 Hz, 1H), 4.11 (s, 3H), 3.83 (s, 1H), 3.75 - 3.68 (m, 2H), 3.54 (s, 1H), 3.24 (s, 1H), 3.00 (d, J = 12.7 Hz, 2H), 2.83 (d, J = 16.5 Hz, 2H), 2.26 (d, J = 2.0 Hz, 6H), 2.02 - 1.93 (m, 2H), 1.68 (t, J = 12.5 Hz, 3H), 1.25 - 1.13 (m, 9H), 0.96 - 0.83 (m, 6H), 0.47 (d, J = 22.6 Hz, 3H).

[0264] Example 18: (3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl ethyl(methyl)aminoformate

[0265] The title compound was prepared by a similar procedure to Example 1. LC / MS (ESI+) calcd for C 53 H 58 F2N 11 O7([M+H] + m / e 998.4, found 998.4; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.40 - 7.35 (m, 1H), 7.27 - 7.24 (m, 1H), 7.18 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.2 Hz, 1H), 6.97 (s, 2H), 6.33 (t, J = 12.9 Hz, 1H), 5.57 (s, 1H), 5.38 - 5.19 (m, 1H), 4.24 (d, J = 13.2 Hz, 1H), 4.11 (s, 3H), 3.74 - 3.69 (m, 2H), 3.55 (s, 1H), 3.33 (s, 3H), 3.03 (q, J = 6.2, 3.7 Hz, 1H), 2.92 - 2.79 (m, 2H), 2.26 (d, J = 2.1 Hz, 6H), 1.98 (d, J = 12.4 Hz, 2H), 1.69 - 1.60 (m, 4H), 1.53 (q, J = 12.8, 10.6 Hz, 3H), 1.40 (d, J = 6.6 Hz, 3H), 1.31 - 1.17 m, 12H), 0.84 (h, J = 7.0, 4.4 Hz, 3H).

[0266] Example 19: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)propyl carbonate

[0267] Dissolve 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (300 mg, 0.36 mmol) in 10 mL of anhydrous acetonitrile, add N,N-diisopropyl ethylamine (450 mg, 3.6 mmol), add chloromethyl propyl carbonate (300 mg, 1.97 mmol), protect with argon, 85 °C overnight. Concentrate dry under reduced pressure, separate and purify with neutral alumina column chromatography, elute with petroleum ether / ethyl acetate, to obtain the target compound 72 mg of white solid, yield: 20%. 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 13.2 Hz, 2H), 7.42 - 7.35 (m, 1H), 7.27 - 7.23 (m, 1H), 7.18 (d, J = 6.3 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.87 (d, J = 70.9 Hz, 2H), 6.27 (d, J = 27.8 Hz, 1H), 5.55 (m, 1H), 5.29 (m, 1H), 4.24 (m, 1H), 3.72 (m, 2H), 3.56 (m, 1H), 3.17 (m, 1H), 3.02 (m, 1H), 2.92 - 2.77 (m, 1H), 2.27 - 2.18 (m, 7H), 1.66 (m, 3H), 1.53 (m, 3H), 1.39 (m, 3H), 1.34 (m, 2H), 1.25 (m, 9H), 1.18 (m, 3H), 0.91 - 0.82 (m, 2H), 0.77 (m, 3H). LC / MS (ESI+) calcd for C 53 H 56 F2N 10 O8([M+H] + )m / z 999.43; found 999.5.

[0268] Example 20: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl) cyclopropylmethyl carbonate

[0269] The target compound was prepared by a method similar to Example 14. LC / MS (ESI+) calcd for C 54 H 56 F2N 10 O8([M+H] + m / z 1011.43; found 1011.5. 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.38 (q, J = 11.4, 10.1 Hz, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.16 (t, J = 6.7 Hz, 2H), 7.08 (d, J = 3.2 Hz, 1H), 6.87 (d, J = 63.9 Hz, 2H), 6.31 (d, J = 27.7 Hz, 1H), 5.55 (s, 1H), 5.28 (s, 1H), 4.22 (, 1H), 3.71 (, 2H), 3.51 (s, 1H), 3.02 (s, 1H), 2.82 (m, 1H), 2.28 - 2.20 (m, 7H), 1.66 (m, 3H), 1.53 (m, 2H), 1.40 - 1.32 (m, 4H), 1.30 - 1.22 (m, 10H), 1.19 - 1.15 (m, 7H), 0.88 (m, 2H).

[0270] Example 21: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl) butyl carbonate

[0271] The title compound was prepared by a similar procedure to Example 14. LC / MS (ESI+) calcd for C 54 H 58 F2N 10 O8([M+H] + m / z 1013.44; found 1013.5. 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 5.9 Hz, 2H), 7.43 - 7.33 (m, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.16 (t, J = 8.6 Hz, 2H), 7.08 (d, J = 3.2 Hz, 1H), 6.87 (d, J = 65.2 Hz, 2H), 6.30 (s, 1H), 5.54 (s, 1H), 5.27 (s, 1H), 4.18 (m, 1H), 3.73 (s, 2H), 3.02 (s, 1H), 2.83 (s, 1H), 2.29 - 2.17 (m, 7H), 1.66 (m, 3H), 1.59 - 1.50 (m, 3H), 1.38 (m, 2H), 1.34 (m, 3H), 1.31 - 1.22 (m, 10H), 1.20 - 1.16 (m, 4H), 0.87 (m, 5H).

[0272] Example 22: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl carbonate

[0273] The title compound was prepared by a similar procedure to Example 14. LC / MS (ESI+) calcd for C 52 H 55 F2N 10 O8([M+H] + m / z 985.41; found 985.5. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.41 - 7.33 (m, 1H), 7.27 - 7.23 (m, 1H), 7.20 - 7.15 (m, 2H), 7.08 (d, J = 3.2 Hz, 1H), 6.99 - 6.83 (m, 2H), 6.35 - 6.14 (m, 1H), 5.55 (dt, J = 16.6, 7.4 Hz, 1H), 5.34 - 5.20 (m, 1H), 4.21 (td, J = 7.1, 4.0 Hz, 1H), 3.72 (d, J = 8.6 Hz, 2H), 3.55 (s, 1H), 3.02 (dd, J = 9.1, 3.8 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.26 (s, 7H), 1.72 - 1.63 (m, 3H), 1.52 (d, J = 10.8 Hz, 2H), 1.43 - 1.31 (m, 6H), 1.25 (dd, J = 8.6, 4.9 Hz, 10H), 1.18 (q, J = 4.0, 3.5 Hz, 6H).

[0274] Example 23: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)methyl carbonate

[0275] The title compound was prepared by a similar procedure to Example 14. LC / MS (ESI+) calcd for C 51 H 53 F2N 10 O8 + ([M+H] + )m / z: 971.1; found 971.1; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.34 (s, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.18 (d, J = 6.4 Hz, 2H), 7.08 (d, J = 3.2 Hz, 1H), 6.95 (d, J = 10.5 Hz, 2H), 6.10 (d, J = 47.6 Hz, 1H), 6.02 - 5.93 (m, 1H), 5.56 (s, 1H), 4.28 (s, 1H), 4.10 (d, J = 8.4 Hz, 4H), 3.72 (d, J = 8.0 Hz, 2H), 3.29 (s, 3H), 3.21 (m, 1H), 3.02 (m, 1H), 2.84 (m, 1H), 2.19 (s, 6H), 1.95 (m, 2H), 1.66 (m, 3H), 1.53 (m, 2H), 1.40 (s, 3H), 1.27 (d, J = 4.9 Hz, 3H), 1.22 (s, 3H), 1.17 (s, 3H).

[0276] Example 24: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)isopropyl carbonate

[0277] The title compound was prepared by a similar procedure to Example 14. LC / MS (ESI+) calcd for C 53 H 57 F2N 10 O8([M+H] + )m / e 999.4, found 999.4; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.49 (t, J = 3.9 Hz, 2H), 7.36 (q, J = 8.4, 6.8 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.18 (d, J = 6.3 Hz, 2H), 7.08 (d, J = 3.2 Hz, 1H), 6.95 (d, J = 11.5 Hz, 2H), 6.35 - 6.10 (m, 1H), 5.60-5.52 (m, 1H), 5.35 - 5.20 (m, 1H), 4.44 - 4.31 (m, 1H), 4.22 (d, J = 13.8 Hz, 1H), 4.11 (s, 3H), 3.73 - 3.70 (m, 2H), 3.63 - 3.51 (m, 1H), 3.19 (d, J = 11.2 Hz, 1H), 3.05-2.98 (m, 1H), 2.82 (d, J = 15.1 Hz, 1H), 2.26 (s, 6H), 1.73 - 1.62 (m, 4H), 1.51 (t, J = 12.3 Hz, 3H), 1.43 - 1.36 (m, 3H), 1.30 - 1.22 (m, 12H), 1.05 - 1.00 (m, 3H).

[0278] Example 25: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)isobutyl carbonate

[0279] The target compound was prepared by a similar method to Example 14 to give the white solid 24 mg, yield: 19%. LC / MS (ESI+) calcd for C 54 H 59 F2N 10 O8([M+H] + m / e 1013, found 1013; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 6.2 Hz, 2H), 7.25 (s, 2H), 7.18 (d, J = 6.1 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.98 - 6.85 (m, 2H), 5.90 (s, 1H), 5.59 (s, 1H), 4.65 (s, 1H), 4.26 (d, J = 13.5 Hz, 1H), 4.09 (d, J = 15.9 Hz, 4H), 3.71 (d, J = 9.0 Hz, 3H), 3.54 (s, 1H), 3.02 (s, 1H), 2.92 - 2.73 (m, 2H), 2.24 (d, J = 13.2 Hz, 7H), 1.90 (d, J = 33.5 Hz, 2H), 1.72 - 1.45 (m, 7H), 1.37 (d, J = 8.6 Hz, 3H), 1.32 - 1.08 (m, 10H).

[0280] Example 26: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl butyl carbonate

[0281] Dissolve 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (120 mg, 0.14 mmol) in 10 mL of anhydrous acetonitrile, add N,N-diisopropyl ethylamine (181 mg, 1.40 mmol), add chloromethyl pentyl carbonate (245 mg, 1.40 mmol), protect with argon gas, 85 °C overnight. Concentrate dry under reduced pressure, separate and purify by column chromatography with petroleum ether / ethyl acetate as eluent to obtain target compound 27 as white solid 42 mg, compound 28 as 16 mg, total yield: 42%. LC / MS (ESI+) calcd for C 55 H 60 F2N 10 O8([M+H] + m / z 1027.4; found 1027.3. 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 26.4 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.43 - 7.32 (m, 1H), 7.28 - 7.22 (m, 1H), 7.17 (d, J = 6.3 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 6.98 - 6.75 (m, 2H), 6.29 (s, 1H), 5.56 (s, 1H), 5.42 - 5.21 (m, 1H), 4.24 (s, 1H), 4.11 (s, 3H), 3.71 (d, J = 8.6 Hz, 2H), 3.56 (s, 2H), 3.18 (s, 1H), 3.01 (s, 1H), 2.97 - 2.68 (m, 2H), 2.61 - 2.51 (m, 1H), 2.34 - 2.15 (m, 6H), 2.06 - 1.85 (m, 3H), 1.66 (d, J = 13.0 Hz, 2H), 1.55 (dt, J = 20.6, 10.2 Hz, 3H), 1.45 - 1.32 (m, 4H), 1.28 - 1.23 (m, 6H), 1.17 (dt, J = 7.2, 3.8 Hz, 6H), 0.84 (d, J = 9.2 Hz, 3H).

[0282] Example 27: ((3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrrolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5-yl)oxy)methyl carbonsulfamid

[0283] As Example 26, the target compound 27 was obtained as 16 mg. LC / MS (ESI+) calcd for C 55 H 60 F2N 10 O8([M+H] + m / z 1027.4; found 1027.3. 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 14.0 Hz, 1H), 7.63 (s, 1H), 7.48 (d, J = 10.1 Hz, 2H), 7.42 - 7.34 (m, 1H), 7.25 (d, J = 11.0 Hz, 1H), 7.15 (d, J = 7.1 Hz, 2H), 7.07 (s, 1H), 6.93 (d, J = 15.5 Hz, 1H), 6.68 (d, J = 13.3 Hz, 1H), 5.94 (s, 1H), 5.69 (d, J = 6.9 Hz, 1H), 5.50 (s, 1H), 4.29 (s, 1H), 4.11 (s, 3H), 3.72 (s, 2H), 3.63 - 3.40 (m, 2H), 3.23 - 3.10 (m, 1H), 3.02 (s, 2H), 2.84 (s, 1H), 2.69 - 2.65 (m, 1H), 2.24 (s, 6H), 2.11 - 1.92 (m, 3H), 1.85 - 1.44 (m, 9H), 1.31 - 1.19 (m, 12H), 0.85 (d, J = 6.7 Hz, 3H).

[0284] Example 28: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)hexyl carbonate

[0285] The target compound was prepared by a method similar to Example 14. LC / MS (ESI + ) calcd for C 56 H 63 F2N 10 O8([M+NH4] + )m / z 1041.5, found 1042.3. 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 15.4 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.29 - 7.23 (m, 2H), 7.17 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 7.01 - 6.90 (m, 2H), 6.29 (s, 1H), 5.55 (d, J = 6.4 Hz, 1H), 5.27 (d, J = 10.5 Hz, 1H), 4.23 (d, J = 14.3 Hz, 1H), 3.82 - 3.57 (m, 2H), 3.57 - 3.50 (m, 1H), 3.19 (d, J = 13.1 Hz, 1H), 3.07 - 2.97 (m, 1H), 2.88 - 2.72 (m, 1H), 2.34 - 2.24 (m, 7H), 1.73 - 1.62 (m, 3H), 1.59 - 1.49 (m, 4H), 1.47 - 1.38 (m, 5H), 1.37 - 1.31 (m, 4H), 1.32 - 1.25 (m, 6H), 1.17 - 1.13 (m, 8H), 0.90 - 0.77 (m, 5H).

[0286] Example 29: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)heptyl) carbamate

[0287] The title compound was prepared by a similar procedure to Example 14. LC / MS (ESI+) calcd for C 57 H 64 F2N 10 O8 + ([M+H] + )m / z: 1056; found 1056; 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 15.4 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.29 - 7.23 (m, 2H), 7.17 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 7.01 - 6.90 (m, 2H), 6.29 (s, 1H), 5.55 (d, J = 6.4 Hz, 1H), 5.27 (d, J = 10.5 Hz, 1H), 4.23 (d, J = 14.3 Hz, 1H), 3.82 - 3.57 (m, 2H), 3.57 - 3.50 (m, 1H), 3.19 (d, J = 13.1 Hz, 1H), 3.07 - 2.97 (m, 1H), 2.88 - 2.72 (m, 1H), 2.34 - 2.24 (m, 7H), 1.73 - 1.62 (m, 3H), 1.59 - 1.49 (m, 4H), 1.47 - 1.38 (m, 5H), 1.37 - 1.31 (m, 4H), 1.32 - 1.20 (m, 8H), 1.17 - 1.13 (m, 8H), 0.90 - 0.77 (m, 5H).

[0288] Example 30: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)octyl carbonate

[0289] The title compound was prepared by a similar procedure to Example 14. LC / MS (ESI+) calcd for C 57 H 64 F2N 10 O8 + ([M+H] + m / z: 1070; found 1070; 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 15.4 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.29 - 7.23 (m, 2H), 7.17 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 7.01 - 6.90 (m, 2H), 6.29 (s, 1H), 5.55 (d, J = 6.4 Hz, 1H), 5.27 (d, J = 10.5 Hz, 1H), 4.23 (d, J = 14.3 Hz, 1H), 3.82 - 3.57 (m, 2H), 3.57 - 3.50 (m, 1H), 3.19 (d, J = 13.1 Hz, 1H), 3.07 - 2.97 (m, 1H), 2.88 - 2.72 (m, 1H), 2.34 - 2.24 (m, 7H), 1.73 - 1.62 (m, 3H), 1.59 - 1.49 (m, 4H), 1.47 - 1.38 (m, 5H), 1.37 - 1.31 (m, 4H), 1.32 - 1.20 (m, 10H), 1.17 - 1.13 (m, 8H), 0.90 - 0.77 (m, 5H).

[0290] Example 31: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)nonyl carbonate

[0291] The title compound was prepared by a similar procedure to Example 14. LC / MS (ESI+) calcd for C 57 H 64 F2N 10 O8 + ([M+H] + )m / z: 1084; found 1084; 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 15.4 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.29 - 7.23 (m, 2H), 7.17 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 7.01 - 6.90 (m, 2H), 6.29 (s, 1H), 5.55 (d, J = 6.4 Hz, 1H), 5.27 (d, J = 10.5 Hz, 1H), 4.23 (d, J = 14.3 Hz, 1H), 3.82 - 3.57 (m, 2H), 3.57 - 3.50 (m, 1H), 3.19 (d, J = 13.1 Hz, 1H), 3.07 - 2.97 (m, 1H), 2.88 - 2.72 (m, 1H), 2.34 - 2.24 (m, 7H), 1.73 - 1.62 (m, 3H), 1.59 - 1.49 (m, 4H), 1.47 - 1.38 (m, 5H), 1.37 - 1.31 (m, 4H), 1.32 - 1.20 (m, 12H), 1.17 - 1.13 (m, 8H), 0.90 - 0.77 (m, 5H).

[0292] Example 32: (3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)methyl)decyl carbonate

[0293] The title compound was prepared by a similar procedure to Example 14. LC / MS (ESI+) calcd for C 57 H 64 F2N 10 O8 + ([M+H] + m / z: 1098; found 1098; 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 15.4 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.29 - 7.23 (m, 2H), 7.17 (d, J = 6.2 Hz, 2H), 7.08 (d, J = 3.1 Hz, 1H), 7.01 - 6.90 (m, 2H), 6.29 (s, 1H), 5.55 (d, J = 6.4 Hz, 1H), 5.27 (d, J = 10.5 Hz, 1H), 4.23 (d, J = 14.3 Hz, 1H), 3.82 - 3.57 (m, 2H), 3.57 - 3.50 (m, 1H), 3.19 (d, J = 13.1 Hz, 1H), 3.07 - 2.97 (m, 1H), 2.88 - 2.72 (m, 1H), 2.34 - 2.24 (m, 7H), 1.73 - 1.62 (m, 3H), 1.59 - 1.49 (m, 4H), 1.47 - 1.38 (m, 5H), 1.37 - 1.31 (m, 4H), 1.32 - 1.20 (m, 14H), 1.17 - 1.13 (m, 8H), 0.90 - 0.77 (m, 5H).

[0294] Example 33: 1-(3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)ethyl ethanoate

[0295] Dissolve 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (100 mg, 0.12 mmol) in 5 mL of anhydrous acetonitrile, add N,N-diisopropylethylamine (450 mg, 3.6 mmol), add ethyl 1- chloroacetate (147 mg, 1.20 mmol), protect with argon, 85 °C overnight. Concentrate dry under reduced pressure, separate and purify with neutral alumina column chromatography, elute with petroleum ether / ethyl acetate, to obtain the target compound ethyl 1-(3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)acetate 21 mg as a white solid. LC / MS (ESI+) calcd for C 52 H 54 F2N 10 O7([M+H] + )m / z 969.4; found 969.4. 1HNMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 14.2 Hz, 2H), 7.29 (s, 2H), 7.18 (s, 2H), 7.08 (s, 1H), 6.93 (d, J = 22.3 Hz, 2H), 5.55 (s, 1H), 4.34 (s, 1H), 4.10 (d, J = 15.3 Hz, 4H), 3.71 (d, J = 8.4 Hz, 2H), 3.05 (d, J = 14.7 Hz, 2H), 2.88 (s, 2H), 2.26 (s, 6H), 2.00 (s, 3H), 1.65 (d, J = 6.3 Hz, 3H), 1.54 (d, J = 13.1 Hz, 3H), 1.42 (d, J = 6.8 Hz, 2H), 1.27 (t, J = 12.6 Hz, 9H), 1.18 (s, 5H).

[0296] Example 34: 1-(3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4- fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)ethyl ethyl carbonate

[0297] A round bottom flask was charged with 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro- 2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H- imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (50 mg, 0.06 mmol), and dry acetonitrile (3 mL) was added after vacuum and backfilling with argon three times. The mixture was stirred at room temperature after the addition of DIPEA (78 mg, 0.60 mmol) and the replacement of argon gas. 1-Chloroethyl ethyl carbonate (92 mg, 0.60 mmol) was added and the system was moved to an 85 °C oil bath for heating overnight. The next day, the system was cooled to room temperature and neutral silica gel was added to the mixture. The mixture was purified by column chromatography to give the target compound 1-(3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H- indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl- 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)- 5-oxo-1,2,4-oxadiazol-4(5H)-yl)ethyl ethyl carbonate (24 mg). Yield: 42%. LC / MS (ESI) calcd for C + )calcd for C 53 H 56 F2N 10 O8([M+H] + )m / z,999.4;found,999.1; 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 11.8 Hz, 2H), 7.38 (d, J = 11.3 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 7.18 - 7.14 (m, 3H), 7.06 (s, 1H), 6.92 (s, 2H), 5.70 (s, 1H), 5.51 (s, 1H), 4.29 (d, J = 12.7 Hz, 1H), 4.11 (br, 4H), 3.89 (dd, J = 10.9, 3.5 Hz, 1H), 3.71 (s, 3H), 3.59 - 3.48 (m, 1H), 3.05 - 3.00 (m, 2H), 2.86 - 2.79 (m, 1H), 2.24 (s, 6H), 1.68 - 1.57 (m, 11H), 1.33 (s, 3H), 1.30 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H).

[0298] Example 35: 1-(3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1- methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrrolo[4,3-c]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4(5H)-yl)ethyl propyl carbonate.

[0299] The title compound was prepared in a similar manner as Example 34. LC / MS (ESI+) calcd for C 55 H 59 F2N 10 O8 + ([M+H] + )m / z: 1013.4; found 1013.4; 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 4.4 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.47 (d, J = 12.7 Hz, 2H), 7.42 - 7.33 (m, 1H), 7.16 (dd, J = 13.0, 6.8 Hz, 3H), 7.07 (s, 1H), 6.91 (d, J = 13.6 Hz, 2H), 5.70 (d, J = 6.8 Hz, 1H), 5.50 (d, J = 6.6 Hz, 1H), 4.29 (m, 1H), 4.10 (m, 4H), 3.90 (m, 1H), 3.71 (m, 3H), 3.03 (m, 2H), 2.82 (m, 1H), 2.25 (s, 6H), 1.72 - 1.54 (m, 12H), 1.34 (s, 3H), 1.28 - 1.27 (m, 3H), 1.24 (s, 3H), 1.18 (s, 3H).

[0300] Other compounds of the present application can be prepared by methods analogous to those described in the above examples.

[0301] The beneficial effects of the compounds of the present application are demonstrated by the following specific experimental examples.

[0302] Experimental Example 1, Oral pharmacokinetics of the compounds of the present application

[0303] The compound (orforglipron and prodrug) was weighed according to the administration dose of 3 mg / kg, and was prepared into a corresponding concentration of drug solution with a solvent (DMSO / HS-15 / PBS:5 / 10 / 85). Three animals (male rats, provided by Chengdu Dashuo Experimental Animal Co., Ltd.) were orally administered, and three animals were sampled at nine time points within 24 hours after administration. The samples were anticoagulated with EDTA-K2 and centrifuged at 4°C for 5 min to separate the plasma. The plasma samples were vortexed and mixed. An appropriate amount of internal standard working solution was added to a 96-well plate containing standard curve samples, quality control samples or test samples; an appropriate amount of methanol was added to the blank sample, vortexed and mixed, and then centrifuged for 15 min to take the supernatant for LC-MS / MS sampling to analyze the prodrug and the parent drug. The plasma drug concentration data at each time point was calculated using Winnolin 8.3 non-compartment model to obtain the main pharmacokinetic parameters. The pharmacokinetic parameters are shown in Table 1.

[0304] Table 1. Oral pharmacokinetics of the compounds of the present application

[0305] The experimental results show that the compounds of the present application have better oral pharmacokinetic properties than the parent drug orforglipron.

[0306] Experimental Example 2, Pharmacokinetics of injection administration of the compounds of the present application

[0307] Pharmacokinetic experiment procedure: The compound was weighed according to the dosage of 30 mg / kg, and a proper amount of solvent was used to prepare a drug solution with a corresponding concentration. Three animals (male rats, provided by Chengdu Dashuo Experimental Animal Co., Ltd.) were single-dose injected intramuscularly, and three animals were sampled every 24 h after administration for 3-4 weeks. The samples were anticoagulated with EDTA-K2 and centrifuged at 4°C for 5 min to separate the plasma. The plasma samples were vortexed and mixed. A proper amount of internal standard working solution was added to a 96-well plate containing standard curve samples, quality control samples or test samples. A proper amount of methanol was added to the blank sample, vortexed and mixed, and then centrifuged for 15 min to take the supernatant for LC-MS / MS sample analysis. The plasma drug concentration data at each time point was calculated using Winnolin 8.3 non-compartment model to calculate the main pharmacokinetic parameters. The plasma drug concentration at each time point is shown in Table 2.

[0308] Table 2. Pharmacokinetics of the compound of the present application by injection

[0309] The experimental results show that the compound of the present application has good long-acting sustained-release pharmacokinetic properties.

[0310] Experimental Example 3, GLP-1R efficacy test: mouse intraperitoneal glucose tolerance test (IPGTT)

[0311] The mice expressing human GLP-1R were divided into a solvent group and different dose administration groups, and were changed into clean cages at 5 pm the day before the experiment, fasted for 16 h, and then fed at 9 am the next day. During the fasting period, the mice were allowed to drink normally. After overnight fasting, different administration compounds were prepared into solutions at a dose of 30 mg / kg with a solvent, and were single-dose injected intramuscularly according to the grouping. Five hours later, intraperitoneal injection of glucose was performed at a dose of 2 g / kg. Before the administration of glucose, 1-2 mm of the tail of the mouse was cut off, the tail vein was squeezed to discard the first drop of blood, and the second drop of blood was used to determine the fasting blood glucose using a blood glucose meter, and the reading value was taken as the blood glucose at 0 min. After the administration of glucose, the blood glucose was monitored and recorded using a blood glucose meter at 15, 30, 45, 60, 90 and 120 min. The blood glucose data was analyzed to calculate the area under the curve (AUC 0-120min ) of 0-120 min. Then the glucose tolerance test was repeated every 7 days at the same time point. The experimental results are shown in Table 3.

[0312] Table 3. Blood glucose AUC of long-acting glucose tolerance test of single-dose administration of the compound of the present application

[0313] As shown in Table 3, single-dose administration of the compound of the present application can provide significant hypoglycemic efficacy for at least 4 weeks. The experimental results show that the compound of the present application has good long-acting hypoglycemic efficacy.

[0314] In summary, the application provides a heterocyclic compound, a preparation method thereof and a use of the preparation method for preparing GLP-1 receptor agonist prodrugs with oral PK characteristics and long-acting PK characteristics, and belongs to the field of pharmaceutical chemistry. The compound provided by the application can be used as a GLP-1 receptor agonist prodrug, and the GLP-1 receptor agonist prodrug compound can be hydrolyzed in vivo to release a parent drug having a GLP-1 receptor agonizing effect. The compound provided by the application can be used as a GLP-1 receptor agonist prodrug compound for preparing a drug for preventing and / or treating a GLP-1 receptor related disease. The compound has good oral and long-acting pharmacokinetics, better medication compliance, and a wide application prospect.

Claims

1. A compound represented by Formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: ###00001### I wherein, G is a GLP-1 receptor agonist; including but not limited to: Orforglipron, ECC5004, GSBR1290, SYH2086, HS10535, IBI3032, ASC30; Y is nothing, -OY1-, -OCR Y1 R Y2 -; Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl groups; R Y3 R Y1 R Y2 -; Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl groups; R Y1 R Y2 R Y3 are each independently selected from H, C1-C6 alkyl; Y and G can be linked via a heteroatom bearing exchangeable hydrogen; R is selected from -COLR L L is selected from none, C1-C6 alkylene groups, O, S, and NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 40 Straight-chain or branched saturated alkyl groups, C1-C2 40 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 8-membered cycloalkyl group, or aromatic group; phenyl; 3- to 8-membered cycloalkyl group; NR A1 R A2 ; R A1 , R A2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, or R 10 and R A1 , taken together with the nitrogen to which they are attached, form a 3- to 8-membered nitrogen-containing heterocycloalkyl group which is unsubstituted or substituted with one or two or more C1-C6alkyl groups. A2 , taken together with the nitrogen to which they are attached, form a 3- to 8-membered nitrogen-containing heterocycloalkyl group which is unsubstituted or substituted with one or two or more C1-C6alkyl groups. 10 , taken together with the nitrogen to which they are attached, form a 3- to 8-membered nitrogen-containing heterocyc 2. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 1, wherein: The structure of the compound is shown in formula II: wherein ring A is selected from an aromatic ring, an unsaturated nitrogen-containing heterocyclic ring, an aromatic ring containing a hydroxyl group or an amino group or a carboxyl group, an unsaturated nitrogen-containing heterocyclic ring containing a hydroxyl group or an amino group or a carboxyl group, or a tautomer thereof; R A Selected from LR L L is selected from none, C1-C6 alkylene groups, O, S, and NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 40 Straight-chain or branched saturated alkyl groups, C1-C2 40 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 8-membered cycloalkyl group, or aromatic group; phenyl; 3- to 8-membered cycloalkyl group; NR A1 R A2 ; R A1 R A2 Each is independently selected from hydrogen, C1 to C1. 10 Alkyl, or R A1 R A2 The connection is formed without being replaced or by one or more C1~C1. 10 Alkyl-substituted 3- to 8-membered nitrogen-containing heterocyclic alkyl groups; Y is absent, or -OY1-, Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl; X is selected from O, S, SO2, NR X1 , CR X1 R X2 ; R X1 , R X2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen-substituted C1-C6alkyl; or, R X1 and R X2 are joined to form a 3- to 5-membered cycloalkyl group which is substituted or unsubstituted by one or more R X’ , and R X’ are each independently selected from the group consisting of C1-C6alkyl, halogen-substituted C1-C6alkyl; ring B is a 5- or 6-membered heterocyclic ring containing 1-3 nitrogens; R B selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C6 alkyl, 3-6 membered cycloalkyl, halogen substituted C1-C6 alkyl, a group resulting from replacement of one or two or more alkylene groups in a C1-C6 alkyl group with a heteroatom; or R B1 , R B2 are linked to form a 4-6 membered heterocyclyl group; ring C is selected from phenyl, heteroaryl, 5-7-membered cycloalkyl, 5-7-membered heterocyclyl containing 1-2 heteroatoms; R C1 , R C2 , R C3 are each independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, C1-C6alkoxy; or, R C1 , R C2 , R C3 are mutually connected to form a 3- to 5-membered cycloalkyl group; R 1 , R 2 are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, Ci-C6alkoxy, 3- to 6-membered cycloalkyl, halogen; or R 1 and R 2 are linked to form an aromatic or non-aromatic ring; ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl; R D1 , R D2 , R D3 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, carboxy, amido, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy, a group resulting from replacement of one or more alkylene groups in C1-C6alkyl with a heteroatom, C1-C6alkyl substituted with one or more R D’ , R D’ is selected from the group consisting of amine, sulfone, phosphine, halogen; or, R D1 , R D2 , R D3 are connected to each other to form an aromatic or non-aromatic ring; Ring E is selected from: R E1 , R E2 are each independently selected from hydrogen, halogen; U, Y 0 Z is independently selected from C, N, and is not simultaneously N; ring F is selected from phenyl, heteroaryl; R F1 , R F2 , R F3 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, carboxy, amido, C1-C6alkenyl, C1-C6alkynyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy, C1-C6alkyl substituted with one or more R F’ , R F’ is selected from the group consisting of amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6alkyl in which one or more alkylene groups are replaced by a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

3. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 2, wherein: The structure of the compound is shown in formula III: wherein, Ring A is selected from an aromatic ring, an unsaturated nitrogen-containing heterocyclic ring, an aromatic ring containing a hydroxyl or amino or carboxyl group, an unsaturated nitrogen-containing heterocyclic ring containing a hydroxyl or amino or carboxyl group, or a tautomer thereof, including but not limited to: R A Selected from LR L L is selected from none, C1-C3 alkylene, O, S, NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 30 Straight-chain or branched saturated alkyl groups, C1-C2 30 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 6-membered cycloalkyl group, or aromatic group; phenyl group; 3- to 6-membered cycloalkyl group; NR group A1 R A2 ; R A1 R A2 Each is independently selected from hydrogen, C1 to C2. 10 Alkyl, or R A1 R A2 The connection is formed without being replaced or by one or more C1~C1. 10 Alkyl-substituted 3- to 8-membered nitrogen-containing heterocyclic alkyl groups; Y is absent, or -OY1-, Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl; X is selected from O, S, SO2, NR X1 , CR X1 R X2 ; R X1 , R X2 are each independently selected from the group consisting of hydrogen, C1-C3alkyl, halogen-substituted C1-C3alkyl; or, R X1 and R X2 are joined to form a 3- to 4-membered cycloalkyl group which is substituted or unsubstituted by one or more R X’ , and R X’ are each independently selected from the group consisting of C1-C3alkyl, halogen-substituted C1-C3alkyl; Ring B is a 5- or 6-membered heterocycle containing 1-3 nitrogens selected from: R B selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen substituted C1-C3 alkyl, a group resulting from replacement of one or two alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5-6 membered heterocyclyl group; ring C is selected from phenyl, heteroaryl, 5-6-membered cycloalkyl, 5-6-membered non-aromatic heterocyclyl containing 1-2 heteroatoms; R C1 , R C2 , R C3 are each independently selected from the group consisting of hydrogen, halogen, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy; or, R C1 , R C2 , R C3 are mutually connected to form a 3- to 5-membered cycloalkyl group; R 1 , R 2 are each independently selected from the group consisting of hydrogen, C1-C3alkyl, C1-C3alkoxy, 3- to 6-membered cycloalkyl, halogen; or R 1 and R 2 are linked to form an aromatic or non-aromatic ring; ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl; R D1 R D2 R D3 Groups independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amide, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, C1-C6 alkyl, or one or more alkylene groups obtained by replacing one or more heteroatoms with heteroatoms, or groups with one or more R D’ Substituted C1-C3 alkyl groups, R D’ Selected from amino, sulfone, phosphine, and halogen groups; or, R D1 R D2 R D3 They connect to form aromatic or non-aromatic rings; Ring E is selected from: R E1 , R E2 are each independently selected from hydrogen, halogen; ring F is selected from phenyl, heteroaryl; R F1 , R F2 , R F3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’ , R F’ is selected from one or more of amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl, wherein one or more alkylene groups are replaced with a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

4. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 3, wherein: The structure of the compound is shown in formula IV: wherein, Ring A is selected from an aromatic ring, an unsaturated nitrogen-containing heterocyclic ring, an aromatic ring containing a hydroxyl or amino or carboxyl group, an unsaturated nitrogen-containing heterocyclic ring containing a hydroxyl or amino or carboxyl group, or a tautomer thereof, including but not limited to: R A Selected from LR L L is selected from none, C1-C3 alkylene, O, S, NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 30 Straight-chain or branched saturated alkyl groups, C1-C2 30 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 6-membered cycloalkyl group, or aromatic group; phenyl group; 3- to 6-membered cycloalkyl group; NR group A1 R A2 ; R A1 , R A2 are each independently selected from the group consisting of hydrogen, C1-C 10 alkyl, or R A1 and R A2 are joined to form a 3- to 8-membered nitrogen-containing heterocycloalkyl group which is unsubstituted or substituted by one or more C1-C 10 alkyl groups; Y is absent, or -OY1-, Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl; R 3 selected from hydrogen, C1-C6alkyl, halogen-substituted C1-C6alkyl; Ring B is a 5- or 6-membered heterocycle containing 1-3 nitrogens selected from: R B selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen substituted C1-C3 alkyl, a group resulting from replacement of one or two alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5-6 membered heterocyclyl group; ring C is selected from phenyl, heteroaryl, 5-6-membered cycloalkyl, 5-6-membered non-aromatic heterocyclyl containing 1-2 heteroatoms; R C1 , R C2 , R C3 are each independently selected from the group consisting of hydrogen, halogen, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy; or, R C1 , R C2 , R C3 are mutually connected to form a 3- to 5-membered cycloalkyl group; R 1 , R 2 are each independently selected from the group consisting of hydrogen, C1-C3alkyl, C1-C3alkoxy, 3- to 6-membered cycloalkyl, halogen; or R 1 and R 2 are linked to form an aromatic or non-aromatic ring; ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl; R D1 , R D2 , R D3 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, carboxy, amido, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, a group resulting from replacement of one or two alkylene groups of C1-C6 alkyl with a heteroatom, C1-C3 alkyl substituted with one or more R D’ , R D’ is selected from amine, sulfone, phosphine, halogen; or, R D1 , R D2 , R D3 are each independently connected to one another to form an aromatic or non-aromatic ring; Ring E is selected from: R E1 , R E2 are each independently selected from hydrogen, halogen; ring F is selected from phenyl, heteroaryl; R F1 , R F2 , R F3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’ , R F’ is selected from amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl, one or more alkylene groups of which are replaced with a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

5. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 4, wherein: The structure of the compound is shown in formula V: wherein, Ring A is selected from an aromatic ring, an unsaturated nitrogen-containing heterocyclic ring, an aromatic ring containing a hydroxyl or amino or carboxyl group, an unsaturated nitrogen-containing heterocyclic ring containing a hydroxyl or amino or carboxyl group, or a tautomer thereof, including but not limited to: R A Selected from LR L L is selected from none, C1-C3 alkylene, O, S, NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 30 Straight-chain or branched saturated alkyl groups, C1-C2 30 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 6-membered cycloalkyl group, or aromatic group; phenyl group; 3- to 6-membered cycloalkyl group; NR group A1 R A2 ; R A1 R A2 Each is independently selected from hydrogen, C1 to C2. 10 Alkyl, or R A1 R A2 The connection is formed without being replaced or by one or more C1~C1. 10 Alkyl-substituted 3- to 8-membered nitrogen-containing heterocyclic alkyl groups; Y is absent, or -OY1-, Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl; R 3 selected from hydrogen, C1-C3alkyl, halogen-substituted C1-C3alkyl; Ring B is a 5- or 6-membered heterocycle containing 1-3 nitrogens selected from: R B selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen substituted C1-C3 alkyl, a group resulting from replacement of one or two alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5-6 membered heterocyclyl group; ring C is selected from phenyl, heteroaryl, 5-6-membered cycloalkyl, 5-6-membered non-aromatic heterocyclyl containing 1-2 heteroatoms; R C1 , R C2 , R C3 are each independently selected from the group consisting of hydrogen, halogen, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy; or, R C1 , R C2 , R C3 are mutually connected to form a 3- to 5-membered cycloalkyl group; ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl; R D1 R D2 R D3 Groups independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amide, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, C1-C6 alkyl, or one or more alkylene groups obtained by replacing one or more heteroatoms with heteroatoms, or groups with one or more R D’ Substituted C1-C3 alkyl groups, R D’ Selected from amino, sulfone, phosphine, and halogen groups; or, R D1 R D2 R D3 They connect to form aromatic or non-aromatic rings; Ring E is selected from: R E1 , R E2 are each independently selected from hydrogen, halogen; ring F is selected from phenyl, heteroaryl; R F1 R F2 R F3 Each group is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amide, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3-6 membered cycloalkyl, C1-C3 alkoxy, C1-C3 alkyl containing heteroatoms, and is surrounded by one or more R groups. F’ Substituted C1-C3 alkyl groups, R F’ A group selected from amino, thioether, sulfoxide, sulfone, phosphine, halogen, or C1-C6 alkyl groups, obtained by replacing one or more alkylene groups with heteroatoms; or, R F1 R F2 R F3 They connect to form aromatic or non-aromatic rings.

6. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 5, wherein: The structure of the compound is shown in formula VI: wherein, Ring A is selected from an aromatic ring, an unsaturated nitrogen-containing heterocyclic ring, an aromatic ring containing a hydroxyl or amino or carboxyl group, an unsaturated nitrogen-containing heterocyclic ring containing a hydroxyl or amino or carboxyl group, or a tautomer thereof, including but not limited to: R A Selected from LR L L is selected from none, C1-C3 alkylene, O, S, NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 30 Straight-chain or branched saturated alkyl groups, C1-C2 30 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 6-membered cycloalkyl group, or aromatic group; phenyl group; 3- to 6-membered cycloalkyl group; NR group A1 R A2 ; R A1 R A2 Each is independently selected from hydrogen, C1 to C2. 10 Alkyl, or R A1 R A2 The connection is formed without being replaced or by one or more C1~C1. 10 Alkyl-substituted 3- to 8-membered nitrogen-containing heterocyclic alkyl groups; Y is absent, or -OY1-, Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl; R 3 selected from hydrogen, C1-C3alkyl, halogen-substituted C1-C3alkyl; Ring B is a 5- or 6-membered heterocycle containing 1-3 nitrogens selected from: R B selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen substituted C1-C3 alkyl, a group resulting from replacement of one or two alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5-6 membered heterocyclyl group; C 1 is selected from CH or N; R C1 , R C2 , R C3 are each independently selected from the group consisting of hydrogen, halogen, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy; or, R C1 , R C2 , R C3 are mutually connected to form a 3- to 5-membered cycloalkyl group; ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl; R D1 , R D2 , R D3 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, carboxy, amido, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, a group resulting from replacement of one or two alkylene groups of C1-C6 alkyl with a heteroatom, C1-C3 alkyl substituted with one or more R D’ , R D’ is selected from amine, sulfone, phosphine, halogen; or, R D1 , R D2 , R D3 are interconnected to form an aromatic or non-aromatic ring; Ring E is selected from: R E1 , R E2 are each independently selected from hydrogen, halogen; R F1 , R F2 , R F3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’ , R F’ is selected from one or more of amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl, wherein one or more alkylene groups are replaced with a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

7. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 6, wherein: The structure of the compound is shown in formula VII: wherein, R A Selected from LR L L is selected from none, C1-C3 alkylene, O, S, NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 30 Straight-chain or branched saturated alkyl groups, C1-C2 30 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 6-membered cycloalkyl group, or aromatic group; phenyl group; 3- to 6-membered cycloalkyl group; NR group A1 R A2 ; R A1 R A2 Each is independently selected from hydrogen, C1 to C2. 10 Alkyl, or R A1 R A2 The connection is formed without being replaced or by one or more C1~C1. 10 Alkyl-substituted 3- to 8-membered nitrogen-containing heterocyclic alkyl groups; Y is absent, or -OY1-, Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl; R 3 selected from hydrogen, C1-C3alkyl, halogen-substituted C1-C3alkyl; Ring B is a 5- or 6-membered heterocycle containing 1-3 nitrogens selected from: R B selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen substituted C1-C3 alkyl, a group resulting from replacement of one or two alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5-6 membered heterocyclyl group; C 1 is selected from CH or N; R C1 , R C2 , R C3 are each independently selected from the group consisting of hydrogen, halogen, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy; or, R C1 , R C2 , R C3 are mutually connected to form a 3- to 5-membered cycloalkyl group; ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl; R D1 , R D2 , R D3 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, carboxy, amido, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, a group resulting from replacement of one or two alkylene groups of C1-C6 alkyl with a heteroatom, C1-C3 alkyl substituted with one or more R D’ , R D’ is selected from amine, sulfone, phosphine, halogen; or, R D1 , R D2 , R D3 are interconnected to form an aromatic or non-aromatic ring; Ring E is selected from: R E1 , R E2 are each independently selected from hydrogen, halogen; R F1 , R F2 , R F3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’ , R F’ is selected from amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl, one or more alkylene groups of which are replaced with a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

8. The compound according to claim 7, its pharmaceutically acceptable salt, or its stereoisomer, characterized in that: The structure of the compound is shown in formula VIII: wherein, R A Selected from LR L L is selected from none, C1-C3 alkylene, O, S, NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 30 Straight-chain or branched saturated alkyl groups, C1-C2 30 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 6-membered cycloalkyl group, or aromatic group; phenyl group; 3- to 6-membered cycloalkyl group; NR group A1 R A2 ; R A1 R A2 Each is independently selected from hydrogen, C1 to C2. 10 Alkyl, or R A1 R A2 The connection is formed without being replaced or by one or more C1~C1. 10 Alkyl-substituted 3- to 8-membered nitrogen-containing heterocyclic alkyl groups; Y is absent, or -OY1-, Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl; R 3 selected from hydrogen, C1-C3alkyl, halogen-substituted C1-C3alkyl; Ring B is a 5- or 6-membered heterocycle containing 1-3 nitrogens selected from: R B selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen substituted C1-C3 alkyl, a group resulting from replacement of one or two alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5-6 membered heterocyclyl group; C 1 is selected from CH or N; R C1 , R C2 , R C3 are each independently selected from the group consisting of hydrogen, halogen, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy; or, R C1 , R C2 , R C3 are mutually connected to form a 3- to 5-membered cycloalkyl group; ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl; R D1 , R D2 , R D3 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, carboxy, amido, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, a group resulting from replacement of one or two alkylene groups of C1-C6 alkyl with a heteroatom, C1-C3 alkyl substituted with one or more R D’ , R D’ is selected from amine, sulfone, phosphine, halogen; or, R D1 , R D2 , R D3 are connected to each other to form an aromatic or non-aromatic ring; Ring E is selected from: R E1 , R E2 are each independently selected from hydrogen, halogen; R F1 , R F2 , R F3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’ , R F’ is selected from amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl, one or more alkylene groups of which are replaced with a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

9. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 7, wherein: The structure of the compound is shown in formula IX: wherein, R A Selected from LR L L is selected from none, C1-C3 alkylene, O, S, NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 30 Straight-chain or branched saturated alkyl groups, C1-C2 30 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 6-membered cycloalkyl group, or aromatic group; phenyl group; 3- to 6-membered cycloalkyl group; NR group A1 R A2 ; R A1 R A2 Each is independently selected from hydrogen, C1 to C2. 10 Alkyl, or R A1 R A2 The connection is formed without being replaced or by one or more C1~C1. 10 Alkyl-substituted 3- to 8-membered nitrogen-containing heterocyclic alkyl groups; Y is absent, or -OY1-, Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl; R 3 selected from hydrogen, C1-C3alkyl, halogen-substituted C1-C3alkyl; Ring B is a 5- or 6-membered heterocycle containing 1-3 nitrogens selected from: R B selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen substituted C1-C3 alkyl, a group resulting from replacement of one or two alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5-6 membered heterocyclyl group; C 1 is selected from CH or N; R C1 , R C2 , R C3 are each independently selected from the group consisting of hydrogen, halogen, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy; or, R C1 , R C2 , R C3 are mutually connected to form a 3- to 5-membered cycloalkyl group; ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl; R D1 , R D2 , R D3 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, carboxy, amido, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, a group resulting from replacement of one or two alkylene groups of C1-C6 alkyl with a heteroatom, C1-C3 alkyl substituted with one or more R D’ , R D’ is selected from amine, sulfone, phosphine, halogen; or, R D1 , R D2 , R D3 are connected to each other to form an aromatic or non-aromatic ring; Ring E is selected from: R E1 , R E2 are each independently selected from hydrogen, halogen; R F1 , R F2 , R F3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’ , R F’ is selected from one or more of amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl, with one or more alkylene groups replaced by a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

10. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 8, wherein: The structure of the compound is shown in formula X: wherein, R A Selected from LR L L is selected from none, C1-C3 alkylene, O, S, NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 30 Straight-chain or branched saturated alkyl groups, C1-C2 30 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 6-membered cycloalkyl group, or aromatic group; phenyl group; 3- to 6-membered cycloalkyl group; NR group A1 R A2 ; R A1 R A2 Each is independently selected from hydrogen, C1 to C2. 10 Alkyl, or R A1 R A2 The connection is formed without being replaced or by one or more C1~C1. 10 Alkyl-substituted 3- to 8-membered nitrogen-containing heterocyclic alkyl groups; R 3 selected from hydrogen, C1-C3alkyl, halogen-substituted C1-C3alkyl; Ring B is a 5- or 6-membered heterocycle containing 1-3 nitrogens selected from: R B selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen substituted C1-C3 alkyl, a group resulting from replacement of one or two alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5-6 membered heterocyclyl group; C 1 is selected from CH or N; R C1 , R C2 , R C3 are each independently selected from the group consisting of hydrogen, halogen, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy; or, R C1 , R C2 , R C3 are mutually connected to form a 3- to 5-membered cycloalkyl group; ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl; R D1 , R D2 , R D3 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, carboxy, amido, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, a group resulting from replacement of one or two alkylene groups of C1-C6 alkyl with a heteroatom, C1-C3 alkyl substituted with one or more R D’ , R D’ is selected from amine, sulfone, phosphine, halogen; or, R D1 , R D2 , R D3 are each independently connected to one another to form an aromatic or non-aromatic ring; Ring E is selected from: R E1 , R E2 are each independently selected from hydrogen, halogen; R F1 , R F2 , R F3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’ , R F’ is selected from one or more of amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl, with one or more alkylene groups replaced by a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

11. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 10, wherein: The structure of the compound is shown in formula XI: wherein, n is an integer selected from 0-29; R 3 selected from hydrogen, C1-C3alkyl, halogen-substituted C1-C3alkyl; Ring B is a 5- or 6-membered heterocycle containing 1-3 nitrogens selected from: R B selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen substituted C1-C3 alkyl, a group resulting from replacement of one or two alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5-6 membered heterocyclyl group; C 1 is selected from CH or N; R C1 , R C2 , R C3 are each independently selected from the group consisting of hydrogen, halogen, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy; or, R C1 , R C2 , R C3 are mutually connected to form a 3- to 5-membered cycloalkyl group; ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl; R D1 , R D2 , R D3 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, carboxy, amido, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, a group resulting from replacement of one or two alkylene groups of C1-C6 alkyl with a heteroatom, C1-C3 alkyl substituted with one or more R D’ , R D’ is selected from the group consisting of amine, sulfone, phosphine, halogen; or, R D1 , R D2 , R D3 are connected to each other to form an aromatic or non-aromatic ring; Ring E is selected from: R E1 , R E2 are each independently selected from hydrogen, halogen; R F1 , R F2 , R F3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’ , R F’ is selected from amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl, or one or more alkylene groups of the above are replaced with a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

12. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 10, wherein: The structure of the compound is shown in formula XII: wherein, n is an integer selected from 0-29; R 3 selected from hydrogen, C1-C3alkyl, halogen-substituted C1-C3alkyl; Ring B is a 5- or 6-membered heterocycle containing 1-3 nitrogens selected from: R B selected from hydrogen, halogen, CH2NR B1 R B2 ; wherein R B1 , R B2 are each independently selected from hydrogen, C1-C3 alkyl, 3-4 membered cycloalkyl, halogen substituted C1-C3 alkyl, a group resulting from replacement of one or two alkylene groups in C1-C3 alkyl with a heteroatom; or R B1 , R B2 are linked to form a 5-6 membered heterocyclyl group; C 1 is selected from CH or N; R C1 , R C2 , R C3 are each independently selected from the group consisting of hydrogen, halogen, C1-C3alkyl, halogen-substituted C1-C3alkyl, C1-C3alkoxy; or, R C1 , R C2 , R C3 are mutually connected to form a 3- to 5-membered cycloalkyl group; ring D is selected from phenyl, heteroaryl, benzo-heterocyclyl; R D1 , R D2 , R D3 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, carboxy, amido, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, a group resulting from replacement of one or two alkylene groups of C1-C6 alkyl with a heteroatom, C1-C3 alkyl substituted with one or more R D’ , R D’ is selected from amine, sulfone, phosphine, halogen; or, R D1 , R D2 , R D3 are each independently connected to one another to form an aromatic or non-aromatic ring; Ring E is selected from: R E1 , R E2 are each independently selected from hydrogen, halogen; R F1 , R F2 , R F3 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carboxyl, amido, C1-C3 alkenyl, C1-C3 alkynyl, C1-C3 alkyl, 3- to 6-membered cycloalkyl, C1-C3 alkoxy, heteroatom-containing C1-C3 alkyl, C1-C3 alkyl substituted with one or more R F’ , R F’ is selected from one or more of amine, thioether, sulfoxide, sulfone, phosphine, halogen, C1-C6 alkyl, wherein one or more alkylene groups are replaced with a heteroatom; or, R F1 , R F2 , R F3 are connected to each other to form an aromatic or non-aromatic ring.

13. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 2, wherein: The structure of the compound is shown as formula XIII or XIV: wherein R A is LR L ; L is selected from the group consisting of none, C1-C3 alkylene, O, S; R L is selected from the group consisting of C1-C 40 straight-chain or branched alkyl, C2-C 30 straight-chain or branched alkenyl, C2-C 30 straight-chain or branched dialkenyl, C2-C 30 straight-chain or branched trialkenyl, C2-C 30 straight-chain or branched alkynyl, C2-C 30 straight-chain or branched dialkynyl, C2-C 30 straight-chain or branched trialkynyl, 3-6 membered cycloalkyl, or phenyl, NR A1 R A2 ; R A1 R A2 Each is independently selected from hydrogen, C1 to C2. 10 Alkyl, or R A1 R A2 Together they form 5- to 8-membered cycloalkyl groups that are either unsubstituted or substituted by one or more C1- to C6 alkyl groups; R 3 selected from hydrogen, C1-C6alkyl; R F1 , R F2 , R F3 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6-alkyl, halogen-substituted Ci-C6-alkyl, 3- to 6-membered cycloalkyl.

14. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 7, wherein: The structure of the compound is shown in formula XV: wherein, R A Selected from LR L L is selected from none, C1-C3 alkylene, O, S, NH; R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 30 Straight-chain or branched saturated alkyl groups, C1-C2 30 The group obtained by replacing one or more alkylene groups of a straight-chain or branched saturated alkyl group with an unsaturated double bond, unsaturated triple bond, 3- to 6-membered cycloalkyl group, or aromatic group; phenyl group; 3- to 6-membered cycloalkyl group; NR group A1 R A2 ; R A1 R A2 Each is independently selected from hydrogen, C1 to C2. 10 Alkyl, or R A1 R A2 Together they form 5- to 8-membered cycloalkyl groups that are either unsubstituted or substituted by one or more C1- to C6 alkyl groups; Y is absent, or -OY1-, Y1 is methylene or methylene substituted with 1-2 C1-C6 alkyl.

15. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 14, wherein: The structure of the compound is shown in formula XVI: Among them, R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 20 Straight-chain or branched saturated alkyl groups, C1-C2 20 One or more alkylene groups of a straight-chain or branched saturated alkyl group are independently replaced by heteroatoms, unsaturated double bonds, unsaturated triple bonds or 3- to 6-membered cycloalkyl groups.

16. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 14, wherein: The structure of the compound is shown in formula XVII: Among them, R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 20 Straight-chain or branched saturated alkyl groups, C1-C2 20 One or more alkylene groups of a straight-chain or branched saturated alkyl group are independently replaced by heteroatoms, unsaturated double bonds, unsaturated triple bonds or 3- to 6-membered cycloalkyl groups.

17. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of claim 14, wherein: The structure of the compound is shown in formula XVIII: Among them, R L Selected from the following groups, either unsubstituted or halogenated: C1 to C2 20 Straight-chain or branched saturated alkyl groups, C1-C2 20 One or more alkylene groups of a straight-chain or branched saturated alkyl group are independently replaced by heteroatoms, unsaturated double bonds, unsaturated triple bonds or 3- to 6-membered cycloalkyl groups.

18. The compound, pharmaceutically acceptable salt, or stereoisomer thereof of any one of claims 1-17, wherein: The structure of the compound is shown below:

19. A pharmaceutical composition, characterized by: The pharmaceutical composition is a preparation prepared by taking the compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof according to any one of claims 1-18 as an active ingredient, and adding a pharmaceutically acceptable adjuvant.

20. The pharmaceutical composition of claim 19, wherein: The preparation is an oral preparation.

21. Use of the compound, pharmaceutically acceptable salt thereof, or stereoisomer thereof of any one of claims 1-18 in the manufacture of a GLP-1 receptor agonist prodrug.

22. The use according to claim 21, characterized in that: The GLP-1 receptor agonist prodrug is a drug for preventing and / or treating a GLP-1 receptor related disease.

23. Use according to claim 22, characterized in that: The GLP-1 receptor related disease is diabetes, hyperglycemia, diabetic complications, obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, metabolic adipose liver (MAFLD), metabolic adipose hepatitis (MASH), polycystic ovary syndrome, Parkinson's disease, Alzheimer's disease, sleep apnea syndrome, arthritis.

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